WO2021011428A1 - Heterocyclic kinase inhibitors - Google Patents

Heterocyclic kinase inhibitors Download PDF

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Publication number
WO2021011428A1
WO2021011428A1 PCT/US2020/041730 US2020041730W WO2021011428A1 WO 2021011428 A1 WO2021011428 A1 WO 2021011428A1 US 2020041730 W US2020041730 W US 2020041730W WO 2021011428 A1 WO2021011428 A1 WO 2021011428A1
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Prior art keywords
compound
solvate
hydrate
isomer
tautomer
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PCT/US2020/041730
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French (fr)
Inventor
Dange Vijay Kumar
Craig Alan Coburn
Luis Antonio LOPEZ
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Gb005, Inc.
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Publication of WO2021011428A1 publication Critical patent/WO2021011428A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates generally to protein kinase inhibitors, in particular Bruton tyrosine kinase (BTK) inhibitors, pharmaceutical compositions comprising them, processes for preparing them and uses of the inhibitors to treat or prevent diseases, disorders and conditions associated with kinase function.
  • BTK Bruton tyrosine kinase
  • the present invention relates to selective BTK inhibitors.
  • Protein kinase inhibitors are known to be useful for the treatment of diseases such as cancer, autoimmune,
  • Protein kinases are a large group of intracellular and transmembrane signaling proteins in eukaryotic cells. These enzymes are responsible for transfer of the terminal (gamma) phosphate from ATP to specific amino acid residues of target proteins. Phosphorylation of specific amino acid residues in target proteins can modulate their activity leading to profound changes in cellular signaling and metabolism. Protein kinases can be found in the cell membrane, cytosol and organelles such as the nucleus and are responsible for mediating multiple cellular functions including metabolism, cellular growth and differentiation, cellular signaling, modulation of immune responses, and cell death. Serine kinases specifically phosphorylate serine or threonine residues in target proteins.
  • tyrosine kinases including tyrosine receptor kinases, phosphorylate tyrosine residues in target proteins.
  • Tyrosine kinase families include: TEC, SRC, ABL, JAK, CSK, FAK, SYK, FER, ACK and the receptor tyrosine kinase subfamilies including ERBB, FGFR, VEGFR, RET and EPH.
  • Subclass I of the receptor tyrosine kinase superfamily consists of the ERBB receptors and comprises four members: ErbBl (also called epidermal growth factor receptor (EGFR)), ErbB2, ErbB3 and ErbB4.
  • EGFR epidermal growth factor receptor
  • Protein kinases exert control on key biological processes related to health and disease. Furthermore, aberrant activation or excessive expression of various protein kinases are implicated in the mechanism of multiple diseases and disorders characterized by benign and malignant proliferation, as well as diseases resulting from inappropriate activation of the immune system.
  • inhibitors of select kinases or kinase families may be useful in the treatment of cancer, vascular disease, autoimmune diseases, and inflammatory conditions including, but not limited to: solid tumors, hematological malignancies, thrombus, arthritis, graft versus host disease, lupus erythematosus, psoriasis, colitis, illeitis, multiple sclerosis, uveitis, coronary artery vasculopathy, systemic sclerosis, atherosclerosis, asthma, transplant rejection, allergy, ischemia, dermatomyositis, pemphigus, and the like.
  • Tec kinases are a family of non -receptor tyrosine kinases predominantly, but not exclusively, expressed in cells of hematopoietic origin.
  • the Tec family includes TEC, Bruton's tyrosine kinase (BTK), inducible T-cell kinase (ITK), resting lymphocyte kinase (RLK/TXK for Tyrosine Protein Kinase), and bone marrow-expressed kinase (BMX/ETK).
  • BTK is important in B-cell receptor signaling and regulation of B-cell development and activation. Mutation of the gene encoding BTK in humans leads to X- linked agammaglobulinemia which is characterized by reduced immune function, including impaired maturation of B-cells, decreased levels of immunoglobulin and peripheral B cells, diminished T-cell independent immune response. BTK is activated by Src-family kinases and phosphorylates PLC gamma leading to effects on B-cell function and survival. Additionally, BTK is important for cellular function of mast cells, macrophage and neutrophils suggesting that BTK inhibition would be effective in treatment of diseases mediated by these and related cells including inflammation, bone disorders, and allergic disease.
  • BTK inhibition is also important in survival of lymphoma cells suggesting that inhibition of BTK may be useful in the treatment of lymphomas and other cancers.
  • inhibitors of BTK and related kinases are of great interest as anti inflammatory as well as anti -cancer agents.
  • BTK is also important for platelet function and thrombus formation suggesting that BTK-selective inhibitors may prove to be useful antithrombotic agents.
  • BTK is required for inflammasome activation and inhibition of BTK may be useful in treatment of inflammasome-related disorders including; stroke, gout, type 2 diabetes, obesity-induced insulin resistance,
  • BTK is expressed in HIV infected T-cells and treatment with BTK inhibitors sensitizes infected cells to apoptotic death and results in decreased virus production. Accordingly, BTK inhibitors may be useful in the treatment of HIV-AIDS and other viral infections.
  • BMX another Tec family member which has roles in inflammation, cardiovascular disease, and cancer is also important for self-renewal and tumorigenic potential of glioblastoma stem cells.
  • BMX inhibitors may be useful in the treatment of various diseases including cancer, cardiovascular disease and inflammation.
  • ITK is a key signaling molecule downstream of the T-cell receptor and is expressed in T-cells, mast cells and NK cells. Inhibition of ITK has been shown to affect cytokine secretion and polarization of T-cell subtypes. As such ITK inhibitors may be useful in the treatment of allergy, psoriasis, dermatitis, multiple sclerosis and other diseases.
  • Ibrutinib (PCI-32765, Imbruvica) is a highly potent BTK inhibitor approved by the FDA for the treatment of adult patients with Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL); CLL/SLL with 17p deletion; Waldenstrom's macroglobulinemia (WM); Mantle cell lymphoma (who have received at least one prior therapy); Marginal zone lymphoma (who require systemic therapy and have received at least one prior anti-CD20-based therapy); and Chronic graft versus host disease (after failure of one or more lines of systemic therapy), with potential in other indications.
  • CLL Chronic lymphocytic leukemia
  • SLL Mall lymphocytic lymphoma
  • WM Waldenstrom's macroglobulinemia
  • Mantle cell lymphoma who have received at least one prior therapy
  • Marginal zone lymphoma who require systemic therapy and have received at least one prior anti-CD20-based therapy
  • Ibrutinib Side effects of Ibrutinib include hemorrhage, infections (including bacterial, viral, or fungal), cytopenias (including neutropenia, thrombocytopenia and anemia), cardiac arrhythmias (including ventricular tachyarrhythmias, atrial fibrillation and atrial flutter), hypertension and Tumor Lysis Syndrome. Other side effects that have been observed include diarrhea, nausea, fatigue, headache, rash, bruising, pyrexia, musculoskeletal pain & muscle spasms, stomatitis, sepsis and hypokalemia. Adverse effects of Ibrutinib, consistent with off-target effects, include diarrhea, atrial fibrillation, hypertension and panniculitis. Ibrutinib targets BTK and other members of the Tec family as well as select other kinases, e.g. Ibrutinib is not selective against EGFR.
  • the therapeutic dose of Ibrutinib is high, with recommended daily doses up to 560mg. Data indicates idiosyncratic drug toxicities are more likely to occur with high dose (>100mg) drugs.
  • selectivity against other kinases including cysteine homologous kinases such as EGFR, is highly desirable. It is known that inhibiting wild type EGFR is associated with dermatologic toxicities (Holcmann & Sibilia, "Mechanisms underlying skin disorders induced by EGFR inhibitors" Mol Cell Oncol. 2015, Vol 2(4)). However, given that EGFR has equally reactive Cysteine residues in homologous positions as BTK, it has proven challenging to attain selective EGFR BTK inhibitors.
  • BTK inhibitors with increased safety and tolerability.
  • BTK inhibitors with improved pharmacokinetics There is a need for BTK inhibitors for administration at lower doses.
  • BTK inhibitors with improved selectivity against various kinases, including EGFR.
  • a compound having the structure of
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • R 3 is H, alkyl, halo, or cyano
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • L is -O-, -S-, -NH-, -NMe-, -CH 2- , -CF 2- , -C(O)-, -C(O)NH-
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3.
  • a compound having the structure of
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • R 3 is H, alkyl, halo, or cyano
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3.
  • a compound having the structure of
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • L is -O-, -S-, -NH-, -NMe-, -CH 2- , -CF 2- , -C(O)-, -C(O)N)-
  • ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3;
  • R 4 is not -F when m is 1 and n is 0;
  • R 5 is not -F when m is 0 and n is 2.
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • L is -O-, -S-, -NH-, -NMe-, -CH 2- , -CF 2- , -C(O)-, -C(O)NH-
  • ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3.
  • a pharmaceutical composition comprising a compound having the structure of any one of Formulas (I), (I-SS), (II), (II-SS), (III), (III-SS), (IV), or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, and at least one pharmaceutically acceptable excipient.
  • a method of inhibiting a protein kinase comprising contacting the protein kinase with an effective amount of a compound having the structure of any one of Formulas (I), (I-SS), (II), (II-SS), (III), (III-SS), (IV), or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.
  • the protein kinase is BTK.
  • the compound or pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof is selective to BTK over EGFR.
  • a method for treating a BTK dependent condition comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I), (I-SS), (II), (II-SS), (III), (III-SS), (IV), or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.
  • ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5pL” means “about 5pL” and also “5pL.” Generally, the term “about” includes an amount that would be expected to be within experimental error.
  • alkyl means a straight chain or branched saturated hydrocarbon group.
  • “Lower alkyl” means a straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms.
  • straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, «-propyl, «-butyl, «-pentyl, «-hexyl, «-heptyl, and «-octyl groups.
  • branched lower alkyl groups include, but are not limited to, isopropyl, iso butyl , sec-butyl, /-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to
  • alkylene means a divalent alkyl group.
  • straight chain lower alkylene groups include, but are not limited to, methylene (i.e.,
  • heteroalkyl ene is an alkylene group of which one or more carbon atoms is replaced with a heteroatom such as, but not limited to, N, O, S, or P.
  • Alkoxy refers to an alkyl as defined above joined by way of an oxygen atom (i.e., ⁇ 0 ⁇ alkyl).
  • Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, //-propoxy, //-butoxy, isopropoxy, .vfc-butoxy, /er/-butoxy, and the like.
  • Carbocyclic and “carbocycle” denote a ring structure wherein the atoms of the ring are carbon. Carbocycles may be monocyclic or polycyclic.
  • Carbocycle encompasses both saturated and unsaturated rings. Carbocycle encompasses both cycloalkyl and aryl groups. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N substituents wherein N is the size of the carbocyclic ring with for example, alkyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Cycloalkyl groups are alkyl groups forming a ring structure, which can be substituted or unsubstituted.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbomyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6- disubstituted cyclohexyl groups or mono-, di- or tri- substituted norbomyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons in the ring portions of the groups.
  • aryl and aryl groups include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).
  • Carbocyclealkyl refers to an alkyl as defined above with one or more hydrogen atoms replaced with carbocycle.
  • Examples of carbocyclealkyl groups include, but are not limited to, benzyl and the like.
  • heterocycle or “heterocyclyl” groups include aromatic and non-aromatic ring compounds (heterocyclic rings) containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P.
  • a heterocycle group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom.
  • heterocycle groups include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom.
  • a dioxolanyl ring and a benzodioxolanyl ring system are both heterocycle groups within the meaning herein.
  • a heterocycle group designated as a C2-heterocycle can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth.
  • a C4- heterocycle can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a saturated heterocyclic ring refers to a heterocyclic ring containing no unsaturated carbon atoms.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • a heteroaryl group designated as a C 2 -heteroaryl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heteroaryl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quina
  • heteroaryl and “heteroaryl groups” include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl.
  • Heterocyclealkyl refers to an alkyl as defined above with one or more hydrogen atoms replaced with heterocycle.
  • heterocyclealkyl groups include, but are not limited to, morpholinoethyl and the like.
  • Halo or “halogen” refers to fluorine, chlorine, bromine and iodine.
  • Haloalkyl refers to an alkyl as defined above with one or more hydrogen atoms replaced with halogen.
  • Examples of lower haloalkyl groups include, but are not limited to, — CF 3 , — CH 2 CF 3 , and the like.
  • Haloalkoxy refers to an alkoxy as defined above with one or more hydrogen atoms replaced with halogen.
  • Examples of lower haloalkoxy groups include, but are not limited to -OCF 3 , -OCH 2 CF 3 , and the like.
  • Hydroalkyl refers to an alkyl as defined above with one or more hydrogen atoms replaced with -OH.
  • Examples of lower hydroxyalkyl groups include, but are not limited to -CH 2 OH, -CH 2 CH 2 OH, and the like.
  • the term "optionally substituted” refers to a group (e.g., an alkyl, carbocycle, or heterocycle) having 0, 1, or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents.
  • substituents include, but are not limited to -OR a , -NR a R b , -S(O) 2 R a or -S(0) 2 0R a , halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl, wherein each R a and R b is,
  • Racemic is used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the disclosure.
  • the isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers.”
  • Single enantiomers of a pure compound are optically active (i.e., they can rotate the plane of plane polarized light and designated R or S).
  • isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
  • the isolated isomer may be at least about 80%, at least 80% or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight.
  • substantially enantiomerically or diastereomerically pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.
  • racemate and “racemic mixture” refer to an equal mixture of two enantiomers.
  • a racemate is labeled “( ⁇ )” because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).
  • a “hydrate” is a compound that exists in combination with water molecules.
  • the combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a "hydrate” refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.
  • a “solvate” is similar to a hydrate except that a solvent other that water is present.
  • a solvent other that water For example, methanol or ethanol can form an “alcoholate", which can again be stoichiometric or non-stoichiometric.
  • a “solvate” refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.
  • Isotope refers to atoms with the same number of protons but a different number of neutrons
  • an isotope of a compound of Formulas (I)-(IV) includes any such compound wherein one or more atoms are replaced by an isotope of that atom.
  • carbon 12 the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons.
  • Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has several isotopes, fluorine 19 is longest-lived.
  • an isotope of a compound having the structure of Formulas (I)-(IV) includes, but not limited to, compounds of Formulas (I)-(IV) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine- 19.
  • Salt generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion.
  • acids in their anionic form and cations
  • bases in the cationic form and anions
  • pharmaceutically acceptable refers an agent that has been approved for human consumption and is generally non-toxic.
  • pharmaceutically acceptable salt refers to nontoxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).
  • Pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’ dibenzyl ethyl enediamine,
  • chloroprocaine choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine), and procaine.
  • Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4- hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic
  • salts may be useful, for example as intermediates in the synthesis of the compounds described herein, for example in their purification by recrystallization.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the active compound When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters,
  • the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • composition refers to a composition containing one or more of the compounds described herein, or a
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
  • unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
  • topical administration e.g., as a cream, gel, lotion, or ointment
  • intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • a composition of a compound described herein including formulating a compound of the disclosure with a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable carrier or diluent is suitable for oral administration.
  • the methods can further include the step of formulating the composition into a tablet or capsule.
  • the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration.
  • the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
  • the term "pharmaceutically acceptable carrier” refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example:
  • antiadherents antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, B
  • the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
  • auxiliary agents which do not deleteriously react with the active compounds.
  • Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances, preserving agents, sweetening agents, or flavoring agents.
  • the compositions can also be sterilized if desired.
  • the route of administration can be any route which effectively transports the active compound of the disclosure to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment, the oral route being preferred.
  • Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician.
  • Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment and/or to minimize or avoid unwanted side effects associated with the treatment.
  • Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians’ Desk Reference, incorporated herein by reference.
  • administering refers to providing a compound, a pharmaceutical composition comprising the same, to a subject by any acceptable means or route, including (for example) by oral, parenteral (e.g., intravenous), or topical administration.
  • treatment refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition.
  • treatment refers to any observable beneficial effect of the treatment.
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • a prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology.
  • a therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed.
  • subject refers to an animal (e.g., a mammal, such as a human).
  • a subject to be treated according to the methods described herein may be one who has been diagnosed with a neurodegenerative disease involving
  • demyelination, insufficient myelination, or underdevelopment of a myelin sheath e.g., a subject diagnosed with multiple sclerosis or cerebral palsy, or one at risk of developing the condition.
  • Diagnosis may be performed by any method or technique known in the art.
  • a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.
  • an effective amount refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent.
  • an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject.
  • the effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure.
  • a compound having the structure of
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • R 3 is H, alkyl, halo, or cyano
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • L is -O-, -S-, -NH-, -NMe-, -CH 2- , -CF 2- , -C(O)-, -C(O)NH-
  • ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3.
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • R 3 is H, alkyl, halo, or cyano
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • L is -O-, -S-, -NH-, -NMe-, -CH 2- , -CF 2- , -C(O)-, -C(O)NH-
  • ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R 1 is H, methyl, -CHF 2 , -CF 3 , ethyl, isopropyl, cyclopropyl, or fluoroethyl.
  • R 1 is H, methyl, or ethyl.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R 3 is H, -CH 3 , -F, or -C1.
  • R 3 is H.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl.
  • ring A is phenyl.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl.
  • ring A is oxazolyl, pyridinyl, pyrimidinyl, lH-benzo[d]imidazolyl, benzo[d]oxazolyl, or benzo[d]thiazolyl.
  • ring A is pyrimidinyl or pyrazolyl.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is:
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3.
  • m is 1.
  • m is 2.
  • m is 3.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is halo.
  • at least one R 4 is -F or -C1.
  • m is 2 and each R 4 is -F.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is alkyl.
  • at least one R 4 is methyl.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -CN.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -OR a and R a is alkyl.
  • at least one R 4 is -OR a and R a is methyl.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -OR a and R a is haloalkyl.
  • at least one R 4 is -OR a and R a is -CHF 2 or -CF 3.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH 2 -, or -C(O)NH-.
  • L is -O-.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle.
  • ring B is cyclohexyl or phenyl.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle.
  • ring B is pyridinyl.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3. In one embodiment, n is 1. In another embodiment, n is 2. In still another embodiment, n is 3.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is halo.
  • at least one R 5 is -F or -C1.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R 5 is -F.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is alkyl.
  • at least one R 5 is methyl.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -CN.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -OR a and R a is alkyl.
  • at least one R 5 is -OR a and R a is methyl.
  • a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -OR a and R a is haloalkyl.
  • at least one R 5 is -OR a and R a is -CHF 2 or -CF 3.
  • a compound of Formula (I) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 1, below:
  • a compound of Formula (I-SS)) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 2, below:
  • a compound having the structure of
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • R 3 is H, alkyl, halo, or cyano
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • L is -O-, -S-, -NH-, -NMe-, -CH 2- , -CF 2- , -C(O)-, -C(O)NH-
  • ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl; m is 0, 1, 2, or 3; and
  • n 0, 1, 2, or 3.
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • R 3 is H, alkyl, halo, or cyano
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • L is -O-, -S-, -NH-, -NMe- -CH 2- -CF 2- , -C(O)-, -C(O)NH
  • ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R 1 is H, methyl, -CHF 2 , -CF 3 , ethyl, isopropyl, cyclopropyl, or fluoroethyl.
  • R 1 is H or methyl.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R 3 is H, -CH 3 , -F, or -C1.
  • R 3 is H.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl.
  • ring A is phenyl.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl.
  • ring A is oxazolyl, pyridinyl, pyrimidinyl, lH-benzo[d]imidazolyl,
  • ring A is pyrimidinyl or pyrazolyl.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is:
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3.
  • m is 1.
  • m is 2.
  • m is 3.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is halo.
  • at least one R 4 is -F or -C1.
  • m is 2 and each R 4 is -F.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is alkyl.
  • at least one R 4 is methyl.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -CN.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -OR a and R a is alkyl.
  • at least one R 4 is -OR a and R a is methyl.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -OR a and R a is haloalkyl.
  • at least one R 4 is -OR a and R a is -CHF 2 or -CF 3 .
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH 2 -, or -C(0)NH-
  • L is -O-, -NH-, -CH 2 -, or -C(0)NH-
  • a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -O- in one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle.
  • ring B is cyclohexyl or phenyl.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle.
  • ring B is pyridinyl.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3. In one embodiment, n is 1. In another
  • n is 2. In still another embodiment, n is 3.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is halo.
  • at least one R 5 is -F or -C1.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R 5 is -F.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is alkyl.
  • at least one R 5 is methyl.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -CN.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -OR a and R a is alkyl.
  • at least one R 5 is -OR a and R a is methyl.
  • a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -OR a and R a is haloalkyl.
  • R a is haloalkyl.
  • at least one R 5 is -OR a and R a is -CHF 2 or -CF 3 .
  • a compound of Formula (II) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 3, below:
  • a compound of Formula (II-SS)) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 4, below:
  • a compound having the structure of
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • L is -O-, -S-, -NH-, -NMe-, -CH 2- , -CF 2- , -C(O)-, -C(O)NH-
  • ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl;
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3;
  • n and n are not both 0;
  • R 4 is not -F when m is 1 and n is 0;
  • R 5 is not -F when m is 0 and n is 2.
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • L is -O-, -S-, -NH-, -NMe -CH 2- -CF 2- , -C(O)-, -C(O)NH-
  • ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl
  • n 0, 1, 2, or 3;
  • n and n are not both 0;
  • R 4 is not -F when m is 1 and n is 0;
  • R 5 is not -F when m is 0 and n is 2.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R 1 is H, methyl, -CHF 2 , -CF 3 , ethyl, isopropyl, cyclopropyl, or fluoroethyl.
  • R 1 is H, methyl, or ethyl.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl.
  • ring A is phenyl.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl.
  • ring A is oxazolyl, pyridinyl, pyrimidinyl, lH-benzo[d]imidazolyl,
  • ring A is pyrimidinyl or pyrazolyl.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is:
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3.
  • m is 1.
  • m is 2.
  • m is 3.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is halo.
  • at least one R 4 is -F or -C1.
  • m is 2 and each R 4 is -F.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is alkyl.
  • at least one R 4 is methyl.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -CN.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -OR a and R a is alkyl.
  • R 4 is -OR a and R a is methyl.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -OR a and R a is haloalkyl.
  • at least one R 4 is -OR a and R a is -CHF 2 or -CF 3 .
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH2-, -C(O)-, or -C(O)NH-
  • L is -O-.
  • L is -NH-.
  • L is -CH2-
  • L is -C(O)-.
  • L is -C(O)NH-
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle.
  • ring B is cyclohexyl or phenyl.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle.
  • ring B is pyridinyl.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3. In one embodiment, n is 1. In another
  • n is 2. In still another embodiment, n is 3.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is halo.
  • at least one R 5 is -F or -C1.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R 5 is -F.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is alkyl.
  • at least one R 5 is methyl.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -CN.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -OR a and R a is alkyl.
  • at least one R 5 is -OR a and R a is methyl.
  • a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -OR a and R a is haloalkyl.
  • at least one R 5 is -OR a and R a is -CHF 2 or -CF 3 .
  • a compound of Formula (III) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 5, below:
  • a compound of Formula (III-SS)) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 6, below:
  • a compound having the structure of or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
  • R 1 is H, alkyl, haloalkyl, or cycloalkyl
  • ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
  • R 4 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • L is -O-, -S-, -NH-, -NMe-, -CH 2- , -CF 2- , -C(O)-, -C(O)NH-
  • ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle
  • R 5 is halo, alkyl, haloalkyl, -CN, or -OR a ;
  • R a is alkyl or haloalkyl
  • n 0, 1, 2, or 3;
  • n 0, 1, 2, or 3.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R 1 is H, methyl, -CHF 2 , -CF 3 , ethyl, isopropyl, cyclopropyl, or fluoroethyl.
  • R 1 is H, methyl, or ethyl.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl.
  • ring A is phenyl.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl.
  • ring A is oxazolyl, pyridinyl, pyrimidinyl, lH-benzo[d]imidazolyl,
  • ring A is pyrimidinyl or pyrazolyl.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is:
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3.
  • m is 1.
  • m is 2.
  • m is 3.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is halo.
  • at least one R 4 is -F or -C1.
  • m is 2 and each R 4 is -F.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is alkyl.
  • at least one R 4 is methyl.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -CN.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -OR a and R a is alkyl.
  • at least one R 4 is -OR a and R a is methyl.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 4 is -OR a and R a is haloalkyl.
  • at least one R 4 is -OR a and R a is -CHF 2 or -CF 3 .
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH2-, -C(O)-, or -C(O)NH-
  • L is -O-.
  • L is -NH-.
  • L is -CH 2 -
  • L is -C(O)-.
  • L is -C(O)NH-
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle.
  • ring B is cyclohexyl or phenyl.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle.
  • ring B is pyridinyl.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3. In one embodiment, n is 1. In another
  • n is 2. In still another embodiment, n is 3.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is halo.
  • at least one R 5 is -F or -C1.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R 5 is -F.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is alkyl.
  • at least one R 5 is methyl.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -CN.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -OR a and R a is alkyl.
  • at least one R 5 is -OR a and R a is methyl.
  • a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R 5 is -OR a and R a is haloalkyl.
  • at least one R 5 is -OR a and R a is -CHF 2 or -CF 3 .
  • a compound of Formula (IV) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 7, below:
  • a compound of Formula (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 8, below:
  • Described herein are methods of treating a disease treatable by inhibition of BTK in a mammal in need thereof comprising administering to the mammal, a therapeutically effective amount of a compound of Formula (I), Formula (I-SS), Formula (II), Formula (II-SS), Formula (III), Formula (III-SS), Formula (IV), or Formula (IV-SS)
  • the disease is cancer, an autoimmune, inflammatory, or thromboembolic diseases.
  • the disease is acute necrotizing hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, alopecia areata, alopecia universalis, amyloidosis, ankylosing spondylitis, anti-GBM/Anti-TBM nephritis, antiphospholipid syndrome (APS), antiphospholipid antibody syndrome, aplastic anemia, arthritis, autoimmune angioedema, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatiti
  • Neuropsychiatric Disorders Associated with Streptococcus paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, pemphigus such as pemphigus vulgaris, pemphigus foliaceus, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, progesterone dermatitis, psoriasis, psoriatic arthritis, psoriaticarthritis, pure red cell aplasia, py
  • vesiculobullous dermatosis vitiligo, vulvodynia, or lupus.
  • the disease is an autoimmune disease, e.g., inflammatory bowel disease, arthritis, lupus including Lupus Nephritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, granulomatosis with polyangiitis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, dry eye (including Sjogren's dry eye and non-Sjogren's dry eye), multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuriti
  • the autoimmune disease is lupus, pemphigus vulgaris, myasthenia gravis, Sjogren's syndrome, dry eye, multiple sclerosis, Wegener's granulomatosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Granulomatosis with Polyangiitis, or rheumatoid arthritis.
  • the disease is a hetero-immune condition or disease, e.g., graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis.
  • the disease is atopic dermatitis.
  • the disease is an inflammatory disease, e.g., asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,
  • inflammatory disease e.g., asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enterit
  • the mammal is suffering from inflammatory skin disease which includes, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring psoriatic lesions in the skin, joints, or other tissues or organs.
  • inflammatory skin disease includes, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring psoriatic lesions in the skin, joints, or other tissues or organs.
  • the inflammatory disease is asthma or dermatitis.
  • the disease is an inflammatory and/or autoimmune disease, including acute inflammatory and/or autoimmune disease, where corticosteroid therapy is used as the first- or second-line therapy or first- or second-line maintenance therapy.
  • Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice: synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance); congenital adrenal hyperplasia;
  • nonsuppurative thyroiditis hypercalcemia associated with cancer.
  • Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy), ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, gout, acute gouty arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis, epicondylitis.
  • Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis
  • Dermatologic Diseases Pemphigus; bullous dermatitis herpetiformis; severe erythema multiforme (Stevens- Johnson syndrome); exfoliative dermatitis; mycosis fungoides; severe psoriasis; severe seborrheic dermatitis.
  • Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: seasonal or perennial allergic rhinitis; bronchial asthma; contact dermatitis; atopic dermatitis; serum sickness; drug hypersensitivity reactions.
  • Ophthalmic Diseases Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: allergic corneal marginal ulcers, herpes zoster ophthalmicus, anterior segment inflammation, diffuse posterior uveitis and choroiditis, sympathetic ophthalmia, allergic conjunctivitis, keratitis, chorioretinitis, optic neuritis, ulceris and iridocyclitis.
  • Respiratory Diseases Symptomatic sarcoidosis; Loeffler's syndrome not manageable by other means; berylliosis; aspiration pneumonitis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy
  • Hematologic Disorders Idiopathic thrombocytopenic purpura in adults; secondary thrombocytopenia in adults; acquired (autoimmune) hemolytic anemia;
  • erythroblastopenia (RBC anemia); congenital (erythroid) hypoplastic anemia.
  • Neoplastic Diseases For palliative management of: leukemias and lymphomas in adults, acute leukemia of childhood.
  • Edematous States To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus.
  • Gastrointestinal Diseases To tide the patient over a critical period of the disease in: ulcerative colitis, regional enteritis.
  • the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof may be useful for the treatment of the above listed diseases optionally in combination with a corticosteroid, noncorticosteroidal,
  • immunosuppressive agent is selected from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, an anti-CD20 agent (such as rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar version thereof), anti -TNF alpha agent (such as entanercept, infliximab, golilumab, adalimumab, or certolizumab pegol or a biosimilar version thereof), anti-IL6 agent toward ligand or its receptors (such as tocilizumab, sarilumab, olokizumab, elsililumab, or siltuximab), anti-IL17 agent to ligand or its receptors (such as secukinuma
  • the mammal is suffering from cancer.
  • the cancer is a B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma (CLL), chronic lymphocytic leukemia, chromic myleogenous leukemia, B-cell acute lymphoblastic leukemia (B-ALL), Philadelphia chromosome positive B-ALL, B-cell prolymphocytic leukemia, small lymphocytic lymphoma (SLL), multiple myeloma, B-cell non-Hodgkin lymphoma, lymphoplamascytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (th) a B-cell pro
  • the mammal is suffering from a thromboembolic disorder, e.g., myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombosis.
  • a thromboembolic disorder e.g., myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombosis.
  • the use of the compound of Formula (I) or (I-SS) and/or a pharmaceutically acceptable salt thereof is for treating a disease mediated by BTK, for example, the disease is cancer, an inflammatory disease, an autoimmune disease or a thromboembolic disease.
  • the disease is cancer, an autoimmune, inflammatory, or thromboembolic disease.
  • the compounds of Formula (I), Formula (I-SS), Formula (II), Formula (II-SS), Formula (III), Formula (III-SS), Formula (IV), or Formula (IV-SS) may be administered in combination with an anticancer agent.
  • the agents can be administered simultaneously (such as a fixed combination drug product) or sequentially.
  • the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day.
  • the dosage level will be about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • the compositions may be provided in the form of tablets containing about 1.0 to about 1000 mg of the active ingredient, particularly about l.Og, 5.0g, lOg, 15g, 20g, 25g, 50g, 75g, lOOg, 150g, 200g, 250g, 300g, 400g, 500g, 600g, 750g, 800g, 900g, and lOOOg of the active ingredient.
  • the actual amount of the compound, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.
  • the amount of the compound described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof in a formulation may vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound as described herein or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %.
  • compositions by any suitable route of administration, including, but not limited to oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • systemic e.g., transdermal, intranasal or by suppository
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • the preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
  • compositions are comprised of, in general, a compound as described herein and/or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof in combination with a pharmaceutically acceptable excipient such as binders, surfactants, diluents, buffering agents, anti adherents, glidants, hydrophilic or hydrophobic polymers, retardants, stabilizing agents or stabilizers, disintegrants or superdisintegrants, antioxidants, antifoaming agents, fillers, flavors, colors, lubricants, sorbents,
  • a pharmaceutically acceptable excipient such as binders, surfactants, diluents, buffering agents, anti adherents, glidants, hydrophilic or hydrophobic polymers, retardants, stabilizing agents or stabilizers, disintegrants or superdisintegrants, antioxidants, antifoaming agents, fillers, flavors, colors, lubricants, sorbents,
  • preservatives plasticizers, or sweeteners, or mixtures thereof, which facilitate processing of the compound or a pharmaceutically acceptable salt thereof into preparations which can be used pharmaceutically.
  • plasticizers or sweeteners, or mixtures thereof, which facilitate processing of the compound or a pharmaceutically acceptable salt thereof into preparations which can be used pharmaceutically.
  • sweeteners or mixtures thereof, which facilitate processing of the compound or a pharmaceutically acceptable salt thereof into preparations which can be used pharmaceutically.
  • Any of the well-known techniques and excipients may be used as appropriate and understood in the art.
  • Formulations may include one or more pH adjusting agents or buffering agents, for example, acids such as acetic, boric, citric, fumaric, maleic, tartaric, malic, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate, ammonium chloride, and the like.
  • Such buffers used as bases may have other counterions than sodium, for example, potassium, magnesium, calcium, ammonium, or other counterions.
  • Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • Formulations may include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • Formulations may include one or more antifoaming agents to reduce foaming during processing which can result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing.
  • anti-foaming agents include silicon emulsions or sorbitan sesquoleate.
  • Formulations may include one or more antioxidants, such as non -thiol antioxidants, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid or its derivative, and tocopherol or its derivatives.
  • antioxidants such as non -thiol antioxidants, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid or its derivative, and tocopherol or its derivatives.
  • BHT butylated hydroxytoluene
  • Other agents such as citric acid or citrate salts or EDTA may also be added to slow oxidation.
  • Formulations may include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyl trimethyl ammonium bromide, and cetylpyridinium chloride.
  • Formulations may include one or more binders to impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,
  • hydroxyethylcellulose hydroxypropylcellulose, ethylcellulose, and microcrystalline cellulose
  • microcrystalline dextrose amylose
  • magnesium aluminum silicate magnesium aluminum silicate
  • polysaccharide acids include bentonites; gelatin; polyvinyl-pyrrolidone/vinyl acetate copolymer; crosspovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose, glucose, dextrose, molasses, mannitol, sorbitol, xylitol, and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum mucilage of isapol husks, polyvinylpyrrolidone, larch arabogalactan, polyethylene glycol, polyethylene oxide, waxes, sodium alginate, and the like.
  • Formulations may include one or more dispersing agents and/or viscosity modulating agents to control the diffusion and homogeneity of a drug through liquid media or a granulation method or blend method.
  • Formulations may include one or more diluents.
  • Salts dissolved in buffered solutions may be utilized as diluents, including, but not limited to a phosphate buffered saline solution.
  • diluents increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling.
  • Such compounds include e.g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugar, hydroxypropyl-methylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.
  • Formulations may include one or more disintegrants which includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid.
  • Disintegration agents or disintegrants facilitate the breakup or disintegration of a substance.
  • disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or sodium starch glycolate, a cellulose such as a wood product, methylcrystalline cellulose, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethyl-cellulose, cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crosspovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay, a
  • Formulations may include one or more filling agents which include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • filling agents include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
  • Formulations may include one or more flavoring agents and/or sweeteners.
  • Formulations may include one or more lubricants and glidants which may prevent, reduce or inhibit adhesion or friction of materials.
  • exemplary lubricants include, e.g., stearic acid, calcium hydroxide, talc, sodium stearyl lumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil, higher fatty acids and their alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica, a starch such as corn starch, silicone oil, a surfactant, and the like
  • Formulations may include one or more solubilizers which include compounds such as triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins for example Captisol®, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide and the like.
  • the solubilizer is vitamin E TPGS and/or Captisol® or b-hydroxypropylcyclodextrin.
  • Formulations may include one or more surfactants which include compounds such as sodium lauryl sulfate, sodium docusate, Tween 20, 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like.
  • surfactants which include compounds such as sodium lauryl sulfate, sodium docusate, Tween 20, 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene
  • surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g. octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included to enhance physical stability or for other purposes.
  • compositions disclosed herein may be obtained by mixing one or more solid excipient such as carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable excipients, if desired, to obtain tablets.
  • solid excipient such as carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or
  • compositions disclosed herein also include capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules may also be made of polymers such as hypromellose.
  • the capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, lipids, solubilizers, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • formulations may be manufactured by conventional pharmacological techniques.
  • Conventional pharmacological techniques include, one or a combination of methods: dry mixing, direct compression, milling, dry or non-aqueous granulation, wet granulation, fusion or extrusion.
  • Other methods include spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding,
  • extrusion/spheronization and the like. It should be appreciated that there is considerable overlap between excipients used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of excipient that can be included in solid dosage forms described herein. The type and amounts of such excipient can be readily determined by one skilled in the art, according to the particular properties desired.
  • the compounds of the present disclosure or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of the present disclosure or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure.
  • a compound of the present disclosure is used contemporaneously with one or more other drugs, a
  • the combination therapy may also include therapies in which the compound of the present disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly.
  • compositions of the present disclosure also include those that contain one or more other active ingredients, in addition to a compound of the present disclosure.
  • the above combinations include combinations of the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present disclosure may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present disclosure are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure.
  • compositions of the present disclosure When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition, such as a fixed-combination drug product, containing such other drugs in addition to the compound of the present disclosure is preferred. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of the present disclosure.
  • the weight ratio of the compound of the present disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof can be used with one or more of the following therapeutic agents in any combination: immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin,
  • glucocorticoids e.g., prednisone, cortisone acetate, prednisolone,
  • methylprednisolone dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2-arylpropionic acids, N- arylanthranilic acids, oxicams, coxibs, or sulphonanilides), Cox -2-specific inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, TNF-a binding proteins (e.g., infliximab, etanercept, or adalimumab), abatacept
  • the subject can be treated with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof in any combination with one or more other anti-cancer agents.
  • one or more of the anti-cancer agents are proapoptotic agents.
  • anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib
  • TaxolTM also referred to as“paclitaxel,” which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of TaxolTM, such as TaxotereTM.
  • TaxolTM also referred to as“paclitaxel”
  • TaxotereTM analogs of TaxolTM, such as TaxotereTM.
  • Compounds that have the basic taxane skeleton as a common structure feature, have also been shown to have the ability to arrest cells in the G2-M phases due to stabilized microtubules and may be useful for treating cancer in combination with the compounds described herein.
  • anti-cancer agents for use in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).
  • mitogen-activated protein kinase signaling e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002
  • Syk inhibitors e.g., mTOR inhibitors
  • antibodies e.g., rituxan
  • anti -cancer agents that can be employed in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;
  • anastrozole anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin;
  • batimastat batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefmgol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate;
  • cyclophosphamide cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin;
  • doxorubicin hydrochloride droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
  • estramustine estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; trasrabine; fenretinide; floxuridine;
  • fludarabine phosphate fluorouracil; flurocitabine; fosquidone; fostriecin sodium;
  • gemcitabine gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;
  • ifosfamide; ilmofosine; interleukin II including recombinant interleukin II, or rIL2
  • interleukin II including recombinant interleukin II, or rIL2
  • interferon alfa-2a interferon alfa-2b
  • interferon alfa-nl interferon alfa-n3
  • interferon beta- la interferon beta- la
  • interferon gamma- 1 b iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;
  • methotrexate methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;
  • porfiromycin prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safmgol; safmgol hydrochloride; semustine; pumprazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfm; teniposide; teroxirone;
  • testolactone thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfm; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
  • vinzolidine sulfate sulfate
  • vorozole zeniplatin
  • zinostatin zinostatin
  • zorubicin hydrochloride
  • anti-cancer agents that can be employed in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include: 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;
  • amrubicin amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1;
  • antiandrogen prostatic carcinoma; antiestrogen; antineoplaston; antisense
  • oligonucleotides oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;
  • axinastatin 1 atrimustine
  • axinastatin 2 atrimustine
  • axinastatin 3 azasetron
  • azatoxin azatyrosine
  • baccatin III derivatives balanol
  • batimastat BCR/ABL antagonists
  • benzochlorins benzochlorins
  • calcipotriol calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine;
  • carboxamide-amino-triazole carboxyamidotri azole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
  • cladribine clomifene analogues
  • clotrimazole collismycin A
  • collismycin B collismycin
  • combretastatin A4 combretastatin analogue
  • conagenin crambescidin 816; crisnatol
  • cryptophycin 8 cryptophycin A derivatives
  • curacin A cyclopentanthraquinones
  • losoxantrone lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin;
  • methioninase metoclopramide
  • MTF inhibitor mifepristone
  • miltefosine mirimostim
  • mismatched double stranded RNA mitoguazone
  • mitolactol mitomycin analogues
  • mitonafide mitotoxin fibroblast growth factor-saporin
  • mitoxantrone mofarotene
  • molgramostim monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted
  • benzamides nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin;
  • nartograstim nedaplatin
  • nemorubicin nedaplatin
  • neridronic acid neutral endopeptidase
  • nilutamide nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06- benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
  • ondansetron oracin
  • oral cytokine inducer ormaplatin
  • osaterone oxaliplatin
  • oxaunomycin palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium;
  • pentostatin pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenyl acetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin;
  • sargramostim Sdi 1 mimetics; semustine; senescence derived 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenyl acetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D;
  • spiromustine splenopentin
  • spongistatin 1 squalamine
  • stem cell inhibitor stem-cell division inhibitors
  • stipiamide stem-cell division inhibitors
  • stromelysin inhibitors sulfmosine
  • superactive vasoactive intestinal peptide antagonist suradista; suramin; swainsonine; synthetic
  • glycosaminoglycans tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfm;
  • temozolomide teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
  • titanocene bichloride topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide;
  • variolin B vector system, erythrocyte gene therapy; velaresol; veramine; verdins;
  • verteporfm verteporfm; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
  • anticancer agents that can be employed in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.
  • alkyl sulfonates e.g., busulfan
  • nitrosoureas e.g., carmustine, lomusitne, etc.
  • triazenes decarbazine, etc.
  • antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., Cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
  • Examples of natural products useful in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
  • vinca alkaloids e.g., vinblastin, vincristine
  • epipodophyllotoxins e.g., etoposide
  • antibiotics e.g., daunorubicin, doxorubicin, bleomycin
  • enzymes e.g., L-asparaginase
  • biological response modifiers e.g., interferon alpha
  • alkylating agents that can be employed in combination the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include, but are not limited to, nitrogen mustards (e.g.,
  • ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
  • alkyl sulfonates e.g., busulfan
  • nitrosoureas e.g., carmustine, lomusitne, semustine, streptozocin, etc.
  • triazenes decarbazine, etc.
  • antimetabolites include, but are not limited to, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., fluorouracil, floxuridine, Cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin.
  • hormones and antagonists useful in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).
  • adrenocorticosteroids e.g., prednisone
  • progestins e.g., hydroxyprogesterone caproate, megestrol a
  • platinum coordination complexes e.g., cisplatin, carboblatin
  • anthracenedione e.g., mitoxantrone
  • substituted urea e.g., hydroxyurea
  • methyl hydrazine derivative e.g., procarbazine
  • adrenocortical suppressant e.g., mitotane, aminoglutethimide
  • anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with an BTK inhibitor compound of the disclosure include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX- A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin
  • the subject can be treated with a compound as described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof in any combination with one or more other anti-thromboembolic agents.
  • a compound as described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof in any combination with one or more other anti-thromboembolic agents.
  • anti-thromboembolic agents include, but are not limited any of the following: thrombolytic agents (e.g., alteplase anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, or BIBR 1048.
  • thrombolytic agents e.g., alteplase anistreplase, streptokinase, urokinase, or tissue plasminogen activator
  • reactions may be carried out in any suitable solvent, or other reagents to perform the transformation[s] necessary.
  • suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures).
  • a given reaction may be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular work-up following the reaction may be employed.
  • MS mass spectroscopy
  • LCMS liquid chromatography -mass spectroscopy
  • NMR nuclear magnetic resonance
  • HPLC HPLC
  • protein chemistry biochemistry
  • recombinant DNA techniques and pharmacology
  • Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 7th Edition, John Wiley and Sons, Inc (2013). Alternate reaction conditions for the synthetic
  • transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. As necessary, the use of appropriate protecting groups may be required. The incorporation and cleavage of such groups may be carried out using standard methods described in Peter G. M. Wuts and Theodora W. Green, Protecting Groups in Organic Synthesis, 4th Edition, Wiley-Interscience. (2006). All starting materials and reagents are commercially available or readily prepared.
  • N-(2,4-dimethoxybenzyl)-3-iodo-lH-pyrazolo[4,3-c]pyridin-4-amine was synthesized in two steps from 4-chloro-lH-pyrazolo[4,3-c]pyridine.
  • R — A --(B)
  • compounds of Formula (I) were prepared from N-(2,4- dimethoxybenzyl)-3-iodo-lH-pyrazolo[4,3-c]pyridin-4-amine, which was synthesized in two steps from 4-chloro-lH-pyrazolo[4,3-c]pyridine:
  • STEP 3-1 Synthesis of Compound I-Int-1 (tert-butyl (3-(4-((2A- dimethoxybenzyl )amino)-3-iodo- l H-pyrazololAJ-clpyridin- l -yl level obutyl lcarbamate)
  • STEP 8 Synthesis of 4-amino-l-( ' (1s.3s)-3-( ' methylamino)cvclobutvP-3-(4- phenoxyphenv1)-1Hl-imidazor4.5-c]pyridin-2(3H)-one hydrochloride
  • Compound II-Int-2 was prepared according to Steps 1-6 of Example 20.
  • Compound II-Int-1 was prepared as follows:
  • STEP 5 Synthesis of tert-butyl ((ls.3s)-3-(4-amino-2-oxo-2.3-dihvdro-lH-imidazor4.5- clpyridin- 1 -yl level obutyl icarbamate
  • Compound IV-2 was prepared in a similar fashion, by reacting 6-amino-9- ((ls,3s)-3-aminocyclobutyl)-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one with acrylic acid.
  • Solutions of compounds (test or control) in DMSO were prepared at the desired concentrations, and serially diluted to 11 concentrations by 3 -fold dilution in 384pp-plate using TECAN EVO200. 20nL of stock were transferred to 384 plate using Echo550. DMSO was used as vehicle control.
  • BTK was obtained from Cama; FLPeptide2 was obtained from PerkinElmer and Ibrutinib was obtained from Selleck.) 5uL of ATP solution were added to each well, followed by addition of 15uL of BTK solution to initiate the reaction.
  • the % remaining activity was calculated using read conversion ratio (CR) according to the equation:
  • XLFit (equation 201) was used to calculate IC 50 's by floating both bottom and top.
  • BTK IC 50 values are provided for the compounds of the present invention in Table 15, below. With respct to BTK activity:“A” denotes and IC 50 of less than lOnM, “B” denotes and IC 50 of of from 10 nM to less than 100 nM, and“C” denotes and IC 50 of 100 nM or more.
  • Solutions of compounds (test or control) in DMSO were prepared at the desired concentrations, and serially diluted to 11 concentrations by 3 -fold dilution in 384pp-plate using TECAN EVO200. 20nL of stock were transferred to 384 plate using Echo550. DMSO was used as vehicle control.
  • the % remaining activity was calculated using read conversion ratio (CR) according to the equation:
  • XLFit (equation 201) was used to calculate ICso's by floating both bottom and top.
  • EFGR IC 50 values are provided for the compounds of the present invention in Table 15, below. With respct to EGFR activity:“A” denotes and IC 50 of less than lOnM,“B” denotes and IC 50 of of from 10 nM to less than 100 nM, and“C” denotes and IC 50 of 100 nM or more.

Abstract

Disclosed herein, are protein kinase inhibitors (I), (II), (III) or (IV), in particular Bruton tyrosine kinase (BTK) inhibitors, pharmaceutical compositions comprising them, processes for preparing them and uses of the inhibitors to treat or prevent diseases, disorders and conditions associated with kinase function. In particular, the present invention relates to selective BTK inhibitors.

Description

HETEROCYCLIC KINASE INHIBITORS
FIELD OF THE INVENTION
The present invention relates generally to protein kinase inhibitors, in particular Bruton tyrosine kinase (BTK) inhibitors, pharmaceutical compositions comprising them, processes for preparing them and uses of the inhibitors to treat or prevent diseases, disorders and conditions associated with kinase function. In particular, the present invention relates to selective BTK inhibitors. Protein kinase inhibitors are known to be useful for the treatment of diseases such as cancer, autoimmune,
inflammatory and thromboembolic diseases.
BACKGROUND
Protein kinases are a large group of intracellular and transmembrane signaling proteins in eukaryotic cells. These enzymes are responsible for transfer of the terminal (gamma) phosphate from ATP to specific amino acid residues of target proteins. Phosphorylation of specific amino acid residues in target proteins can modulate their activity leading to profound changes in cellular signaling and metabolism. Protein kinases can be found in the cell membrane, cytosol and organelles such as the nucleus and are responsible for mediating multiple cellular functions including metabolism, cellular growth and differentiation, cellular signaling, modulation of immune responses, and cell death. Serine kinases specifically phosphorylate serine or threonine residues in target proteins. Similarly, tyrosine kinases, including tyrosine receptor kinases, phosphorylate tyrosine residues in target proteins. Tyrosine kinase families include: TEC, SRC, ABL, JAK, CSK, FAK, SYK, FER, ACK and the receptor tyrosine kinase subfamilies including ERBB, FGFR, VEGFR, RET and EPH. Subclass I of the receptor tyrosine kinase superfamily consists of the ERBB receptors and comprises four members: ErbBl (also called epidermal growth factor receptor (EGFR)), ErbB2, ErbB3 and ErbB4.
Kinases exert control on key biological processes related to health and disease. Furthermore, aberrant activation or excessive expression of various protein kinases are implicated in the mechanism of multiple diseases and disorders characterized by benign and malignant proliferation, as well as diseases resulting from inappropriate activation of the immune system. Thus, inhibitors of select kinases or kinase families may be useful in the treatment of cancer, vascular disease, autoimmune diseases, and inflammatory conditions including, but not limited to: solid tumors, hematological malignancies, thrombus, arthritis, graft versus host disease, lupus erythematosus, psoriasis, colitis, illeitis, multiple sclerosis, uveitis, coronary artery vasculopathy, systemic sclerosis, atherosclerosis, asthma, transplant rejection, allergy, ischemia, dermatomyositis, pemphigus, and the like.
Tec kinases are a family of non -receptor tyrosine kinases predominantly, but not exclusively, expressed in cells of hematopoietic origin. The Tec family includes TEC, Bruton's tyrosine kinase (BTK), inducible T-cell kinase (ITK), resting lymphocyte kinase (RLK/TXK for Tyrosine Protein Kinase), and bone marrow-expressed kinase (BMX/ETK).
BTK is important in B-cell receptor signaling and regulation of B-cell development and activation. Mutation of the gene encoding BTK in humans leads to X- linked agammaglobulinemia which is characterized by reduced immune function, including impaired maturation of B-cells, decreased levels of immunoglobulin and peripheral B cells, diminished T-cell independent immune response. BTK is activated by Src-family kinases and phosphorylates PLC gamma leading to effects on B-cell function and survival. Additionally, BTK is important for cellular function of mast cells, macrophage and neutrophils suggesting that BTK inhibition would be effective in treatment of diseases mediated by these and related cells including inflammation, bone disorders, and allergic disease. BTK inhibition is also important in survival of lymphoma cells suggesting that inhibition of BTK may be useful in the treatment of lymphomas and other cancers. As such, inhibitors of BTK and related kinases are of great interest as anti inflammatory as well as anti -cancer agents. BTK is also important for platelet function and thrombus formation suggesting that BTK-selective inhibitors may prove to be useful antithrombotic agents. Furthermore, BTK is required for inflammasome activation and inhibition of BTK may be useful in treatment of inflammasome-related disorders including; stroke, gout, type 2 diabetes, obesity-induced insulin resistance,
atherosclerosis and Muckle-Wells syndrome. In addition, BTK is expressed in HIV infected T-cells and treatment with BTK inhibitors sensitizes infected cells to apoptotic death and results in decreased virus production. Accordingly, BTK inhibitors may be useful in the treatment of HIV-AIDS and other viral infections.
BMX, another Tec family member which has roles in inflammation, cardiovascular disease, and cancer is also important for self-renewal and tumorigenic potential of glioblastoma stem cells. As such, BMX inhibitors may be useful in the treatment of various diseases including cancer, cardiovascular disease and inflammation.
ITK is a key signaling molecule downstream of the T-cell receptor and is expressed in T-cells, mast cells and NK cells. Inhibition of ITK has been shown to affect cytokine secretion and polarization of T-cell subtypes. As such ITK inhibitors may be useful in the treatment of allergy, psoriasis, dermatitis, multiple sclerosis and other diseases.
Ibrutinib (PCI-32765, Imbruvica) is a highly potent BTK inhibitor approved by the FDA for the treatment of adult patients with Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL); CLL/SLL with 17p deletion; Waldenstrom's macroglobulinemia (WM); Mantle cell lymphoma (who have received at least one prior therapy); Marginal zone lymphoma (who require systemic therapy and have received at least one prior anti-CD20-based therapy); and Chronic graft versus host disease (after failure of one or more lines of systemic therapy), with potential in other indications.
Side effects of Ibrutinib include hemorrhage, infections (including bacterial, viral, or fungal), cytopenias (including neutropenia, thrombocytopenia and anemia), cardiac arrhythmias (including ventricular tachyarrhythmias, atrial fibrillation and atrial flutter), hypertension and Tumor Lysis Syndrome. Other side effects that have been observed include diarrhea, nausea, fatigue, headache, rash, bruising, pyrexia, musculoskeletal pain & muscle spasms, stomatitis, sepsis and hypokalemia. Adverse effects of Ibrutinib, consistent with off-target effects, include diarrhea, atrial fibrillation, hypertension and panniculitis. Ibrutinib targets BTK and other members of the Tec family as well as select other kinases, e.g. Ibrutinib is not selective against EGFR.
The therapeutic dose of Ibrutinib is high, with recommended daily doses up to 560mg. Data indicates idiosyncratic drug toxicities are more likely to occur with high dose (>100mg) drugs. To improve the therapeutic index of chronically administered BTK inhibitors, selectivity against other kinases, including cysteine homologous kinases such as EGFR, is highly desirable. It is known that inhibiting wild type EGFR is associated with dermatologic toxicities (Holcmann & Sibilia, "Mechanisms underlying skin disorders induced by EGFR inhibitors" Mol Cell Oncol. 2015, Vol 2(4)). However, given that EGFR has equally reactive Cysteine residues in homologous positions as BTK, it has proven challenging to attain selective EGFR BTK inhibitors.
Accordingly, there is a need for BTK inhibitors with increased safety and tolerability. There is a need for BTK inhibitors with improved pharmacokinetics. There is a need for BTK inhibitors for administration at lower doses. In particular, there is a significant unmet need for BTK inhibitors with improved selectivity against various kinases, including EGFR.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
BRIEF SUMMARY
In one embodiment, a compound is provided having the structure of
Formula (I):
Figure imgf000006_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl; R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
R3 is H, alkyl, halo, or cyano;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)NH-
NHC(O)-, -CH(OH)-, -C(=N-O-Ra)- ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
In one embodiment, a compound is provided having the structure of
Formula (II):
Figure imgf000007_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
R3 is H, alkyl, halo, or cyano;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)NH- NHC(O)-, -CH(OH)-, -C(=N-O-Ra)-,
Figure imgf000007_0002
ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
In one embodiment, a compound is provided having the structure of
Formula (III):
Figure imgf000008_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)N)-
-NHC(O)- -CH(OH)- -C(=N-O-Ra)-
Figure imgf000008_0002
ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3;
with the proviso that when L is -O-, ring A is phenyl, and ring B is phenyl: m and n are not both 0;
R4 is not -F when m is 1 and n is 0; and
R5 is not -F when m is 0 and n is 2.
In one embodiment, a compound is provided having the structure of Formula (IV):
Figure imgf000009_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)NH-
-NHC(O)-, -CH(OH)-, -C(=N-O-Ra)-
Figure imgf000009_0002
ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
In one embodiment, a pharmaceutical composition is provided comprising a compound having the structure of any one of Formulas (I), (I-SS), (II), (II-SS), (III), (III-SS), (IV), or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, and at least one pharmaceutically acceptable excipient.
In one embodiment, a method of inhibiting a protein kinase is provided comprising contacting the protein kinase with an effective amount of a compound having the structure of any one of Formulas (I), (I-SS), (II), (II-SS), (III), (III-SS), (IV), or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof. In one embodiment, the protein kinase is BTK. In another embodiment, the compound or pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof is selective to BTK over EGFR.
In one embodiment, a method for treating a BTK dependent condition is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I), (I-SS), (II), (II-SS), (III), (III-SS), (IV), or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.
In one embodiment, the use of a compound having the structure of any one of Formulas (I), (I-SS), (II), (II-SS), (III), (III-SS), (IV), or (IV-SS), or a
pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof is provided in the manufacture of a medicament.
DETAILED DESCRIPTION
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized.
Certain Terminologies
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the detailed description is exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.
Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment.
Reference in the specification to "some embodiments", "an embodiment", "one embodiment" or "other embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the inventions.
As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes the exact amount. Hence "about 5pL" means "about 5pL" and also "5pL." Generally, the term "about" includes an amount that would be expected to be within experimental error.
The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
Chemical Terminology
As used herein, "alkyl" means a straight chain or branched saturated hydrocarbon group. "Lower alkyl" means a straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms. Examples of straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, «-propyl, «-butyl, «-pentyl, «-hexyl, «-heptyl, and «-octyl groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, iso butyl , sec-butyl, /-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
"Alkenyl" groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -CH=CH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2,
-C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -CH=CHCH2CH3, -CH=CH(CH2)2CH3, -CH=CH(CH2)3CH3, -CH=CH(CH2)4CH3, vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
"Alkynyl" groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to
-CºCH, -CºC(CH3), -CºC(CH2CH3), -CH2CºCH, -CH2CºC(CH3), and
-CH2CºC(CH2CH3), among others.
As used herein, "alkylene" means a divalent alkyl group. Examples of straight chain lower alkylene groups include, but are not limited to, methylene (i.e.,
— CH2— ), ethylene (i.e., -CH2CH2-), propylene (i.e., -CH2CH2CH2-), and butylene (i.e., — CH2CH2CH2CH2— ). As used herein, " heteroalkyl ene" is an alkylene group of which one or more carbon atoms is replaced with a heteroatom such as, but not limited to, N, O, S, or P.
"Alkoxy" refers to an alkyl as defined above joined by way of an oxygen atom (i.e., ~0~ alkyl). Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, //-propoxy, //-butoxy, isopropoxy, .vfc-butoxy, /er/-butoxy, and the like.
The terms "carbocyclic" and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon. Carbocycles may be monocyclic or polycyclic.
Carbocycle encompasses both saturated and unsaturated rings. Carbocycle encompasses both cycloalkyl and aryl groups. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N substituents wherein N is the size of the carbocyclic ring with for example, alkyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
"Cycloalkyl" groups are alkyl groups forming a ring structure, which can be substituted or unsubstituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.
Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbomyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6- disubstituted cyclohexyl groups or mono-, di- or tri- substituted norbomyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
"Aryl" groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons in the ring portions of the groups. The terms "aryl" and "aryl groups" include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).
"Carbocyclealkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with carbocycle. Examples of carbocyclealkyl groups include, but are not limited to, benzyl and the like.
As used herein, "heterocycle" or "heterocyclyl" groups include aromatic and non-aromatic ring compounds (heterocyclic rings) containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P. A heterocycle group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom. In some embodiments, heterocycle groups include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom. For example, a dioxolanyl ring and a benzodioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocycle groups within the meaning herein. A heterocycle group designated as a C2-heterocycle can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C4- heterocycle can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A saturated heterocyclic ring refers to a heterocyclic ring containing no unsaturated carbon atoms.
"Heteroaryl" groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. A heteroaryl group designated as a C2-heteroaryl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise, a C4-heteroaryl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms "heteroaryl" and "heteroaryl groups" include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl.
"Heterocyclealkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with heterocycle. Examples of heterocyclealkyl groups include, but are not limited to, morpholinoethyl and the like. "Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
"Haloalkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkyl groups include, but are not limited to,— CF3,— CH2CF3, and the like.
"Haloalkoxy" refers to an alkoxy as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkoxy groups include, but are not limited to -OCF3, -OCH2CF3, and the like.
"Hydroxyalkyl" refers to an alkyl as defined above with one or more hydrogen atoms replaced with -OH. Examples of lower hydroxyalkyl groups include, but are not limited to -CH2OH, -CH2CH2OH, and the like.
As used herein, the term "optionally substituted" refers to a group (e.g., an alkyl, carbocycle, or heterocycle) having 0, 1, or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents. Substituents include, but are not limited to -ORa, -NRaRb, -S(O)2Ra or -S(0)20Ra, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl, wherein each Ra and Rb is,
independently, H, alkyl, haloalkyl, carbocycle, or heterocycle, or Ra and Rb, together with the atom to which they are attached, form a 3-8 membered carbocycle or heterocycle.
"Isomer" is used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the disclosure. The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers." Single enantiomers of a pure compound are optically active (i.e., they can rotate the plane of plane polarized light and designated R or S).
"Isolated optical isomer" means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer may be at least about 80%, at least 80% or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight.
"Substantially enantiomerically or diastereomerically" pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.
The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled "(±)" because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).
A "hydrate" is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.
A "solvate" is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometric or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.
"Isotope" refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formulas (I)-(IV) includes any such compound wherein one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has several isotopes, fluorine 19 is longest-lived. Thus, an isotope of a compound having the structure of Formulas (I)-(IV) includes, but not limited to, compounds of Formulas (I)-(IV) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine- 19.
"Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as "acid addition salts". Conversely, salts formed between bases in the cationic form and anions are referred to as "base addition salts."
Other Terminology
The term "pharmaceutically acceptable" refers an agent that has been approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to nontoxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).
Pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’ dibenzyl ethyl enediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine), and procaine.
Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4- hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic,
trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, phydroxybutyric, salicylic, -galactaric, and galacturonic acid.
Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of the compounds described herein, for example in their purification by recrystallization.
In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound as described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters,
polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or a
pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.
In other embodiments, there are provided methods of making a composition of a compound described herein including formulating a compound of the disclosure with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
As used herein, the term "pharmaceutically acceptable carrier" refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example:
antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.
The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances, preserving agents, sweetening agents, or flavoring agents. The compositions can also be sterilized if desired.
The route of administration can be any route which effectively transports the active compound of the disclosure to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment, the oral route being preferred.
Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment and/or to minimize or avoid unwanted side effects associated with the treatment. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians’ Desk Reference, incorporated herein by reference.
As used herein, the term "administering" or "administration" refers to providing a compound, a pharmaceutical composition comprising the same, to a subject by any acceptable means or route, including (for example) by oral, parenteral (e.g., intravenous), or topical administration.
As used herein, the term "treatment" refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition. As used herein, the terms "treatment", "treat" and "treating," with reference to a disease, pathological condition or symptom, also refers to any observable beneficial effect of the treatment.
The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. A prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed.
As used herein, the term "subject" refers to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein may be one who has been diagnosed with a neurodegenerative disease involving
demyelination, insufficient myelination, or underdevelopment of a myelin sheath, e.g., a subject diagnosed with multiple sclerosis or cerebral palsy, or one at risk of developing the condition. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.
As used herein, the term "effective amount" refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure.
Compounds
In one embodiment, a compound is provided having the structure of
Formula (I):
Figure imgf000022_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
R3 is H, alkyl, halo, or cyano;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)NH-
-NHC(O)- -CH(OH)- -C(=N-O-Ra)- ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
In one embodiment, a compound is provided the structure of Formula
(I-SS):
Figure imgf000022_0002
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
R3 is H, alkyl, halo, or cyano;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)NH-
-NHC(O)-, -CH(OH)-, -C(=N-O-Ra)-,
ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H, methyl, -CHF2, -CF3, ethyl, isopropyl, cyclopropyl, or fluoroethyl. In another embodiment of a compound having the structure of Formula (I) or (I SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, R1 is H, methyl, or ethyl.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R2 is -CH=CH2 or -CºC-CC3
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R3 is H, -CH3, -F, or -C1. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, R3 is H. In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is phenyl.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is oxazolyl, pyridinyl, pyrimidinyl, lH-benzo[d]imidazolyl, benzo[d]oxazolyl, or benzo[d]thiazolyl. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is pyrimidinyl or pyrazolyl.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is:
Figure imgf000024_0001
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3. In one embodiment, m is 1. In another embodiment, m is 2. In still another embodiment, m is 3.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is halo. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -F or -C1. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, m is 2 and each R4 is -F.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is alkyl. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is methyl.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -CN.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is alkyl. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -ORa and Ra is methyl.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is haloalkyl. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -ORa and Ra is -CHF2 or -CF3.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH2-, or -C(O)NH-. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -O-. In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring B is cyclohexyl or phenyl.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring B is pyridinyl.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3. In one embodiment, n is 1. In another embodiment, n is 2. In still another embodiment, n is 3.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is halo. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -F or -C1.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R5 is -F.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is alkyl. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is methyl. In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -CN.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is alkyl. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -ORa and Ra is methyl.
In one embodiment, a compound of Formula (I) or (I-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is haloalkyl. In another embodiment of a compound having the structure of Formula (I) or (I-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -ORa and Ra is -CHF2 or -CF3.
In one embodiment, a compound of Formula (I) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 1, below:
TABLE 1
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
In one embodiment, a compound of Formula (I-SS)) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 2, below:
TABLE 2
COMPOUNDS OF FORMULA (I-SS)
Figure imgf000036_0002
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0002
In one embodiment, a compound is provided having the structure of
Formula (II):
Figure imgf000045_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
R3 is H, alkyl, halo, or cyano;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)NH-
-NHC(O)-, -CH(OH)-, -C(=N-O-Ra)- ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl; m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
In one embodiment, a compound is provided the structure of Formula
(II-SS):
Figure imgf000046_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
R3 is H, alkyl, halo, or cyano;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe- -CH2- -CF2-, -C(O)-, -C(O)NH
-NHC(O)-, -CH(OH)-, -C(=N-O-Ra)-,
Figure imgf000046_0002
ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H, methyl, -CHF2, -CF3, ethyl, isopropyl, cyclopropyl, or fluoroethyl. In another embodiment of a compound having the structure of Formula (II) or (II SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, R1 is H or methyl.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R2 is -CH=CH2 or -CºC-CH3
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R3 is H, -CH3, -F, or -C1. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, R3 is H.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is phenyl.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is oxazolyl, pyridinyl, pyrimidinyl, lH-benzo[d]imidazolyl,
benzo[d]oxazolyl, or benzo[d]thiazolyl. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is pyrimidinyl or pyrazolyl.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is:
Figure imgf000048_0001
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3. In one embodiment, m is 1. In another embodiment, m is 2. In still another embodiment, m is 3.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is halo. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -F or -C1. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, m is 2 and each R4 is -F.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is alkyl. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is methyl.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -CN.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is alkyl. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -ORa and Ra is methyl.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is haloalkyl. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -ORa and Ra is -CHF2 or -CF3.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH2-, or -C(0)NH- In another
embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -O- in one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring B is cyclohexyl or phenyl.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring B is pyridinyl.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3. In one embodiment, n is 1. In another
embodiment, n is 2. In still another embodiment, n is 3.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is halo. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -F or -C1.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R5 is -F.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is alkyl. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is methyl.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -CN.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is alkyl. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -ORa and Ra is methyl.
In one embodiment, a compound of Formula (II) or (II-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is haloalkyl. In another embodiment of a compound having the structure of Formula (II) or (II-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -ORa and Ra is -CHF2 or -CF3. In one embodiment, a compound of Formula (II) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 3, below:
TABLE 3
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0002
In one embodiment, a compound of Formula (II-SS)) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 4, below:
TABLE 4
COMPOUNDS OF FORMULA (II-SS)
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0003
In one embodiment, a compound is provided having the structure of
Formula (III):
Figure imgf000059_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)NH-
-NHC(O)-, -CH(OH)-, -C(=N-O-Ra)-
Figure imgf000059_0002
ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa; Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3;
with the proviso that when L is -O-, ring A is phenyl, and ring B is phenyl:
m and n are not both 0;
R4 is not -F when m is 1 and n is 0; and
R5 is not -F when m is 0 and n is 2.
In one embodiment, a compound is provided the structure of Formula
(III-SS):
Figure imgf000060_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe -CH2- -CF2-, -C(O)-, -C(O)NH-
-NHC(O)-, -CH(OH)-, -C(=N-O-Ra)-,
Figure imgf000060_0002
ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3;
with the proviso that when L is -O-, ring A is phenyl, and ring B is phenyl:
m and n are not both 0;
R4 is not -F when m is 1 and n is 0; and
R5 is not -F when m is 0 and n is 2.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H, methyl, -CHF2, -CF3, ethyl, isopropyl, cyclopropyl, or fluoroethyl. In another embodiment of a compound having the structure of Formula (III) or (III SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, R1 is H, methyl, or ethyl.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R2 is -CH=CH2 or -CºC-CH3
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is phenyl.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is oxazolyl, pyridinyl, pyrimidinyl, lH-benzo[d]imidazolyl,
benzo[d]oxazolyl, or benzo[d]thiazolyl. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is pyrimidinyl or pyrazolyl. In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is:
Figure imgf000062_0001
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3. In one embodiment, m is 1. In another embodiment, m is 2. In still another embodiment, m is 3.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is halo. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -F or -C1. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, m is 2 and each R4 is -F.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is alkyl. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is methyl.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -CN. In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is alkyl. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -ORa and Ra is methyl.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is haloalkyl. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -ORa and Ra is -CHF2 or -CF3.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH2-, -C(O)-, or -C(O)NH- In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -O-. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -NH-. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -CH2- In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -C(O)-. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -C(O)NH-
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring B is cyclohexyl or phenyl.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring B is pyridinyl.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3. In one embodiment, n is 1. In another
embodiment, n is 2. In still another embodiment, n is 3.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is halo. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -F or -C1.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R5 is -F.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is alkyl. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is methyl. In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -CN.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is alkyl. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -ORa and Ra is methyl.
In one embodiment, a compound of Formula (III) or (III-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is haloalkyl. In another embodiment of a compound having the structure of Formula (III) or (III-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -ORa and Ra is -CHF2 or -CF3.
In one embodiment, a compound of Formula (III) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 5, below:
TABLE 5
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
In one embodiment, a compound of Formula (III-SS)) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 6, below:
TABLE 6
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0002
In one embodiment, a compound is provided having the structure of
Figure imgf000081_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)NH-
-NHC(O)-, -CH(OH)-, -C(=N-O-Ra)-,
Figure imgf000082_0001
ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
In one embodiment, a compound is provided the structure of Formula
(IV-SS):
Figure imgf000082_0002
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, or isotope thereof. In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H, methyl, -CHF2, -CF3, ethyl, isopropyl, cyclopropyl, or fluoroethyl. In another embodiment of a compound having the structure of Formula (III) or (III SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, R1 is H, methyl, or ethyl.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R2 is -CH=CH2 or -CºC-CH3
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is phenyl.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is oxazolyl, pyridinyl, pyrimidinyl, lH-benzo[d]imidazolyl,
benzo[d]oxazolyl, or benzo[d]thiazolyl. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring A is pyrimidinyl or pyrazolyl.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is:
Figure imgf000083_0001
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3. In one embodiment, m is 1. In another embodiment, m is 2. In still another embodiment, m is 3.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is halo. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -F or -C1. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, m is 2 and each R4 is -F.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is alkyl. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is methyl.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -CN.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is alkyl. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -ORa and Ra is methyl.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is haloalkyl. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R4 is -ORa and Ra is -CHF2 or -CF3.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH2-, -C(O)-, or -C(O)NH- In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -O-. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -NH-. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -CH2- In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -C(O)-. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, L is -C(O)NH-
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring B is cyclohexyl or phenyl.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, ring B is pyridinyl.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3. In one embodiment, n is 1. In another
embodiment, n is 2. In still another embodiment, n is 3.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is halo. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -F or -C1.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R5 is -F.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is alkyl. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is methyl.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -CN.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is alkyl. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -ORa and Ra is methyl.
In one embodiment, a compound of Formula (IV) or (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is haloalkyl. In another embodiment of a compound having the structure of Formula (IV) or (IV-SS), or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, at least one R5 is -ORa and Ra is -CHF2 or -CF3.
In one embodiment, a compound of Formula (IV) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 7, below:
TABLE 7
COMPOUNDS OF FORMULA (IV)
Figure imgf000087_0001
Figure imgf000088_0002
In one embodiment, a compound of Formula (IV-SS) is provided, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of a compound of Table 8, below:
TABLE 8 COMPOUNDS OF FORMULA (IV-SS)
Figure imgf000088_0001
Figure imgf000089_0001
Diseases
Described herein are methods of treating a disease treatable by inhibition of BTK in a mammal in need thereof comprising administering to the mammal, a therapeutically effective amount of a compound of Formula (I), Formula (I-SS), Formula (II), Formula (II-SS), Formula (III), Formula (III-SS), Formula (IV), or Formula (IV-SS)
, (or any embodiment thereof as described herein) and/or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof. In some embodiments the disease is cancer, an autoimmune, inflammatory, or thromboembolic diseases. In other embodiments, the disease is acute necrotizing hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, alopecia areata, alopecia universalis, amyloidosis, ankylosing spondylitis, anti-GBM/Anti-TBM nephritis, antiphospholipid syndrome (APS), antiphospholipid antibody syndrome, aplastic anemia, arthritis, autoimmune angioedema, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, autoimmune hemolytic anemia, axonal & neuronal neuropathies, Balo disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, coeliac disease, Cogans syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST disease, Crohn's disease, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), diabetes, discoid lupus, Dressler's syndrome, dry eye, dysautonomia, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, experimental allergic encephalomyelitis, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) (formerly called Wegener's Granulomatosis), Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4- related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, inflammatory bowel disease, interstitial cystitis, juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus (SLE), lupus including lupus nephritis, lyme disease, chronic, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), mooren's ulcer, Mucha-Habermann disease, mucous membrane pemphigoid, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyotonia, neutropenia, ocular cicatricial pemphigoid, opsoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, osteoarthritis, palindromic rheumatism, PANDAS (Pediatric Autoimmune
Neuropsychiatric Disorders Associated with Streptococcus ), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonnage-Turner syndrome, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, pemphigus such as pemphigus vulgaris, pemphigus foliaceus, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, progesterone dermatitis, psoriasis, psoriatic arthritis, psoriaticarthritis, pure red cell aplasia, pyoderma gangrenosum, raynauds phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm & testicular autoimmunity, stiff person syndrome, Still's disease, subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis/Giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, Type I, II, & III autoimmune polyglandular syndromes, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis,
vesiculobullous dermatosis, vitiligo, vulvodynia, or lupus.
In other embodiments, the disease is an autoimmune disease, e.g., inflammatory bowel disease, arthritis, lupus including Lupus Nephritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, granulomatosis with polyangiitis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjogren's syndrome, dry eye (including Sjogren's dry eye and non-Sjogren's dry eye), multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, pemphigus such as pemphigus vulgaris and/or foliaceus, bullous pemphigoid, age-related macular degeneration (wet and dry), diabetic macular edema, corneal transplantation, abdominal aortic aneurysm, mucous membrane pemphigoid, or vulvodynia.
In other embodiments, the autoimmune disease is lupus, pemphigus vulgaris, myasthenia gravis, Sjogren's syndrome, dry eye, multiple sclerosis, Wegener's granulomatosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Granulomatosis with Polyangiitis, or rheumatoid arthritis. In other embodiments, the disease is a hetero-immune condition or disease, e.g., graft versus host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopic dermatitis. In another embodiment, the disease is atopic dermatitis.
In other embodiments, the disease is an inflammatory disease, e.g., asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,
epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. In another embodiment, the mammal is suffering from inflammatory skin disease which includes, by way of example, dermatitis, contact dermatitis, eczema, urticaria, rosacea, and scarring psoriatic lesions in the skin, joints, or other tissues or organs. In another embodiment, the inflammatory disease is asthma or dermatitis.
In other embodiments, the disease is an inflammatory and/or autoimmune disease, including acute inflammatory and/or autoimmune disease, where corticosteroid therapy is used as the first- or second-line therapy or first- or second-line maintenance therapy.
The compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof may be useful for the treatment of:
Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice: synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance); congenital adrenal hyperplasia;
nonsuppurative thyroiditis; hypercalcemia associated with cancer.
Rheumatic Disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy), ankylosing spondylitis, acute and subacute bursitis, acute nonspecific tenosynovitis, gout, acute gouty arthritis, post-traumatic osteoarthritis, synovitis of osteoarthritis, epicondylitis.
Collagen Diseases: During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis
(polymyositis), acute rheumatic carditis.
Dermatologic Diseases: Pemphigus; bullous dermatitis herpetiformis; severe erythema multiforme (Stevens- Johnson syndrome); exfoliative dermatitis; mycosis fungoides; severe psoriasis; severe seborrheic dermatitis.
Allergic States: Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment: seasonal or perennial allergic rhinitis; bronchial asthma; contact dermatitis; atopic dermatitis; serum sickness; drug hypersensitivity reactions.
Ophthalmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: allergic corneal marginal ulcers, herpes zoster ophthalmicus, anterior segment inflammation, diffuse posterior uveitis and choroiditis, sympathetic ophthalmia, allergic conjunctivitis, keratitis, chorioretinitis, optic neuritis, iritis and iridocyclitis.
Respiratory Diseases: Symptomatic sarcoidosis; Loeffler's syndrome not manageable by other means; berylliosis; aspiration pneumonitis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy
Hematologic Disorders: Idiopathic thrombocytopenic purpura in adults; secondary thrombocytopenia in adults; acquired (autoimmune) hemolytic anemia;
erythroblastopenia (RBC anemia); congenital (erythroid) hypoplastic anemia.
Neoplastic Diseases: For palliative management of: leukemias and lymphomas in adults, acute leukemia of childhood.
Edematous States: To induce a diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus. Gastrointestinal Diseases: To tide the patient over a critical period of the disease in: ulcerative colitis, regional enteritis.
Miscellaneous: Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous
chemotherapy; trichinosis with neurologic or myocardial involvement.
The compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof may be useful for the treatment of the above listed diseases optionally in combination with a corticosteroid, noncorticosteroidal,
immunosupressive, and/or antiinflammatory agents. In one embodiment, the
immunosuppressive agent is selected from interferon alpha, interferon gamma, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, an anti-CD20 agent (such as rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar version thereof), anti -TNF alpha agent (such as entanercept, infliximab, golilumab, adalimumab, or certolizumab pegol or a biosimilar version thereof), anti-IL6 agent toward ligand or its receptors (such as tocilizumab, sarilumab, olokizumab, elsililumab, or siltuximab), anti-IL17 agent to ligand or its receptors (such as secukinumab, ustekinumab, brodalumab, or ixekizumab), anti- IL1 agent to ligand or its receptors (such as with rilonacept, canakinumab, or anakinra), anti-IL2 agent to ligand or its receptors (such as basiliximab or daclizumab), anti-CD2 agent such as alefacept, anti-CD3 agent such as muromonab-cd3, anti-CD80/86 agent such as abatacept or belatacept, anti-sphingosine-1 -phosphate receptor agent such as fmgolimod, anti-C5 agent such as eculizumab, anti-integrin alpha4 agent such as natalizumab, anti-a4b7 agent such as vedolizumab, anti-mTOR agent such as sirolimus or everolimus, anti-calcineurin agent such as tacrolimus, and anti-BAFF/BlyS agent (such as belimumab, VAY736, or blisibimod), leflunomide and teriflunomide. Preferably, the immunosuppressive agent is rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar version thereof.
In other embodiments, the mammal is suffering from cancer. In some embodiments, the cancer is a B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma (CLL), chronic lymphocytic leukemia, chromic myleogenous leukemia, B-cell acute lymphoblastic leukemia (B-ALL), Philadelphia chromosome positive B-ALL, B-cell prolymphocytic leukemia, small lymphocytic lymphoma (SLL), multiple myeloma, B-cell non-Hodgkin lymphoma, lymphoplamascytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid
granulomatosis.
In other embodiments, the mammal is suffering from a thromboembolic disorder, e.g., myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, or deep venous thrombosis.
Also described herein are compounds of Formula I, Formula II, Formula III, Formula IV, (or any embodiment thereof as described herein) and/or a
pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof for use as a medicament. In one embodiment, the use of the compound of Formula (I) or (I-SS) and/or a pharmaceutically acceptable salt thereof is for treating a disease mediated by BTK, for example, the disease is cancer, an inflammatory disease, an autoimmune disease or a thromboembolic disease.
Also described herein are compounds of Formula (I), Formula (I-SS), Formula (II), Formula (II-SS), Formula (III), Formula (III-SS), Formula (IV), or Formula (IV-SS) , (or any embodiment thereof as described herein) and/or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, useful in the manufacture of a medicament for treating a disease in a mammal in which BTK contributes to the pathology and/or symptoms of the disease. In one embodiment, the disease is cancer, an autoimmune, inflammatory, or thromboembolic disease.
In any of the aforementioned embodiments involving the treatment of cancer, the compounds of Formula (I), Formula (I-SS), Formula (II), Formula (II-SS), Formula (III), Formula (III-SS), Formula (IV), or Formula (IV-SS) , (or any embodiment thereof as described herein) and/or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, may be administered in combination with an anticancer agent. When combination therapy is used, the agents can be administered simultaneously (such as a fixed combination drug product) or sequentially.
Doses
In general, the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. In one embodiment, the dosage level will be about 0.1 to about 250 mg/kg per day. In another embodiment the dosage level will be about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing about 1.0 to about 1000 mg of the active ingredient, particularly about l.Og, 5.0g, lOg, 15g, 20g, 25g, 50g, 75g, lOOg, 150g, 200g, 250g, 300g, 400g, 500g, 600g, 750g, 800g, 900g, and lOOOg of the active ingredient. The actual amount of the compound, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.
The amount of the compound described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof in a formulation may vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound as described herein or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %.
Formulations
In general, the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof, are administered as
pharmaceutical compositions by any suitable route of administration, including, but not limited to oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
The compositions are comprised of, in general, a compound as described herein and/or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof in combination with a pharmaceutically acceptable excipient such as binders, surfactants, diluents, buffering agents, anti adherents, glidants, hydrophilic or hydrophobic polymers, retardants, stabilizing agents or stabilizers, disintegrants or superdisintegrants, antioxidants, antifoaming agents, fillers, flavors, colors, lubricants, sorbents,
preservatives, plasticizers, or sweeteners, or mixtures thereof, which facilitate processing of the compound or a pharmaceutically acceptable salt thereof into preparations which can be used pharmaceutically. Any of the well-known techniques and excipients may be used as appropriate and understood in the art.
Formulations may include one or more pH adjusting agents or buffering agents, for example, acids such as acetic, boric, citric, fumaric, maleic, tartaric, malic, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate, ammonium chloride, and the like. Such buffers used as bases may have other counterions than sodium, for example, potassium, magnesium, calcium, ammonium, or other counterions. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
Formulations may include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
Formulations may include one or more antifoaming agents to reduce foaming during processing which can result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing. Exemplary anti-foaming agents include silicon emulsions or sorbitan sesquoleate.
Formulations may include one or more antioxidants, such as non -thiol antioxidants, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid or its derivative, and tocopherol or its derivatives. Other agents such as citric acid or citrate salts or EDTA may also be added to slow oxidation.
Formulations may include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyl trimethyl ammonium bromide, and cetylpyridinium chloride.
Formulations may include one or more binders to impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, and microcrystalline cellulose; microcrystalline dextrose; amylose; magnesium aluminum silicate;
polysaccharide acids; bentonites; gelatin; polyvinyl-pyrrolidone/vinyl acetate copolymer; crosspovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose, glucose, dextrose, molasses, mannitol, sorbitol, xylitol, and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum mucilage of isapol husks, polyvinylpyrrolidone, larch arabogalactan, polyethylene glycol, polyethylene oxide, waxes, sodium alginate, and the like.
Formulations may include one or more dispersing agents and/or viscosity modulating agents to control the diffusion and homogeneity of a drug through liquid media or a granulation method or blend method.
Formulations may include one or more diluents. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) may be utilized as diluents, including, but not limited to a phosphate buffered saline solution. In certain embodiments, diluents increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling. Such compounds include e.g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugar, hydroxypropyl-methylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.
Formulations may include one or more disintegrants which includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid. Disintegration agents or disintegrants facilitate the breakup or disintegration of a substance. Examples of disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or sodium starch glycolate, a cellulose such as a wood product, methylcrystalline cellulose, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethyl-cellulose, cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crosspovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay, a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.
Formulations may include one or more filling agents which include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.
Formulations may include one or more flavoring agents and/or sweeteners.
Formulations may include one or more lubricants and glidants which may prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, e.g., stearic acid, calcium hydroxide, talc, sodium stearyl lumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil, higher fatty acids and their alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica, a starch such as corn starch, silicone oil, a surfactant, and the like.
Formulations may include one or more solubilizers which include compounds such as triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins for example Captisol®, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide and the like. In one embodiment, the solubilizer is vitamin E TPGS and/or Captisol® or b-hydroxypropylcyclodextrin.
Formulations may include one or more surfactants which include compounds such as sodium lauryl sulfate, sodium docusate, Tween 20, 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g. octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included to enhance physical stability or for other purposes.
Pharmaceutical preparations disclosed herein may be obtained by mixing one or more solid excipient such as carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable excipients, if desired, to obtain tablets.
Pharmaceutical preparations disclosed herein also include capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules may also be made of polymers such as hypromellose. The capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, lipids, solubilizers, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
These formulations may be manufactured by conventional pharmacological techniques. Conventional pharmacological techniques include, one or a combination of methods: dry mixing, direct compression, milling, dry or non-aqueous granulation, wet granulation, fusion or extrusion. Other methods include spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding,
extrusion/spheronization, and the like. It should be appreciated that there is considerable overlap between excipients used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of excipient that can be included in solid dosage forms described herein. The type and amounts of such excipient can be readily determined by one skilled in the art, according to the particular properties desired.
Combinations
The compounds of the present disclosure or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of the present disclosure or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a
pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present disclosure is preferred. However, the combination therapy may also include therapies in which the compound of the present disclosure and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly.
Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other active ingredients, in addition to a compound of the present disclosure. The above combinations include combinations of the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present disclosure may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present disclosure are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition, such as a fixed-combination drug product, containing such other drugs in addition to the compound of the present disclosure is preferred. Accordingly, the pharmaceutical compositions of the present disclosure also include those that also contain one or more other active ingredients, in addition to a compound of the present disclosure. The weight ratio of the compound of the present disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
Where the subject is suffering from or at risk of suffering from an autoimmune disease, an inflammatory disease, or an allergy disease, the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof can be used with one or more of the following therapeutic agents in any combination: immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin,
methotrexate, cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids (e.g., prednisone, cortisone acetate, prednisolone,
methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate, aldosterone), non-steroidal anti inflammatory drugs (e.g., salicylates, arylalkanoic acids, 2-arylpropionic acids, N- arylanthranilic acids, oxicams, coxibs, or sulphonanilides), Cox -2-specific inhibitors (e.g., valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline, TNF-a binding proteins (e.g., infliximab, etanercept, or adalimumab), abatacept, anakinra, interferon-b, interferon-g, interleukin-2, allergy vaccines, antihistamines, antileukotrienes, beta- agonists, theophylline, or anticholinergics.
Where the subject is suffering from or at risk of suffering from a B-cell proliferative disorder (e.g., plasma cell myeloma), the subject can be treated with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof in any combination with one or more other anti-cancer agents. In some embodiments, one or more of the anti-cancer agents are proapoptotic agents. Examples of anti-cancer agents include, but are not limited to, any of the following: gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'-deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib
(Gleevec™), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or
PD184352, Taxol™, also referred to as“paclitaxel,” which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of Taxol™, such as Taxotere™. Compounds that have the basic taxane skeleton as a common structure feature, have also been shown to have the ability to arrest cells in the G2-M phases due to stabilized microtubules and may be useful for treating cancer in combination with the compounds described herein.
Further examples of anti-cancer agents for use in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan). Other anti -cancer agents that can be employed in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin;
altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;
anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin;
batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefmgol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate;
cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine;
fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride;
ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta- la; interferon gamma- 1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;
methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;
porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safmgol; safmgol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfm; teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfm; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.
Other anti-cancer agents that can be employed in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include: 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;
amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense
oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;
atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins;
benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;
bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;
calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine;
carboxamide-amino-triazole; carboxyamidotri azole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B;
combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5- azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin;
fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum
compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;
losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin;
methioninase; metoclopramide; MTF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;
molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted
benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin;
nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase;
nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06- benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;
oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium;
pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenyl acetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin;
prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A- based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; R11 retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safmgol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenyl acetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D;
spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfmosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic
glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfm;
temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine;
titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide;
variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins;
verteporfm; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
Yet other anticancer agents that can be employed in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
Examples of natural products useful in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
Examples of alkylating agents that can be employed in combination the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include, but are not limited to, nitrogen mustards (e.g.,
mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.
Examples of hormones and antagonists useful in combination with the compounds described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof include, but are not limited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide).
Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with an BTK inhibitor compound of the disclosure include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX- A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D- 669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21- hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26- fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378
(Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS- 39.HC1), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L- Ser.HCl, and RPR-258062A), Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI- 261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B. Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetyl acetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D- 43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI- 286 (also known as SPA- 110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D- 82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).
Where the subject is suffering from or at risk of suffering from a thromboembolic disorder (e.g., stroke), the subject can be treated with a compound as described herein or pharmaceutically acceptable salts, solvates, hydrates or tautomers thereof in any combination with one or more other anti-thromboembolic agents.
Examples of anti-thromboembolic agents include, but are not limited any of the following: thrombolytic agents (e.g., alteplase anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, or BIBR 1048.
Compounds having the structure of any one of Formulas (I), (II), (III), or (IV) can be synthesized using standard synthetic techniques known to those of skill in the art. For examples, compounds of the present disclosure can be synthesized using the general synthetic procedures set forth in Schemes 1-4.
To this end, the reactions, processes and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation[s] necessary. Generally, suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed.
Unless otherwise indicated, conventional methods of mass spectroscopy (MS), liquid chromatography -mass spectroscopy (LCMS), NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed. Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 7th Edition, John Wiley and Sons, Inc (2013). Alternate reaction conditions for the synthetic
transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. As necessary, the use of appropriate protecting groups may be required. The incorporation and cleavage of such groups may be carried out using standard methods described in Peter G. M. Wuts and Theodora W. Green, Protecting Groups in Organic Synthesis, 4th Edition, Wiley-Interscience. (2006). All starting materials and reagents are commercially available or readily prepared.
SCHEME 1
Compounds of Formula (I) were prepared according to the following general synthetic route Scheme 1 :
Figure imgf000113_0001
N-(2,4-dimethoxybenzyl)-3-iodo-lH-pyrazolo[4,3-c]pyridin-4-amine was synthesized in two steps from 4-chloro-lH-pyrazolo[4,3-c]pyridine. Compound of Formula (I) were prepared by reacting tert-butyl (3-(4-((2,4-dimethoxybenzyl)amino)-3- iodo-lH-pyrazolo[4,3-c]pyridin-l-yl)cyclobutyl)carbamate (R1 = H) or tert-butyl (3-(4- ((2,4-dimethoxybenzyl)amino)-3-iodo-lH-pyrazolo[4,3-c]pyridin-l-yl)cyclobutyl) (methyl)carbamate (R1 = methyl) with an R boronic acid reagent (R1 =— ®-L-(B)). The isolated products were then deprotected with TFA and R2 introduced by reaction with acrylic acid (R2 = -CH=CH2) or butynoic acid (R2 = -CºC-CH3). SCHEME 2
Compounds of Formula (II) were prepared according to the following general synthetic route Scheme 2:
Figure imgf000114_0001
Compound of Formula (II) were prepared by reacting tert-butyl ((ls,3s)-3- (4-(((E)-(dimethylamino) methyl ene)amino)-2-oxo-2,3-dihydro-lH-imidazo[4, 5- c]pyridin-l-yl)cyclobutyl) carbamat (R1 = H) or tert-butyl ((ls,3s)-3-(4-(((E)- (dimethylamino) methyl ene)amino)-2-oxo-2,3-dihydro-lH-imidazo[4,5-c]pyri din- 1- yl)cyclobutyl) (methyl)carbamate (R1 = methyl) with an R boronic acid reagent
(R =— A --(B)) via a Suzuki coupling, followed by treatment with HC1 to provide the free amine groups. Finally, R2 was introduced via coupling with the R2 acid, acrylic acid (R2 = -CH=CH2) or butynoic acid (R2 = -CºC-CH3). SCHEME 3
Compounds of Formula (III) were prepared according to the following general synthetic route:
Figure imgf000115_0001
Compound of Formula (III) were prepared from 3-bromo-lH- pyrazolo[3,4-d]pyrimidin-4-amine, which was synthesized by bromination of 1H- pyrazolo[3,4-d]pyrimidin-4-amine. 3-bromo-lH-pyrazolo[3,4-d]pyrimidin-4-amine was then alkylated by reaction with 3-aminocyclobutyl methanesulfonate or 3-
(methylamino)cyclobutyl methanesulfonate, to provide respectively, either intermediate III-Int-1 (R1 = H) or intermediate III-Int-2 (R1 = Me). Compounds of Formula (III) were prepared by reacting III-Int-1 (R1 = H) or III-Int-2 (R1 = methyl) with an R’ boronic acid reagent (R1 = - A-L-A), followed by introduction of R2 by reaction with acrylic acid (R2 = -CH=CH2) or butynoic acid (R2 = -CºC-CH3).
SCHEME 4
Compounds of Formula (IV) were prepared according to the following general synthetic route:
Figure imgf000116_0001
EXAMPLES
These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. EXAMPLE 1
Synthesis of N-r3-r4-amino-3-(4-phenoxyphenyl )pyrazolor4.3-c1pyridin- l - yl1cvclobutvH-N-methyl-but-2-vnamide (Compound 1-1)
Figure imgf000117_0001
Thus, compounds of Formula (I) were prepared from N-(2,4- dimethoxybenzyl)-3-iodo-lH-pyrazolo[4,3-c]pyridin-4-amine, which was synthesized in two steps from 4-chloro-lH-pyrazolo[4,3-c]pyridine:
STEP 1 : Synthesis of 4-Chloro-3-iodo-lH-pyrazolor4.3-c1pyridine
Figure imgf000117_0002
To a solution of 4-chloro-lH-pyrazolo[4,3-c]pyridine (2.0g, 13.02mmol) in DMF (25mL) was added NIS (2.93g, 13.02mmol) at room temp and the resulting mixture was heated to 100°C for 16 hours. The reaction mixture was cooled to RT and diluted with water (25mL), which resulted in the formation of light yellow-orange solid that turned dark after stirring for 10 min. The resulting precipitate was collected by vacuum filtration and dried under high vacuum to provide 4-chloro-3-iodo-lH- pyrazolo[4,3-c]pyridine (3.13g, 11.18 mmol, 86% yield) as a light green solid. LC/MS (M+H) = 281.77
STEP 2: Synthesis of N-(2.4-dimethoxybenzv1)-3-iodo-lH-pyrazolor4.3-c1pyridin-4- amine
Figure imgf000118_0001
A solution of 4-chloro-3-iodo-lH-pyrazolo[4,3-c]pyridine (1.56g,
5.59mmol) and (2,4-dimethoxyphenyl)methanamine (2.80g, 16.77mmol, 2.10mL) in DMSO (lOmL) was heated to 120° for 16 hours. The mixture was cooled to RT, diluted with ethyl acetate and washed with water, brine, dried over NaiSCL filtered and concentrated. The residue was purified by silica gel chromatography using a gradient of 5%-100% ethyl acetate in heptane to give N-(2,4-dimethoxybenzyl)-3-iodo-lH- pyrazolo[4,3-c]pyridin-4-amine (1.37 g, 3.34 mmol, 59.75% yield). LC/MS (M+H) = 411.81
STEP 3-1: Synthesis of Compound I-Int-1 (tert-butyl (3-(4-((2A- dimethoxybenzyl )amino)-3-iodo- l H-pyrazololAJ-clpyridin- l -yl level obutyl lcarbamate)
STEP 3-2: Synthesis of Compound I-Int-2 (tert-butyl N-[3-[4-[(2.4- dimethoxyphenyl )methylaminol-3-iodo-pyrazolor4.3-clpyridin- l -yl level obutyll-N- methyl-carbamate)
Figure imgf000119_0001
N-(2,4-dimethoxybenzyl)-3-iodo-lH-pyrazolo[4,3-c]pyridin-4-amine was alkylated by reaction with 3-(Boc-amino)cyclobutyl methanesulfonate or 3-(Boc- (methyl)amino)cyclobutyl methanesulfonate, to provide respectively, either intermediate I-Int-1 (R1 = H) or intermediate I-Int-2 (R1 = Me):
A mixture of N-[(2,4-dimethoxyphenyl)methyl]-3-iodo-lH-pyrazolo[4,3- c]pyridin-4-amine (300 mg, 731.34 pmol), [3-(tert-butoxycarbonylamino)cyclobutyl] methanesulfonate (220 mg, 804 pmol) and cesium carbonate (357 mg, 1.10 mmol) in DMF (3 mL) was heated to 110 °C for 2 hr, reaction was complete. The reaction mixture was cooled to RT, diluted with EtOAc and washed with water (2X), brine (IX), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography using a gradient of 0%-60% EtOAc in heptane to give tert-butyl N-[3-[4-[(2,4-dimethoxyphenyl)methylamino]-3-iodo-pyrazolo[4,3- c]pyridin-l-yl]cyclobutyl]carbamate (312 mg) as an off-white gummy solid.
A mixture of N-(2,4-dimethoxybenzyl)-3-iodo-lH-pyrazolo[4,3-c]pyridin-
4-amine (1.37g, 3.34mmol), [3-[tert-butoxycarbonyl(methyl)amino]cyclobutyl] methanesulfonate (1.06g, 3.67mmol) and cesium carbonate (1.63g, 5.01mmol) in DMF (16mL) was heated to 110°C for 16 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate and washed with water (2X), brine (IX), dried over na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography using a gradient of 5%-100% ethyl acetate in heptane to give tert-butyl N-[3-[4-[(2,4-dimethoxyphenyl)methylamino]-3-iodo-pyrazolo[4,3-c]pyridin- l-yl]cyclobutyl]-N-methyl-carbamate (0.801 g, 1.35 mmol, 40.41% yield) as an off-white solid. LC/MS (M+H) = 595.66.
STEP 4: Synthesis of tert-butyl N-r3-r4-r(2.4-dimethoxyphenyl )methylamino1-3-(4- phenoxyphenvnpyrazolor4.3-c1pyridin-l-yl1cvclobutyl1-N-methyl -carbamate
Figure imgf000120_0001
A mixture of tert-butyl N-[3-[4-[(2,4-dimethoxyphenyl)methylamino]-3- iodo-pyrazolo[4,3-c]pyridin-l-yl]cyclobutyl]-N-methyl-carbamate (0.801g, 1.35 mmol), (4-phenoxyphenyl)boronic acid (317.76 mg, 1.48 mmol) and tripotassium-phosphate (859.50 mg, 4.05 mmol) in THF (8mL):Water (4mL) was degassed under N2 for 5 min. To this was added [l,r-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with di chi orom ethane (55.1 mg, 67.5 pmol) and the reaction mixture was heated to 70°C for 16 hours. The mixture was diluted with ethyl acetate and water, and the layers separated. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography using a gradient of 5%-100% ethyl acetate in heptane to give tert-butyl N-[3-[4-[(2,4-dimethoxyphenyl)methylamino]-3-(4-phenoxyphenyl)pyrazolo[4,3- c]pyridin-l-yl]cyclobutyl]-N-methyl-carbamate (684 mg) as a slight pink solid. LC/MS (M+H) = 638.3 STEP 5: Synthesis of 1 -[3 -(methyl amino)cvclobutyl1-3-(4-phenoxyphenyl )pyrazolor4.3- c1pyridin-4-amine
Figure imgf000121_0001
A solution of tert-butyl N-[3-[4-[(2,4-dimethoxyphenyl)methylamino]-3- (4-phenoxyphenyl)pyrazolo[4,3-c]pyridin-l-yl]cyclobutyl]-N-methyl-carbamate (684 mg, 1.08 mmol) in trifluoroacetic acid (3.86 g, 33.86 mmol, 2.61 mL) was heated to 60°C for 15 min and then concentrated under reduced pressure. The resulting residue was taken up in sat NaHC03(aq) and extracted with ethyl acetate (3X). The combined organic layers were washed with water, brine, dried over MgSCri, filtered and concentrated. The obtained residue was dried under high vac to give l-[3-(methylamino)cyclobutyl]-3-(4- phenoxyphenyl)pyrazolo[4,3-c]pyridin-4-amine (263.6 mg). Used as is in the next step. LC/MS (M+H) = 286.2
STEP 6: Synthesis of Compound 1-1 N-[3 -14-ami no-3 -(4-phenoxyphenyl )pyrazolol4.3- cIpyridin- 1 -yl ] cyclobutyl ] -N -methyl -but-2- ynamide
Figure imgf000121_0002
To a solution of l-[3-(methylamino)cyclobutyl]-3-(4- phenoxyphenyl)pyrazolo[4,3-c]pyridin-4-amine (100 mg, 259.43 pmol) in THF (2.0 mL) was added but-2-ynoic acid (26.17 mg, 311.32 mmol), DIPEA (134.1 mg, 1.04 mmol) followed by BOP (137 mg, 311 pmol), reaction was allowed to continue at RT for 30min. To the reaction mixture was added water and the product was extracted twice with ethyl acetate. The combined organic layer was washed with sat NaHCO3(aq), followed by brine, dried over Na2SO4 filtered and concentrated under reduced pressure. The residue obtained was purified by reverse phase chromatography using a gradient of 5%-40% MeCN in water w/0.10% Formic Acid. The like fractions were combined and freeze dried on the lyophilizer to give N-[3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[4,3- c]pyridin-l-yl]cyclobutyl]-N-methyl-but-2-ynamide (48.9 mg) as a white solid.
LC/MS (M+H) =452.1 1HNMR (300 MHz, DMSO-d6) d 2.05 (d,
J=13.25 Hz, 3 H) 2.61 - 3.02 (m, 6 H) 4.65 - 5.08 (m, 2 H) 5.88 (s, 2 H) 6.89 (d, J=6.15 Hz, 1 H) 7.09 - 7.24 (m, 5 H) 7.40 - 7.49 (m, 2 H) 7.65 - 7.73 (m, 2 H) 7.76 (dd, J=6.12, 2.22 Hz, 1 H)
EXAMPLES 2-24
Synthesis of Compounds 1-2 to 1-24
Compounds 1-2 to 1-24 were prepared in a similar fashion as Compound 1-1 with the corresponding R' boronic acid intermediates, as indicted in Table 9 below:
TABLE 9
COMPOUNDS PREPARED ACCORDING TO SCHEME 1
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
The LC/MS [M+H]+ and 1HNMR (d) for compounds 1-1 to 1-24 were determined as shown in Table 10, as follows:
TABLE 10
LC/MS [M+H]+ AND 'H NMR
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0003
EXAMPLE 25
Synthesis of N-(( s.3s)-3-(4-amino-2-oxo-3-(4-phenoxyphenv1)-2.3-dihydrc>imidazo r4.5-c1pyridin- l -yl icyclobutyl )-N-methylbut-2-ynamide (Compound II-l)
Figure imgf000134_0001
STEP 1: Synthesis of tert-Butyl ( 1 s.3 s)-3-(2-chloro-3-nitropyridin-4-yl ami no icyclobutyl (methyl) carbamate
Figure imgf000134_0002
To a mixture of 2,4-dichloro-3-nitro-pyridine (2.5 g, 12.95 mmol) in DMF (20 mL) was added tert-butyl (Is, 3s) N-(3-aminocyclobutyl)-N-methyl-carbamate (2.59 g, 12.95 mmol) and triethylamine (1.31 g, 12.9 mmol). The reaction mixture was stirred for 16 h at 25°C. LCMS showed the reaction was complete. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (25%) to afford tert-butyl N-[3-[(2- chloro-3-nitro-4-pyridyl)amino]cyclobutyl]-N-methyl-carbamate (3.98 g, 86%) as a yellow solid.
1HNMR (300 MHz, DMSO-d6) d 8.03 (d, J= 6.0 Hz, 1H), 7.47 (d, J= 6.6 Hz, 1H), 6.90 (d, J= 6.0 Hz, 1H), 4.44-4.02 (m, 1H), 3.85-3.69 (m, 1H), 2.74 (s, 3H), 2.60-2.53 (m, 2H), 2.25-2.10 (m, 2H), 1.40 (s, 9H). ESI-MS [M+H]+ calc’d for
(C15H21CIN4O4) 357.13, 359.13 found: 357.15, 359.15 STEP 2: Synthesis of tert-Butyl (Ί s.3s)-3-(2-(bis(4-methoxybenzyl )amino)-3- nitropyridin-4-ylamino)cvclobutyl(methvncarbamate
Figure imgf000135_0001
oc
To a mixture of tert-butyl N-[3-[(2-chloro-3-nitro-4- pyridyl)amino]cyclobutyl]-N-methyl-carbamate (3.98 g, 11.15 mmol) in isopropyl alcohol (50 mL) was added l-(4-methoxyphenyl)-N-[(4- methoxyphenyl)methyl]methanamine (2.87 g, 11.15 mmol) and triethylamine (1.47 g, 14.5 mmol) under N2. The resulting mixture was stirred for 16 h at 95 °C. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under vacuum to afford tert-butyl N-[3-[[2-[bis[(4- methoxyphenyl)methyl]amino]-3-nitro-4-pyridyl]amino]cyclobutyl]-N-methyl-carbamate (6.0 g, 93%) as a yellow oil.
1HNMR (300 MHz, DMSO-d6) d 7.86 (d, J= 6.0 Hz, 1H), 7.48 (d, J= 6.3 Hz, 1H), 7.12-6.99 (m, 4H), 6.91-6.79 (m, 4H), 6.27 (d, J= 6.0 Hz, 1H), 4.32 (s, 4H), 3.72 (s, 7H), 2.76 (s, 3H), 2.65-2.55 (m, 3H), 2.25-2.10 (m, 2H), 1.40 (s, 9H). ESI-MS
[M+H]+ calc’d for (C31H39N5O6) 579.29 found: 579.25
STEP 3: Synthesis of tert-Butyl (Ί .s.3.s)-3-(3-amino-2-(bis(4-methoxybenzyl )amino) pyridin-4-ylamino)cvclobutyl(methvncarbamate
Figure imgf000136_0001
To a mixture of tert-butyl N-[3-[[2-[bis[(4-methoxyphenyl)methyl] amino]-3-nitro-4-pyridyl]amino]cyclobutyl]-N-methyl-carbamate (6 g, 10.39 mmol) in THF (40 mL), ethanol (10 mL) and water (10 mL) were added ammonium chloride (8.33 g, 155.8 mmol) and zinc (6.79 g, 103.9 mmol) at 0 °C. The reaction mixture was stirred for 2 h at 25 °C. LCMS showed the reaction was complete. The reaction mixture was filtered. The filtrate was diluted with water (40 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers was washed with brine (100 mL), dried over Na2S04 and concentrated to afford tert-butyl N-[3-[[3-amino-2-[bis[(4- methoxyphenyl)methyl]amino]-4-pyridyl]amino]cyclobutyl]-N-methyl-carbamate (5 g, 87%) as a red solid.
ESI-MS [M+H]+ calc’d for (C31H41N5O4) 548.32 found: 548.25 STEP 4: Synthesis of tert-Butyl (Ί s.3s)-3-(4-(bis(4-methoxybenzyl )amino)-2-oxo-2.3- dihvdroimidaz[r4.5-c1pyridin- l -yl icvclobutvKmethyl )carbamate
Figure imgf000137_0001
To a mixture of tert-butyl N-[3-[[3-amino-2-[bis[(4-methoxyphenyl) methyl]amino]-4-pyridyl]amino]cyclobutyl]-N-methyl-carbamate (5 g, 9.13 mmol) in acetonitrile (50 mL) was added carbonyl diimidazole (2.22 g, 13.7 mmol). The reaction mixture was stirred for 16 h at 80 °C. The reaction mixture was cooled to room temperature and concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (40%) to afford tert-butyl N-[3-[4-[bis[(4-methoxyphenyl)methyl]amino]-2-oxo-3H-imidazo[4,5- c]pyridin-l-yl]cyclobutyl]-N-methyl-carbamate (5 g) as a white solid.
1HNMR (300 MHz, DMSO-d6) d 10.91 (s, 1H), 7.80 (d, J= 5.4 Hz, 1H), 7.13-7.02 (m, 4H), 6.87-6.77 (m, 5H), 4.55-4.07 (m, 6 H), 3.71( s, 6H), 3.09-2.94 (m, 3H), 2.87 (s, 3H), 2.50-2.40 (m, 1H), 1.41 (s, 9H). ESI-MS [M+H]+ calc’d for
(C32H39N5O5) 574.30 found: 574.50
STEP 5: Synthesis of tert-Butyl (1s.3s)-3-(4-amino-2-oxo-2.3-dihydroimidazor4.5-c1 pyridin- 1 -y1)cvclobuty1(methy1)carbamate
Figure imgf000137_0002
To a mixture of tert-butyl N-[3-[4-[bis[(4-methoxyphenyl)methyl]amino]- 2-oxo-3H-imidazo[4,5-c]pyridin-l-yl]cyclobutyl]-N-methyl-carbamate (5 g, 8.72 mmol) in methanol (200 mL) was added 20% Pd(OH)2 on carbon (2 g) and concentrated hydrochloric acid (300 mg, 8.23 mmol). The reaction mixture was stirred for 5 h at 60 °C under hydrogen (2 atm). The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to afford tert-butyl N-[3-(4-amino-2-oxo-3H- imidazo[4,5-c]pyridin-l-yl)cyclobutyl]-N-methyl-carbamate (2.2 g) as an off-white solid.
ESI-MS [M+H]+ calc’d for (C16H23N5O3) 334.18 found:334.25
STEP 6: Synthesis of tert-butyl P .s.3.s )-3 -(4-((E-( tdi methyl ami no imethyleneami no )-2- oxo-2.3-dihvdroimidazor4.5-clpyridin- l -yl lcvclobutvhmethyl icarbamate
Figure imgf000138_0001
A mixture of tert-butyl N-[3-(4-amino-2-oxo-3H-imidazo[4,5-c]pyridin-l- yl)cyclobutyl]-N-methyl-carbamate (900 mg, 2.70 mmol) in l,l-dimethoxy-N,N- dimethyl-methanamine (5.46 g, 45.86 mmol) was stirred for 1 h at 40 °C. The mixture was cooled to room temperature and concentrated to afford tert-butyl N-[3-[4-[(E)- dimethylaminomethyleneamino]-2-oxo-3H-imidazo[4,5-c]pyridin-l-yl]cyclobutyl]-N- methyl-carbamate (1 g) as a yellow solid.
1HNMR (300 MHz, DMSO-d6) d 10.85 (s, 1H), 8.56 (s, 1H), 7.81 (d, J = 5.4 Hz, 1H), 6.87 (d, J= 5.4 Hz, 1H), 4.55-4.06 (m, 2H), 3.08 (d, J= 7.5 Hz, 6H), 3.05- 2.93 (m, 2H), 2.88 (s, 3H), 2.50-2.38 (m, 2H), 1.42 (s, 9H). ESI-MS [M+H]+ calc’d for (C H28N6O3) 389.22 found: 389.30 STEP 7: Synthesis of tert-butyl (Ί s.3s)-3-(4-((E)-(dimethylamino)methyleneamino)-2- oxo-3-(4-phenoxyphenv1)-2.3-dihvdroimidazo[4.5-c1pyridin-l- v1)cvclobuty1(methy1)carbamate
Figure imgf000139_0001
A mixture containing tert-butyl N-[3-[4-[(E)- dimethylaminomethyleneamino]-2-oxo-3H-imidazo[4,5-c]pyridin-l-yl]cyclobutyl]-N- methyl-carbamate (500 mg, 1.29 mmol), triethylamine (520.98 mg, 5.15 mmol), TEMPO (221.22 mg, 1.42 mmol) and copper acetate (116.89 mg, 643.56 pmol) in DCM (10 mL) was stirred for 0.5 h at 25°C under O2. Then to this was added (4-phenoxyphenyl)boronic acid (550.95 mg, 2.57 mmol). The reaction mixture was stirred for 16 h at 25°C under O2. The reaction mixture was filtered and the filtrate was concentrated to give a residue, which was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether to afford tert-butyl N-[3-[4-[(E)-dimethylaminomethyleneamino]-2-oxo- 3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-l-yl]cyclobutyl]-N-methyl-carbamate (400 mg, crude) as a brown solid.
ESI-MS [M+H]+ calc’d for (C31H36N6O4) 557.28 found: 557.40
STEP 8: Synthesis of 4-amino-l-('(1s.3s)-3-('methylamino)cvclobutvP-3-(4- phenoxyphenv1)-1Hl-imidazor4.5-c]pyridin-2(3H)-one hydrochloride
Figure imgf000140_0001
To a mixture of tert-butyl N-[3-[4-[(E)-dimethylaminomethyleneamino]- 2-oxo-3-(4-phenoxyphenyl)imidazo[4,5-c]pyridin-l-yl]cyclobutyl]-N-methyl -carbamate (350 mg, 628.76 pmol) in dioxane (8 mL) was added concentrated hydrochloric acid (4 mL). The reaction mixture was stirred for 2 h at 85°C. The reaction mixture was cooled to room temperature and concentrated to afford cis-4-amino-l-(3- (methylamino)cyclobutyl)-3-(4-phenoxyphenyl)-lH-imidazo[4,5-c]pyridin-2(3H)-one hydrochloride (250 mg, crude) as a red oil.
ESI-MS [M+H-MHCI]+ calc’d for (C23H24CIN5O2) 402.19 found: 402.30
STEP 9: Synthesis of N-((ls.3s)-3-(4-amino-2-oxo-3-(4-phenoxyphenvO-2.3- dihvdroimidazor4.5-clpyridin- l -yl )cvclobutyl)-N-methylbut-2-vnamide
Figure imgf000140_0002
To a mixture of but-2-ynoic acid (42.2 mg, 502.4 pmol) in DMF (2 mL) was added HATU (208.4 mg, 548 mmol), 4-amino-l-((ls,3s)-3- (methylamino)cyclobutyl)-3-(4-phenoxyphenyl)-lH-imidazo[4,5-c]pyridin-2(3H)-one hydrochloride (200 mg, 456.70 pmol) and DIPEA (295 mg, 2.28 mmol). The reaction mixture was stirred for 1 h at 25°C. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC with following conditions: Column: XBridge Prep OBD C18 Column, 19*250mm, 5um; Mobile Phase A: Water (10 mmol/L
NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 40 B to 60 B in 7 min; 220 nm; RT 1.5.98 to afford N-((ls,3s)-3-(4-amino-2-oxo-3-(4- phenoxyphenyl)-2,3-dihydroimidazo[4,5-c]pyridin-l-yl)cyclobutyl)-N-methylbut-2- ynamide (46.9 mg, 21%) as a white solid.
1HNMR (300 MHz, DMSO-d6) d 7.78 (dd, 7= 5.4, 2.1 Hz, 1H), 7.51-7.41 (m, 4H), 7.25-7.18 (m, 1H), 7.18-7.11 (m, 4H), 6.81 (dd, J = 5.4, 2.1 Hz, 1H), 4.98-4.48 (m, 4H), 3.33-3.20 (m, 3H), 3.19-3.05 (m, 1H), 2.97 (s, 2H), 2.65-2.53 (m, 1H), 2.06 (s, 3H).
ESI-MS [M+H]+ calc’d for (C27H25N5O3) 468.20 found: 468.30
EXAMPLES 26-35
Synthesis of Compounds II-2 to 11-11
The compounds of Formula II were prepared from one of two intermediates II-Int-1 (R1 = H) or II-Int-2 (R1 = methyl) as shown below:
Figure imgf000141_0001
Compound II-Int-2 was prepared according to Steps 1-6 of Example 20. Compound II-Int-1 was prepared as follows:
STEP 1: Synthesis of tert-butyl ((1 s.3s)-3-((2-chloro-3-nitropyridin-4-y1)amino) cvclobutv1) carbamate
Figure imgf000142_0001
To a solution of tert-butyl N-(3-aminocyclobutyl)carbamate (5.0 g, 26.85 mmol) in DMF (50 mL) were added 2,4-dichloro-3-nitro-pyridine (5.18 g, 26.85 mmol) and triethylamine (5.43 g, 53.6 mmol, 7.48 mL). The resulting mixture was stirred at 25°C for 16 h. LCMS showed the reaction was complete. The reaction mixture was quenched with ice water (200 mL) and stirred at 0°C for 10 min. The solid formed was collected by filtration and dried in vacuo. This resulted in tert-butyl N-[3-[(2-chloro-3- nitro-4-pyridyl)amino]cyclobutyl]carbamate (9.0 g) as a yellow solid.
1HNMR (300 MHz, DMSO-d6) d 8.02 (d, J= 6.0 Hz, 1H), 7.53 (d, J= 5.4 Hz, 1H), 7.16 (d, J= 7.8 Hz, 1H), 6.80 (d, J= 6.0 Hz, 1H), 3.64-3.74 (m, 2H), 2.69-2.63 (m, 2H), 1.93-1.89 (m, 2H), 1.38 (s, 9H). ESI-MS [M+H]+ calc’d for (C14H19CIN4O4)
342.11 found: 343.20.
STEP 2: Synthesis of tert-butyl ((ls.3s)-3-((2-(bis(4-methoxybenzyl)amino)-3- nitropyridin-4-y1)amino)cvclobutvDcarbamate
Figure imgf000142_0002
To a solution of tert-butyl N-[3-[(2-chloro-3-nitro-4- pyridyl)amino]cyclobutyl]carbamate (9.0 g, 26.26 mmol) and l-(4-methoxyphenyl)-N- [(4-methoxyphenyl)methyl]methanamine (6.76 g, 26.26 mmol) in iso-propanol (120 mL) was added triethylamine (3.99 g, 39.38 mmol, 5.49 mL) . The resulting mixture was stirred at 95°C for 16 hr. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under vacuum to give tert-butyl N-[3- [[2-[bis[(4-methoxyphenyl)methyl]amino]-3-nitro-4-pyridyl]amino]cyclobutyl]carbamate (15.0 g, crude) as a yellow solid.
ESI-MS [M+H]+ calc’d for (C30H37N5O6) 563.27 found: 564.40 STEP 3: Synthesis of tert-butyl ((1 s.3s)-3-((3-amino-2-(bis(4-methoxybenzyl iamino) pyridin-4-vPamino)cvclobutvDcarbamate
Figure imgf000143_0001
To a mixture of tert-butyl N-[3-[[2-[bis[(4- methoxyphenyl)methyl]amino]-3-nitro-4-pyridyl]amino]cyclobutyl]carbamate (15.0 g, 26.61 mmol) and ammonium chloride (21.4 g, 399.19 mmol) in THF (120 mL), ethanol
(30 mL) and water (30 mL) was added zinc (17.4 g, 266.13 mmol). The resulting mixture was stirred at 25°C for 16 h. LCMS showed the reaction was complete. After removing the solvents under reduced pressure, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with water 100 mL and saturated brine 100 mL, dried over sodium sulphate and filtered. The filtrate was concentrated under vacuum to give the crude product tert-butyl
N-[3-[[3-amino-2-[bis[(4-methoxyphenyl)methyl]amino]-4- pyridyl]amino]cyclobutyl]carbamate (14.0 g, crude) as a yellow solid.
ESI-MS [M+H]+ calc’d for (C30H39N5O4) 533.30 found: 534.45 STEP 4: Synthesis of tert-butyl (T1 s.3s)-3-(4-(bis(4-methoxybenzy1 )amino)-2-oxo-2.3- dihydro- 1 H-imidazor4.5-clpyridin- 1 -yl )cvclobutyl icarbamate
Figure imgf000144_0001
To a solution of tert-butyl N-[3-[[3-amino-2-[bis[(4- methoxyphenyl)methyl]amino]-4-pyridyl]amino]cyclobutyl]carbamate (14.0 g, 26.23 mmol) in acetonitrile (150 mL) was added carbonyl diimidazole(6.4 g, 39.3 mmol). The resulting mixture was stirred at 80°C for 16 hr. LCMS showed the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluted with ethyl acetate / petroleum ether (50:50) to give the product tert-butyl N-[3-[4-[bis[(4- methoxyphenyl)methyl]amino]-2-oxo-3H-imidazo[4,5-c]pyridin-l- yl]cyclobutyl]carbamate (12.0 g) as a white solid.
1HNMR (300 MHz, DMSO-d6) d 10.91 (s, 1H), 7.81 (d, J= 5.4 Hz, 1H), 7.45 (d, J= 8.4 Hz, 1H), 7.19 (d, J= 5.4 Hz, 1H), 7.08 (d, J= 8.7 Hz, 4H), 6.83 (d, J = 8.7 Hz, 4H), 4.51-4.42 (m, 5H), 3.86-3.81 (m, 1H), 3.71 (s, 6H), 2.69-2.62 (m, 4H), 1.40
(s, 9H). ESI-MS [M+H]+ calc’d for (C3 1H37N5O5) 559.28 found: 560.25
STEP 5: Synthesis of tert-butyl ((ls.3s)-3-(4-amino-2-oxo-2.3-dihvdro-lH-imidazor4.5- clpyridin- 1 -yl level obutyl icarbamate
Figure imgf000144_0002
To a solution of tert-butyl N-[3-[4-[bis[(4-methoxyphenyl)methyl]amino]- 2-oxo-3H-imidazo[4,5-c]pyridin-l-yl]cyclobutyl]carbamate (12.0 g, 21.44 mmol) in methanol (200 mL) were added Pd(OH)2 (5.0 g, 7.12 mmol, 20%) and 0.5 mL cone HC1. The resulting mixture was stirred at 65°C for 6 hr under hydrogen gas atmosphere.
LCMS showed the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give crude product tert- butyl N-[3-(4-amino-2-oxo-3H-imidazo[4,5-c]pyridin-l-yl)cyclobutyl]carbamate (5.5 g, crude) as a yellow solid.
ESI-MS [M+H]+ calc’d for (C15H21N5O3) 319.16 found:320.1 STEP 6: Synthesis of tert-butyl (Yls.3s)-3-(4-(((E)-(dimethylamino)methylene)amino)-2- oxo-2.3-dihydro- l H-imidazor4.5-clpyridin- l -y level obutv1)carbam ate
Figure imgf000145_0001
A mixture of tert-butyl N-[3-(4-amino-2-oxo-3H-imidazo[4,5-c]pyridin-l- yl)cyclobutyl]carbamate (5.5 g, 17.22 mmol) and N,N-dimethylformamide
dimethylacetal(89.0 g, 747 mmol, 100 mL) was stirred for 1 h at 40°C. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude was stirred for 30 min in 50% ethyl acetate in petroleum ether (100 mL).. The solid formed was collected by filtration and dried in vacuo. to give tert-butyl N- [3-[4-[(E)-dimethylaminomethyleneamino]-2-oxo-3H-imidazo[4,5-c]pyridin-l- yl]cyclobutyl]carbamate (6.0 g, 16.02 mmol) as a white solid.
1HNMR (300 MHz, DMSO-d6) d10.82 (s, 1H), 8.55 (s, 1H), 7.81 (d, 7 = 5.4 Hz, 1H), 7.46 (d, J= 8.4 Hz, 1H), 7.23 (d, J= 5.4 Hz, 1H), 4.54-4.42 (m, 1H), 3.92- 3.80 (m, 1H), 3.19 - 2.99 (m, 6H), 2.66 - 2.50 (m, 4H), 1.40 (s, 9H). ESI-MS [M+H]+ calc’d for (C18H N6O3) 374.21 found: 375.30 Compounds II-2 to 11-11 were prepared in a similar fashion as Compound I-1 with the corresponding R' boronic acid intermediates, as indicted in Table 11 below:
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
The LC/MS [M+H]+ and 1HNMR (d) for compounds II-1 to II-11 were determined as shown in Table 12, as follows: TABLE 12
LC/MS [M+H]+ AND 'HNMR
Figure imgf000150_0001
Figure imgf000151_0002
EXAMPLE 36
Synthesis of 4-r4-amino- 1 -r3-(prop-2-enoyl amino)cyclobutyllpyrazolor3.4-dlpyrimidin-
3-yll-N-(2-pyridvObenzamide (Compound III-l)
Figure imgf000151_0001
STEP 1: Synthesis of 4-(4-amino-l-((1s.3s)-3-aminocvclobutv1)-1H[-pyrazolor3.4- dlpyrimidin-3-v1)-N-(pyridin-2-v1)benzamide
To a mixture of [4-(2-pyridylcarbamoyl)phenyl]boronic acid (130 mg, 537 mmol), l-(3-aminocyclobutyl)-3-bromo-pyrazolo[3,4-d]pyrimidin-4-amine (182 mg, 644 mmol) and potassium carbonate (220 mg, 1.61 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was added 1, 1'-bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (43.86 mg, 53.71 mmol) under N2 atmosphere. The resulting mixture was stirred for 1 at 100 °C. After cooling to room temperature, the reaction mixture was quenched with water (5 ml) and extracted with DCM (5 ml x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under reducing pressure. The residue was purified by prep-TLC (eluent: 100% ethyl acetate) to afford 4-(4-amino-l-((ls,3s)-3-aminocyclobutyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide (120 mg) as a white solid.
1HNMR (400 MHz, DMSO-d6) d 10.91 (s, 1H), 8.43 (d, J= 4.4 Hz, 1H),
8.28-8.21 (m, 4H), 7.91-7.82 (m, 3H), 7.22-7.18 (m, 1H), 4.98-4.89 (m, 1H), 3.27-3.22 (m, 1H), 2.73-2.70 (m, 2H), 2.42-2.35 (m, 2H). ESI-MS [M+H]+ calc’d for (C21H20N8O) 401.18 found: 401.25.
STEP 2: Synthesis of 4-(1-((1s.3s)-3-acrylamidocvclobutv1)-4-amino-lH-pyrazolor3.4- dlpyrimidin-3-y1)-N-(pyridin-2-y1)benzamide
To a mixture of 4-(4-amino-l-((ls,3s)-3-aminocyclobutyl)-lH- pyrazolo[3,4-d]pyrimidin-3-yl)-N-(pyridin-2-yl)benzamide (220 mg, 549.4 pmol) in THF (5 mL) were added DIPEA (355 mg, 2.75 mmol) and acryloyl chloride (50 mg, 549 pmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. After completed, the reaction mixture was quenched with saturated aqueous NH4C1 (10 ml) and extracted with DCM (10 ml x 3). The combined organic layers was washed with brine (10 ml), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by prep-HPLC with the flowing condition: column: XBridge Shield RP18 OBD Column, 19*250 mm, 10 um; Mobile Phase A: water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 29 B to 49 B in 7 min; 220 nm; RT1 : 5.40 to give 4-[4-amino-l-[3-(prop-2-enoylamino)cyclobutyl]pyrazolo[3,4-d]pyrimidin-3-yl]-N-(2- pyridyl)benzamide (50.1 mg) as a white solid.
1HNMR (300 MHz, DMSO-d6) d 10.89 (s, 1H), 8.63 (d, J= 7.8 Hz, 1H), 8.42 (dd, J= 4.8, 0.9 Hz, 1H), 8.29-8.21 (m, 4H), 7.90-7.81 (m, 3H), 7.22-7.17 (m, 3H),
6.29-6.07 (m, 2H), 5.61 (dd, J= 9.9, 2.7 Hz, 1H), 5.22-5.11 (m, 1H), 4.37-4.25 (m, 1H), 2.77-2.62 (m, 4H). ESI-MS [M+H]+ calc’d for (C24H22N8O2) 455.19 found: 455.20.
EXAMPLES 37-55
Compounds III-2 to III-20 were prepared in a similar fashion as
Compound III-l, as indicted in Table 13 below: TABLE 13
COMPOUNDS PREPARED ACCORDING TO SCHEME 3
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0002
The LC/MS [M+H]+ and 1HNMR (d) for compounds III-2 to III-21 were determined as shown in Table 14, as follows:
TABLE 14 LC/MS [M+H]+ AND 1HNMR
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
EXAMPLE 56
Synthesis of N-((ls.3s)-3-(6-amino-8-oxo-7-(4-phenoxyphenv1)-7.8-dihydrc>-9H-purin-9- v1)cvclobutv1)but-2-ynamide (Compound IV-1)
Figure imgf000162_0001
To a mixture of but-2-ynoic acid (35.6 mg, 423 mihoΐ) in DMF (4 mL) were added HATU (193 mg, 508 mmol), 6-amino-9-((ls,3s)-3-aminocyclobutyl)-7-(4- phenoxyphenyl)-7,9-dihydro-8H-purin-8-one (120 mg, 280 pmol) and DIPEA (182.5 mg, 1.41 mmol) at 0°C. The resulting mixture was stirred for 1 hour at 0°C. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by prep-HPLC: Column:
XBridge Prep OBD C18 Column 100 A, 19*250mm, 5um; Mobile Phase A: Water (0.05%NH3.H20), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27 B to 51 B in 7 min; 220 nm; RTL6.37 to afford N-((ls,3s)-3-(6-amino-8-oxo-7-(4-phenoxyphenyl)- 7,8-dihydro-9H-purin-9-yl)cyclobutyl)but-2-ynamide (61.0 mg) as a white solid.
1HNMR (300 MHz, DMSO-d6) d 8.96 (d, J= 6.8 Hz, 1H), 8.15 (s, 1H), 7.48-7.38 (m, 4H), 7.23-7.06 (m, 5H), 5.75 (s, 2H), 4.64-4.53 (m, 1H), 4.03-3.91 (m, 1H), 3.02-2.90 (m, 2H), 2.64-2.53 (m, 2H), 1.96 (s, 3H).
ESI-MS [M+H]+ calc’d for (C25H22N6O3) 455.18 found: 455.30 EXAMPLE 57
Synthesis of Compound IV-2
Compound IV-2 was prepared in a similar fashion, by reacting 6-amino-9- ((ls,3s)-3-aminocyclobutyl)-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one with acrylic acid.
Figure imgf000163_0001
EXAMPLE A
Assay to determine activity against BTK
Solutions of compounds (test or control) in DMSO were prepared at the desired concentrations, and serially diluted to 11 concentrations by 3 -fold dilution in 384pp-plate using TECAN EVO200. 20nL of stock were transferred to 384 plate using Echo550. DMSO was used as vehicle control.
Two separate solutions were prepared - an ATP solution containing MgCh (10mM), Brij-35 (0.01%), DTT (2mM), BSA (0.05%), EGTA (ImM), HEPE (pH7.5) (50mM), FLPeptide (6uM) and ATP (4mM); and a B TK solution containing MgCh
(10mM), Brij-35 (0.01%), DTT (2mM), BSA (0.05%), EGTA (ImM), HEPE (pH7.5) (50mM) and BTK (2.67nM). (BTK was obtained from Cama; FLPeptide2 was obtained from PerkinElmer and Ibrutinib was obtained from Selleck.) 5uL of ATP solution were added to each well, followed by addition of 15uL of BTK solution to initiate the reaction. (Note the final volume of each well was 20uL containing MgCh (lOmM), Brij-35 (0.01%), DTT (2mM), BSA (0.05%), EGTA (ImM), HEPE (pH7.5) (50mM), FLPeptide (1.5uM), ATP (ImM) and BTK (2nM).
The plates were incubated at room temperature for 90 minutes and then stopping buffer added (75uL, containing 0.5 M EDTA) to terminate the reaction. Samples from each well were analyzed using EZ reader.
The % remaining activity was calculated using read conversion ratio (CR) according to the equation:
Figure imgf000164_0001
XLFit (equation 201) was used to calculate IC50's by floating both bottom and top.
BTK IC50 values are provided for the compounds of the present invention in Table 15, below. With respct to BTK activity:“A” denotes and IC50 of less than lOnM, “B” denotes and IC50 of of from 10 nM to less than 100 nM, and“C” denotes and IC50 of 100 nM or more.
EXAMPLE B
Assay to determine activity against EGFR
Solutions of compounds (test or control) in DMSO were prepared at the desired concentrations, and serially diluted to 11 concentrations by 3 -fold dilution in 384pp-plate using TECAN EVO200. 20nL of stock were transferred to 384 plate using Echo550. DMSO was used as vehicle control.
Two separate solutions were prepared - an ATP solution containing MgCh (lOmM), Brij-35 (0.01%), DTT (2mM), BSA (0.05%), EGTA (ImM), HEPE (pH7.5) (50mM), FLPeptide (6uM) and ATP (4mM); and an EGFR solution containing MgCh (lOmM), Brij-35 (0.01%), DTT (2mM), BSA (0.05%), EGTA (ImM), HEPE (pH7.5) (50mM) and EGFR (3.99nM). (EGFR was obtained from Carna; FLPeptide 22 was obtained from PerkinElmer and Afatinib was obtained from MCE.)
15uL of EGFR solution was added to each well, followed by addition of 5uL of ATP solution to initiate the reaction. . (Note the final volume of each well should be 20uL containing MgCh (lOmM), Brij-35 (0.01%), DTT (2mM), BSA (0.05%), EGTA (ImM), HEPE (pH7.5) (50mM), FLPeptide (1.5uM), ATP (ImM) and EGFR (3nM). The plates were incubated at room temperature for 90 minutes and then stopping buffer added (75uL, containing 0.5 M EDTA) to terminate the reaction. Samples from each well were analyzed using EZ reader.
The % remaining activity was calculated using read conversion ratio (CR) according to the equation:
Figure imgf000165_0001
XLFit (equation 201) was used to calculate ICso's by floating both bottom and top.
EFGR IC50 values are provided for the compounds of the present invention in Table 15, below. With respct to EGFR activity:“A” denotes and IC50 of less than lOnM,“B” denotes and IC50 of of from 10 nM to less than 100 nM, and“C” denotes and IC50 of 100 nM or more.
TABLE 15
ACTIVITY OF REPRESENTATIVE COMPOUNDS
Figure imgf000165_0002
Figure imgf000166_0001
The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.
This application claims the benefit of priority to U.S. Provisional
Application No. 62/873,761, filed July 12, 2019, which application is hereby
incorporated by reference in its entirety.

Claims

1 A compound having the structure of Formula I:
Figure imgf000168_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
R3 is H, alkyl, halo, or cyano;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)NH-
NHC(O)-, -CH(OH)-, -C(=N-O-Ra)-
Figure imgf000168_0002
ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H, methyl, — CHF2,— CF3, ethyl, isopropyl, cyclopropyl, or fluoroethyl.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H, methyl, or ethyl.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R2 is -CH=CH2 or -CºC-CH3.
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R3 is H, -CH3, -F, or -C1.
6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R3 is H.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl.
8. The compound of claim 7, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is phenyl.
9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl.
10. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is
pyrimidinyl or pyrazolyl.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0
12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3.
13. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is halo.
14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -F or -C1.
15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 2 and each R4 is -F.
16. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is alkyl.
17. The compound of claim 16, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is methyl.
18. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -CN.
19. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is alkyl.
20. The compound of claim 19, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is methyl.
21. The compound of claim 12, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is haloalkyl.
22. The compound of claim 21, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is -CHF2 or
-CF3.
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH2 _, or -C(O)NH-
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is 0
25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle.
26. The compound of claim 25, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is cyclohexyl or phenyl.
27. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle.
28. The compound of claim 27, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is pyridinyl.
29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0
30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3.
31. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is halo.
32. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -F or -C1.
33. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R5 is -F.
34. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is alkyl.
35. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is methyl.
36. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -CN.
37. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is alkyl.
38. The compound of claim 37, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is methyl.
39. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is haloalkyl.
40. The compound of claim 39, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is -CHF2 or
-CF3.
41. The compound of any one of claims 1-40, having the structure of
Formula I-SS:
Figure imgf000174_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, or isotope thereof.
42. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of:
Figure imgf000174_0002
Figure imgf000175_0001
Figure imgf000176_0001
43. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of:
Figure imgf000176_0002
Figure imgf000177_0001
44 A compound having the structure of Formula II:
Figure imgf000177_0002
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
R3 is H, alkyl, halo, or cyano;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(O)NH
NHC(O)-, -CH(OH)-, -C(=N-O-Ra)- ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
45. The compound of claim 44, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H, methyl,
— CHF2,— CF3, ethyl, isopropyl, cyclopropyl, or fluoroethyl.
46. The compound of claim 44 or 45, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H or methyl.
47. The compound of any one of claims 44-46, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R2 is -CH=CH2 or -Cºc-CH3.
48. The compound of any one of claims 44-47, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R3 is H, -CH3, -F, or -C1.
49. The compound of any one of claims 44-48, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R3 is
H.
50. The compound of any one of claims 44-49, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl.
51. The compound of claim 50, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is phenyl.
52. The compound of any of claims 44-51, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl.
53. The compound of claim 52, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is
pyrimidinyl or pyrazolyl.
54. The compound of any one of claims 44-53, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0
55. The compound of any one of claims 44-54, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3.
56. The compound of claim 55, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is halo.
57. The compound of claim 56, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -F or -C1.
58. The compound of any one of claims 44-57, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 2 and each R4 is -F.
59. The compound of claim 55, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is alkyl.
60. The compound of claim 59, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is methyl.
61. The compound of claim 55, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -CN.
62. The compound of claim 55, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is alkyl.
63. The compound of claim 62, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is methyl.
64. The compound of claim 63, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is haloalkyl.
65. The compound of claim 64, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is -CHF2 or
-CF3.
66. The compound of any one of claims 44-65, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH2 _, or -C(O)NH-
67. The compound of any one of claims 44-66, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is 0
68. The compound of any one of claims 44-67, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle.
69. The compound of claim 68, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is cyclohexyl or phenyl.
70. The compound of any one of claims 44-67, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle.
71. The compound of claim 70, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is pyridinyl.
72. The compound of any one of claims 44-71, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0
73. The compound of any one of claims 44-71, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3.
74. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is halo.
75. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -F or -C1.
76. The compound of any one of claims 44-71, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R5 is -F.
77. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is alkyl.
78. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is methyl.
79. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -CN.
80. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is alkyl.
81. The compound of claim 80, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is methyl.
82. The compound of claim 73, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is haloalkyl.
83. The compound of claim 82, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is -CHF2 or
-CF3.
84. The compound of any one of claims 44-83, having the structure of
Formula II-SS:
Figure imgf000183_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, or isotope thereof.
85. The compound of claim 44, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of:
Figure imgf000184_0001
86. The compound of claim 84, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of:
Figure imgf000185_0001
87. A compound having the structure of F ormula III.
Figure imgf000186_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(0)NH-
NHC(O)-, -CH(OH)-, -C(=N-O-Ra)- ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3;
with the proviso that when L is -O-, ring A is phenyl, and ring B is phenyl:
m and n are not both 0;
R4 is not -F when m is 1 and n is 0; and
R5 is not -F when m is 0 and n is 2.
88. The compound of claim 87, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H, methyl, — CHF2,— CF3, ethyl, isopropyl, cyclopropyl, or fluoroethyl.
89. The compound of claim 87 or 88, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H, methyl, or ethyl.
90. The compound of any one of claims 87-89, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R2 is -CH=CH2 or -CºC-CH3.
91. The compound of any one of claims 87-90, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl.
92. The compound of claim 91, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is phenyl.
93. The compound of any of claims 87-90, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl.
94. The compound of claim 93, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is
pyrimidinyl or pyrazolyl.
95. The compound of any one of claims 87-94, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0
96. The compound of any one of claims 87-94, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3.
97. The compound of claim 96, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is halo.
98. The compound of claim 97, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -F or -C1.
99. The compound of any one of claims 87-98, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 2 and each R4 is -F.
100. The compound of claim 96, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is alkyl.
101. The compound of claim 100, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is methyl.
102. The compound of claim 96, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -CN.
103. The compound of claim 96, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is alkyl.
104. The compound of claim 103, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is methyl.
105. The compound of claim 96, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is haloalkyl.
106. The compound of claim 105, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is -CHF2 or -CF3.
107. The compound of any one of claims 87-106, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH2 _, -C(O)-, or -C(O)NH-
108. The compound of any one of claims 87-107, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is 0
109. The compound of any one of claims 87-107, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -NH-.
110. The compound of any one of claims 87-107, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is
-CH2-
111. The compound of any one of claims 87-107, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -C(O)-.
112. The compound of any one of claims 87-107, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -C(O)NH-
113. The compound of any one of claims 87-112, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle.
114. The compound of claim 113, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is cyclohexyl or phenyl.
115. The compound of any one of claims 87-112, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle.
116. The compound of claim 115, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is pyridinyl.
117. The compound of any one of claims 87-116, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0
118. The compound of any one of claims 87-116, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3.
119. The compound of claim 118, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is halo.
120. The compound of claim 119, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -F or -C1.
121. The compound of any one of claims 87-116, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R5 is -F.
122. The compound of claim 118, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is alkyl.
123. The compound of claim 122, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is methyl.
124. The compound of claim 118, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -CN.
125. The compound of claim 118, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is alkyl.
126. The compound of claim 125, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is methyl.
127. The compound of claim 118, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is haloalkyl.
128. The compound of claim 127, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is -CHF2 or
-CF3.
129. The compound of any one of claims 87-128, having the structure of
Formula III-SS:
Figure imgf000192_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, or isotope thereof.
130. The compound of claim 87, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of:
Figure imgf000192_0002
Figure imgf000193_0001
Figure imgf000194_0001
131. The compound of claim 129, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of:
Figure imgf000195_0001
132 A compound having the structure of Formula IV:
Figure imgf000196_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein:
R1 is H, alkyl, haloalkyl, or cycloalkyl;
R2 is -CH=CH2, -CºC-CH3 or -CºC-CH2CH3;
ring A is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; R4 is halo, alkyl, haloalkyl, -CN, or -ORa;
L is -O-, -S-, -NH-, -NMe-, -CH2-, -CF2-, -C(O)-, -C(0)NH-
NHC(O)-, -CH(OH)-, -C(=N-O-Ra)- or
ring B is monocyclic or bicyclic carbocycle or monocyclic or bicyclic heterocycle;
R5 is halo, alkyl, haloalkyl, -CN, or -ORa;
Ra is alkyl or haloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
133. The compound of claim 132, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H, methyl, -CHF2, -CF3, ethyl, isopropyl, cyclopropyl, or fluoroethyl.
134. The compound of claim 132 or 132, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R1 is H or methyl.
135. The compound of any one of claims 132-134, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein R2 is -CH=CH2 or -Cºc-CH3.
136. The compound of any one of claims 132-135, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic aryl.
137. The compound of claim 136, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is phenyl.
138. The compound of any of claims 132-137, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is monocyclic or bicyclic heteroaryl.
139. The compound of claim 138, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring A is
pyrimidinyl or pyrazolyl.
140. The compound of any one of claims 132-139, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 0
141. The compound of any one of claims 132-139, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 1, 2, or 3.
142. The compound of claim 141, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is halo.
143. The compound of claim 142, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -F or -C1.
144. The compound of any one of claims 132-143, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein m is 2 and each R4 is -F.
145. The compound of claim 141, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is alkyl.
146. The compound of claim 145, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is methyl.
147. The compound of claim 141, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -CN.
148. The compound of claim 141, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is alkyl.
149. The compound of claim 148, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is methyl.
150. The compound of claim 149, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R4 is -ORa and Ra is haloalkyl.
151. The compound of claim 150, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is -CHF2 or
-CF3.
152. The compound of any one of claims 132-151, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is -O-, -NH-, -CH2 _, or -C(O)NH-
153. The compound of any one of claims 132-152, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein L is 0
154. The compound of any one of claims 142-153, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic carbocycle.
155. The compound of claim 154, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is cyclohexyl or phenyl.
156. The compound of any one of claims 132-153, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is monocyclic heterocycle.
157. The compound of claim 156, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein ring B is pyridinyl.
158. The compound of any one of claims 132-157, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 0
159. The compound of any one of claims 132-157, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 1, 2, or 3.
160. The compound of claim 159, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is halo.
161. The compound of claim 160, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -F or -C1.
162. The compound of any one of claims 132-161, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein n is 2 and each R5 is -F.
163. The compound of claim 159, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is alkyl.
164. The compound of claim 163 or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is methyl.
165. The compound of claim 159, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -CN.
166. The compound of claim 159, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is alkyl.
167. The compound of claim 166, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is methyl.
168. The compound of claim 159, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein at least one R5 is -ORa and Ra is haloalkyl.
169. The compound of claim 168, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, wherein Ra is -CHF2 or
-CF3.
170. The compound of any one of claims 132-169, having the structure of
Formula II-SS:
Figure imgf000201_0001
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, or isotope thereof.
171. The compound of claim 132, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of:
Figure imgf000202_0001
172. The compound of claim 170, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, having the structure of:
Figure imgf000202_0002
173. A pharmaceutical composition comprising the compound of any one of claims 1-172, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, or isotope thereof, and at least one pharmaceutically acceptable excipient.
174. A method of inhibiting a protein kinase comprising contacting the protein kinase with an effective amount of a compound of any one of claims 1-172, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.
175. The method of claim 174, wherein the protein kinase is BTK.
176. The method of claim 175, wherein the compound or pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof is selective to BTK over EGFR.
177. A method for treating a BTK dependent condition, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-172, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof.
178. The method of claim 177, wherein the compound or pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof is selective to BTK over EGFR.
179. The method of claim 177 or 178, wherein the BTK dependent condition is cancer, an autoimmune disease, an inflammatory disease, or a theromboembolic disease.
180. The method of claim 179, wherein the autoimmune disease is multiple sclerosis, rheumatoid arthrisis, psoriasis, Sjogren’s syndrome, or systemic lupus
erythematosus.
181. The method of claim 179, wherein the inflammatory disease is urticaria.
182. Use of a compound of any one of claims 1-172, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, tautomer, racemate, isotope, or pharmaceutical composition thereof in the manufacture of a medicament.
183. The use of claim 182, wherein the medicament is for the treatment of cancer, an autoimmune disease, an inflammatory disease, or a theromboembolic disease.
184. The use of claim 183, wherein the autoimmune disease is multiple sclerosis, rheumatoid arthrisis, psoriasis, Sjogren’s syndrome, or systemic lupus erythematosus.
185. The use of claim 183, wherein the inflammatory disease is urticaria.
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