Classifications

• • 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
• • 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
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
  • A61K31/4985—Pyrazines or piperazines 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
  • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further 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
  • A61K31/63—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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • 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
• • 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
  • C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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
• MDS are heterogeneous diseases with few treatment options, as there is a lack of effective medicines capable of providing a durable response.
• Current treatment options for MDS are limited but include allogeneic HSC transplantation, demethylating agents, and immunomodulatory therapies (Ebert, 2010).
• HSC hemopoietic stem cell
• HSC clones can persist in the marrow even after HSC transplantation, and the disease invariably advances (Tehranchi et al., 2010).
• MDS multiple myeloma
• patients may also receive immunosuppressive therapy, epigenetic modifying drugs, and/or chemotherapy (Greenberg, 2010).
• epigenetic modifying drugs include epigenetic modifying drugs, and/or chemotherapy.
• chemotherapy Greenberg, 2010
• MDS patients exhibit treatment-related toxi cities or relapse (Sekeres, 2010a).
• the efficacy of these treatments is variable, and generally life expectancies are only slightly improved as compared to supportive care.
• the complexity and heterogeneity of MDS, and the lack of human xenograft models are obstacles which are challenging for identifying and evaluating novel molecular targets for this disease.
• AML hematopoietic stem/progenitor cell
• the present disclosure relates to a compound of Formula (I): or a salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof, wherein:
• R 6 is selected from
• R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are each 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, wherein 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
• 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 each 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, wherein 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,
• the compound of Formula (I) is a compound of Formula (Ilf): Formula (Ilf), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein: R20f is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C3-C6 cycloalkyl, -O- (CH 2 ) a -(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 C3-C6 cycloalkyl is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl and halogen, and wherein C 3 -C 9 heterocyclyl is optionally substituted
• 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.
• R20f is H.
• R 21f , R 22f , and R 23f are each H;
• R 21f and R 23f are each F and R22f is H;
• R21f and R23f are each H and R22f is F;
• R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb are each H;
• R25fa, R25fb, R26fa, and R26fb are each H and
• the compound of Formula (I) is a compound of Formula
• (ng): Formula (Ilg), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; is l, wherein C1-C6 alkyl and C1-C6 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 C3-C9 heterocycyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C3-C6-cycloalkyl, -OH, and O; R21g, R22g, and R23g are each independently selected from H and halogen; and R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga
• R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R 28ga , and R 28gb is independently selected from halogen, -OH, and C 1 -C 6 alkyl.
• R 20g is H.
• R 20g is selected unsubstituted C 3 cycloalkyl, -CH ;
• R 21g , R 22g , and R 23g are each H;
• R 21g and R 23g are each F a d R 23g are each H and R 22g is F;
• each of R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb d R 27gb is H and R 24gb is F;
• each of R 24ga , R 24gb , R 25ga , , is or b is selected from:
• m y 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 C1-C6 alkyl and halogen; and
• R21h, R22h, and R23h are each independently selected from H and halogen.
• R 20h is H.
• R 20h is selected from ;
• R 21h , R 22h , and R23h are each H;
• R21h and R23h are each F and R22h is H;
• R21h and R23h are each H and G m: or of at least one of IRAK1, IRAK4, and FLT3.
• the compound of Formula (I) is an inhibitor of at least two of IRAK1, IRAK4, and FLT3.
• the compound of Formula (I) is an inhibitor of IRAK1 and IRAK4.
• the compound of Formula (I) 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 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, a smoothened receptor antagonist, an ERK inhibitor including an ERK2/MAPK1 or ERK1/MAPK3 inhibitor, a PI3K inhibitor, an mTOR inhibitor, a steroid or glu
• the present disclosure provides 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 Formula (I) or a composition comprising a compound of Formula (I).
• 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.
• IRAK interleukin-1 receptor-associated kinase
• FLT3 fms-like tyrosine kinase 3
• 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 of Formula (I) 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.
• 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 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 IRAKI and/or IRAK4, or combinations thereof.
• 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
• the disease or disorder comprises one or more inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’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, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’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 additional therapy is a BCL2 inhibitor.
• 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.
• disease or disorder is BCL2 inhibitor resistant acute myeloid leukemia (AML). In one embodiment, the disease or disorder is venetoclax resistant acute myeloid leukemia (AML). In one embodiment, the disease or disorder is FLT3 inhibitor resistant acute myeloid leukemia (AML). In one embodiment, 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).
• AML BCL2 inhibitor resistant acute myeloid leukemia
• 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 Formula (I) or the composition comprising a compound of Formula (I) and the one or more additional therapies are administered together in one administration or composition. In one embodiment, the compound of Formula (I) or the composition comprising a compound of Formula (I) and the one or more additional therapies are administered separately in more than one administration or more than one composition.
• the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
• the disease or disorder is alleviated by inhibiting at least two of IRAKI, IRAK4, and FLT3 in the subject. In one embodiment, the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject. In one embodiment, the disease or disorder is alleviated by inhibiting IRAK1, IRAK4, and FLT3 in the subject. In one embodiment, 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.
• inventive compounds e.g., compounds of Formula (I)
• compositions e.g., pharmaceutical compositions
• compositions for treating for example, certain diseases using the inventive compounds.
• methods of using the inventive compound e.g., in compositions or in pharmaceutical compositions
• methods for making the inventive compound include methods for determining whether a particular patient is likely to be responsive to such treatment with the inventive compounds and compositions.
• substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.
• 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., C1-C10 means one to ten carbons).
• C1-C10 means one to ten carbons.
• C 1 -C 7 alkyl or C1-C4 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 C1-C4 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 butyl oxy.
• 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.
• bicyclic cycloalkyl if one ring is aromatic, then the other is not aromatic.
• a bicyclic cycloalkyl one or both rings can be substituted.
• heteroalkyl by itself or in combination with another term, 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 -SO2R'.
• 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.
• halogen or “halo” means monovalent Cl, F, Br, or I. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
• halo(Ci-C4)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. For an aryl that is bicyclic, one or both rings can be substituted.
• 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 quatemized.
• 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, C1-16alkyl, arylC1-16alkyl, C0-16alkyloxyC0-16alkyl, arylC0-16alkyloxyC0- 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 - 16alkyl, arylC1-16alkylcarbonylC0-16alkyl, C1-16alkylcarboxyC0-16alkyl, ary
• 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., phenoxy methyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like), or a sulfur atom.
• an oxygen atom e.g., phenoxy methyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like
• sulfur atom e.g.
• (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.
• Examples of cycloalkyl 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. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
• heterocycloalkyl examples include, but are not limited to, l-(l,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-l-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or pyrrolidin-4-yl), piperazinyl (e.g., piperazin- 1-yl, piperazin-2-yl, piperazin-3 -yl, or piperazin-4-yl), piperidinyl (e.g.,
• 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 means an oxygen that is double bonded to a carbon atom.
• alkylsulfonyl means a moiety having the formula -S(O2)-R', where R' is an alkyl group as defined above. R' can have a specified number of carbons (e.g., “C1-C4 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 11 or -OCOR n ), carbonyl (-CO-R n ), urea (-NHCONH-R n ), thiourea (-NHCSNH-R n ), sulfonamido (-NHSO2-R 11 or -SO2NH-R 11 ), ether (-O-R n ), sulfonyl (-SO2-R 11 ), sulfoxyl (-SO-R n ), carbamoyl (-NHCO 2 -R 11 or -OCONH-R n ), or amino (-NHR n ) linking moieties.
• 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.
• optionally substituted means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but is not required to be substituted.
• 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 “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 C5- C 7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5-7-membered heterocycloalkyl.
• Some compounds of the disclosure 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 disclosure e.g., Formula I
• 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.
• monitoring 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. In some embodiments, 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.
• modulated or modulation can refer to both up regulation (z.e., activation or stimulation, e.g., by agonizing or potentiating) and down regulation (z.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting), unless otherwise specified or clear from the context of a specific usage.
• up regulation z.e., activation or stimulation, e.g., by agonizing or potentiating
• down regulation z.e., inhibition or suppression, e.g., by antagonizing, decreasing or inhibiting
• the term “subject” refers to any suitable (e.g., treatable) member of the animal kingdom.
• the subject is preferably a mammal.
• 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.
• treating is, unless stated otherwise, to be considered in its broadest context and refers to obtaining a desired pharmacologic and/or physiologic effect.
• 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, z.e., arresting its development; and (c) relieving the disease, z.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.
• a therapeutically effective amount is an amount appropriate to treat an indication.
• 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.
• Such achievement can be measured by any suitable method, such as measurement of tumor size or blood cell count, or any other suitable measurement.
• 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 disclosure 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 disclosure 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. Additional embodiments of the disclosure are also discussed herein.
• Some embodiments of the disclosure include compounds having a structure according to Formula (I): 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).
• the compound is not an ester, not a solvate, and not a prodrug.
• R 2 , R 3 , R 4 , and R 5 are independently selected from H, halogen, hydroxy, oxo, -CN, amino, amido, -O-aryl, 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 amino, amido, -O-aryl, 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,
• R 2 can be H, halogen, hydroxy, oxo, -CN, amino, amido, -O-aryl, 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, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, which amino, amido, -O-aryl, 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, heterocyclyl, spiro-fused cycloal
• R 6 can be
• 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 cycloalkyl, heterocyclyl, aryl, heteroaryl, or
• 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, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, 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 (- SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO- morpholin-4-yl, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2
• 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 (- SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO- morpholin-4-yl, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2
• 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 (- SO3H), heterocyclyl, aryl, heteroaryl, pyrrolyl, piperidyl, piperazinyl, morpholinyl, -CO- morpholin-4-yl, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2
• 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, an S chiral center, or a racemate.
• the chiral center can be represented by the following bonds , or - Where a chiral center is possible at other positions of the compounds according to Formula (I), as would appreciated by one skilled in the art, the straight bond shown can also be can be
• 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 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 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
• 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.
• 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.
• Some embodiments of the disclosure include compounds having a structure according to Formula (I):
• the wavy bond can indicate an R chiral center, an S chiral center, or a racemate. In certain embodiments, can be , or . Where a chiral cente ssible at o F I), as would appreciated by one skilled in the art, the straight bond shown can also be can be , , , , or .
• 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 , DB1/ 125145907.1 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, cycloalkyl, 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, cycloalkyl, 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, cycloalkyl, 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, cycloalkyl, 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, cycloalkyl, 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 - Ce alkoxy, cycloalkyl, 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 - C7 alkyl, C 1 -C 7 haloalkyl, C 1 -C 7 alkoxy, cycloalkyl, or spiro-fused cycloalkyl.
• at least one of R 7 , R 8 , R 9 , and R 10 is F, hydroxyl, methyl, methoxy, -CHF2, - CF 3 , cyclopropyl, 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, cycloalkyl, or spiro-fused cycloalkyl.
• At least one of R 11 , R 12 , R 13 , and R 14 is F, hydroxyl, methyl, methoxy, -CHF2, -CF 3 , cyclopropyl, 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 (Ila)-(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.
• R 20f is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, -O- (CH 2 )a-(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 C3-C9 heterocyclyl is optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, -OH
• R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb 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 , R26fa, and R26fb is H.
• R20f is H.
• R20f is not H.
• R 20f is unsubstituted C 1 -C 6 alkyl.
• R 20f is t-butyl.
• R20f is C1-C6 alkyl substituted with one or more -OH and/or halogen. In one embodiment, R20f is C1-C6 alkyl substituted with one or more -OH and/or F. In one embodiment, R20f is selected fro , an . In another embodiment, R 20f is unsubstituted C 1 -C 6 alko odim is selected from -OCH 3 , - OCH2CH3, and . In another embodiment, R20f is C1-C6 alkoxy substituted with one or more fluorine atoms. In one embodiment, R 20f is selected fro and . In another embodiment, R 20f is C 3 -C 6 cycloalkyl.
• R 20f is ted C3 cycloalkyl. In one embodiment, R20f is C3 cycloalkyl substituted with C1-C6 alkyl. In one embodiment, R 20f i In one embodiment, R 20f is C 3 cycloalkyl substituted with one or more fluor e a o s. In one embodiment, R 20f is . In another embodiment, R20f is -O-(CH2)a-(C3 cycloalkyl). In one embod R20f is . In another embodiment, R 20f is unsubstituted C 3 -C 9 heterocyclyl. In one embodiment, R20f is selected from pyrrolidinyl and .
• R20f is wherein R20f 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 and C 3 -C 6 cycloalkyl are each optionally substituted with one or more halogen and/or -OH.
• R29fa and R29fl> are each independently selected from H, C 1 -C 6 alkyl, -OH, and halogen, wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen, and b is 1 or 2.
• R29fa and R29fl> are each independently selected from H, -CH 3 ,
• R28f is O and R220fa and R220fb bond or fuse to form ox bodiment
• R20f is O O S wherein b is 1 or 2.
• R20f is selected fro d N .
• each of R21f, R22f, and R23f is H.
• R 21f and R 23f are each independently halogen and R 22f is H.
• R 21f and R 23f are each F and R 22f is H.
• R 21f and R 23f are each H and R 22f is halogen.
• R21f and R23f are each H and R22f is F.
• each of R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb 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 R24fb, R25fa, R25fb, R26fa, and R26fb is H and R24fa is F. In one embodiment, each of R25fa, R25fb, R26fa, and R26fb is H and each of R24fa and R24fb 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 R25fa, R25fb, R26fa, and R26fb is H and each of R24fa and R24fb is -CH3. In one embodiment, each of R24fb, R25fa, R25fb, R26fa, and R26fb is H and R24fa is -CH3. 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 substituted with one or more halogen.
• R 25fa , R 25fb , R 26fa , and R 26fb are each H and R24fa and/or R24fb is C1 alkyl substituted with one or more F.
• R24fa, R25fa, R25fb, R26fa, and R26fb are each H and R24fb is -CF3.
• the compound of Formula (IIf) has one or more stereocenters.
• the compouind of Formula (IIf) comprises a stereocenter where the moiet connects to the remaining portion of Formula (IIf).
• Formula (IIf) comprises a stereocenter at one or more of R 24fa , R 24fb , R 25fa , R 25fb , R 26fa , and/or R 26fb .
• the compound of Formula (IIf) comprises a stereocenter on R20f. [0095] In an embodiment, the compound of Formula (IIf) is selected from: , , , ,
• the compound of Formula (II) is a compound of
• R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and R28gb is independently selected from halogen and C1-C6 alkyl.
• each of R 24ga , R 24gb , R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R28gb is H.
• R20g is H.
• R20g is unsubstituted C 1 -C 6 alkyl.
• R 20g is t-butyl. In another embodiment, R 20g is C1-C6 alkyl substituted with one or more F and/or -OH. In one embodiment, R21i is selected fro , and . In another embodiment, R20g is unsubstituted C 1 -C 6 alkoxy. In one embodiment, R 20g is . In another embodiment, R 20g is is C 1 -C 6 alkoxy substituted with one or more F an . In one embodiment, R 20g is selected from . In another embodiment, R 20g is unsubstituted C 3 -C 6 cycloalkyl. s unsubstituted C 3 cycloalkyl.
• R20g is wherein R29g is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C9 wherein C1-C6 alkyl and C3-C6 cycloalkyl are each optionally substituted with one or more halogen and/or -OH.
• R20g i wherein R29g is unsubstituted C 1 -C 6 alkyl.
• R 20g is wherein R 29g is -CH 3 .
• R20g is wherein R29g is selected from .
• R21g and R23g are each H and R22g is halogen. In one embodiment, R21g and R23g are each H and R22g is F. [00100] In an embodiment , each of R24ga, R24gb, R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R ch of R 25ga , R 25gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 24ga and/or R 24gb is halogen.
• each of R24ga, R25ga, R25gb, R26ga, R26gb, R27ga, and R27gb is H and R24gb is F.
• each of R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , and R 27gb is H and R 25ga and/or R 25gb is unsubstituted C 1 -C 6 alkyl.
• each of R 24ga , R 24gb , R 25ga , R 26ga , R 26gb , R 27ga , and R 27gb is H and R25gb is -CH3.
• each of R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , R 27gb , R 28ga , and R h of R 24ga , R 24gb , R 26ga , R26gb, R28ga, and R28gb is H and R27ga and/or R27gb is halogen.
• each of R 24ga , R 24gb , R 26ga , R 26gb , R 28ga , and R 28gb is H and each of R 27ga and R 27gb is F.
• each of R 24ga , R 24gb , R 26ga , R 26gb , R 27ga , R 28ga , and R 28gb is H and R 27gb is F.
• each of R24ga, R24gb, R26ga, R26gb, R28ga, and R28gb is H and R27ga and/or R27gb is unsubstituted C1-C6 alkyl.
• each of R24ga, R24gb, R26ga, R26gb, R28ga, and R 28gb is H and each of R 27ga and R 27gb is -CH 3 .
• each of R 24ga , R 24gb , R27ga, R27gb, R28ga, and R28gb is H and R26ga and/or R26gb is halogen. In one embodiment, each of R24ga, R24gb, R26ga, R27ga, R27gb, R28ga, and R28gb is H and R26gb is F. In an embodiment, each of R 24ga , R 24gb , R 27ga , R 27gb , R 28ga , and R 28gb is H and R 26ga and/or R 26gb is unsubstituted C 1 -C 6 alkyl.
• each of R 24ga , R 24gb , R 26ga, R 27ga , R 27gb , R 28ga , and R 28gb is H and R26gb is -CH3.
• the compound of Formula (IIg) comprises one or more stereocenters. In one embodiment, the compound of Formula (IIg) comprises a stereocenter on R20g. In one embodiment, the compound of Formula (IIg) comprises a stereocenter where E the moiety connects to the remaining portion of Formula (IIg).
• R24ga, R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and/or R28gb comprises a stereocenter.
• the compound of Formula (IIg) is selected from:
• the compound of Formula (II) is a compound of
• Formula (Ilh) Formula (Ilh), or a salt, ester, solvate, optical isomer, geometric isomer, or salt of an isomer thereof; wherein:
• R2011 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkyl, wherein Ci- Ce 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
• R2ih, R22h, and R2311 are each independently selected from H and halogen.
• R20h is H.
• R2011 is C 1 -C 6 alkyl
• R2011 is F
• R2011 is C 1 -C 6 alkoxy substituted with one or more halogen.
• R20h is .
• R20h is unsubstituted C3-C6 cycloalkyl.
• R20h is unsubstituted C3 cycloalkyl.
• R 20h is C 3 -C 6 cycloalkyl substituted with one or more C 1 -C 6 alkyl.
• R 20h is .
• R20h is C3-C6 cycloalkyl substituted with one or more C1- C6 alkyl and one or more fluorine atoms. In one embodiment, R20h is . [00106] In an embodiment, R 21h , R 22h , and R 23h are eac an embodiment, R 21h and R 23h are each independently halogen and R 22h is H. In one embodiment, R 21h and R23h are each F and R22h is H. In an embodiment, R21h and R23h are each H and R22h is halogen. In one embodiment, R 21h and R 23h are each H and R 22h is F. G [00107] In an embodiment .
• ormula (IIh) comprises one or more stereocenters.
• the compound of Formula (IIh) comprises a stereocenter on R 20h .
• the compound of Formula (IIh) comprises a stereocenter where G th moiety connects to the remaining portion of Formula (IIh).
• the compound of Formula (IIh) is selected from: , Formula (III), as follows:
• q, r, s, t, u, v, w, and x are independently 0, 1, or 2.
• 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
• 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, C2- Ce 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 (Illa)-(IIIp), as follows:
• the compounds of Formula (I), such as compounds of Formula (II) or Formula (III), can be any of those specified in Compounds 1-132, as listed in Tables 1-21.
• the compound can be Compound 1, Compound 5, Compound 6, Compound 8, Compound 12, Compound 14, Compound 16, Compound 35, Compound 40, Compound 44, Compound 45, Compound 46, Compound 47, Compound 51, or Compound 55.
• 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.
• 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. In general, the 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%.
• Some embodiments of the present disclosure include methods for the preparation of compounds of Formula (I).
• a compound of Formula (I) can be prepared comprising one or more of the steps set forth in Examples 1-24 herein.
• the synthetic routes shown and described in Examples 1-24 can, for example, be used to prepare Compounds 1-132, as set forth in Tables 1-21, and structurally related compounds.
• 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.).
• 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 1-21, or a pharmaceutically acceptable salt, ester, solvate, optical isomer, geometric isomer, salt of an isomer, prodrug, or derivative thereof. In some embodiments, the compound is set forth in any of Tables 1-21 herein.
• 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.
• salts can exist as salts, such as with pharmaceutically acceptable acids. Accordingly, the compounds contemplated herein include such salts. Examples of such salts 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.
• 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 50%, from about 0.1% to about 99%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%.
• 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.
• the composition 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.
• 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.
• 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.
• a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
• 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. For in vitro studies 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 nontoxic 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.
• compositions and methods suitable for use in the pharmaceuticals compositions and methods disclosed herein include those described, for example, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
• preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
• nonaqueous 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.
• 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.
• Other pharmaceutically acceptable carriers 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.
• 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.
• 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, plant oils, plant oils
• 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.
• 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.
• 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.
• 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. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.
• 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 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.
• 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 IRAKI, 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
• an animal e.g.
• 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, IRAKI (interleukin- 1 receptor associated kinase 1), isoforms of IRAKI, and/or mutations of IRAKI.
• FLT3, mutations of FLT3 e.g., mutations in the juxtamembrane region of FLT3, mutations in the kinase domain of FLT3, FLT3
• 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, IRAKI, isoforms of IRAKI, or mutations of IRAKI.
• 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 IRAKI, or an isoform or mutation thereof.
• the compounds of the disclosure can inhibit FLT3 in combination with IRAK4, IRAKI, or with IRAK4 and IRAKI.
• compounds exhibit inhibitory activity against IRAK and/or FLT-3 with activities > 1 pM, 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 pM, 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 pM, 1-10 pM, 10-100 pM, 100-200 pM, 200- 500 pM, or even 500-1000 pM.
• 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 IRAKI and/or IRAK4.
• compounds of the present disclosure can be used to inhibit overactive IRAKI and/or IRAK4 in conditions such as inflammatory diseases and autoimmune disease, wherein said inflammatory diseaess and autoimmune diseases are characterized by overactive IRAKI and/or IRAK4.
• inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAKI 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, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’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
• hidradenitis suppurativa systemic lupus erythematosus
• inflammatory bowel disease multiple sclerosis
• 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), IRAKI (e.g., using IRAK 1 inhibitors), and/or mutations of IRAKI (e.g., using inhibitors of IRAKI 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
• IRAKI e.g., using IRAK 1 inhibitors
• IRAKI e
• 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 IRAKI (or its mutations), or MDS that can be treated by inhibiting IRAK4 (or its mutations) and IRAKI (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, IRAKI, or both IRAK4 and IRAKI.
• inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI 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. Patent Application No.
• 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), IRAKI (e.g., using IRAK 1 inhibitors), and/or mutations of IRAKI (e.g., using inhibitors of IRAKI 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
• IRAKI e.g., using IRAK 1 inhibitors
• IRAKI e.g., using inhibitors
• 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 IRAKI (or its mutations), or AML that can be treated by inhibiting IRAK4 (or its mutations) and IRAKI (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, IRAKI, or both IRAK4 and IRAKI.
• inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI 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. Patent Application No.
• 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 e.g
• 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 IRAKI (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 IRAKI (or its isoforms 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, IRAKI, or both IRAK4 and IRAKI.
• inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI 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, IRAKI, or both IRAK4 and IRAKI.
• inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI 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. Patent Application No.
• inflammatory and autoimmune diseases characterized by dysregulated (e.g., hyperactive) IRAK expression (IRAKI 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, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’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, IRAKI, or both IRAK4 and IRAKI.
• chronic inflammation i.e., associated with viral and bacterial infection
• sepsis rheumatoid arthritis
• hidradenitis suppurativa
• inhibiting FLT3 in combination with IRAK4, IRAKI, or both IRAK4 and IRAKI 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.
• 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
• 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 1-132, as listed in Tables 1-21) (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 1-132, as listed in Tables 1-21
• 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 1-132, as listed in Tables 1-21) (which can be administered to a subject such as mammals, rodents, mice, rabbits, feline, porcine, or canine) 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 Com
• an effective amount of at least one compound of the disclosure (e.g., Formula (I) such as but not limited to Compounds 1-132, as listed in Tables 1-21) (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 1-132, as listed in Tables 1-21
• an effective amount of at least one compound of the disclosure can
• 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 1-132, as listed in Tables 1-21) (which can be administered to an animal such as mammals, rodents, mice, rabbits, feline, porcine, or canine) 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, anti angiogenic 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., anti angiogenic therapy
• 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 combination with known or new therapies.
• 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. In some embodiments, 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.
• 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).
• IVIG intravenous immunoglobulin
• 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, antibodydrug 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 inhibitor
• 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), HA 14-1, SI, 2-methoxy antimycin A3, gossypol, AT- 101, apogossypol, WEHL539, A-l 155463, BXL61, BXL72, TW37, MIMI, UMI-77, and the like, and combinations thereof.
• 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 1-132, 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.
• 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.
• 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 (HD AC) 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, clad
• Anti-CD70 e.g. ARGX-110, cusatuzumab
• a bispecific antibody e.g. floteuzumab (CD123 x CD3)
• Anti- CTLA4 e.g. ipilimumab
• Anti-PDl/PDLl 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 RARa agonist), and the like
• 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.
• Chemotherapies and targeted therapies which are approved and/or in the clinical trial stage are known to those skilled in the art. Any such compound can be utilized in the practice of the present disclosure.
• approved chemotherapies include abitrexate (Methotrexate Injection), abraxane (Paclitaxel Injection), adcetris (Brentuximab Vedotin Injection), adriamycin (Doxorubicin), adrucil Injection (5-FU (fluorouracil)), Armazolar Injection (fluorouracil)), Armazolin Injection, Van 14-FU (fluorouracil)), Armor (Everolimus), Adjustitor Disperz (Everolimus), alimta (PEMETREXED), alkeran Injection (Melphalan Injection), alkeran Tablets (Melphalan), aredia (Pamidronate), arimidex (Anastrozole), aromasin (Exemestane), arranon (Nelarabine), arzerra (Ofatumumab Injection), avastin (Bevacizumab), beleoda
• 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, Cometriq), canakinumab (Haris), carfilzomib (Kyprolis), ceritinib (Zykadia), cetuximab (Erbitux), cobimetinib (Cotellic), crizot
• 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.
• Nonspecific 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
• cancer can additionally be treated by other strategies. These include surgery, radiation therapy, hormone therapy, stem cell transplant, precision medicine, and the like; such treatments and the compounds and compositions utilized therein are known to those skilled in the art. Any such treatment strategies can be utilized in the practice of the present disclosure.
• inventions of the disclosure 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.
• an amount of at least one 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 pM, 1- 10 pM, 10-100 pM, 100-200 pM, 200-500 pM, or even 500-1000 pM, preferably about 1-10 nM, 10-100 nM, or 0.1-1 pM.
• 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.
• different daily doses can be used 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.
• 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.
• 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 can be administered to subjects by any number of suitable administration routes or formulations.
• 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.
• 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). Of course, 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.
• 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.
• the ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LDso (the amount of compound lethal in 50% of the population) and EDso (the amount of compound effective in 50% of the population).
• LDso the amount of compound lethal in 50% of the population
• EDso 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 EDso with little or no toxicity.
• the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.
• R 2 is H, halogen, hydroxy, oxo, -CN, amino, -O-aryl, 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, heterocyclyl, spiro-fused cycloalkyl, aryl, heteroaryl, or fused ring heteroaryl, which amino, -O-aryl, 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, heterocyclyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl
• R 3 , R 4 , and R 5 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 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fused ring heteroaryl is optionally substituted with one or more of halogen
• 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 1 -C 7 alkoxy, cycloalkyl, spiro-fused cycloalkyl, heterocyclyl, aryl, heteroaryl, or fuse
• Clause 4 The compound of any of clauses 1-3, wherein R 2 is H, Cl, hydroxy, -NHCH 3 , -N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -OCHF2, -OPh, -CF 3 , -CHF2, unsubstituted Ci- C7 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 7 The compound of any of clauses 1-6, wherein R 3 is H, halogen, hydroxy, -CN, methyl, -CF 3 , or methoxy.
• Clause 15 The compound of any of clauses 1-14, 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 24 The compound of any of clauses 1-23, wherein 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, cycloalkyl, or spiro-fused cycloalkyl.
• 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 33 The compound of any of clauses 27-32, wherein R 6 is: [ 00241]
• Clause 34 The compound of any of clauses 1-33, wherein the compound is selected from Compounds 1-64, as listed in Examples 1-14 and Tables 1-10.
• Clause 36 The compound of any of clauses 1-35, wherein the compound is selected from Compound 1, Compound 5, Compound 8, Compound 12, Compound 14, Compound 16, Compound 35, Compound 44, Compound 45, Compound 46, Compound 47, Compound 51, and Compound 55.
• Clause 37 A composition comprising a compound of any of clauses 1-36.
• Clause 38 The composition of clause 37, wherein the amount of the compound is from about 0.0001% (by weight total composition) to about 99%.
• Clause 39 The composition of clause 37 or clause 38, further comprising a formulary ingredient, an adjuvant, or a carrier.
• Clause 40 The composition of any of clauses 37-39, wherein the composition further comprises a BCL2 inhibitor.
• Clause 43 The composition of any of clauses 37-42, 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
• 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 clof arabine; wherein the isocitrate dehydrogenase 1 or 2 (IDH1 and/or IDH2) inhibitor comprises ivosiden
• 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-PDl/PDLl (e.g.
• Anti- CD70 e.g. ARGX-110, cusatuzumab
• a bispecific antibody e.g. floteuzumab (CD123 x CD3)
• Anti-CTLA4 e.g. ipilimumab
• Anti-PDl/PDLl 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 RARa agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK2/
• Clause 45 A method for providing a subj ect with a compound comprising one or more administrations of one or more compositions comprising the compound of any of clauses 1-36, wherein the compositions may be the same or different if there is more than one administration.
• Clause 46 The method of clause 45, wherein at least one of the one or more compositions further comprises a formulary ingredient.
• Clause 47 The method of clause 45 or clause 46, wherein at least one of the one or more compositions comprises the composition of any of clauses 37-44.
• Clause 48 The method of any of clauses 45-47, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, or intramuscular administration.
• Clause 50 The method of any of clauses 45-49, 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 51 The method of any of clauses 45-50, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
• Clause 52 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 1-36, wherein the compositions may be the same or different if there is more than one administration.
• Clause 54 The method of clause 52 or clause 53, wherein at least one of the one or more compositions further comprises a formulary ingredient.
• Clause 55 The method of clause 53 or clause54, wherein at least one of the one or more compositions comprises the composition of any of clauses 37-44.
• Clause 56 The method of any of clauses 52-55, 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 57 The method of any of clauses 52-56, wherein at least one of the one or more administrations comprises an oral administration.
• Clause 58 The method of any of clauses 52-57, 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 60 The method of any of clauses 52-59, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
• Clause 62 The method of any of clauses 52-61, wherein the method is for treating a hematopoietic cancer.
• Clause 64 The method of any of clauses 52-62, wherein 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, nonHodgkin 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 nonHodgkin lymphoma
• Waldenstrom’s macroglobulinemia B cell lymphoma, diffuse large B- cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or marginal zone lymphoma
• Clause 65 The method of any of clauses 52-61, 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 IRAKI and/or IRAK4, or combinations thereof.
• glioblastoma multiforme endometrial cancer, melanoma, prostate cancer, lung cancer, breast cancer, kidney cancer, bladder cancer, basal cell carcinoma, thyroid cancer, squamous cell carcinoma, neuroblast
• Clause 66 The method of clause 65, 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, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’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
• hidradenitis suppurativa systemic lupus erythematosus
• inflammatory bowel disease i.e., multiple sclerosis
• psoriasis psoriasis
• Sjogren’s syndrome Ankylosing spondylitis
• Clause 67 The method of any of clauses 52-63, wherein 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 wherein the method is for treating 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.
• Clause 72 The method of any of clauses 52-71, wherein the method occurs after one or more of having MDS, having myeloproliferative disease, an occurrence of chemical exposure, an exposure to ionizing radiation, or a treatment for cancer.
• Clause 73 The method of any of clauses 52-71, wherein the method further comprises administration of a composition comprising a BCL2 inhibitor, or wherein the at least one or more compositions comprises the compound of any of clauses 1-36 and further comprises a BCL2 inhibitor.
• Clause 74 The method of clause 73 wherein the compound of any of claims 1-36 and the BCL2 inhibitor may be administered together or separately, in one or more administrations of one or more compositions.
• Clause 76 The method of any of clauses 52-75, 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 de
• 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 comprises ivo
• 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-PDl/PDLl (e.g.
• Anti-CD70 e.g. ARGX-110, cusatuzumab
• a bispecific antibody e.g. floteuzumab (CD123 x CD3)
• Anti-CTLA4 e.g. ipilimumab
• Anti-PDl/PDLl 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 RARa agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK2/
• Clause 78 A compound according to any one of clauses 1-36, 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 79 The compound for use of clause 78, 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 80 The compound for use of clause 78 or clause 79, wherein at least one of the one or more compositions further comprises a formulary ingredient.
• Clause 82 The compound for use of any one of clauses 78-81, 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 83 The compound for use of any one of clauses 78-82, wherein at least one of the one or more administrations comprises an oral administration.
• Clause 84 The compound for use of any one of clauses 78-83, 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 85 The compound for use of any one of clauses 78-84, wherein the compound 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 86 The compound for use of any one of clauses 78-85, wherein the subject is a mammal, preferably wherein the subject is a human, a rodent, or a primate.
• Clause 87 The compound for use of any one of clauses 78-86, wherein the subject is in need of the treatment.
• Clause 88 The compound for use of any one of clauses 78-87, wherein the method is for treating a hematopoietic cancer.
• Clause 90 The compound for use of any one of clauses 78-88, wherein 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, diffuse large B-cell lymphoma (DLBCL), DLBCL with MYD88 mutation, follicular lymphoma, or
• Clause 92 The compound for use of clause 91, 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, hidradenitis suppurativa, 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
• hidradenitis suppurativa systemic lupus erythematosus
• inflammatory bowel disease multiple sclerosis
• psoriasis psoriasis
• Sjögren’s syndrome Ankylosing spondylitis
• Clause 95 The compound for use of clause 94, wherein the method is for treating DLBCL, and wherein the DLBCL comprises a L265P MYD88 mutant (ABC) subtype of DLBCL.
• the method further comprises administration of a composition comprising a BTK inhibitor.
• Clause 96 The compound for use of clause 95, wherein the BTK inhibitor comprises ibrutinib.
• Clause 97 The compound for use of any one of clauses 78-96, wherein the subject is susceptible to AML and/or MDS, and/or wherein the method prevents or ameliorates future AML and/or MDS.
• Clause 98 Clause 98.
• Clause 99 The compound for use of any one of clauses 78-98, wherein the method further comprises administration of a composition comprising a BCL2 inhibitor, or wherein the at least one or more compositions comprises the compound of any of clauses 1-36 and further comprises a BCL2 inhibitor.
• Clause 100 The compound for use of clause 99, wherein the compound of any of clauses 1-36 and the BCL2 inhibitor may be administered together or separately, in one or more administrations of the one or more compositions.
• Clause 101 The compound for use of clause 99 or clause 100, wherein the BCL2 inhibitor comprises venetoclax, or a salt, isomer, derivative or analog thereof.
• Clause 102 The compound for use of any one of clauses 78-101, 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, antibodydrug 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
• Clause 103 The compound for use of any one of clauses 78-102, 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 I
• 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-PDl/PDLl (e.g.
• Anti-CD70 e.g. ARGX-110, cusatuzumab
• a bispecific antibody e.g. floteuzumab (CD123 x CD3)
• Anti-CTLA4 e.g. ipilimumab
• Anti-PDl/PDLl 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 RARa agonist); wherein the TP53 activator comprises APR-246 (Eprenetapopt); wherein the smoothened receptor antagonist comprises glasdegib; wherein the ERK inhibitor comprises an ERK2/
• R 6 is selected from
• R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are each 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, wherein 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
• 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 each 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, wherein 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,
• R2if, R22f, and R23f are each independently selected from H and halogen;
• R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb are each independently selected from H, halogen, -OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl and C 1 -C 6 alkoxy are each optionally substituted with one or more halogen atoms; and a is selected from 0, 1, 2, 3, 4, 5, and 6.
• Clause 205 The compound of clause 202 or 203, wherein at least one of
• R20f is selected from t-butyl, unsubstituted C 3 cycloalkyl, pyrrolidinyl, -OCH 3 , - O O S ; or R220fa
• R21f, R22f, and R23f are each H
• R 21f and R 23f are each F and R 22f is H
• R 21f and R 23f are each H and R 22f is F
• R24fa, R24fb, R25fa, R25fb, R26fa, and R26fb are each H
• R 25fa , R 25fb , R 26fa , and R 26fb are each H and R 24fa and/or R 24fb are selected from F, -CH 3 , and -CF 3 .
• Clause 206 The compound of any one of clauses 202-205, wherein the compound is selected from: , , [00317] Clause 207.
• Clause 208 The compound of clause 207, wherein one or more of R 24ga , R24gb, R25ga, R25gb, R26ga, R26gb, R27ga, R27gb, R28ga, and R28gb is independently selected from halogen, -OH, and C1-C6 alkyl. [00319] Clause 209. The compound of clause 207 or 208, wherein R 20g is H. [00320] Clause 210.
• R 20g is selected from t-butyl, unsubstituted C 3 cycloalkyl, , , - (iv) R 21g and R 23g are each F and R 22g is H; (v) R21g and R23g are each H and R22g is F; b, ga, g a , , each of R24ga, R24gb, R26ga, R26gb, R27ga, R27gb, R 28ga , , each of R24ga, R24gb, R26ga, R26gb, R28ga, and R28gb is H a , each of R 24ga , R 24gb , R 27ga , R 27gb , R 26ga , R 28ga , and R [00321] Clause 211.
• R 24ga , R 24gb R 27ga , R 27gb , R 26ga , R 28ga , and R
• R2011 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkyl, wherein Ci- Ce 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
• R2ih, R22h, and R2311 are each independently selected from H and halogen.
• a composition comprising a compound of any one of clauses 201-221, wherein the composition further comprises a formulary ingredient, an adjuvant, or a carrier.
• Clause 223. The composition of clause 222, wherein 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,
• Clause 224 The composition of clause 223, wherein the composition is used in combination with a BCL2 inhibitor.
• Clause 225 The composition of clause 224, wherein the BCL2 inhibitor is venetoclax or a pharmaceutically acceptable salt therof.
• Clause 226 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 201-221 or a composition of any one of clauses 222-225.
• Clause 227 Clause 227.
• Clause 228 The method of clause 226 or 227, 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 230 The method of any one of clauses 226-229, 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.
• 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
• 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 IRAKI 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, thyroid cancer, squamous cell carcinoma, neuroblastoma,
• the disease or disorder comprises one or more inflammatory diseases or autoimmune disease selected from chronic inflammation, sepsis, rheumatoid arthritis, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’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, hidradenitis suppurativa, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, psoriasis, Sjogren’s syndrome, Ankylosing spondylitis, systemic sclerosis, Type 1 diabetes mellitus, or combinations thereof.
• MDS, MDS with a splicing factor mutation MDS with a mutation in isocitrate dehydrogenase 1, MDS with a mutation in isocitrate dehydrogenase 2;
• 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.
• Clause 240 The method of clause 239, wherein the additional therapy is a BCL2 inhibitor.
• Clause 248 The method of any one of clauses 226-241, wherein the disease or disorder is BCL2 inhibitor resistant refractory acute myeloid leukemia (AML).
• AML BCL2 inhibitor resistant refractory acute myeloid leukemia
• Clause 250 The method of any one of clauses 226-241, wherein the disease or disorder is FLT3 inhibitor resistant refractory acute myeloid leukemia (AML).
• AML FLT3 inhibitor resistant refractory acute myeloid leukemia
• Clause 254 The method of clause 239, wherein the compound of any one of clauses 201-221 or the composition of any one of clauses 222-225 and the one or more additional therapies are administered together in one administration or composition.
• Clause 256 The method of any one of clauses 226-255, wherein the disease or disorder is alleviated by inhibiting at least one of IRAKI, IRAK4, and FLT3 in the subject.
• Clause 258 The method of any one of clauses 226-255, wherein the disease or disorder is alleviated by inhibiting IRAKI and IRAK4 in the subject.
• Clause 260 The method of any one of clauses 256, 257, or 259, wherein FLT3 is selected from WT FLT3, activated FLT3, and mutated FLT3.
• c-Bu cyclobutyl
• c-Pr cyclopropyl
• Cy cyclohexyl
• DAST (diethylamino)sulfur trifluoride
• dba dibenzylideneacetone
• DCM dichloromethane
• DIAD diisopropylazodicarboxylate
• DIBAL, DIBAL-H diisobutylaluminum hydried
• DIEA diisopropylethylamine
• DME 1,2- dimethoxy ethane
• DMEM Dulbecco’s modified eagle medium
• DMAP 4- dimethylaminopyridine
• DMF A,A-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)-lH-l,2,3-triazolo[4,5-b]pyridin-l-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
• HOAc acetic acid
• HOAt 3H-[l,2,3]-triazolo[4,5- b]pyridin-3-ol
• HOBt IH-benzotriazol-l-ol
• HPLC High pressure liquid chromatography
• HTRF homogen
• 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-l, 1 '-biphenyl)[2-(2'-amino-l
• Example 1 Exemplary Synthetic Procedure #1 (Compounds 1 – 7) Compound 1, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-(1- methylcyclopropyl)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-amine
• Step A 5-bromo-N,N-bis(4-metho ne
• T ne 27.00 g, 155.2 mmol
• sodium hydried 15.52 g, 387.9 mmol, 60% purity
• N,N-dimethylacetamide 200 mL
• 1-(chloromethyl)-4-methoxy-benzene 60.75 g, 387.9 mmol, 52.83 mL).
• the resulting reaction mixture was stirred at 0 °C for 2 hours, and was then poured into ice water and extracted with ethyl acetate (3 x 300 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (2 x 250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 – 15% ethyl acetate in petroleum ether) to provide the title compound.
• Step B 5-isopropenyl-N,N-bis[(4-methoxyphenyl)methyl]pyrazin-2-amine
• N,N-bis[(4-methoxyphenyl)methyl]-5-(1-methylcyclopropyl)pyrazin-2-amine [00 , 103.87 mmol) was added to dichloromethane (100 mL) at 0 o C.
• Diiodomethane 46.37 g, 173.1 mmol, 13.97 mL was added dropwise, and the resulting reaction mixture was stirred at 0 °C for 30 minutes.
• Step D 5-(1-methylcyclopropyl)pyrazin-2-amine [00380 xyphenyl)methyl]-5-(1- methylcyclopropyl)pyrazin-2-amine (8.00 g, 20.5 mmol) in trifluoroacetic acid (100 mL) was stirred at room temperature for 5 hours. The reaction was then diluted with methanol (100 mL), and the resulting mixture was filtered and concentrated under reduced pressure.
• Step F 3-(6-bromo-2-pyridyl)-6-(l-methylcyclopropyl)imidazo[l,2-a]pyrazine
• Step G tert-butyl (3S,4S)-3-fhioro-4-[[6-[6-(l-methylcyclopropyl)imidazo[l,2-a]pyrazin-3- yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate l)imidazo[1,2- a]pyrazine (0.501 g, 1.52 mmol), tert-butyl (3S,4S)-3-amino-4-fluoro-pyrrolidine-1- carboxylate (0.310 g, 1.52 mmol), cesium carbonate (1.24 g, 3.80 mmol), and (2- dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)[2-(2’-amino-1,1’- biphenyl)]palladium(II)methanesulfonate (0.127 g, 0.152 mmol) in
• Step H N-[(3S,4S)-4-fluoropyrrolidin-3-yl]-6-[6-(1-methylcyclopropyl)imidazo[1,2- a]pyrazin-3-yl]pyridin-2-amine oro-4-[[6-[6-(1- methylcyclopropyl)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate (0.400 g, 0.884 mmol,) in dichloromethane (15 mL) was added trifluoroacetic acid (2.31 g, 20.3 mmol, 1.50 mL).
• reaction mixture was then cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 x 15 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
• Step B.6-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-a]pyrazine [00387 nyl]imidazo[1,2- a]pyrazine (2.00 g, 9.38 mmol) and methyl(diphenyl)sulfonium tetrafluoroborate (2.27 g, 11.3 mmol) in tetrahydrofuran (30 mL) was added a solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1 M, 18.77 mL). The resulting mixture was stirred for 10 hours while warming to room temperature.
• Step C 3-(6-bromo-2-pyridyl)-6-[l-(trifluoromethyl)cyclopropyl]imidazo[l,2-a]pyrazine
• Step D tert-butyl (3S,4S)-3-fhioro-4-[[6-[6-[l-(trifhioromethyl)cyclopropyl]imidazo[l,2- a]pyrazin-3-yl]-2-pyridyl]amino]pyrrolidine-l-carboxylate
• Step E 5-(tert-butyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine
• reaction mixture was then cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (2 x 150 mL). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (2 x 75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
• Step D 3-(6-bromo-2-pyridyl)-6-(difluoromethyl)imidazo[l,2-a]pyrazine
• Step E 5-(tert-butyl)-N,N-bis(4-methoxybenzyl)pyridin-2-amine
• Step F 6-[6-(difluoromethyl)imidazo[l,2-a]pyrazin-3-yl]-N-[(3S,4S)-4-fluoropyrrolidin-3- yl]pyridin-2-amine
• Step A l-imidazo[l,2-a]pyrazin-6-ylethanone tr ibuty l( 1 -ethoxyvinyl)stannane Cui, Pd(dppf)CI 2 1 N HCI, MeCN
• Step B 5-isopropenyl-N,N-bis[(4-methoxyphenyl)methyl]pyrazin-2-amine
• Step B 3-(6-bromopyridin-2-yl)-6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyrazine [ 00 g, 4.61 mmol), 2,6-dibromopyridine (3.27 g, 13.8 mmol), triphenylphosphine (0.121 g, 0.461 mmol), potassium carbonate (1.91 g, 13.8 mmol), and palladium acetate (0.103 g, 0.461 mmol) in 1,4-dioxane (10 mL) and ethyl alcohol (5 mL) was purged with nitrogen, and was then heated at 100 °C for 16 hours under nitrogen atmosphere.
• Step C tert-butyl (3S,4S)-3-fluoro-4-[[6-[6-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyrazin-3- yl]-2-pyridyl]amino]pyrrolidine-1-carboxylate H 2 N N N N N F oc midazo[1,2- a]pyrazine (0.060 g, 0.161 mmol), tert-butyl (3S,4S)-3-amino-4-fluoro-pyrrolidine-1- carboxylate (0.036 g, 0.177 mmol), cesium carbonate (0.131 g, 0.402 mmol), and (2- dicyclohexylphosphino-2',6'-d
• Step A tert-butyl (3R)-3-[[6-(6-chloroimidazo[l,2-a]pyrazin-3-yl)-2- pyridyl]amino]piperidine-l-carboxylate
• Step B tert-butyl (3R)-3-[[6-[6-(l-methylpyrazol-4-yl)imidazo[l,2-a]pyrazin-3-yl]-2- pyridyl]amino]piperidine-l-carboxylate
• Step C 6-[6-(l-methylpyrazol-4-yl)imidazo[l,2-a]pyrazin-3-yl]-N-[(3R)-3- piperidyl]pyridin-2-amine ylpyrazol-4- yl)imidazo[l,2-a]pyrazin-3-yl]-2-pyridyl]amino]piperidine-l-carboxylate (0.065 g, 0.137 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.770 g, 6.75 mmol, 0.500 mL). The resulting reaction mixture was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure.
• Step A (3S,4S)-tert-butyl 3-fluoro-4-((6-(6-methoxyimidazo[l,2-a]pyrazin-3-yl)pyridin-2- yl)amino)pyrrolidine- 1 -carboxylate
• Step B N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-methoxyimidazo[l,2-a]pyrazin-3- yl)pyridin-2-amine
• Step B 6-(6-(2,2-difluoroethoxy)imidazo[1,2-a]pyrazin-3-yl)-N-((3S,4S)-4-fluoropyrrolidin- 3-yl)pyridin-2-amine [00 [[6-[6-(2,2- difluoroethoxy)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]-4-fluoro-pyrrolidine-1- carboxylate (0.050 g, 0.105 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.54 g, 13.5 mmol, 1.00 mL).
• Example 9 Exemplary Synthetic Procedure #9 (Compounds 59 – 60) Compound 59, N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(6-isopropoxyimidazo[1,2- a]pyrazin-3-yl)pyridin-2-amine Step A.
• Step B N-[(3S,4S)-4-fluoropyrrolidin-3-yl]-6-(6-isopropoxyimidazo[1,2-a]pyrazin-3- yl)pyridin-2-amine [004 oro-4-[[6-(6- isopropoxyimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]pyrrolidine-1-carboxylate (0.015 g, 0.033 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.232 g, 2.03 mmol, 0.150 mL).
• Step A tert-butyl (3S,4S)-3-((6-(6-(3,3-dimethyl-2-oxopyrrolidin-l-yl)imidazo[l,2- a]pyrazin-3-yl)pyridin-2-yl)amino)-4-fluoropyrrolidine-l -carboxylate
• Step B 1 -(3-(6-(((3 S,4S)-4-fluoropyrrolidin-3-yl)amino)l 76yridine-2-yl)imidazo[ 1 ,2- a]pyrazin-6-yl)-3,3-dimethylpyrrolidin-2-one
• Step B 1-(3-(6-(((3S,4S)-4-fluoropyrrolidin-3-yl)amino)pyridin-2-yl)imidazo[1,2-a]pyrazin- 6-yl)-4,4-dimethylpyrrolidin-2-one 2-oxo- pyrrolidin-1-yl)imidazo[1,2-a]pyrazin-3-yl]-2-pyridyl]amino]-4-fluoro-pyrrolidine-1- carboxylate (0.080 g, 0.157 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.23 g, 10.8 mmol, 0.800 mL).
• Step A tert-butyl (3S,4S)-3-fluoro-4-((6-(6-(pyrrolidin-l-yl)imidazo[l,2-a]pyrazin-3- yl)pyridin-2-yl)amino)pyrrolidine-l -carboxylate
• Step B N-((3S,4S)-4-fhioropyrrolidin-3-yl)-6-(6-(pyrrolidin-l-yl)imidazo[l,2-a]pyrazin-3- yl)pyridin-2-amine [0 in-1- ylimidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]amino]pyrrolidine-1-carboxylate (0.020 g, 0.043 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.513 g, 4.50 mmol, 0.333 mL). The resulting reaction was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure.
• Step A 6-(3,3-difhioropyrrolidin-l-yl)imidazo[l,2-a]pyrazine t- u a, o uene
• Step B 3 -(6-bromopyridin-2-yl)-6-(3 ,3 -difluoropyrrolidin- 1 -yl)imidazo[ 1 ,2-a]pyrazine
• Step C (3S,4S)-tert-butyl 3-((6-(6-(3,3-difluoropyrrolidin-l-yl)imidazo[l,2-a]pyrazin-3- yl)pyridin-2-yl)amino)-4-fluoropyrrolidine- 1 -carboxylate
• Step D 6-(6-(3 ,3 -difluoropyrrolidin- 1 -yl)imidazo[ 1 ,2-a]pyrazin-3 -yl)-N-((3 S,4S)-4- fluoropyrrolidin-3-yl)pyridin-2-amine
• Step B (3S,4S)-tert-butyl 3-fluoro-4-((6-(imidazo[l,2-a]pyrazin-3-yl)pyridin-2- yl)amino)pyrrolidine- 1 -carboxylate
• Step C N-((3S,4S)-4-fluoropyrrolidin-3-yl)-6-(imidazo[1,2-a]pyrazin-3-yl)pyridin-2-amine [0043 idazo[1,2-a]pyrazin-3- yl-2-pyridyl)amino]pyrrolidine-1-carboxylate (0.080 g, 0.201 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.50 mL).
• Step B 3-(6-bromopyridin-2-yl)-6-(2,2-difluoroethoxy)imidazo[l,2-a]pyrazine
• Step C (R)-tert-butyl 3-((6-(6-(2,2-difluoroethoxy)imidazo[l,2-a]pyrazin-3-yl)pyridin-2- yl)amino)piperidine- 1 -carboxylate
• Step D (R)-6-(6-(2,2-difhioroethoxy)imidazo[l,2-a]pyrazin-3-yl)-N-(piperi din-3 -yl)pyridin- 2-amine
• Step C l,l,l-trifluoro-2-(imidazo[l,2-a]pyrazin-6-yl)propan-2-ol
• Step D 2-(3 -(6-bromopyridin-2-yl)imidazo[ 1 ,2-a]pyrazin-6-yl)- 1,1,1 -trifluoropropan-2-ol
• a mixture of l,l,l-trifluoro-2-imidazo[l,2-a]pyrazin-6-yl-propan-2-ol (0.240 g, 1.04 mmol), 2,6-dibromopyridine (0.737 g, 3.11 mmol), palladium acetate (0.023 g, 0.104 mmol), triphenylphosphine (0.054 g, 0.208 mmol), 2,2-dimethylpropanoic acid (0.031 g, 0.311 mmol, 0.036 mL), and potassium carbonate (0.430 g, 3.11 mmol) in toluene (10 mL) was purged with nitrogen, and was then heated at 100 °C for 15 hours under nitrogen atmosphere.
• Step E (3S,4S)-tert-butyl 3-fluoro-4-((6-(6-(l,l,l-trifhioro-2-hydroxypropan-2- yl)imidazo[l,2-a]pyrazin-3-yl)pyridin-2-yl)amino)pyrrolidine-l -carboxylate
• Step F Fast- and slow-eluting diastereomers of l,l,l-trifluoro-2-(3-(6-(((3S,4S)-4- fluoropyrrolidin-3-yl)amino)pyridin-2-yl)imidazo[l,2-a]pyrazin-6-yl)propan-2-ol
• Step B (3S,4S)-tert-butyl 3-fluoro-4-((4-fluoro-6-(6-(l,l,l-trifluoro-2-hydroxypropan-2- yl)imidazo[l,2-a]pyrazin-3-yl)pyri din-2 -yl)amino)pyrrolidine-l -carboxylate yrazin-6- yl]-1,1,1-trifluoro-propan-2-ol (0.060 g, 0.148 mmol), tert-butyl (3R)-3-aminopiperidine-1- carboxylate (0.030 g, 0.148 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium[1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane (0.020 g, 0.020 mmol), ces
• Step B 2-(3-(6-bromopyridin-2-yl)imidazo[l,2-a]pyrazin-6-yl)isothiazolidine 1,1-dioxide
• Step C (3S,4S)-tert-butyl 3-((6-(6-(l,l-dioxidoisothiazolidin-2-yl)imidazo[l,2-a]pyrazin-3- yl)pyridin-2-yl)amino)-4-fluoropyrrolidine- 1 -carboxylate
• Step D 2-(3-(6-(((3S,4S)-4-fluoropyrrolidin-3-yl)amino)pyridin-2-yl)imidazo[l,2-a]pyrazin- 6-yl)isothiazolidine 1,1-dioxide
• Step A l-(imidazo[l,2-a]pyrazin-6-yl)pyrrolidin-2-one [00459] A mixture of 6-bromoimidazo[l,2-a]pyrazine (5.00 g, 25.3 mmol), pyrrolidin-2-one (2.58 g, 30.3 mmol), cesium carbonate (24.7 g, 75.8 mmol), (1R,2R)- Nl,N2-dimethylcyclohexane-l,2-diamine (3.59 g, 25.4 mmol), and bis[(tetrabutylammonium iodide)copper(I) iodide] (1.41 g, 1.26 mmol) in dioxane (70 mL) was purged with nitrogen, and was then heated at 120 °C for 2 hours under nitrogen atmosphere.
• reaction 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 (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure.
• Step B l-(3-(6-bromo-3,5-difluoropyridin-2-yl)imidazo[l,2-a]pyrazin-6-yl)pyrrolidin-2-one
• Step C (3S,4S)-tert-butyl 3-((3,5-difhioro-6-(6-(2-oxopyrrolidin-l-yl)imidazo[l,2- a]pyrazin-3-yl)pyridin-2-yl)amino)-4-fluoropiperidine-l -carboxylate
• Step D l-(3-(3,5-difhioro-6-(((3S,4S)-4-fhioropiperidin-3-yl)amino)pyridin-2- yl)imidazo[l,2-a]pyrazin-6-yl)pyrrolidin-2-one
• Step A (R)-tert-butyl 3-((6-(6-chloroimidazo[l,2-a]pyrazin-3-yl)pyridin-2- yl)amino)piperidine- 1 -carboxylate
• Step B (R)-tert-butyl 3-((6-(6-(2-oxoimidazolidin-l-yl)imidazo[l,2-a]pyrazin-3-yl)pyridin- 2-yl)amino)piperidine-1-carboxylate zin-3- yl)pyridin-2-yl)amino)piperidine-1-carboxylate (0.060 g, 0.140 mmol), imidazolidin-2-one (0.024 g, 0.280 mmol), copper iodide (0.013 g, 0.070 mmol), (1R,2R)-cyclohexane-1,2- diamine (0.008 g, 0.070 mmol), and potassium carbonate (0.058 g, 0.420 mmol) in dioxane (7 mL) was purged with nitrogen, and was then heated at 120 °C for 16 hours under nitrogen atmosphere.
• Step A (3S,4S)-tert-butyl 3-((6-(6-chloroimidazo[l,2-a]pyrazin-3-yl)pyridin-2-yl)amino)-4- fluoropiperidine- 1 -carboxylate
• Step B (3S,4S)-tert-butyl 4-fluoro-3-((6-(6-(2-oxopyrrolidin-l-yl)imidazo[l,2-a]pyrazin-3- yl)pyridin-2-yl)amino)piperidine- 1 -carboxylate
• Step C l-(3-(6-(((3S,4S)-4-fluoropiperidin-3-yl)amino)pyridin-2-yl)imidazo[l,2-a]pyrazin- 6-yl)pyrrolidin-2-one
• Step D (3S,4S)-tert-butyl 3-((6-(6-(tert-butyl)imidazo[l,2-a]pyrazin-3-yl)-4-fluoropyridin-2- yl)amino)-4-fluoropyrrolidine- 1 -carboxylate
• Step E 6-(6-(tert-butyl)imidazo[l,2-a]pyrazin-3-yl)-4-fluoro-N-((3S,4S)-4-fluoropyrrolidin-
• Step B.3-(6-bromopyridin-2-yl)-6-isopropoxyimidazo[1,2-a]pyrazine [00 1.13 mmol), 2,6-dibromopyridine (0.802 g, 3.39 mmol), palladuim(II)acetate (0.025 g, 0.113 mmol), triphenylphosphine (0.044 g, 0.169 mmol), 2,2-dimethylpropanoic acid (0.035 g, 0.339 mmol), and potassium carbonate (0.468 g, 3.39 mmol) in toluene (5 mL) was purged with nitrogen, and was then heated at 100 °C for 16 hours under nitrogen atmosphere.
• Step D (R)-6-(6-isopropoxyimidazo[1,2-a]pyrazin-3-yl)-N-(piperidin-3-yl)pyridin-2-amine 1,2-a]pyrazin- 3-yl)-2-pyridyl]amino]piperidine-1-carboxylate (0.170 g, 0.376 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.50 mL). The resulting reaction was stirred at room temperature for 1 hour, and was then concentrated under reduced pressure.
• 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. Unlike kinase binding assays that measure competition for ATP, 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. (Sometimes the carboxy terminus has been truncated to aid in expression, or, if it is a receptor kinase, the enzyme itself is isolated from the other parts of the receptor that are involved in regulating kinase activity.)
• the reagent used was as follows: Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgC12, 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.
• Kinase binding data were obtained for various exemplary compounds prepared according to Examples 1-24 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 (Kd values), rather than IC50 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.
• kinase-tagged T7 phage strains were prepared in an E. coll host derived from the BL21 strain. E. coll 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.
• Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 11 lx stocks in 100% DMSO. Kds were determined using an 11-point 3- fold compound dilution series with three DMSO control points.
• All compounds for Kd 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.
• the assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20).
• the beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 pM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes.
• the kinase concentration in the eluates was measured by qPCR.
• 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 nonlinear least square fit with the Levenberg-Marquardt algorithm.
• 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 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 (Labcytelnc, Sunnyvale, CA).
• Transfected cells were harvested and mixed with NanoBRETTracer Reagent and dispensed into 384 well plates and incubated at 37 °C 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 En Visionplate reader.
• the BRET Ratios were calculated.
• BRET Ratio [(Acceptor sample Donor sample) - (Acceptor no-tracer control HTonor no-tracer control)].
• the IC50 values of compounds were calculated with Prism GraphPad program.
• lipid DNA complexes as follows: a. Prepare a 10 pg/ml solution of DNA in Opti-MEM without serum that consists of the following ratios of carrier DNA and DNA encoding NanoLuc® fusion. 9.0 pg/mL of Transfection Carrier DNA, 1.0 pg/mL of NanoLuc fusion vector DNA and 1 mL of Opti- MEM without phenol red. Mix thoroughly. b. Add 30 pl of FuGENE HD Transfection Reagent into each milliliter of DNA mixture to form lipid: DNA complex. c. Mix by inversion 10 times. d. Incubate at ambient temperature for 20 minutes to allow complexes to form.
• Dispense cells + lipid DNA complex into a sterile tissue culture dish and incubate for 22-24 hours.
• Each test compound is delivered from the compound source plate to the wells of 384- well white NBS plate by Echo 550.
• NanoBRETTM ratio equation including optional background correction:
• ICso curves are plotted and IC50 values are calculated using the GraphPad Prism program based on a sigmoidal dose-response equation.
• THP-l-Blue NF-KB cells (InvivoGen) carrying a stable integrated NF-KB- 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 (Ing/mL) or hILIB (Ing/mL). After 10 - 20 minutes, 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
• DMSO vehicle
• the cells were centrifuged and 20 pL supernatant was incubated with 180 pL QUANTI-Blue reagent at 37 °C for 30 - 60 minutes.
• the levels of NF-KB-induced was measured in a microplate reader at 620 nm.
• M0LM14 D835Y and M0LM14 F691L cells were grown in RPMI-1640 media supplemented with 20% fetal bovine serum (FBS).
• FBS fetal bovine serum
• 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 pM) via a 1536 pin-tool.
• Bortezomib (final concentration 2.3 p.M) was used as a positive control for cell cytotoxicity. Plates were incubated for 48 hours at standard incubator conditions covered by a stainless steel gasketed lid to prevent evaporation. 48 hours post compound addition, 3 pL of Cell Titer Gio (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.
• Combination drug therapy has the potential to produce enhanced effects with lower side effects not obtained using either agent alone, or beyond the additive effect of the different concentrations of the two different agents.
• combination drug screening was performed as previously described (Mathews-Griner, L. A. et al., Proc. Nat. Acad. Sci., 2014, 111 :2439-2454; Lin, G. L. et al., Sci. Trans. Med., 2019, l l :eaaw0064).
• Luminescence readings were taken using a Viewlux imager (PerkinElmer) with a 2 second exposure time per plate. The results can be seen in Table 28.
• Table 28. Sum excess HSA scores for a combination therapy of Compounds 25, 31, 35, 50, 51, 80, 82, 97, 118, and 119 with Venetoclax obtained in MOLM14 (D835Y) cells in a 10 x 10 dataset.
• Compound # Sum Excess HSA Interaction with Venetoclax [00501]
• the sum excess HSA scores for Compounds 25, 31, 35, 50, 51, 80, 82, 97, 118, and 119 in Table 28 are used herein to quantitate drug interactions for enhanced pharmacological effects in the MOLM14 (D835Y) cell line.
• Table 28 summarizes the combination results of Compounds 25, 31, 35, 50, 51, 80, 82, 97, 118, and 119 with Venetoclax.
• a large negative sum excess HSA score indicates profound synergism with Venetoclax, whereas a positive excess HSA score indicates antagonism with Venetoclax in certain drug combinations.
• 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.
• sequences disclosed herein are included in publicly available databases, such as GENBANK® and SWISSPROT. Unless otherwise indicated or apparent the references to such publicly available databases are references to the most recent version of the database as of the filing date of this Application.
• the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

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