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WO2024159094A1 - Pyrimidinyl (hetero)aromatic aminopyridine compounds for inhibition of raf kinases - Google Patents

Pyrimidinyl (hetero)aromatic aminopyridine compounds for inhibition of raf kinases Download PDF

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Publication number
WO2024159094A1
WO2024159094A1 PCT/US2024/013105 US2024013105W WO2024159094A1 WO 2024159094 A1 WO2024159094 A1 WO 2024159094A1 US 2024013105 W US2024013105 W US 2024013105W WO 2024159094 A1 WO2024159094 A1 WO 2024159094A1
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compound
pharmaceutically acceptable
acceptable salt
alkyl
optionally substituted
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French (fr)
Inventor
Li Ren
Joseph P. Lyssikatos
Samuel Kintz
Alex Andrew KELLUM
David Austin MORENO
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Enliven Inc
Enliven Inc
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Enliven Inc
Enliven Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the RAF family of serine/threonine protein kinases operate as an essential signaling node within the Ras/Raf/MEK/ERK pathway. Also referred to as the mitogen activated kinase (MAPK) pathway, this signaling cascade is critically involved in the regulation of a diverse array of basic physiological processes.
  • the MAPK pathway is responsive to a variety of stimuli mediated through the input of numerous intracellular second messengers and transmembrane receptors including the receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • upon ligand binding they act on the MAPK pathway through the recruitment/activation of the RAS GTPases which then bind and activate RAF.
  • MEK mitogen activated kinase kinase 1 & 2
  • MAPK1/2 mitogen-activated protein kinases 1 & 2
  • Activated ERK then acts as a broad-based effector of the pathway, modulating the activity of a variety of proteins including other protein kinases, structural proteins, metabolic enzymes and transcription factors that in turn modulate the broad cellular response to these stimuli.
  • the primary output of the MAPK pathway is to drive cell growth and proliferation as well as to suppress apoptosis (regulated cell death). Given its central role in the regulation of these processes, it is not surprising that the majority of genetic alterations associated with cellular transformation act entirely or at least in part via the aberrant activation of the MAPK pathway. Therefore, as an essential node in the MAPK pathway, the RAF kinases represent an important therapeutic intervention point for the treatment of a variety of malignancies whose dysregulated growth and survival rely upon this pathway.
  • Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R 4 groups;
  • the compound of formula (I) is a compound of formula (I-1), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • the compound of formula (I) is a compound of formula (I-2): (I-2) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • the compound is a compound of formula (I-3): (I-3) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • the compound is a compound of formula (I-1-a), (I-1-b), (I-2-a), (I-2-b), (I-3-a), or (I-3-b), wherein A 1 and A 5 are each independently C, N, O, or S; A 2 -A 4 are each independently C-R 4 , N, N-R 4 , O, or S; provided that at least one of A 1 -A 5 is a heteroatom; A 6 and A 11 are each independently C, N, O, or S, and A 7 -A 10 are each independently C-R 4 , N, N-R 4 , O, or S.
  • the compound is a compound of formula (I-1-a) or a compound of formula (I-1-b). In other embodiments, the compound is a compound of formula (I-2-a) or a compound of formula (I-2-b). In yet other embodiments, the compound is a compound of formula (I-3-a) or a compound of formula (I-3-b).
  • Ring A is phenyl optionally substituted with 1 to 4 R 4 groups. In some embodiments, Ring wherein ⁇ indicates the point of attachment to the pyrimidinyl ring and ⁇ indicates the point of attachment to the amino moiety.
  • Ring A is 5- to 6-membered heteroaryl optionally substituted with 1 to 4 R 4 groups. In certain embodiments, Ring A is an optionally substituted 5- membered heteroaryl. In some embodiments, Ring A is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 3 R 4 groups. In some embodiments, Ring A attachment to the pyrimidinyl ring and ⁇ indicates the point of attachment to the amino moiety.
  • Ring A is an optionally substituted 6-membered heteroaryl.
  • Ring A is pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted with 1 to 4 R 4 groups.
  • ⁇ indicates the point of attachment to the amino moiety.
  • Ring A is a 5- to 6-membered heteroaryl comprising at least one nitrogen atom. In some embodiments, Ring A is a 5- to 6-membered heteroaryl comprising two heteroatoms. In some embodiments, Ring A is a 5- to 6-membered heteroaryl comprising at least two nitrogen atoms. [0017] In some embodiments, R 1 is cyclopropyl optionally substituted by 1-2 R 5 groups. In some embodiments, R 1 is unsubstituted cyclopropyl. In some embodiments, the moiety In some embodiments, R 1 is cyclopropyl substituted by 1-2 O fluorine atoms.
  • R 3 is -CH3.
  • a compound which is selected from the group consisting of Table 3, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing.
  • a pharmaceutical composition comprising any compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable excipients.
  • the present disclosure provides a method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • a method of treating a cancer or neoplastic disease in a human in need thereof comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • a method of treating a cancer or neoplastic disease in a human in need thereof comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation.
  • the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E.
  • the cancer or neoplastic disease is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L.
  • the cancer or neoplastic disease is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H.
  • the cancer or neoplastic disease is associated with one or more mutations in ARAF selected from the group consisting of S214C and S214F. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in BRAF selected from the group consisting of Class I, Class Ila, Class lib, Class lie, and Class III mutations. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in CRAF selected from the group consisting of P261 A, P261L, E478K, R391W, R391S and T491I, or is associated with a CRAF fusion.
  • the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • the one or more genetic lesions is a point mutation, a fusion or any combination thereof.
  • the one or more receptor tyrosine kinase is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROSE
  • the cancer is a refractory cancer.
  • the cancer is a refractory cancer associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events.
  • the cancer is a refractory BRAF Class I mutant cancer.
  • the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R.
  • the refractory cancer is associated with one or more Class II or Class III mutations in BRAF.
  • the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and
  • the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10.
  • the cancer is a solid tumor or a hematological malignancy.
  • the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, or colorectal carcinoma.
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the method further comprises administering one or more pharmaceutical agents including anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro- apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation.
  • RTK inhibitors including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1
  • RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II)
  • MEK1/2 inhibitors ERK1/2 inhibitors
  • excipient means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the present disclosure as an active ingredient.
  • a drug or pharmaceutical such as a tablet containing a compound of the present disclosure as an active ingredient.
  • Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • the terms “individual”, “subject” and “patient” refer to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human.
  • patient refers to a human.
  • mammal includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.
  • “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (e.g., C1-C6 means one to six carbons).
  • alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like.
  • alkyl may encompass C1-C6 alkyl, C2-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C1-C5 alkyl, C2-C5 alkyl, C3-C5 alkyl, C4-C5 alkyl, C1-C4 alkyl, C2-C4 alkyl, C3-C4 alkyl, C1-C3 alkyl, C2-C3 alkyl, or C1-C2 alkyl.
  • alkenyl refers to an unsaturated branched or straight- chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond.
  • the group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s).
  • Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1- yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).
  • propenyl e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl
  • butenyl e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-
  • the alkenyl group may be attached to the rest of the molecule by a carbon atom in the carbon-carbon double bond.
  • the “alkenyl” may be attached to the rest of the molecule by a saturated carbon atom, and the carbon-carbon double bond is located elsewhere along the branched or straight-chain alkyl group.
  • the term “cycloalkyl”, “carbocyclic”, or “carbocycle” refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices.
  • cycloalkyl As used herein, “cycloalkyl”, “carbocyclic”, or “carbocycle” is also meant to refer to bicyclic, polycyclic and spirocyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norborene, spirocyclic C5-12 alkane, etc.
  • cycloalkyl encompasses C3-C7 cycloalkyl, C4-C7 cycloalkyl, C5-C7 cycloalkyl, C5-C7 cycloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, C5-C6 cycloalkyl, C3-C5 cycloalkyl, C4-C5 cycloalkyl, or C3-C4 cycloalkyl.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain hydrocarbon radical, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized.
  • the heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group.
  • the heteroatom Si can be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
  • heterocycloalkyl refers to a cycloalkyl radical group having the indicated number of ring atoms (e.g., 5-6 membered heterocycloalkyl) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, nitrogen atom(s) are optionally quaternized, as ring atoms.
  • a “heterocycloalkyl”, “heterocyclic”, or “heterocycle” ring can be a monocyclic, a bicyclic, spirocyclic or a polycylic ring system.
  • heterocycloalkyl examples include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(lH,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3 -pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine, tropane and the like.
  • heterocycloalkyl can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms.
  • heterocycloalkyl encompasses 4- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkyl, 6- to 8-membered heterocycloalkyl, 7- to 8-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 6- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl, or 4- to 5-membered heterocycloalkyl.
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms. In some embodiments, an alkyl (or alkylene) group will have 10 or fewer carbon atoms.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedi oxy, alkyleneamino, alkylenediamino, and the like).
  • heterocycloalkylene by itself or as part of another substituent means a divalent radical, saturated or unsaturated or polyunsaturated, derived from heterocycloalkyl.
  • heteroatoms can also occupy either or both of the chain termini.
  • alkoxy and alkylamino are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom or an amino group, respectively.
  • heterocycloalkoxy refers to a heterocycloalkyl-O- group in which the heterocycloalkyl group is as previously described herein.
  • halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • C1-C4 haloalkyl is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, difluoromethyl, and the like.
  • haloalkyl-OH refers to a haloalkyl group as described above which is also substituted by one or more hydroxyl groups.
  • haloalkyl-OH is meant to include haloalkyl substituted by one hydroxyl group, as well as haloalkyl substituted by multiple hydroxyl groups.
  • haloalkyl-OH also encompasses haloalkyl groups substituted by one or more hydroxyl groups on any carbon of the haloalkyl group.
  • the term “haloalkyl-OH” includes -CH(F)OH, -CH2CFHCH2OH, -CH(OH)CF3, and the like.
  • alkyl-OH refers to an alkyl or alkylene substituted by one or more hydroxyl groups.
  • alkyl-OH is meant to include alkyl substituted by one hydroxyl group, as well as alkyl substituted by multiple hydroxyl groups.
  • alkylene-OH is meant to include alkylene substituted by one hydroxyl group, as well as alkylene substituted by multiple hydroxyl groups.
  • alkyl-OH and alkylene-OH also encompass alkyl groups and alkylene groups, respectively, that are substituted by one or more hydroxyl groups on any carbon of the alkyl or alkylene group, as valency permits.
  • alkyl-OH includes -CH2OH, -CH(OH)CH 3 , -CH2CH2OH, -C(CH 3 ) 2 OH, and the like.
  • alkyl-OR 6 refers to an alkyl substituted by one or more -OR 6 groups.
  • alkyl-OR 6 is meant to include alkyl substituted by one -OR 6 group, as well as alkyl substituted by multiple -OR 6 groups.
  • alkyl-OR 6 also encompasses alkyl groups substituted by one or more OR 6 groups on any carbon of the alkyl, as valency permits.
  • alkyl-CN refers to an alkyl substituted by one or more cyano groups.
  • alkyl-CN is meant to include alkyl substituted by one cyano group, as well as alkyl substituted by multiple cyano groups.
  • alkyl-CN also encompasses alkyl groups substituted by one or more cyano groups on any carbon of the alkyl group.
  • alkyl-CN includes -CH2CN, -CH2CH2CN, -CH(CN)CH3, and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group, which can be a single ring or multiple rings (up to three rings) which are fused together.
  • aryl encompasses Ce-Cuaryl, Cs-Cuaryl, Cio-Cuaryl, Ci2-Ci4aryl, Ce-Cn aryl, Cs-Cn aryl, Cio-Cn aryl, Ce-Cio aryl, Cs-Cio aryl, or Ce-Cs aryl.
  • heteroaryl refers to aryl groups (or rings) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while nonlimiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl
  • heteroaryl encompasses 5- to 10-membered heteroaryl, 6- to 10-membered heteroaryl, 7- to 10-membered heteroaryl, 8- to 10-membered heteroaryl, 9- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 6- to 9-membered heteroaryl, 7- to 9- membered heteroaryl, 8- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 6- to 8- membered heteroaryl, 7- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, 6- to 7- membered heteroaryl, or 5- to 6-membered heteroaryl.
  • heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • a wavy line “•'w'-'” that intersects a bond in a chemical structure indicates the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule.
  • the representation of a group e.g., X a in parenthesis followed by a subscript integer range (e.g., (X a )o-i) means that the group can have the number of occurrences as designated by the integer range.
  • (X a )o-i means the group X a can be absent or can occur one time.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the present disclosure can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • solvate refers to an association or complex of one or more solvent molecules and a compound of the present disclosure.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • co-crystal refers to a solid that is a crystalline single phase material composed of two or more different molecular or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts.
  • a co-crystal consists of two or more components that form a unique crystalline structure having unique properties. Cocrystals are typically characterized by a crystalline structure, which is generally held together by freely reversible, non-covalent interactions.
  • a co-crystal refers to a compound of the present disclosure and at least one other component in a defined stoichiometric ratio that form a crystalline structure.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functional group on a compound.
  • an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc).
  • a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include acetyl and silyl.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like.
  • protecting groups and their use see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006.
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom.
  • isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present disclosure and include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H (“D”), 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Certain isotopically labeled compounds of the present disclosure e.g., those labeled with 3 H or 14 C are useful in compound and/or substrate tissue distribution assays.
  • Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (z.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as 15 O, 13 N, n C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Treating” or “treatment” of a disease in a patient refers to inhibiting the disease or arresting its development; or ameliorating or causing regression of the disease.
  • treatment or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient.
  • treatment is a reduction of pathological consequence of the disease or disorder. The methods of the present disclosure contemplate any one or more of these aspects of treatment.
  • Preventing”, “prevention”, or “prophylaxis” of a disease in a patient refers to preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease.
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R 4 groups;
  • R 1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R 1 is optionally substituted with 1 to 5 R 5 groups;
  • R 2 is C1-C6 alky
  • is a double bond, and X 1 is O.
  • the compound of formula (I) is a compound of formula (I-1), (I-1) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R 4 groups;
  • R 1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R 1 is optionally substituted with 1 to 5 R 5 groups;
  • R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R 2 is optionally substituted with 1 to 5 R 5 groups, R 2’ is H or D; and
  • R 3 is H or C1-C6 alky
  • the compound of formula (I) is a compound of formula (I-2), (I-2) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R 4 groups;
  • R 1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R 1 is optionally substituted with 1 to 5 R 5 groups;
  • R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R 2 is optionally substituted with 1 to 5 R 5 groups,
  • the compound of formula (I) is a compound of formula (I-3), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R 4 groups;
  • R 1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R 1 is optionally substituted with 1 to 5 R 5 groups;
  • R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R 2 is optionally substituted with 1 to 5 R 5 groups,
  • R 1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R 1 is optionally substituted with 1 to 5 R 5 groups. In some embodiments, R 1 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein R 1 is optionally substituted with 1 to 5 R 5 groups. In some embodiments, R 1 is C1-C6 alkyl or 4- to 7-membered heterocycloalkyl, wherein R 1 is optionally substituted with 1 to 5 R 5 groups.
  • R 1 is C3-C7 cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein R 1 is optionally substituted with 1 to 5 R 5 groups.
  • R 1 is C1-C6 alkyl optionally substituted by one or more R 5 groups.
  • R 1 is C1-C4 alkyl optionally substituted by one or more R 5 groups.
  • R 1 is C1-C3 alkyl optionally substituted by one or more R 5 groups.
  • R 1 is C2-C4 alkyl optionally substituted by one or more R 5 groups.
  • R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl, each of which is optionally substituted by one or more R 5 groups.
  • R 1 is -CH3, -CH2CH3, -(CH2)2CH3, -CH2(CH3)2, -(CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, or -CH(CH3)3.
  • R 1 is -CH3 or -CH2CH3.
  • R 1 is -CH3.
  • R 1 is -CH2CH3.
  • R 1 is C3-C7 cycloalkyl optionally substituted by one or more R 5 groups.
  • R 1 is C3-C6 cycloalkyl optionally substituted by one or more R 5 groups.
  • R 1 is C3-C5 cycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 1 is C3-C4 cycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 1 is C4-C6 cycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 1 is C4-C5 cycloalkyl. In some embodiments, R 1 is C5-C6 cycloalkyl optionally substituted by one or more R 5 groups.
  • R 1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted by one or more R 5 groups. In some embodiments, R 1 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally substituted by one or more R 5 groups. In some embodiments, R 1 is cyclopropyl or cyclobutyl, each of which is optionally substituted by one or more R 5 groups. In some embodiments, R 1 is cyclobutyl, cyclopentyl or cyclohexyl.
  • R 1 is cyclobutyl or cyclopentyl, each of which is optionally substituted by one or more R 5 groups. In some embodiments, R 1 is cyclopentyl or cyclohexyl. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is cyclopentyl. In some embodiments, R 1 is cyclohexyl. In some embodiments, R 1 is cyclopropyl substituted by 1-2 R 5 groups. In some embodiments, R 1 is cyclopropyl substituted by 1-2 R 5 groups.
  • R 1 is unsubstituted C3- C7 cycloalkyl. In some embodiments, R 1 is unsubstituted C3-C4 cycloalkyl. In some embodiments, R 1 is unsubstituted cyclopropyl. [0088] In still other embodiments, R 1 is 4- to 7-membered heterocycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 1 is 4- to 6-membered heterocycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 1 is 4- to 5-membered heterocycloalkyl optionally substituted by one or more R 5 groups.
  • R 1 is 5- to 7-membered heterocycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 1 is 5- to 6-membered heterocycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 1 is 6- to 7-membered heterocycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 1 is 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R 1 is 4- to 7-membered heterocycloalkyl containing 1-2 nitrogen atoms.
  • R 1 is 4- to 7-membered heterocycloalkyl containing 1-2 oxygen atoms. In some embodiments, R 1 is 4- to 7- membered heterocycloalkyl containing 1 oxygen atom and 1 nitrogen atom. In some embodiments, R 1 is 4- to 6-membered heterocycloalkyl. In some embodiments, R 3 is pyrrolidinyl or piperidinyl.
  • R 1 is cyclopropyl optionally substituted by 1-2 R 5 groups.
  • R 1 is unsubstituted cyclopropyl.
  • R 1 is cyclopropyl
  • R 2 is C1-C3 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R 2 is optionally substituted by 1-5 R 5 groups. In some embodiments, R 2 is C1-C3 alkyl or C2-C6 alkenyl, wherein R 2 is optionally substituted by 1-5 R 5 groups. In some embodiments, R 2 is C1-C3 alkyl or C3-C7 cycloalkyl, wherein R 2 is optionally substituted by 1-5 R 5 groups. In some embodiments, R 2 is C2-C6 alkenyl or C3-C7 cycloalkyl, wherein R 2 is optionally substituted by 1-5 R 5 groups.
  • R 2 is C1-C6 alkyl optionally substituted by 1-5 R 5 groups. In some embodiments, R 2 is C1-C4 alkyl optionally substituted by one or more R 5 groups. In some embodiments, R 2 is C1-C3 alkyl optionally substituted by one or more R 5 groups. In some embodiments, R 2 is C2-C4 alkyl optionally substituted by one or more R 5 groups.
  • R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl, each of which is optionally substituted by one or more R 5 groups.
  • R 2 is -CH3, - CH2CH3, -(CH2)2CH3, -CH2(CH3)2, -(CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, or -CH(CH3)3.
  • R 2 is -CH3 or -CH2CH3.
  • R 2 is -CH3.
  • R 2 is -CH2CH3.
  • R 2 is C2-C6 alkenyl optionally substituted by 1-5 R 5 groups.
  • R 2 is C2-C5 alkenyl optionally substituted by 1-5 R 5 groups.
  • R 2 is C3-C6 cycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 2 is C3-C5 cycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 2 is C3-C4 cycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 2 is C4-C6 cycloalkyl optionally substituted by one or more R 5 groups. In some embodiments, R 2 is C4-C5 cycloalkyl. In some embodiments, R 2 is C5-C6 cycloalkyl optionally substituted by one or more R 5 groups.
  • R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted by one or more R 5 groups. In some embodiments, R 2 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally substituted by one or more R 5 groups. In some embodiments, R 2 is cyclopropyl or cyclobutyl, each of which is optionally substituted by one or more R 5 groups. In some embodiments, R 2 is cyclobutyl, cyclopentyl or cyclohexyl.
  • R 2 is cyclobutyl or cyclopentyl, each of which is optionally substituted by one or more R 5 groups. In some embodiments, R 2 is cyclopentyl or cyclohexyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is cyclobutyl. In some embodiments, R 2 is cyclopentyl. In some embodiments, R 2 is cyclohexyl. In some embodiments, R 2 is cyclopropyl substituted by 1-2 R 5 groups. In some embodiments, R 2 is cyclopropyl substituted by 1-2 R 5 groups. [0094] In some embodiments, R 2 ’, when present, is H or D.
  • R 2 ’ when present, is H. In some embodiments, R 2 ’, when present, is D. [0097] In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is C1-C4 alkyl. In some embodiments, R 3 is C1-C3 alkyl. In some embodiments, R 3 is C2-C4 alkyl.
  • R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec- butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl.
  • R 3 is -CH3, -CH2CH3, -(CH2)2CH3, -CH2(CH3)2, -(CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, or -CH(CH3)3.
  • R 3 is -CH3 or -CH2CH3. In some embodiments, R 3 is -CH3. In some embodiments, R 3 is -CH2CH3. [0098] In some embodiments, Ring A is a phenyl or 5- to 6-membered heteroaryl, each of which is optionally substituted with 1 to 5 R 4 groups. In some embodiments, Ring A is phenyl or 5- to 6-membered heteroaryl, each of which is substituted with 1 to 5 R 4 groups. In some embodiments, Ring A is unsubstituted phenyl or unsubstituted 5- to 6-membered heteroaryl.
  • Ring A is unsubstituted phenyl or phenyl substituted with 1 to 5 R 4 groups. In some embodiments, Ring A is 5-membered heteroaryl optionally substituted with 1 to 4 R 4 groups. In some embodiments, Ring A is unsubstituted 5- membered heteroaryl. In some embodiments, Ring A is 6-membered heteroaryl optionally substituted with 1 to 4 R 4 groups. In some embodiments, Ring A is unsubstituted 6- membered heteroaryl. In some embodiments, Ring A is 6-membered heteroaryl substituted with 1 to 4 R 4 groups.
  • Ring A is phenyl optionally substituted with 1 to 4 R 4 groups. In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 R 4 groups. In some embodiments, Ring A is phenyl substituted with 1 to 2 R 4 groups. In some embodiments, Ring A is unsubstituted phenyl.
  • Ring A is 5- to 6-membered heteroaryl optionally substituted with 1 to 4 R 4 groups. In some embodiments, Ring A is a 5- to 6-membered heteroaryl comprising two heteroatoms optionally substituted with 1 to 4 R 4 groups. In some embodiments, Ring A is a 5- to 6-membered heteroaryl comprising at least two nitrogen atoms optionally substituted with 1 to 4 R 4 groups. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, and S.
  • Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of O and N. In some embodiments, Ring A is an optionally substituted 5- to 6- membered heteroaryl containing 1-2 nitrogen atoms. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 1 nitrogen atom. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 1 oxygen atom. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 1 sulfur atom.
  • Ring A is an optionally substituted 5-membered heteroaryl.
  • Ring A is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 3 R 4 groups.
  • Ring A is an optionally substituted 6-membered heteroaryl.
  • Ring A is pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted with 1 to 4 R 4 groups.
  • each R 4 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl.
  • each R 4 is independently H, F, Cl, Br, or I.
  • R 4 is H.
  • R 4 is F.
  • R 4 is Cl.
  • R 4 is Br.
  • R 4 is I.
  • R 4 is -SCF3.
  • R 4 is -OR 6 , and R 6 is H or methyl. In some embodiments, R 4 is -OH. In some embodiments, R 4 is -O(C1-C6 alkyl). In some embodiments, R 4 is -OCH3. [0104] In some embodiments, R 4 is -N(R 6 )R 6 . In some embodiments where R 4 is - N(R 6 )R 6 , each R 6 is the same. In other embodiments where R 4 is -N(R 6 )R 6 , each R 6 is different. [0105] In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is C1-C4 alkyl.
  • R 4 is C 1 -C 3 alkyl. In some embodiments, R 4 is C 2 -C 4 alkyl. In some embodiments, R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec- butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl.
  • R 4 is -CH3, -CH2CH3, -(CH2)2CH3, -CH2(CH3)2, -(CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, or -CH(CH3)3.
  • R 4 is -CH3 or -CH2CH3.
  • R 4 is -CH3.
  • R 4 is -CH2CH3.
  • R 4 is C1-C6 haloalkyl.
  • R 4 is C1-C6 haloalkyl containing 1-13 halogen atoms.
  • R 4 is C1-C3 haloalkyl. In some embodiments, R 4 is C1-C3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R 4 is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms.
  • the halogen atoms are a combination of chloro and fluoro atoms.
  • R 4 is -CF3, -CCl3, -CF2Cl, -CFCl2, -CHF2, -CH2F, -CHCl2, -CH2F, or -CHFCl.
  • R 4 is -CF3.
  • R 4 is C1-C6 haloalkyl-OH.
  • R 4 is C1- C6 haloalkyl-OH containing 1-12 halogen atoms and one hydroxyl group.
  • R 4 is C1-C6 haloalkyl-OH containing 1-12 halogen atoms and one hydroxyl group. In some embodiments, R 4 is C1-C6 haloalkyl-OH containing 1-11 halogen atoms and two hydroxyl groups. In some embodiments, R 4 is C1-C6 haloalkyl-OH containing 1-10 halogen atoms and three hydroxyl groups. In some embodiments, R 4 is C1-C6 haloalkyl-OH containing 1-9 halogen atoms and 4 hydroxyl groups. In some embodiments, R 4 is C1-C3 haloalkyl-OH.
  • R 4 is C1-C3 haloalkyl-OH containing 1-6 halogen atoms and one hydroxyl group. In some embodiments, R 4 is C1-C3 haloalkyl-OH containing 1-5 halogen atoms and two hydroxyl groups. In some embodiments, R 4 is C1-C3 haloalkyl- OH containing 1-4 halogen atoms and three hydroxyl groups. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms.
  • the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms.
  • R 4 is -CH(OH)CF3, -CHF(OH)CH3, -CF2(OH)CH3, or -CF2(OH)CF3. In some embodiments, R 4 is -CH(OH)CF3. [0108] In some embodiments, R 4 is C1-C6 alkyl-OH. In some embodiments, R 4 is C1-C6 alkyl-OH containing 1-6 hydroxyl groups.
  • R 4 is C1-C6 alkyl-OH containing 1 hydroxyl group. In some embodiments, R 4 is C1-C6 alkyl-OH containing 2 hydroxyl groups. In some embodiments, R 4 is C1-C6 alkyl-OH containing 3 hydroxyl groups. In some embodiments, R 4 is C1-C3 alkyl-OH. In some embodiments, R 4 is C1-C3 alkyl-OH containing 1-3 hydroxyl groups. In some embodiments, R 4 is C1-C3 alkyl-OH containing 1 hydroxyl group.
  • R 4 is -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH(OH)CH2CH3, -CH(OH)CH2CH2,CH3, -CH2CH(OH)CH3, or - C(CH3)2OH.
  • R 4 is -CH2OH, -CH(OH)CH3, -CH(OH)CH2CH3, or - C(CH3)2OH.
  • R 4 is C1-C6 alkyl-CN. In some embodiments, R 4 is C1-C6 alkyl-CN containing 1-6 cyano groups.
  • R 4 is C1-C6 alkyl-CN containing 1 cyano group. In some embodiments, R 4 is C1-C6 alkyl-CN containing 2 cyano groups. In some embodiments, R 4 is C1-C6 alkyl-CN containing 3 cyano groups. In some embodiments, R 4 is C1-C3 alkyl-CN. In some embodiments, R 4 is C1-C3 alkyl-CN containing 1-3 cyano groups. In some embodiments, R 4 is C1-C3 alkyl-CN containing 1 cyano group.
  • R 4 is -CH2CN, -CH2CH2CN, -CH(CN)CH3, -CH2CH2CH2CN, - CH(CN)CH2CH3, or -CH2CH(CN)CH3.
  • R 4 is -CH2CN or - CH2CH2CN.
  • R 4 is -CH2CN.
  • R 4 is - CH2CH2CN.
  • R 4 is C1-C6 heteroalkyl.
  • R 4 is C1-C6 heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O.
  • R 4 is C1-C6 heteroalkyl containing 1 nitrogen atom. In some embodiments, R 4 is C1-C6 heteroalkyl containing 1 oxygen atom. In some embodiments, R 4 is C1-C3 heteroalkyl. In some embodiments, R 4 is -CH2-CH2-O-CH3, -CH2-O-CH3, -CH2-CH2- NH-CH3, or -CH2-NH-CH3. [0111] In some embodiments, R 4 is C3-C7 cycloalkyl. In some embodiments, R 4 is C3-C6 cycloalkyl.
  • R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Ring wherein ⁇ indicates the point of attachment to the pyrimidinyl ring and indicates the point of attachment to the amino moiety.
  • Ring wherein f indicates the point of attachment to the pyrimidinyl ring and ⁇ indicates the point of attachment to the amino moiety. In some embodiments, Ring , wherein f indicates the point of attachment to the pyrimidinyl ring and ⁇ indicates the point of attachment to the amino moiety. In some embodiments, Ring A is , wherein ⁇ indicates the point of attachment to the pyrimidinyl ring and indicates the point of attachment to the amino moiety.
  • each R 5 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, - SF5, -OCF3, -OR 6 , -N(R 6 )R 6 , -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl.
  • each R 5 is independently H, F, Cl, Br, I, -OCF3, - OR 6 , -N(R 6 )R 6 , -OCHF2, -CF3, -CHF2, or -CN.
  • each R 5 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl.
  • each R 5 is independently H, F, Cl, Br, or I.
  • each R 5 is independently H, F, - OCF3, -OR 6 , -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl.
  • R 5 is H.
  • R 5 is F.
  • R 5 is Cl.
  • R 5 is Br.
  • R 5 is I.
  • R 5 is - SCF3.
  • R 5 is -SCHF2. In some embodiments, R 5 is -SF5. In some embodiments, R 5 is -OCF3. In some embodiments, R 5 is -OCHF2. In some embodiments, R 5 is -CF3. In some embodiments, R 5 is -CHF2. In some embodiments, R 5 is -CN. [0115] In some embodiments, R 5 is -OR 6 . In some embodiments, R 5 is -OR 6 , and R 6 is H or C1-C6 alkyl. In some embodiments, R 5 is -OR 6 , and R 6 is H or C1-C3 alkyl. In some embodiments, R 5 is -OR 6 , and R 6 is H or methyl.
  • R 5 is -OH. In some embodiments, R 5 is -O(C1-C6 alkyl). In some embodiments, R 5 is -OCH3. [0116] In some embodiments, R 5 is -N(R 6 )R 6 . In some embodiments where R 5 is - N(R 6 )R 6 , each R 6 is the same. In other embodiments where R 5 is -N(R 6 )R 6 , each R 6 is different. [0117] In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is C1-C4 alkyl. In some embodiments, R 5 is C1-C3 alkyl.
  • R 5 is C2-C4 alkyl. In some embodiments, R 5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec- butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl.
  • R 5 is -CH3, -CH2CH3, -(CH2)2CH3, -CH2(CH3)2, -(CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, or -CH(CH3)3.
  • R 5 is -CH3 or -CH2CH3.
  • R 5 is -CH3.
  • R 5 is -CH2CH3.
  • R 5 is C1-C6 haloalkyl.
  • R 5 is C1-C6 haloalkyl containing 1-13 halogen atoms.
  • R 5 is C1-C3 haloalkyl. In some embodiments, R 5 is C1-C3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R 5 is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms.
  • the halogen atoms are a combination of chloro and fluoro atoms.
  • R 5 is -CF3, -CCl3, -CF2Cl, -CFCl2, -CHF2, -CH2F, -CHCl2, -CH2F, or -CHFCl.
  • R 5 is -CF3.
  • R 5 is C1-C6 haloalkyl-OH.
  • R 5 is C1- C6 haloalkyl-OH containing 1-12 halogen atoms and one hydroxyl group.
  • R 5 is C1-C6 haloalkyl-OH containing 1-12 halogen atoms and one hydroxyl group. In some embodiments, R 5 is C1-C6 haloalkyl-OH containing 1-11 halogen atoms and two hydroxyl groups. In some embodiments, R 5 is C1-C6 haloalkyl-OH containing 1-10 halogen atoms and three hydroxyl groups. In some embodiments, R 5 is C1-C6 haloalkyl-OH containing 1-9 halogen atoms and 4 hydroxyl groups. In some embodiments, R 5 is C1-C3 haloalkyl-OH.
  • R 5 is C1-C3 haloalkyl-OH containing 1-6 halogen atoms and one hydroxyl group. In some embodiments, R 5 is C1-C3 haloalkyl-OH containing 1-5 halogen atoms and two hydroxyl groups. In some embodiments, R 5 is C1-C3 haloalkyl- OH containing 1-4 halogen atoms and three hydroxyl groups. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms.
  • the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms.
  • R 5 is -CH(OH)CF3, -CHF(OH)CH3, -CF2(OH)CH3, or -CF2(OH)CF3. In some embodiments, R 5 is -CH(OH)CF3. [0120] In some embodiments, R 5 is C1-C6 alkyl-OH. In some embodiments, R 5 is C1-C6 alkyl-OH containing 1-6 hydroxyl groups.
  • R 5 is C1-C6 alkyl-OH containing 1 hydroxyl group. In some embodiments, R 5 is C1-C6 alkyl-OH containing 2 hydroxyl groups. In some embodiments, R 5 is C1-C6 alkyl-OH containing 3 hydroxyl groups. In some embodiments, R 5 is C1-C3 alkyl-OH. In some embodiments, R 5 is C1-C3 alkyl-OH containing 1-3 hydroxyl groups. In some embodiments, R 5 is C1-C3 alkyl-OH containing 1 hydroxyl group.
  • R 5 is -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH(OH)CH2CH3, -CH(OH)CH2CH2,CH3, -CH2CH(OH)CH3, or - C(CH3)2OH.
  • R 5 is -CH2OH, -CH(OH)CH3, -CH(OH)CH2CH3, or - C(CH3)2OH.
  • R 5 is C1-C6 alkyl-CN. In some embodiments, R 5 is C1-C6 alkyl-CN containing 1-6 cyano groups.
  • R 5 is C1-C6 alkyl-CN containing 1 cyano group. In some embodiments, R 5 is C1-C6 alkyl-CN containing 2 cyano groups. In some embodiments, R 5 is C1-C6 alkyl-CN containing 3 cyano groups. In some embodiments, R 5 is C1-C3 alkyl-CN. In some embodiments, R 5 is C1-C3 alkyl-CN containing 1-3 cyano groups. In some embodiments, R 5 is C1-C3 alkyl-CN containing 1 cyano group.
  • R 5 is -CH2CN, -CH2CH2CN, -CH(CN)CH3, -CH2CH2CH2CN, - CH(CN)CH2CH3, or -CH2CH(CN)CH3.
  • R 5 is -CH2CN or - CH2CH2CN.
  • R 5 is -CH2CN.
  • R 5 is - CH2CH2CN.
  • R 5 is C1-C6 heteroalkyl.
  • R 5 is C1-C6 heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O.
  • R 5 is C1-C6 heteroalkyl containing 1 nitrogen atom. In some embodiments, R 5 is C1-C6 heteroalkyl containing 1 oxygen atom. In some embodiments, R 5 is C1-C3 heteroalkyl. In some embodiments, R 5 is -CH2-CH2-O-CH3, -CH2-O-CH3, -CH2-CH2- NH-CH3, or -CH2-NH-CH3. [0123] In some embodiments, R 5 is C3-C7 cycloalkyl. In some embodiments, R 5 is C3-C6 cycloalkyl.
  • R 5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each R 6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 10- membered heteroaryl.
  • each R 6 is independently H or C1-C6 alkyl.
  • each R 6 is H.
  • each R 6 is C1-C6 alkyl.
  • R 6 is C1-C4 alkyl. In some embodiments, R 6 is C1-C3 alkyl. In some embodiments, R 6 is C2-C4 alkyl. In some embodiments, R 6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl.
  • R 6 is -CH3, -CH2CH3, -(CH2)2CH3, -CH2(CH3)2, - (CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, or -CH(CH3)3.
  • R 6 is -CH3 or -CH2CH3.
  • R 6 is -CH3.
  • R 6 is -CH2CH3. [0125]
  • R 6 is C1-C6 haloalkyl.
  • R 6 is C1-C6 haloalkyl containing 1-13 halogen atoms.
  • R 6 is C1-C3 haloalkyl. In some embodiments, R 6 is C1-C3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R 6 is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms.
  • the halogen atoms are a combination of chloro and fluoro atoms.
  • R 6 is -CF3, -CCl3, -CF2Cl, -CFCl2, -CHF2, -CH2F, -CHCl2, -CH2F, or -CHFCl.
  • R 6 is -CF3.
  • R 6 is C1-C6 heteroalkyl.
  • R 6 is C1-C6 heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O.
  • R 6 is C1-C6 heteroalkyl containing 1 nitrogen atom.
  • R 6 is C1-C6 heteroalkyl containing 1 oxygen atom. In some embodiments, R 6 is C1-C3 heteroalkyl. In some embodiments, R 6 is -CH2-CH2-O-CH3, -CH2-O-CH3, -CH2-CH2- NH-CH3, or -CH2-NH-CH3. [0127] In some embodiments, R 6 is C3-C7 cycloalkyl. In some embodiments, R 6 is C3-C6 cycloalkyl. In some embodiments, R 6 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 6 is 4- to 7-membered heterocycloalkyl. In some embodiments, R 6 is 4- to 6-membered heterocycloalkyl. In some embodiments, R 6 is 4- to 5- membered heterocycloalkyl. In some embodiments, R 6 is 5- to 7-membered heterocycloalkyl. In some embodiments, R 6 is 5- to 6-membered heterocycloalkyl. In some embodiments, R 6 is 6- to 7-membered heterocycloalkyl. [0129] In some embodiments, R 6 is phenyl. In some embodiments, R 6 is 5- to 10- membered heteroaryl. In some embodiments, R 6 is 5- to 6-membered heteroaryl.
  • R 6 is a 5- to 6-membered heteroaryl comprising two heteroatoms. In some embodiments, R 6 is a 5- to 6-membered heteroaryl comprising at least two nitrogen atoms. In some embodiments, R 6 is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, R 6 is a 5- to 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of O and N. In some embodiments, R 6 is a 5- to 6-membered heteroaryl containing 1-2 nitrogen atoms. In some embodiments, R 6 is a 5- to 6-membered heteroaryl containing 1 nitrogen atom.
  • R 6 is a 5- to 6-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, R 6 is a 5- to 6-membered heteroaryl containing 1 oxygen atom. In some embodiments, R 6 is a 5- to 6-membered heteroaryl containing 1 sulfur atom.
  • f indicates the point of attachment to the pyrimidinyl ring and ⁇ indicates the point of attachment to the amino moiety
  • a 2 -A 4 are each independently C-R 4 , N, N-R 4 , O, or S; provided that at least one of A x -A 5 is a heteroatom;
  • a 6 and A 11 are each independently C, N, O, or S;
  • a 7 -A 10 are each independently C-R 4 , N, N-R 4 , O, or S.
  • the compound of formula (I) is a compound of formula (I- 1-a), (I-l-b), (I-2-a), (I-2-b), (I-3-a), or (I-3-b).
  • the compound of formula (1-1) is a compound of formula (I-l-a) or formula (I-l-b).
  • the compound is a compound of formula (I-l-a) or a compound of formula (I-l-b).
  • the compound is a compound of formula (I-l-a).
  • the compound is a compound of formula (I-l-b).
  • the compound of formula (1-2) is a compound of formula (I-2-a) or formula (1-2 -b). In some embodiments, the compound is a compound of formula (I-2-a) or a compound of formula (I-2-b). In some embodiments, the compound is a compound of formula (I-2-a). In some embodiments, the compound is a compound of formula (1-2 -b). In some embodiments, the compound of formula (1-3) is a compound of formula (I-3-a) or formula (I-3-b). In some embodiments, the compound is a compound of formula (I-3-a) or a compound of formula (I-3-b). In some embodiments, the compound is a compound of formula (I-3-a). In some embodiments, the compound is a compound of formula (I-3-b). In some embodiments, the compound is a compound of formula (I-3-a). In some embodiments, the compound is a compound of formula (I-3-b).
  • the compound of formula (I) is a compound of formula (I- 1-a), (I-l-b), (I-2-a), (I-2-b), (I-3-a), or (I-3-b).
  • the compound of formula (1-1) is a compound of formula (I-l-a) or (I-l-b).
  • the compound of formula (1-2) is a compound of formula (I-2-a) or (I-2-b).
  • the compound of formula (1-3) is a compound of formula (I-3-a) or (I-3-b).
  • R 2 , R 3 , R 4 , R 5 are as defined for formula (I) and A ⁇ A 11 are as defined above.
  • the compound of formula (I) is a compound of formula (I- 1-a-l), (I-l-a-2), (I-l-b-1), (I-l-b-2), (I-2-a-l), (I-2-a-2), (I-2-b-l), (I-2-b-2), (I-3-a-l), (I-3-a- 2), (I-3-b-l), or (I-3-b-2).
  • the compound of formula (1-1) is a compound of formula (I-l-a-1), (I-l-a-2), (I-l-b-1), or (I-l-b-2).
  • the compound of formula (1-2) is a compound of formula (I-2-a-l), (I-2-a-2), (I-2-b-l), or (I-2-b- 2).
  • the compound of formula (1-3) is a compound of formula (I-3-a-l), (I-3-a-2), (I-3-b-l), or (I-3-b-2).
  • At least two of A'-A 5 are a heteroatom. In some embodiments of the foregoing, at least one of A'-A 5 is an optionally R 4 - substituted nitrogen atom. In some embodiments of the foregoing, at least two of A'-A 5 are an optionally R 4 - substituted nitrogen atom. In some embodiments of the foregoing, A 6 -A n are each optionally R 4 - substituted carbon atoms. In some embodiments of the foregoing, at least one of A 6 -A n is a heteroatom. In some embodiments of the foregoing, at least two of A 6 -A n are a heteroatom.
  • At least one of A 6 -A n is an optionally R 4 -substituted nitrogen atom. In some embodiments of the foregoing, at least two of A 6 -A n are an optionally R 4 - substituted nitrogen atom. In some embodiments of the foregoing, A'-A" and , wherein f indicates the point of attachment to the pyrimidinyl ring and ⁇ indicates the point of attachment to the amino moiety.
  • a 1 - A 5 are defined such that Ring wherein f indicates the point of attachment to the pyrimidinyl ring and ⁇ indicates the point of attachment to the amino moiety.
  • a compound selected from the compounds in Table 2 or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • Table 2
  • This disclosure also includes all salts, such as pharmaceutically acceptable salts, of compounds referred to herein.
  • This disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms, such as N-oxides, solvates, hydrates, or isotopomers, of the compounds described.
  • the present disclosure also includes co-crystals of the compounds described herein. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention.
  • compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof.
  • compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced.
  • every description, variation, embodiment, or aspect of a moiety can be combined with every description, variation, embodiment, or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed.
  • every description, variation, embodiment, or aspect provided herein with respect to the Ring A moiety of formula (I) may be combined with every description, variation, embodiment, or aspect of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , A 10 , A 11 , Y, X 1 , ““ , R 1 , R 2 , R 2 , R 3 , R 4 , R 5 , R 6 X a , R 2 , R 3 , R 4 , R 5 , and/or R 6 , the same as if each and every combination were specifically and individually listed.
  • the compounds of the present disclosure may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below).
  • the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
  • the intermediates described in the following preparations may contain a number of nitrogen, hydroxy, and acid protecting groups such as esters.
  • the variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed.
  • the protection and deprotection conditions are well known to the skilled artisan and are described in the literature. See e.g., Greene and Wuts, Protective Groups in Organic Synthesis, (T. Greene and P. Wuts, eds., 2d ed. 1991).
  • the compounds of the present invention may be prepared by a variety of procedures known in the art, some of which are illustrated in the Examples below.
  • the specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the present disclosure, or salts thereof.
  • the products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
  • the reagents and starting materials are readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry which are analogous to the syntheses of known structurally-similar compounds and the procedures described in the Examples which follow including any novel procedures.
  • R 1 , R 2 , R 2 , R 3 , R 4 , R 5 , and/or R 6 are as defined for formulae (I), (1-1), (1-2), (1-3), (I- 1-a), (I-l-b), (I-2-a), (I-2-b), (I-3-a), (I-3-b), (I-l-a-1), (I-l-a-2), (I-l-b-1), (I-l-b-2), (I-2-a-l), (I-2-a-2), (I-2-b-l), (I-2-b-2), (I-3-a-l), (I-3-a-2), (I-3-b-l), (I-3-b-2), or any applicable variation thereof as detailed herein.
  • Scheme B shows the installation of one or more protecting groups on aminopyrimidine compounds B-b.
  • the compounds B-a are reacted with protecting groups, such as 4-methoxybenzyl chloride (PMB) under suitable conditions to provide the corresponding protected amino-substituted pyrimidine compounds B-b Scheme B.
  • PMB 4-methoxybenzyl chloride
  • protected compounds A-b or B-b may be coupled with leaving group-substituted amino-substituted Ring A compounds C-a.
  • Suitable leaving groups may include but are not limited to halogen atoms or boronic acid derivative.
  • Ring A may be a Ce-Ci4 aryl or 5- to 6-membered heteroaryl ring. The coupling reaction yields the corresponding protected bicyclic pyrimidinyl Ring A compounds C-b.
  • Compounds of formula (I) may be prepared by the subsequent reaction of intermediate compounds D-c with R ⁇ COOH compounds E-a, thereby providing compounds of formula (1-2).
  • R ⁇ Y-substituted amine compounds G-a are coupled to leaving group-modified pyrimidine compounds A-a to yield the coupled product compounds G-b.
  • the intermediate compounds G-b are reacted with an organotin compound under suitable catalytic conditions to stannylate the pyrimidine ring of intermediate compounds H- a.
  • the organostannane compounds H-a are reacted with intermediate Ring A compounds F-c to generate the coupled product compounds H-b.
  • the coupled product compounds H-b are deprotected to provide the corresponding compounds H-c having a free amine.
  • Compounds of formula (1-1) may also be prepared according to the general synthetic scheme shown in Scheme J.
  • Compounds of formula (1-13 may also be prepared according to the general synthetic scheme shown in Scheme K.
  • the present disclosure also provides for any intermediates of the compounds and methods for synthesizing the compounds as described herein.
  • provided herein are general intermediates as described in any one of Schemes A through K above, or compound-specific intermediates as described in the examples below.
  • the present disclosure also provides for synthetic methods comprising any individual step or combination of individual process steps, or compositions of synthetic intermediates and/or reaction products as described herein.
  • Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition.
  • compositions of any of the compounds detailed herein are embraced by this disclosure.
  • the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein is in substantially pure form.
  • substantially pure intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof.
  • a composition of a substantially pure compound selected from a compound of Table 1, Table 2 and/or Table 3 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound of Table 1, Table 2 and/or Table 3.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing is provided wherein the composition contains no more than 25% impurity.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing is provided wherein the composition contains or no more than 20% impurity.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing is provided wherein the composition contains or no more than 10% impurity.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing is provided wherein the composition contains no more than 5% impurity.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing is provided wherein the composition contains no more than 3% impurity.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing is provided wherein the composition contains no more than 1% impurity.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing is provided wherein the composition contains no more than 0.5% impurity.
  • a composition of substantially pure compound means that the composition contains no more than 15%, no more than 10%, no more than 5%, no more than 3%, or no more than 1% impurity, which impurity may be the compound in a different stereochemical form.
  • a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form.
  • the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided.
  • the purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • the compounds and compositions as provided herein are sterile. Methods for sterilization known in the art may be suitable for any compounds or form thereof and compositions thereof as detailed herein.
  • a compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches
  • a compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, with a pharmaceutically acceptable carrier.
  • a formulation such as a pharmaceutical formulation
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference.
  • a compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • examples of carriers, which may be used for the preparation of such compositions are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • any of the compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated as a 10 mg tablet.
  • Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, provided herein are also described.
  • the composition comprises a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing is provided.
  • the composition is for use as a human or veterinary medicament.
  • the composition is for use in a method described herein.
  • the composition is for use in the treatment of a disease or disorder described herein.
  • compositions formulated for co-administration of a compound provided herein and one or more additional pharmaceutical agents are also described.
  • the co-administration can be simultaneous or sequential in any order.
  • a compound provided herein may be formulated for co-administration with the one or more additional pharmaceutical agents in the same dosage form (e.g., single tablet or single i.v.) or separate dosage forms (e.g., two separate tablets, two separate i.v., or one tablet and one i.v.).
  • co-administration can be, for example, 1) concurrent delivery, through the same route of delivery (e.g., tablet or i.v.), 2) sequential delivery on the same day, through the same route or different routes of delivery, or 3) delivery on different days, through the same route or different routes of delivery.
  • Compounds and compositions detailed herein such as a pharmaceutical composition containing a compound of formula (I) or any variation thereof provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
  • methods of a method of treating a cancer or neoplastic disease in a human in need thereof are provided herein are methods of treating a disease or disorder mediated by a RAF kinase.
  • a method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell comprising exposing the cell with an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • the compounds and compositions described herein may be used in a method of treating a disease or disorder mediated by ARAF, BRAF, or CRAF kinase activity.
  • the compound or composition is administered according to a dosage described herein.
  • a method for treating a disease or disorder mediated by RAF kinase activity comprising administering to an individual in need of treatment an effective amount of a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • the disease or disorder is a cancer or neoplastic disease.
  • a method of treating a cancer or neoplastic disease in a human in need thereof comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • RAF is comprised of a family of three genetically distinct serine/threonine protein kinases designated ARAF, BRAF and CRAF (sometimes referred to as RAF-1). These family members are highly conserved at the primary sequence level (75% amino acid identity across their entire protein sequence and >87% identity within their respective kinase domains) and exhibit the same overall domain architecture.
  • ARAF, BRAF and CRAF are ubiquitously and differentially expressed across all cell and tissue types. As such, they collectively serve as an essential signaling node of the Ras/Raf/MEK/ERK (MAPK) pathway.
  • the RAF kinases represent an important therapeutic intervention point for the treatment of a variety of malignancies whose dysregulated growth and survival rely upon MAPK signaling. Accordingly, multiple RAF kinase inhibitors have been approved for specific indications including melanoma and NSCLC and numerous additional inhibitors are currently undergoing clinical investigation for a variety of other malignancies.
  • RTKs homo- or hetero oligomerize with other receptors and auto-phosphorylate key tyrosine residues in trans. These phosphorylated residues then serve as docking sites for downstream effectors, especially adapter proteins involved in the recruitment and activation of RAS (H-, K- and N-RAS) such as Grb2 and SOS, respectively.
  • RAS H-, K- and N-RAS
  • Activated GTP -bound RAS now binds and recruits RAF thereby inducing conformational changes in the latter to induce its dimerization and concomitant activation.
  • RAF then binds and phosphorylates /activates MEK which then phosphorylates/activates ERK.
  • Activated ERK then redistributes to the cytoplasm, the cytoskeleton and the nucleus to control cell growth/division, differentiation and survival.
  • RAF the primary structure of RAF can be divided into two domains; an N- terminal regulatory domain and a C-terminal kinase domain (KD) connected by a linker region.
  • the regulatory domain contains multiple elements including a RAS-binding domain (RBD) followed immediately downstream by a Cysteine-Rich Domain (CRD).
  • RAS-binding domain RAS-binding domain
  • CCD Cysteine-Rich Domain
  • a key phosphorylation site resides within the linker region and another at the extreme C-terminus downstream of the KD. In its inactive conformation, RAF is located in the cytoplasm in a monomeric, dual-phosphorylated, autoinhibited state.
  • This autoinhibition is mediated via two cooperative mechanisms: (1) direct interaction between the RBD and the KD and (2) 14-3-3 protein dimers that simultaneously interact with the two phosphorylated residues flanking the KD. The combination of these interactions effectively binds up the KD into the inactive conformation.
  • the RBD-KD interaction is effectively disrupted exposing the phosphorylation site within the linker region to phosphatase action via the MRAS/SH0C2/PP1 complex. Subsequent dephosphorylation of this residue abrogates intramolecular 14-3-3 binding thereby fully relieving autoinhibition and exposing residues critical for interaction with the plasma membrane.
  • RAS-bound hemi-phosphorylated RAF can now dimerize with another RAF protein (homo- or heterodimerization) via intermolecular interactions between their respective KDs as well as 14-3-3 cross-linking between the two adjacent phosphorylated residues at the C-terminus of each protomer.
  • this fully active RAF complex functions as an obligate dimer to both bind to and activate MEK, ultimately driving ERK activation to complete the signaling cascade.
  • BRAF is the most commonly mutated RAF isoform with alterations reported in approximately 8% of all solid tumors. Melanomas harbor the greatest proportion of BRAF mutations with 40-50% prevalence followed by thyroid, colorectal (CRC) and non-small cell lung cancers (NSCLC). These mutations can be divided into three distinct functional classes based upon how they elicit aberrant activation of RAF kinase activity. Class I mutations render the kinase constitutively active and independent of the requirement for RAS binding or dimerization with another RAF isoform.
  • These mutations can be further subdivided into 3 subclasses according to which region within the kinase domain the alteration occurs (designated as Class Ila and lib) or the formation of a kinase fusion arising from a chromosome translocation event (designated Class lie) whereby the negative regulatory RBD and CRD domains are removed by deletion and replaced with the fusion partner.
  • the class II mutations include the following: G464V, G469A, G469V, G469R, E586K, K601E, K601N, L597R, L597S, L597Q) These mutations are most common in NSCLC and CRC.
  • Class III mutants confer enhanced RAS-dependent RAF dimerization to drive pathway activation. These mutations substantially attenuate the intrinsic kinase activity of the mutant such that transactivation of the wildtype RAF dimerization partner is key to aberrant pathway activation. Accordingly, other genetic alterations leading to RAS activation are often found co-occurring with these Class III mutations to facilitate dimerization.
  • the class III mutations include the following: G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R.
  • CRAF Compared to BRAF, the prevalence of oncogenic mutations within CRAF are relatively rare and found sporadically across a wide array of cancers including melanoma, NSCLC, pancreatic carcinoma, glioma, colorectal and hematological malignancies.
  • the first mutation type consists of point mutations that reside within the linker region effectively disrupting 14-3-3 binding to the linker domain phosphorylation site and conferring a more open confirmation that is now accessible to phosphatase action and subsequent dimerization/activation. These mutations include P261L and P261 A.
  • the second CRAF mutation type is analogous to the Class II mutations in BRAF.
  • CRAF fusions CRAF fusions
  • inhibitors directed against the RAF family should offer an important treatment option for patients harboring RAF kinase activating mutations found in a number of cancer types including those of the skin, thyroid and lung.
  • numerous small molecule RAF inhibitors have been discovered and several of these have advanced into the clinic and gone on to full regulatory approval.
  • the vast majority of these compounds are ATP-competitive small molecule inhibitors and bind in the kinase active site. They are divided into three types, dependent upon the specific structural conformation they induce within the kinase upon binding. These inhibitor types are designated type 1 inhibitors, type 1.5 inhibitors and type 2 inhibitors.
  • Type 1 inhibitors bind in the active or ‘closed’ form of the kinase domain which is largely defined by the relative inward orientation of the C-helix and the ‘DFG’ loop which both comprise key structural and functional elements of the active site. This binding mode is designated C-helix-in/DFG-in.
  • These compounds make key interactions with what is known as the hinge (the flexible linker between the amino and carboxyl terminal lobes of the kinase domain) as well as the pocket that normally accommodates the adenine ring of ATP.
  • SB590885 and GDC-0879 are two literature examples of type I RAF inhibitors. Both were demonstrated to be almost exclusively active in BRAF Class 1 mutant cell contexts both in vitro and in vivo. Despite this promising activity, to date, no type I inhibitors have entered clinical development.
  • Type 2 inhibitors bind to the kinase domain in an open conformation in which the DFG-loop is oriented in an outward or inactive position. This conformation exposes an allosteric, hydrophobic pocket adjacent to the ATP binding site that can be exploited to gain further enhancements in potency and selectivity via hydrogen bonding, Van der Waals and hydrophobic interactions. Accordingly, Type 2 inhibitors consist of functionalities that interact with both the hinge region as well as the allosteric pocket leaving the C-helix in an inward undisturbed orientation. Accordingly, this conformation is denoted as C-helix- in/DFG-out. In the literature, there exist a number of examples of Type 2 RAF inhibitors including several that have undergone clinical evaluation.
  • these molecules as a class are more broadly active, exhibiting activity across a range of mutant contexts including RAS (KRAS, NRAS, HRAS), BRAF (Class 1, II and III) and CRAF.
  • RAS KRAS, NRAS, HRAS
  • BRAF Class 1, II and III
  • CRAF CRAF
  • Type 1.5 inhibitors bind to both the hinge region as well as the space typically occupied by the adenine moiety of ATP in much the same way as the Type 1 RAF inhibitors. What distinguishes the Type 1.5 inhibitors is that they take advantage of additional interactions at the back of the ATP binding pocket made accessible by the relatively small threonine gatekeeper residue found in all RAF isoforms (T382 in ARAF, T529 in BRAF and T421 in CRAF). Importantly, these back-pocket interactions alter the conformation of the C- helix, forcing it into an outward conformation while the DFG loop is oriented in its active or ‘in’ conformation. This conformation is denoted as C-helix-out/DFG-in.
  • Type 1.5 inhibitors are highly active against BRAF Class I mutants that signal as monomers versus other MAPK pathway mutant contexts and the wildtype state where RAF signals as an obligate dimer.
  • 3 Type 1.5 inhibitors have been approved for the treatment of malignant melanomas harboring Class 1 BRAF mutations: vemurafenib, dabrafenib and encorafenib.
  • ARAF, BRAF and CRAF are primarily regulated at the structural level in which various intra- and inter-molecular protein-protein interactions define both their localization and activity state. Accordingly, the structural changes induced with inhibitor binding exert biological effects beyond simple inhibition of kinase activity and these effects can differ depending upon the genetic context of the cells or tissues being exposed to inhibitor. In addition, dependent upon the inhibitor type, these effects are distinct, having important implications regarding safety as well as sensitivity and resistance to inhibitor treatment.
  • inhibitor binding actually enhances signaling flux through the MAPK pathway in what is known as paradoxical activation.
  • This effect derives from one or more of four distinct yet interdependent mechanisms; (1) attenuation of inhibitory auto-phosphorylation in the linker region, (2) interruption of kinase domain interactions, (3) enhancement of binding to GTP- bound RAS at the plasma membrane and (4) transactivation of the second protomer of the RAF dimer.
  • the first 3 of these mechanisms collectively drive enhanced RAF protomer dimerization and therefore enhance downstream signaling.
  • the fourth mechanism involves inhibitor binding to the first protomer of the RAF dimer to induce a C-helix out conformation that effectively locks the conformation of the active site of the second protomer to the active C-helix-in conformation thereby inducing both its activation and markedly reducing its affinity for inhibitor (negative allostery).
  • the extent and magnitude of activation is dependent upon which of these mechanisms are induced by inhibitor binding and this is ultimately dictated by the binding mode of the inhibitor. Accordingly, Type 1, 2 and 1.5 inhibitors all engage the first 3 mechanisms to induce paradoxical activation. Only the Type 1.5 inhibitors engage the fourth mechanism to further enhance paradoxical activation.
  • Type 1.5 and Type 2 inhibitors Clinical resistance to Type 1.5 and Type 2 inhibitors has been observed, but with distinct mechanisms of action.
  • Patients with BRAF Class I mutant melanoma that become refractory to or relapse on Type 1.5 inhibitor therapies often exhibit mutations that drive RAF dimerization. These alterations typically involve RAF amplification/overexpression or RAS mutations but can also include aberrant alternative splicing events that remove the RBD and CRD and effectively remove the blockade to dimerization.
  • the Class I mutant BRAF protomer acts in the context of a dimer rather than its typical monomeric state, it is much less sensitive to Type 1.5 inhibitor treatment.
  • Type 1.5 inhibitors are not effective at inhibiting RAF activity in the context of a dimer, they are only effective at inhibiting Class I BRAF mutants that signal as monomers. Because Type 2 inhibitors can inhibit both monomeric and dimeric RAF, they are able to inhibit Class II and III BRAF mutants that signal as obligate dimers in addition to the Class I mutants.
  • Type 1.5 inhibitors markedly induce paradoxical activation in normal tissues by binding RAF dimers and transactivating the second unbound protomer. Accordingly, in the clinic, Type 1.5 inhibitor treatment is associated with multiple adverse events associated with aberrant MAPK pathway activation particularly involving the skin such as palmoplantar erythrodysaesthesia syndrome and proliferative skin lesions including keratoacanthomas and cutaneous squamous cell carcinomas. MEK inhibitors have been successfully deployed in combination with Type 1.5 RAF inhibitors to effectively manage these toxicities.
  • vemurafenib, dabrafenib and encorafenib have been approved in combination with cobimetinib, trametinib and binimetinib, respectively, for patients with BRAF Class I mutant metastatic melanoma. Not only have these combinations improved tolerability by attenuating paradoxical activation in normal tissues but they have also improved therapeutic benefit both in terms of overall response rate and long term survival.
  • Type 2 inhibitors can bind and inhibit both protomers equally thereby significantly attenuating paradoxical activation and driving full MAPK inhibition, even in normal unmutated tissues. Consequently, the toxicities associated with Type 2 inhibitors are more in keeping with those elicited by MEK inhibitors.
  • a method of treating a cancer or neoplastic disease in a human in need thereof comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation.
  • the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E.
  • the cancer or neoplastic disease is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L.
  • the cancer or neoplastic disease is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H.
  • the cancer or neoplastic disease is associated with one or more mutations in ARAF selected from the group consisting of S214C and S214F. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in BRAF selected from the group consisting of Class I, Class Ila, Class lib, Class lie, and Class III mutations. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in CRAF selected from the group consisting of P261 A, P261L, E478K, R391W, R391S and T491I, or is associated with a CRAF fusion.
  • the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • the one or more genetic lesions is a point mutation, a fusion or any combination thereof.
  • the one or more receptor tyrosine kinase is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROSE
  • the compounds and compositions of the present disclosure may be suitable for treatment of certain subtypes of cancer or neoplastic diseases, which may also be associated with mutations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF.
  • the cancer is is a solid tumor or a hematological malignancy.
  • the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, or colorectal carcinoma.
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • a method of treating a solid tumor or a hematological malignancy comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • the solid tumor or hematological malignancy is melanoma, lung cancer, pancreatic carcinoma, glioma, or colorectal carcinoma.
  • the lung cancer is non-small cell lung cancer (NSCLC).
  • the cancer is a refractory cancer.
  • the refractory cancer is associated with one or more genetic alterations in KRAS, NRAS, HRAS, BRAF, or one or more RTKs.
  • the refractory cancer is associated with a genetic alteration or alterations in KRAS (including mutants G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E), NRAS (including mutants G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, G61L), HRAS (including mutants G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, Q61H), BRAF (including gene amplification, class II and III mutants [including G464V, G469A, G4
  • the method further comprises administering one or more pharmaceutical agents including anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, T0RC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation.
  • RTK inhibitors including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1
  • RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II)
  • MEK1/2 inhibitors ERK1/2 inhibitors, RSK
  • the cancer is a refractory BRAF Class I mutant cancer.
  • the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R.
  • the refractory cancer is associated with a genetic alteration in KRAS, NRAS, HRAS or BRAF that drives BRAF dimerization and confers resistance to approved Type 1.5 inhibitors (including vemurafenib, dabrafenib and encorafenib) both alone and in the context of MEK inhibitor (including cobimetinib, trametinib and binimetinib) combinations.
  • approved Type 1.5 inhibitors including vemurafenib, dabrafenib and encorafenib
  • MEK inhibitor including cobimetinib, trametinib and binimetinib
  • the refractory cancer is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E.
  • the refractory cancer is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L.
  • the refractory cancer is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, GBR, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H.
  • the refractory cancer is associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events.
  • the refractory cancer is associated with one or more Class II or Class III mutations in BRAF.
  • the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q.
  • the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10.
  • the method further comprises administering one or more pharmaceutical agents including anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation.
  • RTK inhibitors including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1
  • RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II)
  • MEK1/2 inhibitors ERK1/2 inhibitors
  • the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old.
  • the method further comprises administering one or more additional pharmaceutical agents.
  • the method further comprises administering radiation.
  • the method further comprises administering one or more additional pharmaceutical agents, including anti-microtubular therapies (e.g. paclitaxel, vincristine), topoisomerase inhibitors (e.g. adriamycin), alylating agents (e.g. busulfan, cyclophosphamide), nucleotide synthesis inhibitors (hyroxyurea), DNA synthesis inhibtiors (e.g. cytarabine), protein synthesis inhibitors (e.g. omacetaxine), developmental signaling pathway inhibitors (e.g.
  • anti-microtubular therapies e.g. paclitaxel, vincristine
  • topoisomerase inhibitors e.g. adriamycin
  • alylating agents e.g. busulfan, cyclophosphamide
  • nucleotide synthesis inhibitors
  • sonidegib, Hedgehog pathway pro-apoptotic agents
  • pro-apoptotic agents e.g. venetoclax
  • Abl myristoyl-pocket binding inhibitors e.g. asciminib
  • MEK1/2 inhibitors e.g. trametinib, binimetinib
  • AKT inhibitors e.g. ipatasertib
  • PI3K inhibitors e.g. apelisib
  • the dose of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular cancer, such as type and stage of cancer, being treated.
  • the amount of the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing is a therapeutically effective amount.
  • the compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal.
  • the effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg.
  • Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight.
  • An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.
  • Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable excipient.
  • a compound or composition provided herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life.
  • the compound is administered on a daily or intermittent schedule.
  • the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
  • the dosing frequency can also be less than once daily, e.g., about a once weekly dosing.
  • the dosing frequency can be more than once daily, e.g., twice or three times daily.
  • the dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
  • a drug holiday e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more.
  • the present disclosure further provides articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, a composition described herein, or one or more unit dosages described herein in suitable packaging.
  • the article of manufacture is for use in any of the methods described herein.
  • suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • kits for carrying out the methods of the present disclosure which comprises one or more compounds described herein or a composition comprising a compound described herein.
  • the kits may employ any of the compounds disclosed herein.
  • the kit employs a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, thereof.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer or neoplastic disease, such as those associated with or mediated by RAF kinase activity.
  • the kit contains instructions for the treatment of a disease or disorder mediated by or associated with RAF kinase activity.
  • the disease or disorder is associated with one or more genetic alterations in KRAS, NRAS, HR AS, ARAF, BRAF or CRAF.
  • kits optionally further comprise a container comprising one or more additional pharmaceutical agents and which kits further comprise instructions on or in the package insert for treating the subject with an effective amount of the one or more additional pharmaceutical agents.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • Embodiment 1 A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein:
  • Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R 4 groups;
  • R 1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R 1 is optionally substituted with 1 to 5 R 5 groups;
  • R 2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R 2 is optionally substituted with 1 to 5 R 5 groups, R 2’ is H or D; and R
  • Embodiment 2 The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (I-1), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
  • Embodiment 3 The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (1-2):
  • Embodiment 4 The compound of embodiment 1, wherein the compound is a compound of formula (1-3):
  • Embodiment 5 The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Y is a bond.
  • Embodiment 7 The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R 1 is Ci-Ce alkyl optionally substituted by one or more R 5 groups.
  • Embodiment 8 The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R 1 is C3-C7 cycloalkyl optionally substituted by one or more R 5 groups.
  • Embodiment 9 The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R 1 is 4- to 7-membered heterocycloalkyl optionally substituted by one or more R 5 groups.
  • Embodiment 11 The compound of any one of embodiments 1-4, 6, 8 and 10, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the compound is a compound of formula (I-l-a), (I-l-b), (I-2-a), (I- 2-b), (1-3 -a), or (1-3 -b),
  • a 1 and A 5 are each independently C, N, O, or S;
  • a 2 -A 4 are each independently C-R 4 , N, N-R 4 , O, or S; provided that at least one of A x -A 5 is a heteroatom;
  • a 6 and A 11 are each independently C, N, O, or S;
  • a 7 -A 10 are each independently C-R 4 , N, N-R 4 , O, or S.
  • Embodiment 12 The compound of embodiment 11, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the compound is a compound of formula (I-l-a) or a compound of formula (I-l-b).
  • Embodiment 13 The compound of embodiment 11, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the compound is a compound of formula (I-2-a) or a compound of formula (I-2-b).
  • Embodiment 14 The compound of embodiment 11, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the compound is a compound of formula (I-3-a) or a compound of formula (I-3-b).
  • Embodiment 15 The compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is phenyl optionally substituted with 1 to 4 R 4 groups.
  • Embodiment 16 The compound of any one of embodiments 1-15, wherein Ring A is
  • Embodiment 17 The compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is 5- to 6-membered heteroaryl optionally substituted with 1 to 4 R 4 groups.
  • Embodiment 18 The compound of any one of embodiments 1-14 and 17, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is an optionally substituted 5-membered heteroaryl.
  • Embodiment 19 The compound of any one of embodiments 1-14 and 17-18, wherein Ring A is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 3 R 4 groups.
  • Ring A is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 3 R 4 groups.
  • Embodiment 20 The compound of any one of embodiments 1-14 and 17-19, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any t , wherein f indicates the point of attachment to the pyrimidinyl ring and ⁇ indicates the point of attachment to the amino moiety.
  • Embodiment 21 The compound of any one of embodiments 1-14 and 17, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is an optionally substituted 6-membered heteroaryl.
  • Embodiment 22 The compound of any one of embodiments 1-14, 17 and 21, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted.
  • Embodiment 23 The compound of any one of embodiments 1-14, 17 and 21-22, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any attachment to the pyrimidinyl ring and ⁇ indicates the point of attachment to the amino moiety.
  • Embodiment 24 The compound of any one of embodiments 1-14 and 17, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is a 5- to 6-membered heteroaryl comprising at least one nitrogen atom.
  • Embodiment 25 The compound of any one of embodiments 1-14 and 17, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is a 5- to 6-membered heteroaryl comprising two heteroatoms.
  • Embodiment 26 The compound of any one of embodiments 1-14, 17, and 24-25, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is a 5- to 6-membered heteroaryl comprising at least two nitrogen atoms.
  • Embodiment 27 The compound of any one of embodiments 1-4, 6, 8 and 10-26, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R 1 is cyclopropyl optionally substituted by 1-2 R 5 groups.
  • Embodiment 28 The compound of any one of embodiments 1-4, 6, 8 and 10-27, wherein the moiety
  • Embodiment 29 The compound of any one of embodiments 1-4, 6, 8 and 10-27, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R 1 is cyclopropyl substituted by 1-2 fluorine atoms.
  • Embodiment 30 The compound of any one of embodiments 1-4, 6, 8, 10-27 and 29,
  • Embodiment 31 The compound of any one of embodiments 1-2, 5-12 and 15-30, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R 2 ’, when present, is H.
  • Embodiment 32 The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R 2 is C1-C3 alkyl optionally substituted by 1-5 R 5 groups.
  • Embodiment 33 The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, Embodiment 34.
  • Embodiment 35 The compound of any one of embodiments 1-31 and 34, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any Embodiment 36.
  • Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the 5- to 6- membered heteroaryl comprises at least one nitrogen atom and is optionally substituted with 1 to 5 R 4 groups;
  • R 1 is cyclopropyl optionally substituted with 1 to 2 fluorine atoms
  • R 2 is C1-C3 alkyl optionally substituted with 1 to 5 R 5 groups
  • R 2 is H or D
  • Embodiment 41 The compound of embodiment 40, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein:
  • X 1 is -OH
  • R 1 is cyclopropyl optionally substituted with 1 to 2 fluorine atoms
  • R 2 is -CH3 or -CH2CH3, and
  • R 2 is H
  • R 3 is -CH 3 ; each R 5 is independently H, F, or -CH3; and each R 6 is independently H or -CH3.
  • Embodiment 42 A compound, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, which is selected from the group consisting of:
  • Embodiment 43 A compound, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, which is selected from the group consisting of:
  • Embodiment 44 A compound, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, which is selected from the group consisting of:
  • Embodiment 45 A pharmaceutical composition comprising the compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable excipients.
  • Embodiment 46 A method of inhibiting ARAE, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition according to embodiment 45.
  • Embodiment 47 A method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of any one of embodiments 1- 44, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition according to embodiment 45.
  • Embodiment 48 The method of embodiment 47, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation.
  • Embodiment 49 The method of embodiment 47 or 48, wherein the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF.
  • Embodiment 50 The method of any one of embodiments 47-49, wherein the cancer or neoplastic disease is associated with: one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E; or one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, GBR, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L; or one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, GBR, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K,
  • Embodiment 51 The method of any one of embodiments 47-50, wherein the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • Embodiment 52 The method of embodiment 51, wherein the one or more genetic lesions is a point mutation, a fusion or any combination thereof.
  • Embodiment 53 The method of embodiment 51 or 52, wherin the one or more receptor tyrosine kinase is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROSE
  • Embodiment 54 The method of any one of embodiments 47-53, wherein the cancer is a refractory cancer.
  • Embodiment 55 The method of any one of embodiments 47-54, wherein the cancer is a refractory cancer associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events.
  • Embodiment 56 The method of any one of embodiments 47-55, the cancer is a refractory BRAF Class I mutant cancer.
  • Embodiment 57 The method of embodiment 56, wherein the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R.
  • Embodiment 58 The method of any one of embodiments 47-55, wherein the refractory cancer is associated with one or more Class II or Class III mutations in BRAF.
  • Embodiment 59 The method of embodiment 58, wherein the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q.
  • BRAF BRAF
  • Embodiment 60 The method of embodiment 58, wherein the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10.
  • Embodiment 61 The method of any one of embodiments 47-60, wherein the cancer is a solid tumor or a hematological malignancy.
  • Embodiment 62 The method of embodiment 61, wherein the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, or colorectal carcinoma.
  • Embodiment 63 The method of embodiment 62, wherein the lung cancer is non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • Embodiment 64 The method of any one of embodiments 47-63, further comprising administering one or more pharmaceutical agents including anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro- apoptotic agents, RTK inhibitors, RAF inhibitors representing alternative binding modes, MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, T0RC1/2 inhibitors, DNA damage response pathway inhibitors, PI3K inhibitors and/or radiation.
  • pharmaceutical agents including anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro- apoptotic agents, RTK inhibitors, RAF inhibitors representing alternative binding modes, MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, A
  • Step 3 Synthesis of tert-butyl N-(6- ⁇ 2-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyridin-3-yl ⁇ pyrimidin-4-yl)carbamate [0226] To a solution of tert-butyl N-[6-(2-aminopyridin-3-yl)pyrimidin-4-yl]carbamate (380.0 mg, 1.32 mmol) in dioxane (5.0 mL) was added 1-(5-bromo-4-methylpyridin-2- yl)propan-1-one (301.7 mg, 1.32 mmol), Cs2CO3 (68.0 mg, 0.21 mmol) and XantPhos Pd G3 (125.4 mg, 0.13 mmol) at room temperature under N2.
  • Step 2 Synthesis of l-(5-((3-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)pyrazin-2- yl)amino)-4-methylpyridin-2-yl)propan-l-one
  • the resulting mixture was stirred at 100 °C for 4 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered.
  • the resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered.
  • the resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered.
  • the resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered.
  • Step 3 Synthesis of l-(5-((l-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-lH- imidazol-2-yl)amino)-4-methylpyridin-2-yl)propan-l-one
  • Step 4 Synthesis of l-(5-((l-(6-aminopyrimidin-4-yl)-lH-imidazol-2-yl)amino)-4- methylpyridin-2-yl)propan-l-one
  • the resulting mixture was stirred at 100 °C for 3 h under N2. After the reaction was completed, the resulting mixture diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered.
  • Example 14 Synthesis of (1R)-2,2-difluoro-N- ⁇ 6-[3-( ⁇ 6-[(1R)-1-hydroxypropyl]-4- methylpyridin-3-yl ⁇ amino)-1-methylpyrazol-4-yl]pyrimidin-4-yl ⁇ cyclopropane-1- carboxamide (Compound 1.26) and (1R)-2,2-difluoro-N- ⁇ 6-[3-( ⁇ 6-[(1S)-1-hydroxypropyl]- 4-methylpyridin-3-yl ⁇ amino)-1-methylpyrazol-4-yl]pyrimidin-4-yl ⁇ cyclopropane-1- carboxamide (Compound 1.27) Step 1. Synthesis of 1- ⁇ 4-methyl-5-[(1-methylpyrazol-3-yl)amino]pyridin-2-yl ⁇ propan-1- one
  • the resulting mixture was stirred at 100 °C for 3 h under N2. The reaction was then allowed to cool to ambient temperature, diluted with H2O, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.
  • Step 4 Synthesis of l-(5- ⁇ [4-(6-aminopyrimidin-4-yl)-l-methylpyrazol-3-yl]amino ⁇ -4- methylpyridin-2-yl)propan-l-one
  • the resulting mixture was stirred at 0 °C for 1 h under N2. After the reaction was completed, the reaction mixture was quenched with ice water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.
  • the resulting mixture was stirred at 0 °C for 1 h under N2. After the reaction was completed, the reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.
  • Step 4 Synthesis of l-(5-((3-(6-aminopyrimidin-4-yl)-l-methyl-lH-pyrazol-4-yl)amino)- 4-methylpyridin-2-yl)propan-l-one [0336] To a solution of tert-butyl (6-(l-methyl-4-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-pyrazol-3-yl)pyrimidin-4-yl)carbamate (300.0 mg, 0.68 mmol) in CH2CI2 (8.0 mL) was added TFA (4.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h.
  • Step 7 Chiral Separation of (lR,2R)-2-fluoro-N-(6-(4-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-l-methyl-lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.30) and (lR,2R)-2-fluoro-N-(6-(4-((6-((S)-l-hydroxypropyl)- 4-methylpyridin-3-yl)amino)-l-methyl-lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.31)
  • Step 2 Synthesis of l-(5-((5-(6-aminopyrimidin-4-yl)-l-methyl-lH-imidazol-4- yl)amino)-4-methylpyridin-2-yl)propan-l-one
  • N-(4-methyl-1H-imidazol-2-yl)acetamide [0349] To a solution of 1-chloropropan-2-one (15.0 g, 162 mmol) in acetonitrile (300.0 mL) was added N-carbamimidoylacetamide (3.3 g, 32 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 12 h. The reaction was then allowed to cool to ambient temperature and the resulting mixture was concentrated under reduced pressure. The residue was washed with water and then filtered. The solid was collected and dried to afford N-(4-methyl-1H-imidazol-2-yl)acetamide (1.0 g, crude) as a white solid.
  • Step 4 Synthesis of l-(5-((l-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-4-methyl- lH-imidazol-2-yl)amino)-4-methylpyridin-2-yl)propan-l-one
  • Step 5 Synthesis of l-(5-((l-(6-aminopyrimidin-4-yl)-4-methyl-lH-imidazol-2- yl)amino)-4-methylpyridin-2-yl)propan-l-one
  • Step 7 Synthesis of (lR,2R)-2-fluoro-N-(6-(2-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-4-methyl-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
  • Step 8 Chiral Separation of (lR,2R)-2-fluoro-N-(6-(2-((6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-4-methyl-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.34) and (lR,2R)-2-fluoro-N-(6-(2-((6-((R)-l- hydroxypropyl)-4-methylpyridin-3-yl)amino)-4-methyl-lH-imidazol-l-yl)pyrimidin-4- yl)cyclopropane-l-carboxamide (Compound 1.35)
  • the resulting mixture was stirred at 100 °C for 4 h under N2. The reaction was then allowed to cool to ambient temperature and the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.
  • Example 20 Synthesis of (lR,2R)-2-fluoro-N-(6-(4-((6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)anuno)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.38) and (lR,2R)-2-fluoro-N-(6-(4-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.39)
  • Step 7 Chiral Separation of (lR,2R)-2-fluoro-N-(6-(4-((6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.38) and (lR,2R)-2-fluoro-N-(6-(4-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.39)
  • Example 21 Synthesis of (1S,2R)-2-fluoro-N-(6-(5-((6-(1-hydroxypropyl)-4-methylpyridin- 3-yl)amino)-1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.40) and (1S,2R)-2-fluoro-N-(6-(3-((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)- 4H-1,2,4-triazol-4-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.41) Step 1.
  • the resulting mixture was stirred at 100 °C for 16 h under N2. The reaction was then allowed to cool to ambient temperature and the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.
  • the crude product of Isomer A was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH OBD Column 30x150mm, 5umn; Mobile Phase A: Water(0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL/min mL/min; Gradient: 10% B to 20% B in 10 min; Wavelength: 254 nm/220nm; RT1(min): 8.7) to afford Isomer A (retention time 8.7 minutes, 2.2 mg, 0.6%) as a white solid.
  • the crude product of Isomer B was purified by Prep- HPLC with the following conditions: (Column: Xselect CSH OBD Column 30x150 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: 20mm NaOH+10% MeCN; Flow rate: 60 mL/min mL/min; Gradient: 10% B to 20% B in 10 min; Wavelength: 254 nm/220 nm nm; RT1(min): 7.17, RT2(min): 9.22) to afford Isomer B (retention time 9.22 minutes, 3.0 mg, 0.8%) as a white solid.
  • the absolute stereochemistry and bonding configuration of Isomers A and B were not assigned.
  • Example 23 Synthesis of (1R,2R)-2-fluoro-N-(4'- ⁇ [6-(1-hydroxypropyl)-4-methylpyridin-3- yl]amino ⁇ -1'-methyl-2'-oxo-[4,5'-bipyrimidin]-6-yl)cyclopropane-1-carboxamide (Compound 1.42) Step 1. Synthesis of 4-[(6- ⁇ 1-[(tert-butyldimethylsilyl)oxy]propyl ⁇ -4-methylpyridin-3- yl)amino]-1-methylpyrimidin-2-one
  • the resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.
  • Step 3 Synthesis of l-(5-((4-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-4H-l,2,4- triazol-3-yl)amino)-4-methylpyridin-2-yl)propan-l-one
  • Step 4 Synthesis of l-(5-((4-(6-aminopyrimidin-4-yl)-4H-l,2,4-triazol-3-yl)amino)-4- methylpyridin-2-yl)propan-l-one
  • reaction mixture was quenched with water at 0 °C and then extracted with dichloromethane.
  • the combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.
  • reaction mixture was quenched with water at 0 °C and then extracted with dichloromethane.
  • the combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.
  • N-[6-(2-aminophenyl)pyrimidin-4-yl]cyclopropanecarboxamide 48.8 mg, 192 pmol
  • l-(5-bromo-4-methylpyridin-2-yl)butan-l-one 46.5 mg, 192 pmol
  • cesium carbonate 188 mg, 3 eq., 576 pmol
  • XantPhos Pd G3 27.3 mg, 0.15 eq., 28.8 pmol
  • N-(6- ⁇ 2-[(6-butanoyl-4-methylpyridin-3-yl)amino]phenyl ⁇ pyrimidin-4- yl)cyclopropanecarboxamide (Compound 2.26, 30 mg, 72.2 pmol) was dissolved in 1.4 mL of 1 : 1 THF/methanol and sodium borohydride (4.1 mg, 1.5 eq., 108 pmol) was added at ambient temperature. The reaction was left for 20 minutes. The reaction was then partitioned between sat. aq. NaHCCh (10 mL) and ethyl acetate (10 mL). The water layer was extracted 2x more with EtOAc (10 mL).
  • A375, HepG2, SK-MEL-30, OCI-AML-2 and K562 cells were grown in the appropriate growth medium as described in Table 2 below, and harvested at 50-80% confluence. Cells were counted and seeded at their appropriate density (see Table 2) in a 384- well plate (Corning 3570). A375, HepG2 and SK-MEL-30 were allowed to adhere overnight prior to treatment and the OCI-AML-2 were treated immediately for the indicated drug treatment times (Table 4). Table 4 provides the growth media, number of cells seeded per well and drug treatment times for each cell line.
  • lOuL cell lysate was transferred to a new Optiplate (PerkinElmer 6007290) and incubated with 5uL IX acceptor mix for 2 hours in the dark. 5uL of IX donor mix was added to all wells and mixed by shaking followed by overnight incubation in the dark.

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Abstract

The present disclosure relates to compounds and compositions for inhibition of RAF serine/threonine protein kinases, methods of preparing said compounds and compositions, and their use in the treatment of various cancers, such as melanoma, non-small cell lung cancer, and colorectal cancer.

Description

PYRIMIDINYL (HETERO)AROMATIC AMINOPYRIDINE COMPOUNDS FOR
INHIBITION OF RAF KINASES
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 63/441,678 filed January 27, 2023, the entire contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] Provided herein are compounds and compositions for inhibition of RAF serine/threonine protein kinases, methods of preparing said compounds and compositions, and their use in the treatment of various cancers, such as melanoma, non-small cell lung cancer, and colorectal cancer.
BACKGROUND
[0003] The RAF family of serine/threonine protein kinases operate as an essential signaling node within the Ras/Raf/MEK/ERK pathway. Also referred to as the mitogen activated kinase (MAPK) pathway, this signaling cascade is critically involved in the regulation of a diverse array of basic physiological processes. The MAPK pathway is responsive to a variety of stimuli mediated through the input of numerous intracellular second messengers and transmembrane receptors including the receptor tyrosine kinases (RTKs). In the case of the RTKs, upon ligand binding, they act on the MAPK pathway through the recruitment/activation of the RAS GTPases which then bind and activate RAF. RAF then phosphorylates MEK (mitogen activated kinase kinase 1 & 2) at serine residues located within their activation loops that in turn induce certain conformational changes leading to their activation. Activated MEK in turn phosphorylates and activates the ERK kinases (Extracellular Regulated Kinase 1 & 2 also known as MAPK1/2 or mitogen-activated protein kinases 1 & 2) via activation loop phosphorylation. Activated ERK then acts as a broad-based effector of the pathway, modulating the activity of a variety of proteins including other protein kinases, structural proteins, metabolic enzymes and transcription factors that in turn modulate the broad cellular response to these stimuli. Importantly, the primary output of the MAPK pathway is to drive cell growth and proliferation as well as to suppress apoptosis (regulated cell death). Given its central role in the regulation of these processes, it is not surprising that the majority of genetic alterations associated with cellular transformation act entirely or at least in part via the aberrant activation of the MAPK pathway. Therefore, as an essential node in the MAPK pathway, the RAF kinases represent an important therapeutic intervention point for the treatment of a variety of malignancies whose dysregulated growth and survival rely upon this pathway.
[0004] Thus, there remains a need for new compounds and compositions for inhibition RAF kinases.
SUMMARY OF THE INVENTION
[0005] Provided herein are compounds and compositions that inhibit RAF kinases and that are useful for treating disorders mediated by RAF kinases.
[0006] In one aspect, provided herein is a compound of formula (I)
Figure imgf000003_0001
or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein:
Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R4 groups;
Y is a bond or -C(=O)-; is a single or double bond, wherein when is a single bond, then X1 is -OH, and the carbon atom to which X1 is attached is optionally further substituted by R2 ; when is a double bond, then X1 is =O or =N-OH; R1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups; R2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R2 is optionally substituted with 1 to 5 R5 groups, R2’ is H or D; and R3 is H or C1-C6 alkyl; each R4 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; each R5 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; and each R6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 10-membered heteroaryl. [0007] In some embodiments, the compound of formula (I) is a compound of formula (I-1),
Figure imgf000004_0001
or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. [0008] In some embodiments, the compound of formula (I) is a compound of formula (I-2):
Figure imgf000005_0001
(I-2) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. [0009] In some embodiments, the compound is a compound of formula (I-3):
Figure imgf000005_0002
(I-3) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. [0010] In some embodiments, Y is a bond. In other embodiments, Y is -C(=O)-. [0011] In some embodiments, R1 is C1-C6 alkyl optionally substituted by one or more R5 groups. In other embodiments, R1 is C3-C7 cycloalkyl optionally substituted by one or more R5 groups. In yet other embodiments, R1 is 4- to 7-membered heterocycloalkyl optionally substituted by one or more R5 groups. In some embodiments, Y is -C(=O)- and R1 is C3-C7 cycloalkyl, optionally substituted by one or more R5 groups. [0012] In some embodiments, the compound is a compound of formula (I-1-a), (I-1-b), (I-2-a), (I-2-b), (I-3-a), or (I-3-b),
Figure imgf000006_0002
wherein A1 and A5 are each independently C, N, O, or S; A2-A4 are each independently C-R4, N, N-R4, O, or S; provided that at least one of A1-A5 is a heteroatom; A6 and A11 are each independently C, N, O, or S, and A7-A10 are each independently C-R4, N, N-R4, O, or S. [0013] In some embodiments, the compound is a compound of formula (I-1-a) or a compound of formula (I-1-b). In other embodiments, the compound is a compound of formula (I-2-a) or a compound of formula (I-2-b). In yet other embodiments, the compound is a compound of formula (I-3-a) or a compound of formula (I-3-b). [0014] In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 R4 groups. In some embodiments, Ring
Figure imgf000006_0001
wherein † indicates the point of attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety. In other embodiments, Ring A is 5- to 6-membered heteroaryl optionally substituted with 1 to 4 R4 groups. In certain embodiments, Ring A is an optionally substituted 5- membered heteroaryl. In some embodiments, Ring A is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 3 R4 groups. In some embodiments, Ring A
Figure imgf000007_0001
attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
[0015] In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl.
In certain embodiments, Ring A is pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted with 1 to 4 R4 groups. In
Figure imgf000007_0002
attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
[0016] In some embodiments, Ring A is a 5- to 6-membered heteroaryl comprising at least one nitrogen atom. In some embodiments, Ring A is a 5- to 6-membered heteroaryl comprising two heteroatoms. In some embodiments, Ring A is a 5- to 6-membered heteroaryl comprising at least two nitrogen atoms. [0017] In some embodiments, R1 is cyclopropyl optionally substituted by 1-2 R5 groups. In some embodiments, R1 is unsubstituted cyclopropyl. In some embodiments, the moiety In some embodiments, R1 is cyclopropyl substituted by 1-2
Figure imgf000008_0009
O fluorine atoms. In some embodiments, the moiety
Figure imgf000008_0001
,
Figure imgf000008_0002
[0018] In some embodiments, R2’, when present, is H. In some embodiments, R2 is C1-C3 X1 alkyl optionally substituted by 1-5 R5 groups. In some embodiments, the moiety
Figure imgf000008_0003
Figure imgf000008_0004
OH N
Figure imgf000008_0005
. In other embodiments, R2 is C2-C6 alkenyl optionally substituted by 1-5 R5 X1 OH OH OH groups. In some embodiments, the moiety
Figure imgf000008_0006
Figure imgf000008_0007
, OH OH N N
Figure imgf000008_0008
,o . In other embodiments, R2 is C3-C7 cycloalkyl optionally substituted by 1-5 R5 groups. [0019] In some embodiments, R3 is H. In some embodiments, R3 is C1-C6 alkyl. In certain embodiments, R3 is -CH3. [0020] In some embodiments, Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the 5- to 6- membered heteroaryl comprises at least one nitrogen atom and is optionally substituted with 1 to 5 R4 groups; Y is -C(=O)-; R1 is cyclopropyl optionally substituted with 1 to 2 fluorine atoms; R2 is C1-C3 alkyl optionally substituted with 1 to 5 R5 groups, and R2 is H; R3 is independently C1-C3 alkyl; each R4 is independently H, F, Cl, Br, I, -OCF3, -OR6, =0, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, Ci-C6 alkyl, or Ci-C6 haloalkyl; each R5 is independently H, F, Cl, Br, I, -OCF3, -OR6, =0, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, Ci-C6 alkyl, or Ci-Ce haloalkyl; and each R6 is independently H or Ci-Ce alkyl.
Figure imgf000009_0001
attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino
Figure imgf000009_0002
moiety; Y is -C(=O)-; is a single bond, wherein X1 is -OH; R1 is cyclopropyl optionally substituted with 1 to 2 fluorine atoms; R2 is -CH3 or -CH2CH3, and R2 is H or D; R3 is -CH3; each R5 is independently H, F, or -CH3; and each R6 is independently H or -CH3.
[0022] In one aspect, provided herein is a compound which is selected from the group consisting of Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. [0023] In another aspect, provided herein is a compound which is selected from the group consisting of Table 2, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
[0024] In yet another aspect, provided herein is a compound which is selected from the group consisting of Table 3, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing.
[0025] In another aspect, provided herein is a pharmaceutical composition comprising any compound disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable excipients.
[0026] In yet another aspect, the present disclosure provides a method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
[0027] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
[0028] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation. In some embodiments, the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in ARAF selected from the group consisting of S214C and S214F. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in BRAF selected from the group consisting of Class I, Class Ila, Class lib, Class lie, and Class III mutations. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in CRAF selected from the group consisting of P261 A, P261L, E478K, R391W, R391S and T491I, or is associated with a CRAF fusion. In other embodiments, the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs). In some embodiments, the one or more genetic lesions is a point mutation, a fusion or any combination thereof. In some embodiments, the one or more receptor tyrosine kinase is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROSE
[0029] In some embodiments, the cancer is a refractory cancer. In some embodiments, the cancer is a refractory cancer associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. In some embodiments of the present aspect, the cancer is a refractory BRAF Class I mutant cancer. In some embodiments, the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R. In some embodiments, the refractory cancer is associated with one or more Class II or Class III mutations in BRAF. In some embodiments, the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and
L597Q. In some embodiments, the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10.
[0030] In some embodiments, the cancer is a solid tumor or a hematological malignancy. In some embodiments, the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, or colorectal carcinoma. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC).
[0031] In still further embodiments of the foregoing, the method further comprises administering one or more pharmaceutical agents including anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro- apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation.
DETAILED DESCRIPTION
[0032] The following description sets forth exemplary methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.
I. Definitions
[0033] As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.
[0034] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the present disclosure as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc. [0035] The terms “individual”, “subject” and “patient” refer to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human. [0036] As used herein, the term “mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep. [0037] “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration. [0038] As used herein, the term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (e.g., C1-C6 means one to six carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. In some embodiments, the term “alkyl” may encompass C1-C6 alkyl, C2-C6 alkyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C1-C5 alkyl, C2-C5 alkyl, C3-C5 alkyl, C4-C5 alkyl, C1-C4 alkyl, C2-C4 alkyl, C3-C4 alkyl, C1-C3 alkyl, C2-C3 alkyl, or C1-C2 alkyl. [0039] As used herein, the term “alkenyl” refers to an unsaturated branched or straight- chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1- yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl). In some embodiments, the alkenyl group may be attached to the rest of the molecule by a carbon atom in the carbon-carbon double bond. In other embodiments, the “alkenyl” may be attached to the rest of the molecule by a saturated carbon atom, and the carbon-carbon double bond is located elsewhere along the branched or straight-chain alkyl group. [0040] The term “cycloalkyl”, “carbocyclic”, or “carbocycle” refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices. As used herein, “cycloalkyl”, “carbocyclic”, or “carbocycle” is also meant to refer to bicyclic, polycyclic and spirocyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norborene, spirocyclic C5-12 alkane, etc. In some embodiments, “cycloalkyl” encompasses C3-C7 cycloalkyl, C4-C7 cycloalkyl, C5-C7 cycloalkyl, C5-C7 cycloalkyl, C3-C6 cycloalkyl, C4-C6 cycloalkyl, C5-C6 cycloalkyl, C3-C5 cycloalkyl, C4-C5 cycloalkyl, or C3-C4 cycloalkyl. [0041] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain hydrocarbon radical, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group. The heteroatom Si can be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. A “heteroalkyl” can contain up to three units of unsaturation, and also include mono- and poly-halogenated variants, or combinations thereof. Examples include -CH2-CH2-O-CH3, -CH2-CH2-O-CF3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S(0)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH=N(CH3)-CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.
[0042] The term “heterocycloalkyl”, “heterocyclic”, or “heterocycle” refers to a cycloalkyl radical group having the indicated number of ring atoms (e.g., 5-6 membered heterocycloalkyl) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, nitrogen atom(s) are optionally quaternized, as ring atoms. Unless otherwise stated, a “heterocycloalkyl”, “heterocyclic”, or “heterocycle” ring can be a monocyclic, a bicyclic, spirocyclic or a polycylic ring system. Non-limiting examples of “heterocycloalkyl”, “heterocyclic”, or “heterocycle” rings include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(lH,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3 -pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine, tropane and the like. A “heterocycloalkyl”, “heterocyclic”, or “heterocycle” group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms. In some embodiments, “heterocycloalkyl” encompasses 4- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkyl, 6- to 8-membered heterocycloalkyl, 7- to 8-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 6- to 7-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl, or 4- to 5-membered heterocycloalkyl.
[0043] The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms. In some embodiments, an alkyl (or alkylene) group will have 10 or fewer carbon atoms.
[0044] The term “heteroalkylene” by itself or as part of another substituent means a divalent radical, saturated or unsaturated or polyunsaturated, derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2CH2-, -CH2-S-CH2-CH2-NH-CH2-, -O-CH2-CH=CH-, - CH2-CH=C(H)CH2-O-CH2- and -S-CH2-OC-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedi oxy, alkyleneamino, alkylenediamino, and the like).
[0045] The term “heterocycloalkylene” by itself or as part of another substituent means a divalent radical, saturated or unsaturated or polyunsaturated, derived from heterocycloalkyl. For heterocycloalkylene groups, heteroatoms can also occupy either or both of the chain termini.
[0046] The terms “alkoxy” and “alkylamino” are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom or an amino group, respectively.
[0047] The term “heterocycloalkoxy” refers to a heterocycloalkyl-O- group in which the heterocycloalkyl group is as previously described herein.
[0048] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-C4 haloalkyl” is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, difluoromethyl, and the like.
[0049] The term “haloalkyl-OH” refers to a haloalkyl group as described above which is also substituted by one or more hydroxyl groups. The term “haloalkyl-OH” is meant to include haloalkyl substituted by one hydroxyl group, as well as haloalkyl substituted by multiple hydroxyl groups. The term “haloalkyl-OH” also encompasses haloalkyl groups substituted by one or more hydroxyl groups on any carbon of the haloalkyl group. For example, the term “haloalkyl-OH” includes -CH(F)OH, -CH2CFHCH2OH, -CH(OH)CF3, and the like.
[0050] The term “alkyl-OH” or “alkylene-OH” refers to an alkyl or alkylene substituted by one or more hydroxyl groups. The term “alkyl-OH” is meant to include alkyl substituted by one hydroxyl group, as well as alkyl substituted by multiple hydroxyl groups. The term “alkylene-OH” is meant to include alkylene substituted by one hydroxyl group, as well as alkylene substituted by multiple hydroxyl groups. The terms “alkyl-OH” and “alkylene-OH” also encompass alkyl groups and alkylene groups, respectively, that are substituted by one or more hydroxyl groups on any carbon of the alkyl or alkylene group, as valency permits. For example, the term “alkyl-OH” includes -CH2OH, -CH(OH)CH3, -CH2CH2OH, -C(CH3)2OH, and the like.
[0051] The term “alkyl-OR6” refers to an alkyl substituted by one or more -OR6 groups. The term “alkyl-OR6” is meant to include alkyl substituted by one -OR6group, as well as alkyl substituted by multiple -OR6 groups. The term “alkyl-OR6” also encompasses alkyl groups substituted by one or more OR6 groups on any carbon of the alkyl, as valency permits.
[0052] The term “alkyl-CN” refers to an alkyl substituted by one or more cyano groups. The term “alkyl-CN” is meant to include alkyl substituted by one cyano group, as well as alkyl substituted by multiple cyano groups. The term “alkyl-CN” also encompasses alkyl groups substituted by one or more cyano groups on any carbon of the alkyl group. For example, the term “alkyl-CN” includes -CH2CN, -CH2CH2CN, -CH(CN)CH3, and the like.
[0053] The term “aryl” means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group, which can be a single ring or multiple rings (up to three rings) which are fused together. In some embodiments, “aryl” encompasses Ce-Cuaryl, Cs-Cuaryl, Cio-Cuaryl, Ci2-Ci4aryl, Ce-Cn aryl, Cs-Cn aryl, Cio-Cn aryl, Ce-Cio aryl, Cs-Cio aryl, or Ce-Cs aryl. The term “heteroaryl” refers to aryl groups (or rings) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while nonlimiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. In some embodiments, the term “heteroaryl” encompasses 5- to 10-membered heteroaryl, 6- to 10-membered heteroaryl, 7- to 10-membered heteroaryl, 8- to 10-membered heteroaryl, 9- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 6- to 9-membered heteroaryl, 7- to 9- membered heteroaryl, 8- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 6- to 8- membered heteroaryl, 7- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, 6- to 7- membered heteroaryl, or 5- to 6-membered heteroaryl.
[0054] The above terms (e.g., “alkyl”, “aryl” and “heteroaryl”), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical.
[0055] As used herein, the term “heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
[0056] As used herein, the term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
[0057] As used herein, the term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
[0058] As used herein, a wavy line “•'w'-'” that intersects a bond in a chemical structure indicates the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule.
[0059] As used herein, the representation of a group (e.g., Xa) in parenthesis followed by a subscript integer range (e.g., (Xa)o-i) means that the group can have the number of occurrences as designated by the integer range. For example, (Xa)o-i means the group Xacan be absent or can occur one time.
[0060] “Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography.
[0061] “Enantiomers” refer to two stereoisomers of a compound which are non- superimposable mirror images of one another. [0062] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the present disclosure can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present disclosure, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present disclosure. Many organic compounds exist in optically active forms, z.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
[0063] As used herein, the term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.
[0064] As used herein, the term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water. Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure.
[0065] The term “co-crystal” as used herein refers to a solid that is a crystalline single phase material composed of two or more different molecular or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. A co-crystal consists of two or more components that form a unique crystalline structure having unique properties. Cocrystals are typically characterized by a crystalline structure, which is generally held together by freely reversible, non-covalent interactions. As used herein, a co-crystal refers to a compound of the present disclosure and at least one other component in a defined stoichiometric ratio that form a crystalline structure.
[0066] As used herein, the term “protecting group” refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley-Interscience, New York, 2006.
[0067] As used herein, the term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
[0068] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.
[0069] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure. [0070] The compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present disclosure and include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2H (“D”), 3H, nC, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36C1, 123I and 125I. Certain isotopically labeled compounds of the present disclosure (e.g., those labeled with 3H or 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (z.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 15O, 13N, nC, and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
[0071] “Treating” or “treatment” of a disease in a patient refers to inhibiting the disease or arresting its development; or ameliorating or causing regression of the disease. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the present disclosure contemplate any one or more of these aspects of treatment.
[0072] “Preventing”, “prevention”, or “prophylaxis” of a disease in a patient refers to preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease.
[0073] The phrase “therapeutically effective amount” means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
[0074] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
[0075] It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (z.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.
IL Compounds
[0076] In one aspect, provided herein is a compound of formula (I)
Figure imgf000024_0001
or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R4 groups; Y is a bond or -C(=O)-; is a single or double bond, wherein when is a single bond, then X1 is -OH, and the carbon atom to which X1 is attached is optionally further substituted by R2’; when
Figure imgf000024_0002
double bond, then X1 is =O or =N-OH; R1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups; R2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R2 is optionally substituted with 1 to 5 R5 groups, R2’ is H or D; and R3 is H or C1-C6 alkyl; each R4 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; each R5 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; and each R6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 10-membered heteroaryl. [0077] In some embodiments,
Figure imgf000025_0005
is a single bond or a double bond, wherein when is a single bond, t 1 1
Figure imgf000025_0006
hen X is -OH, and the carbon atom to which X is attached is ionally further substituted by R2
Figure imgf000025_0001
opt ’; when is a double bond, then X1 is =O or =N-OH.
Figure imgf000025_0002
In some embodiments, is a single bond, X1 is -OH, and the carbon atom to which X1 is attached is optionally further substituted by R2’. In other embodiments, is a double bond, and X1 is =O or =N-OH. In certain embodiments, is a double bond, and X1 is
Figure imgf000025_0003
=O. In certain other embodiments, is a double bond, and X1 is =N-OH. [0078] In some embodiments wherein is a single bond, X1 is -OH, and the carbon atom to which X1 is attached is optionally further substituted by R2’, the compound of formula (I) is a compound of formula (I-1),
Figure imgf000025_0004
(I-1) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. [0079] In another aspect, provided herein is a compound of formula (I-1),
Figure imgf000026_0001
(I-1) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R4 groups; Y is a bond or -C(=O)-; R1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups; R2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R2 is optionally substituted with 1 to 5 R5 groups, R2’ is H or D; and R3 is H or C1-C6 alkyl; each R4 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; each R5 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; and each R6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 10-membered heteroaryl.
Figure imgf000027_0001
[0080] In some embodiments wherein is a double bond, and X1 is =O, the compound of formula (I) is a compound of formula (I-2),
Figure imgf000027_0002
(I-2) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. [0081] In another aspect, provided herein is a compound of formula (I-2),
Figure imgf000027_0003
(I-2) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R4 groups; Y is a bond or -C(=O)-; R1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups; R2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R2 is optionally substituted with 1 to 5 R5 groups, R3 is H or C1-C6 alkyl; each R4 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; each R5 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; and each R6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 10-membered heteroaryl. [0082] In some embodiments wherein is a double bond and X1 is =N-OH, the compound of formula (I) is a compound of formula (I-3),
Figure imgf000028_0001
or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. [0083] In another aspect, provided herein is a compound of formula (I-3),
Figure imgf000028_0002
(I-3) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein: Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R4 groups; Y is a bond or -C(=O)-; R1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups; R2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R2 is optionally substituted with 1 to 5 R5 groups, R3 is H or C1-C6 alkyl; each R4 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; each R5 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; and each R6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 10-membered heteroaryl. [0084] In some embodiments, Y is a bond. In other embodiments, Y is -C(=O)-. [0085] In some embodiments, R1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups. In some embodiments, R1 is C1-C6 alkyl or C3-C7 cycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups. In some embodiments, R1 is C1-C6 alkyl or 4- to 7-membered heterocycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups. In some embodiments, R1 is C3-C7 cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups. [0086] In some embodiments, R1 is C1-C6 alkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is C1-C4 alkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is C1-C3 alkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is C2-C4 alkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl, each of which is optionally substituted by one or more R5 groups. In some embodiments, R1 is -CH3, -CH2CH3, -(CH2)2CH3, -CH2(CH3)2, -(CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, or -CH(CH3)3. In some embodiments, R1 is -CH3 or -CH2CH3. In some embodiments, R1 is -CH3. In some embodiments, R1 is -CH2CH3. [0087] In other embodiments, R1 is C3-C7 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is C3-C6 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is C3-C5 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is C3-C4 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is C4-C6 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is C4-C5 cycloalkyl. In some embodiments, R1 is C5-C6 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted by one or more R5 groups. In some embodiments, R1 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally substituted by one or more R5 groups. In some embodiments, R1 is cyclopropyl or cyclobutyl, each of which is optionally substituted by one or more R5 groups. In some embodiments, R1 is cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R1 is cyclobutyl or cyclopentyl, each of which is optionally substituted by one or more R5 groups. In some embodiments, R1 is cyclopentyl or cyclohexyl. In some embodiments, R1 is cyclopropyl. In some embodiments, R1 is cyclobutyl. In some embodiments, R1 is cyclopentyl. In some embodiments, R1 is cyclohexyl. In some embodiments, R1 is cyclopropyl substituted by 1-2 R5 groups. In some embodiments, R1 is cyclopropyl substituted by 1-2 R5 groups. In some embodiments, R1 is unsubstituted C3- C7 cycloalkyl. In some embodiments, R1 is unsubstituted C3-C4 cycloalkyl. In some embodiments, R1 is unsubstituted cyclopropyl. [0088] In still other embodiments, R1 is 4- to 7-membered heterocycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is 4- to 6-membered heterocycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is 4- to 5-membered heterocycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is 5- to 7-membered heterocycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is 5- to 6-membered heterocycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is 6- to 7-membered heterocycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R1 is 4- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R1 is 4- to 7-membered heterocycloalkyl containing 1-2 nitrogen atoms. In some embodiments, R1 is 4- to 7-membered heterocycloalkyl containing 1-2 oxygen atoms. In some embodiments, R1 is 4- to 7- membered heterocycloalkyl containing 1 oxygen atom and 1 nitrogen atom. In some embodiments, R1 is 4- to 6-membered heterocycloalkyl. In some embodiments, R3 is pyrrolidinyl or piperidinyl.
[0089] In some embodiments, Y is -C(=O)- and R1 is C3-C7 cycloalkyl, optionally substituted by one or more R5 groups. In some embodiments, R1 is cyclopropyl optionally substituted by 1-2 R5 groups. In some embodiments, R1 is unsubstituted cyclopropyl. In some
O embodiments, the moiety
Figure imgf000031_0001
jn some embodiments, R1 is cyclopropyl
Y \ R1 XNA substituted by 1-2 fluorine atoms. In some embodiments, the moiety H is
Figure imgf000031_0002
[0090] In some embodiments, R2 is C1-C3 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R2 is optionally substituted by 1-5 R5 groups. In some embodiments, R2 is C1-C3 alkyl or C2-C6 alkenyl, wherein R2 is optionally substituted by 1-5 R5 groups. In some embodiments, R2 is C1-C3 alkyl or C3-C7 cycloalkyl, wherein R2 is optionally substituted by 1-5 R5 groups. In some embodiments, R2 is C2-C6 alkenyl or C3-C7 cycloalkyl, wherein R2 is optionally substituted by 1-5 R5 groups. [0091] In some embodiments, R2 is C1-C6 alkyl optionally substituted by 1-5 R5 groups. In some embodiments, R2 is C1-C4 alkyl optionally substituted by one or more R5 groups. In some embodiments, R2 is C1-C3 alkyl optionally substituted by one or more R5 groups. In some embodiments, R2 is C2-C4 alkyl optionally substituted by one or more R5 groups. In some embodiments, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl, each of which is optionally substituted by one or more R5 groups. In some embodiments, R2 is -CH3, - CH2CH3, -(CH2)2CH3, -CH2(CH3)2, -(CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, or -CH(CH3)3. In some embodiments, R2 is -CH3 or -CH2CH3. In some embodiments, R2 is -CH3. In some embodiments, R2 is -CH2CH3. [0092] In some embodiments, R2 is C2-C6 alkenyl optionally substituted by 1-5 R5 groups. In some embodiments, R2 is C2-C5 alkenyl optionally substituted by 1-5 R5 groups. In some embodiments, R2 is C2-C4 alkenyl optionally substituted by 1-5 R5 groups. In some embodiments, R2 is C2-C3 alkenyl optionally substituted by 1-5 R5 groups. In some embodiments, R2 is -CH2CH=CH2, -CH2CH=CH2, or -CH=CHCH3.In some embodiments, R2 is -CH2CH=CH2. In some embodiments, R2 is -CH2CH=CH2. In some embodiments, R2 is - CH=CHCH3. [0093] In some embodiments, R2 is C3-C7 cycloalkyl optionally substituted by 1-5 R5 groups. In some embodiments, R2 is C3-C6 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R2 is C3-C5 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R2 is C3-C4 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R2 is C4-C6 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R2 is C4-C5 cycloalkyl. In some embodiments, R2 is C5-C6 cycloalkyl optionally substituted by one or more R5 groups. In some embodiments, R2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted by one or more R5 groups. In some embodiments, R2 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally substituted by one or more R5 groups. In some embodiments, R2 is cyclopropyl or cyclobutyl, each of which is optionally substituted by one or more R5 groups. In some embodiments, R2 is cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R2 is cyclobutyl or cyclopentyl, each of which is optionally substituted by one or more R5 groups. In some embodiments, R2 is cyclopentyl or cyclohexyl. In some embodiments, R2 is cyclopropyl. In some embodiments, R2 is cyclobutyl. In some embodiments, R2 is cyclopentyl. In some embodiments, R2 is cyclohexyl. In some embodiments, R2 is cyclopropyl substituted by 1-2 R5 groups. In some embodiments, R2 is cyclopropyl substituted by 1-2 R5 groups. [0094] In some embodiments, R2’, when present, is H or D. In some embodiments, R2’, when present, is H. In some embodiments, R2’, when present, is D.
Figure imgf000033_0001
[0097] In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R3 is C1-C4 alkyl. In some embodiments, R3 is C1-C3 alkyl. In some embodiments, R3 is C2-C4 alkyl. In some embodiments, R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec- butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl. In some embodiments, R3 is -CH3, -CH2CH3, -(CH2)2CH3, -CH2(CH3)2, -(CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, or -CH(CH3)3. In some embodiments, R3 is -CH3 or -CH2CH3. In some embodiments, R3 is -CH3. In some embodiments, R3 is -CH2CH3. [0098] In some embodiments, Ring A is a phenyl or 5- to 6-membered heteroaryl, each of which is optionally substituted with 1 to 5 R4 groups. In some embodiments, Ring A is phenyl or 5- to 6-membered heteroaryl, each of which is substituted with 1 to 5 R4 groups. In some embodiments, Ring A is unsubstituted phenyl or unsubstituted 5- to 6-membered heteroaryl. In some embodiments, Ring A is unsubstituted phenyl or phenyl substituted with 1 to 5 R4 groups. In some embodiments, Ring A is 5-membered heteroaryl optionally substituted with 1 to 4 R4 groups. In some embodiments, Ring A is unsubstituted 5- membered heteroaryl. In some embodiments, Ring A is 6-membered heteroaryl optionally substituted with 1 to 4 R4 groups. In some embodiments, Ring A is unsubstituted 6- membered heteroaryl. In some embodiments, Ring A is 6-membered heteroaryl substituted with 1 to 4 R4 groups.
[0099] In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 R4 groups. In some embodiments, Ring A is phenyl optionally substituted with 1 to 4 R4 groups. In some embodiments, Ring A is phenyl substituted with 1 to 2 R4 groups. In some embodiments, Ring A is unsubstituted phenyl.
[0100] In some embodiments, Ring A is 5- to 6-membered heteroaryl optionally substituted with 1 to 4 R4 groups. In some embodiments, Ring A is a 5- to 6-membered heteroaryl comprising two heteroatoms optionally substituted with 1 to 4 R4 groups. In some embodiments, Ring A is a 5- to 6-membered heteroaryl comprising at least two nitrogen atoms optionally substituted with 1 to 4 R4 groups. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of O and N. In some embodiments, Ring A is an optionally substituted 5- to 6- membered heteroaryl containing 1-2 nitrogen atoms. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 1 nitrogen atom. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 1 oxygen atom. In some embodiments, Ring A is an optionally substituted 5- to 6-membered heteroaryl containing 1 sulfur atom.
[0101] In some embodiments, Ring A is an optionally substituted 5-membered heteroaryl. In some embodiments, Ring A is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 3 R4 groups. In some embodiments, Ring A is an optionally substituted 6-membered heteroaryl. In some embodiments, Ring A is pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted with 1 to 4 R4 groups. [0102] In some embodiments, each R4 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, - SF5, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl. In some embodiments, each R4 is independently H, F, Cl, Br, I, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, or -CN. In some embodiments, each R4 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl. In some embodiments, each R4 is independently H, F, Cl, Br, or I. In some embodiments, each R4 is independently H, F, -OCF3, -OR6, =O, -OCHF2, - CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl. In some embodiments, R4 is H. In some embodiments, R4 is F. In some embodiments, R4 is Cl. In some embodiments, R4 is Br. In some embodiments, R4 is I. In some embodiments, R4 is -SCF3. In some embodiments, R4 is - SCHF2. In some embodiments, R4 is -SF5. In some embodiments, R4 is -OCF3. In some embodiments, R4 is =O. In some embodiments, R4 is -OCHF2. In some embodiments, R4 is - CF3. In some embodiments, R4 is -CHF2. In some embodiments, R4 is -CN. [0103] In some embodiments, R4 is -OR6. In some embodiments, R4 is -OR6, and R6 is H or C1-C6 alkyl. In some embodiments, R4 is -OR6, and R6 is H or C1-C3 alkyl. In some embodiments, R4 is -OR6, and R6 is H or methyl. In some embodiments, R4 is -OH. In some embodiments, R4 is -O(C1-C6 alkyl). In some embodiments, R4 is -OCH3. [0104] In some embodiments, R4 is -N(R6)R6. In some embodiments where R4 is - N(R6)R6, each R6 is the same. In other embodiments where R4 is -N(R6)R6, each R6 is different. [0105] In some embodiments, R4 is C1-C6 alkyl. In some embodiments, R4 is C1-C4 alkyl. In some embodiments, R4 is C1-C3 alkyl. In some embodiments, R4 is C2-C4 alkyl. In some embodiments, R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec- butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl. In some embodiments, R4 is -CH3, -CH2CH3, -(CH2)2CH3, -CH2(CH3)2, -(CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, or -CH(CH3)3. In some embodiments, R4 is -CH3 or -CH2CH3. In some embodiments, R4 is -CH3. In some embodiments, R4 is -CH2CH3. [0106] In some embodiments, R4 is C1-C6 haloalkyl. In some embodiments, R4 is C1-C6 haloalkyl containing 1-13 halogen atoms. In some embodiments, R4 is C1-C3 haloalkyl. In some embodiments, R4 is C1-C3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R4 is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R4 is -CF3, -CCl3, -CF2Cl, -CFCl2, -CHF2, -CH2F, -CHCl2, -CH2F, or -CHFCl. In some embodiments, R4 is -CF3. [0107] In some embodiments, R4 is C1-C6 haloalkyl-OH. In some embodiments, R4 is C1- C6 haloalkyl-OH containing 1-12 halogen atoms and one hydroxyl group. In some embodiments, R4 is C1-C6 haloalkyl-OH containing 1-12 halogen atoms and one hydroxyl group. In some embodiments, R4 is C1-C6 haloalkyl-OH containing 1-11 halogen atoms and two hydroxyl groups. In some embodiments, R4 is C1-C6 haloalkyl-OH containing 1-10 halogen atoms and three hydroxyl groups. In some embodiments, R4 is C1-C6 haloalkyl-OH containing 1-9 halogen atoms and 4 hydroxyl groups. In some embodiments, R4 is C1-C3 haloalkyl-OH. In some embodiments, R4 is C1-C3 haloalkyl-OH containing 1-6 halogen atoms and one hydroxyl group. In some embodiments, R4 is C1-C3 haloalkyl-OH containing 1-5 halogen atoms and two hydroxyl groups. In some embodiments, R4 is C1-C3 haloalkyl- OH containing 1-4 halogen atoms and three hydroxyl groups. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R4 is -CH(OH)CF3, -CHF(OH)CH3, -CF2(OH)CH3, or -CF2(OH)CF3. In some embodiments, R4 is -CH(OH)CF3. [0108] In some embodiments, R4 is C1-C6 alkyl-OH. In some embodiments, R4 is C1-C6 alkyl-OH containing 1-6 hydroxyl groups. In some embodiments, R4 is C1-C6 alkyl-OH containing 1 hydroxyl group. In some embodiments, R4 is C1-C6 alkyl-OH containing 2 hydroxyl groups. In some embodiments, R4 is C1-C6 alkyl-OH containing 3 hydroxyl groups. In some embodiments, R4 is C1-C3 alkyl-OH. In some embodiments, R4 is C1-C3 alkyl-OH containing 1-3 hydroxyl groups. In some embodiments, R4 is C1-C3 alkyl-OH containing 1 hydroxyl group. In some embodiments, R4 is -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH(OH)CH2CH3, -CH(OH)CH2CH2CH3, -CH2CH(OH)CH3, or - C(CH3)2OH. In some embodiments, R4 is -CH2OH, -CH(OH)CH3, -CH(OH)CH2CH3, or - C(CH3)2OH. [0109] In some embodiments, R4 is C1-C6 alkyl-CN. In some embodiments, R4 is C1-C6 alkyl-CN containing 1-6 cyano groups. In some embodiments, R4 is C1-C6 alkyl-CN containing 1 cyano group. In some embodiments, R4 is C1-C6 alkyl-CN containing 2 cyano groups. In some embodiments, R4 is C1-C6 alkyl-CN containing 3 cyano groups. In some embodiments, R4 is C1-C3 alkyl-CN. In some embodiments, R4 is C1-C3 alkyl-CN containing 1-3 cyano groups. In some embodiments, R4 is C1-C3 alkyl-CN containing 1 cyano group. In some embodiments, R4 is -CH2CN, -CH2CH2CN, -CH(CN)CH3, -CH2CH2CH2CN, - CH(CN)CH2CH3, or -CH2CH(CN)CH3. In some embodiments, R4 is -CH2CN or - CH2CH2CN. In some embodiments, R4 is -CH2CN. In some embodiments, R4 is - CH2CH2CN. [0110] In some embodiments, R4 is C1-C6 heteroalkyl. In some embodiments, R4 is C1-C6 heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R4 is C1-C6 heteroalkyl containing 1 nitrogen atom. In some embodiments, R4 is C1-C6 heteroalkyl containing 1 oxygen atom. In some embodiments, R4 is C1-C3 heteroalkyl. In some embodiments, R4 is -CH2-CH2-O-CH3, -CH2-O-CH3, -CH2-CH2- NH-CH3, or -CH2-NH-CH3. [0111] In some embodiments, R4 is C3-C7 cycloalkyl. In some embodiments, R4 is C3-C6 cycloalkyl. In some embodiments, R4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0112] In some embodiments, Ring
Figure imgf000037_0001
wherein † indicates the point of attachment to the pyrimidinyl ring and indicates the point of attachment to the amino moiety.
Figure imgf000038_0001
, wherein f indicates the point of attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety. In some embodiments, Ring
Figure imgf000038_0002
Figure imgf000038_0003
Figure imgf000038_0004
, wherein f indicates the point of attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety. In some embodiments, Ring A is
Figure imgf000038_0005
Figure imgf000039_0001
, wherein † indicates the point of attachment to the pyrimidinyl ring and indicates the point of attachment to the amino moiety. [0114] In some embodiments, each R5 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, - SF5, -OCF3, -OR6, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl. In some embodiments, each R5 is independently H, F, Cl, Br, I, -OCF3, - OR6, -N(R6)R6, -OCHF2, -CF3, -CHF2, or -CN. In some embodiments, each R5 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl. In some embodiments, each R5 is independently H, F, Cl, Br, or I. In some embodiments, each R5 is independently H, F, - OCF3, -OR6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl. In some embodiments, R5 is H. In some embodiments, R5 is F. In some embodiments, R5 is Cl. In some embodiments, R5 is Br. In some embodiments, R5 is I. In some embodiments, R5 is - SCF3. In some embodiments, R5 is -SCHF2. In some embodiments, R5 is -SF5. In some embodiments, R5 is -OCF3. In some embodiments, R5 is -OCHF2. In some embodiments, R5 is -CF3. In some embodiments, R5 is -CHF2. In some embodiments, R5 is -CN. [0115] In some embodiments, R5 is -OR6. In some embodiments, R5 is -OR6, and R6 is H or C1-C6 alkyl. In some embodiments, R5 is -OR6, and R6 is H or C1-C3 alkyl. In some embodiments, R5 is -OR6, and R6 is H or methyl. In some embodiments, R5 is -OH. In some embodiments, R5 is -O(C1-C6 alkyl). In some embodiments, R5 is -OCH3. [0116] In some embodiments, R5 is -N(R6)R6. In some embodiments where R5 is - N(R6)R6, each R6 is the same. In other embodiments where R5 is -N(R6)R6, each R6 is different. [0117] In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is C1-C4 alkyl. In some embodiments, R5 is C1-C3 alkyl. In some embodiments, R5 is C2-C4 alkyl. In some embodiments, R5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec- butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl. In some embodiments, R5 is -CH3, -CH2CH3, -(CH2)2CH3, -CH2(CH3)2, -(CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, or -CH(CH3)3. In some embodiments, R5 is -CH3 or -CH2CH3. In some embodiments, R5 is -CH3. In some embodiments, R5 is -CH2CH3. [0118] In some embodiments, R5 is C1-C6 haloalkyl. In some embodiments, R5 is C1-C6 haloalkyl containing 1-13 halogen atoms. In some embodiments, R5 is C1-C3 haloalkyl. In some embodiments, R5 is C1-C3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R5 is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R5 is -CF3, -CCl3, -CF2Cl, -CFCl2, -CHF2, -CH2F, -CHCl2, -CH2F, or -CHFCl. In some embodiments, R5 is -CF3. [0119] In some embodiments, R5 is C1-C6 haloalkyl-OH. In some embodiments, R5 is C1- C6 haloalkyl-OH containing 1-12 halogen atoms and one hydroxyl group. In some embodiments, R5 is C1-C6 haloalkyl-OH containing 1-12 halogen atoms and one hydroxyl group. In some embodiments, R5 is C1-C6 haloalkyl-OH containing 1-11 halogen atoms and two hydroxyl groups. In some embodiments, R5 is C1-C6 haloalkyl-OH containing 1-10 halogen atoms and three hydroxyl groups. In some embodiments, R5 is C1-C6 haloalkyl-OH containing 1-9 halogen atoms and 4 hydroxyl groups. In some embodiments, R5 is C1-C3 haloalkyl-OH. In some embodiments, R5 is C1-C3 haloalkyl-OH containing 1-6 halogen atoms and one hydroxyl group. In some embodiments, R5 is C1-C3 haloalkyl-OH containing 1-5 halogen atoms and two hydroxyl groups. In some embodiments, R5 is C1-C3 haloalkyl- OH containing 1-4 halogen atoms and three hydroxyl groups. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R5 is -CH(OH)CF3, -CHF(OH)CH3, -CF2(OH)CH3, or -CF2(OH)CF3. In some embodiments, R5 is -CH(OH)CF3. [0120] In some embodiments, R5 is C1-C6 alkyl-OH. In some embodiments, R5 is C1-C6 alkyl-OH containing 1-6 hydroxyl groups. In some embodiments, R5 is C1-C6 alkyl-OH containing 1 hydroxyl group. In some embodiments, R5 is C1-C6 alkyl-OH containing 2 hydroxyl groups. In some embodiments, R5 is C1-C6 alkyl-OH containing 3 hydroxyl groups. In some embodiments, R5 is C1-C3 alkyl-OH. In some embodiments, R5 is C1-C3 alkyl-OH containing 1-3 hydroxyl groups. In some embodiments, R5 is C1-C3 alkyl-OH containing 1 hydroxyl group. In some embodiments, R5 is -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH(OH)CH2CH3, -CH(OH)CH2CH2CH3, -CH2CH(OH)CH3, or - C(CH3)2OH. In some embodiments, R5 is -CH2OH, -CH(OH)CH3, -CH(OH)CH2CH3, or - C(CH3)2OH. [0121] In some embodiments, R5 is C1-C6 alkyl-CN. In some embodiments, R5 is C1-C6 alkyl-CN containing 1-6 cyano groups. In some embodiments, R5 is C1-C6 alkyl-CN containing 1 cyano group. In some embodiments, R5 is C1-C6 alkyl-CN containing 2 cyano groups. In some embodiments, R5 is C1-C6 alkyl-CN containing 3 cyano groups. In some embodiments, R5 is C1-C3 alkyl-CN. In some embodiments, R5 is C1-C3 alkyl-CN containing 1-3 cyano groups. In some embodiments, R5 is C1-C3 alkyl-CN containing 1 cyano group. In some embodiments, R5 is -CH2CN, -CH2CH2CN, -CH(CN)CH3, -CH2CH2CH2CN, - CH(CN)CH2CH3, or -CH2CH(CN)CH3. In some embodiments, R5 is -CH2CN or - CH2CH2CN. In some embodiments, R5 is -CH2CN. In some embodiments, R5 is - CH2CH2CN. [0122] In some embodiments, R5 is C1-C6 heteroalkyl. In some embodiments, R5 is C1-C6 heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R5 is C1-C6 heteroalkyl containing 1 nitrogen atom. In some embodiments, R5 is C1-C6 heteroalkyl containing 1 oxygen atom. In some embodiments, R5 is C1-C3 heteroalkyl. In some embodiments, R5 is -CH2-CH2-O-CH3, -CH2-O-CH3, -CH2-CH2- NH-CH3, or -CH2-NH-CH3. [0123] In some embodiments, R5 is C3-C7 cycloalkyl. In some embodiments, R5 is C3-C6 cycloalkyl. In some embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0124] In some embodiments, each R6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 10- membered heteroaryl. In some embodiments, each R6 is independently H or C1-C6 alkyl. In some embodiments, each R6 is H. In some embodiments, each R6 is C1-C6 alkyl. In some embodiments, R6 is C1-C4 alkyl. In some embodiments, R6 is C1-C3 alkyl. In some embodiments, R6 is C2-C4 alkyl. In some embodiments, R6 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, n-pentyl, iso-pentyl, neopentyl, sec-pentyl, 3-pentyl, or n-hexyl. In some embodiments, R6 is -CH3, -CH2CH3, -(CH2)2CH3, -CH2(CH3)2, - (CH2)3CH3, -(CH2)3CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, or -CH(CH3)3. In some embodiments, R6 is -CH3 or -CH2CH3. In some embodiments, R6 is -CH3. In some embodiments, R6 is -CH2CH3. [0125] In some embodiments, R6 is C1-C6 haloalkyl. In some embodiments, R6 is C1-C6 haloalkyl containing 1-13 halogen atoms. In some embodiments, R6 is C1-C3 haloalkyl. In some embodiments, R6 is C1-C3 haloalkyl containing 1-7 halogen atoms. In some embodiments, R6 is C1-C2 haloalkyl containing 1-5 halogen atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, the halogen atoms are all fluoro atoms. In some embodiments, the halogen atoms are all chloro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R6 is -CF3, -CCl3, -CF2Cl, -CFCl2, -CHF2, -CH2F, -CHCl2, -CH2F, or -CHFCl. In some embodiments, R6 is -CF3. [0126] In some embodiments, R6 is C1-C6 heteroalkyl. In some embodiments, R6 is C1-C6 heteroalkyl containing 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, R6 is C1-C6 heteroalkyl containing 1 nitrogen atom. In some embodiments, R6 is C1-C6 heteroalkyl containing 1 oxygen atom. In some embodiments, R6 is C1-C3 heteroalkyl. In some embodiments, R6 is -CH2-CH2-O-CH3, -CH2-O-CH3, -CH2-CH2- NH-CH3, or -CH2-NH-CH3. [0127] In some embodiments, R6 is C3-C7 cycloalkyl. In some embodiments, R6 is C3-C6 cycloalkyl. In some embodiments, R6 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0128] In some embodiments, R6 is 4- to 7-membered heterocycloalkyl. In some embodiments, R6 is 4- to 6-membered heterocycloalkyl. In some embodiments, R6 is 4- to 5- membered heterocycloalkyl. In some embodiments, R6 is 5- to 7-membered heterocycloalkyl. In some embodiments, R6 is 5- to 6-membered heterocycloalkyl. In some embodiments, R6 is 6- to 7-membered heterocycloalkyl. [0129] In some embodiments, R6 is phenyl. In some embodiments, R6 is 5- to 10- membered heteroaryl. In some embodiments, R6 is 5- to 6-membered heteroaryl. In some embodiments, R6 is a 5- to 6-membered heteroaryl comprising two heteroatoms. In some embodiments, R6 is a 5- to 6-membered heteroaryl comprising at least two nitrogen atoms. In some embodiments, R6 is a 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, and S. In some embodiments, R6 is a 5- to 6-membered heteroaryl containing 1-2 heteroatoms selected from the group consisting of O and N. In some embodiments, R6 is a 5- to 6-membered heteroaryl containing 1-2 nitrogen atoms. In some embodiments, R6 is a 5- to 6-membered heteroaryl containing 1 nitrogen atom. In some embodiments, R6 is a 5- to 6-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, R6 is a 5- to 6-membered heteroaryl containing 1 oxygen atom. In some embodiments, R6 is a 5- to 6-membered heteroaryl containing 1 sulfur atom. [0130] In some embodiments, Ring A is 5- to 6- membered heteroaryl, wherein the 5- to 6- membered heteroaryl comprises at least one nitrogen atom and is optionally substituted with 1 to 5 R4 groups; Y is -C(=O)-; R1 is cyclopropyl optionally substituted with 1 to 2 fluorine atoms; R2 is C1-C3 alkyl optionally substituted with 1 to 5 R5 groups, and R2’ is H or D; R3 is independently C1-C3 alkyl; each R4 is independently H, F, Cl, Br, I, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, or C1-C6 haloalkyl; each R5 is independently H, F, Cl, Br, I, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, or C1-C6 haloalkyl; and each R6 is independently H or C1-C6 alkyl.
Figure imgf000043_0001
,
Figure imgf000044_0001
Figure imgf000044_0002
wherein f indicates the point of attachment to the pyrimidinyl
Figure imgf000044_0003
ring and { indicates the point of attachment to the amino moiety; Y is -C(=O)-; is a single bond, wherein X1 is -OH; R1 is cyclopropyl optionally substituted with 1 to 2 fluorine atoms; R2 is -CH3 or -CH2CH3, and R2 is H or D; R3 is -CH3; each R5 is independently H, F, or -CH3; and each R6 is independently H or -CH3.
[0132] In one aspect, provided herein are compounds of formula (I-l-a), (I-l-b), (I-2-a),
(I-2-b), (I-3-a), or (I-3-b),
Figure imgf000044_0004
wherein A1 and A5 are each independently C, N, O, or S;
A2-A4 are each independently C-R4, N, N-R4, O, or S; provided that at least one of Ax-A5 is a heteroatom;
A6 and A11 are each independently C, N, O, or S; and
A7-A10 are each independently C-R4, N, N-R4, O, or S.
[0133] In some embodiments, the compound of formula (I) is a compound of formula (I- 1-a), (I-l-b), (I-2-a), (I-2-b), (I-3-a), or (I-3-b). In some embodiments, the compound of formula (1-1) is a compound of formula (I-l-a) or formula (I-l-b). In some embodiments, the compound is a compound of formula (I-l-a) or a compound of formula (I-l-b). In some embodiments, the compound is a compound of formula (I-l-a). In some embodiments, the compound is a compound of formula (I-l-b). In some embodiments, the compound of formula (1-2) is a compound of formula (I-2-a) or formula (1-2 -b). In some embodiments, the compound is a compound of formula (I-2-a) or a compound of formula (I-2-b). In some embodiments, the compound is a compound of formula (I-2-a). In some embodiments, the compound is a compound of formula (1-2 -b). In some embodiments, the compound of formula (1-3) is a compound of formula (I-3-a) or formula (I-3-b). In some embodiments, the compound is a compound of formula (I-3-a) or a compound of formula (I-3-b). In some embodiments, the compound is a compound of formula (I-3-a). In some embodiments, the compound is a compound of formula (I-3-b).
[0134] In some embodiments, the compound of formula (I) is a compound of formula (I- 1-a), (I-l-b), (I-2-a), (I-2-b), (I-3-a), or (I-3-b). In other embodiments, the compound of formula (1-1) is a compound of formula (I-l-a) or (I-l-b). In other embodiments, the compound of formula (1-2) is a compound of formula (I-2-a) or (I-2-b). In other embodiments, the compound of formula (1-3) is a compound of formula (I-3-a) or (I-3-b). In another aspect, provided herein is a compound of formula (I-l-a), (I-l-b), (I-2-a), (I-2-b), (I- 3 -a), or (1-3 -b), or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing,
Figure imgf000046_0001
wherein R2, R3, R4, R5 are as defined for formula (I) and A^A11 are as defined above.
[0135] In some embodiments, the compound of formula (I) is a compound of formula (I- 1-a-l), (I-l-a-2), (I-l-b-1), (I-l-b-2), (I-2-a-l), (I-2-a-2), (I-2-b-l), (I-2-b-2), (I-3-a-l), (I-3-a- 2), (I-3-b-l), or (I-3-b-2). In other embodiments, the compound of formula (1-1) is a compound of formula (I-l-a-1), (I-l-a-2), (I-l-b-1), or (I-l-b-2). In other embodiments, the compound of formula (1-2) is a compound of formula (I-2-a-l), (I-2-a-2), (I-2-b-l), or (I-2-b- 2). In other embodiments, the compound of formula (1-3) is a compound of formula (I-3-a-l), (I-3-a-2), (I-3-b-l), or (I-3-b-2). In another aspect, provided herein is a compound of formula (I-l-a-1), (I-l-a-2), (I-l-b-1), (I-l-b-2), (I-2-a-l), (I-2-a-2), (I-2-b-l), (I-2-b-2), (1-3 -a- 1), (1-3- a-2), (1-3 -b-1), or (1-3 -b-2), or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing,
Figure imgf000047_0001
wherein A^A11 and R4 are as defined above. [0136] In some embodiments of the foregoing, at least one of Ax-A5 is a heteroatom. In some embodiments of the foregoing, at least two of A'-A5 are a heteroatom. In some embodiments of the foregoing, at least one of A'-A5 is an optionally R4- substituted nitrogen atom. In some embodiments of the foregoing, at least two of A'-A5 are an optionally R4- substituted nitrogen atom. In some embodiments of the foregoing, A6-An are each optionally R4- substituted carbon atoms. In some embodiments of the foregoing, at least one of A6-An is a heteroatom. In some embodiments of the foregoing, at least two of A6-An are a heteroatom. In some embodiments of the foregoing, at least one of A6-An is an optionally R4-substituted nitrogen atom. In some embodiments of the foregoing, at least two of A6-An are an optionally R4- substituted nitrogen atom. In some embodiments of the foregoing, A'-A" and
Figure imgf000048_0001
Figure imgf000048_0002
, wherein f indicates the point of attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
[0137] In some embodiments wherein the compound is a compound of formula (I-l-a),
(I-l-a-1), (I-l-a-2), (I-2-a), (I-2-a-l), (I-2-a-2), (1-3 -a), (1-3 -a- 1), or (1-3 -a-2), A1- A5 are defined such that Ring
Figure imgf000048_0003
Figure imgf000049_0001
wherein f indicates the point of attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
[0138] In some embodiments wherein the compound is a compound of formula (I-l-b),
(I-l-b-1), (I-l-b-2), (I-2-b), (I-2-b-l), (I-2-b-2), (I-3-b), (I-3-b-l), or (I-3-b-2), A6-A11 and
Figure imgf000049_0002
attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
Figure imgf000049_0003
Figure imgf000050_0001
Figure imgf000051_0001
[0140] In some embodiments, provided is a compound selected from the compounds in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
Figure imgf000051_0002
Figure imgf000051_0003
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
[0141] In some embodiments, provided is a compound selected from the compounds in Table 2, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Table 2
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
[0142] In some embodiments, provided is a compound selected from the compounds in Table 3, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Table 3.
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
[0143] Although certain compounds described in Table 1, Table 2 and Table 3 are presented as specific stereoisomers and/or in a non-stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of Table 1, Table 2 and Table 3 are herein described. In some embodiments, the compound described herein is selected from the group consisting of Compound No. 1.1-1.45, Compound No. 2.1-2.26, and Compound No. 3.1-3.26.
[0144] This disclosure also includes all salts, such as pharmaceutically acceptable salts, of compounds referred to herein. This disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms, such as N-oxides, solvates, hydrates, or isotopomers, of the compounds described. The present disclosure also includes co-crystals of the compounds described herein. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced.
[0145] In the descriptions herein, it is understood that every description, variation, embodiment, or aspect of a moiety can be combined with every description, variation, embodiment, or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment, or aspect provided herein with respect to the Ring A moiety of formula (I) may be combined with every description, variation, embodiment, or aspect of A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, Y, X1, ““ , R1, R2, R2 , R3, R4, R5, R6 Xa, R2, R3, R4, R5, and/or R6, the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments, or aspects of formula (I), where applicable, apply equally to any of formulae (1-1), (1-2), (1-3), (I-l-a), (I-l-b), (I-2-a), (I-2-b), (I-3-a), (I-3-b), (I-l-a-1), (I-l-a-2), (I-l-b-1), (I-l-b-2), (I-2-a-l), (I-2-a-2), (I-2-b-l), (I-2-b-2), (I-3-a-l), (I-3-a-2), (I-3-b-l), (I-3-b-2), detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae.
III. General Synthetic Methods
[0146] The compounds of the present disclosure may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
[0147] The intermediates described in the following preparations may contain a number of nitrogen, hydroxy, and acid protecting groups such as esters. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature. See e.g., Greene and Wuts, Protective Groups in Organic Synthesis, (T. Greene and P. Wuts, eds., 2d ed. 1991).
[0148] Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See e.g, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions" , John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds'", Wiley-Interscience, 1994).
[0149] The compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be prepared by a variety of procedures known in the art, some of which are illustrated in the Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the present disclosure, or salts thereof. The products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry which are analogous to the syntheses of known structurally-similar compounds and the procedures described in the Examples which follow including any novel procedures.
[0150] Compounds of formula (I) can be prepared according to Scheme A, Scheme B, Scheme C, Scheme D, Scheme E, Scheme F, Scheme G, Scheme H, Scheme I, Scheme J, or Scheme K, wherein the Ring A moiety, A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, Y, X1,
, R1, R2, R2 , R3, R4, R5, and/or R6 are as defined for formulae (I), (1-1), (1-2), (1-3), (I- 1-a), (I-l-b), (I-2-a), (I-2-b), (I-3-a), (I-3-b), (I-l-a-1), (I-l-a-2), (I-l-b-1), (I-l-b-2), (I-2-a-l), (I-2-a-2), (I-2-b-l), (I-2-b-2), (I-3-a-l), (I-3-a-2), (I-3-b-l), (I-3-b-2), or any applicable variation thereof as detailed herein. Schemes A-E and Schemes F-I depict generalized synthetic schemes for the preparation of compounds of formula (1-2), wherein is a double bond and X1 is =0. Schemes J and K depict the preparation of compounds of formula (1-1), wherein is a single bond and X1 is -OH, and formula (1-3), wherein is a double bond and X1 is =N-0H, from compounds of formula (1-2), respectively.
[0151] In Scheme A, amination of pyrimidine compounds A-a with suitable protected amines, such as B0C-NH2, yields the corresponding protected amino-substituted pyrimidine compounds A-b.
Scheme A.
Figure imgf000068_0001
[0152] In an alternative to Scheme A, Scheme B shows the installation of one or more protecting groups on aminopyrimidine compounds B-b. In Scheme B, the compounds B-a are reacted with protecting groups, such as 4-methoxybenzyl chloride (PMB) under suitable conditions to provide the corresponding protected amino-substituted pyrimidine compounds B-b Scheme B.
Figure imgf000069_0001
p , ,
[0153] In Scheme C, protected compounds A-b or B-b may be coupled with leaving group-substituted amino-substituted Ring A compounds C-a. Suitable leaving groups may include but are not limited to halogen atoms or boronic acid derivative. As defined herein for formula (I), Ring A may be a Ce-Ci4 aryl or 5- to 6-membered heteroaryl ring. The coupling reaction yields the corresponding protected bicyclic pyrimidinyl Ring A compounds C-b.
Scheme C.
Figure imgf000069_0002
p
[0154] Protected bicyclic pyrimidinyl Ring A compounds C-b may be further reacted with acylated pyridine compounds D-a to provide the corresponding tricyclic intermediate compounds D-b. Compounds D-b may be subsequently deprotected to provide free amine moieties in intermediate compounds D-c.
Scheme D.
Figure imgf000070_0001
[0155] Compounds of formula (I) may be prepared by the subsequent reaction of intermediate compounds D-c with R^COOH compounds E-a, thereby providing compounds of formula (1-2).
Scheme
Figure imgf000070_0002
[0156] An alternative preparation of compounds of formula (1-2) is illustrated in Scheme F through Scheme I below. In Scheme F, carboxylic acid-sbustituted Ring A compounds F-a are converted to amino-substituted Ring A compounds F-b. The amino-substituted Ring A compounds F-b may be reacted with a suitable reagent, such as N-iodosuccinimide, to install a suitable leaving group, such as iodo moiety, on Ring A to give intermediate compounds F- c. Scheme F.
Figure imgf000071_0001
F-a F-b F-c
[0157] In Scheme G, R^Y-substituted amine compounds G-a are coupled to leaving group-modified pyrimidine compounds A-a to yield the coupled product compounds G-b. In Scheme H, the intermediate compounds G-b are reacted with an organotin compound under suitable catalytic conditions to stannylate the pyrimidine ring of intermediate compounds H- a. The organostannane compounds H-a are reacted with intermediate Ring A compounds F-c to generate the coupled product compounds H-b. The coupled product compounds H-b are deprotected to provide the corresponding compounds H-c having a free amine.
Scheme G.
Figure imgf000071_0003
Scheme H.
Figure imgf000071_0002
Boc
Figure imgf000072_0001
[0158] In Scheme I, the intermediate compounds H-c are coupled with the acylated pyridinyl compounds D-a to provide compounds of formula (1-2), wherein may also be prepared according to the general synthetic scheme shown in Scheme J. In Scheme J, compounds of formula (1-2), wherein is a double bond and X1 is =0, are reacted with suitable reducing agent, such as sodium borohydride, to convert the oxo moiety of compounds of formula (1-2) to a hydroxyl moiety, thereby providing compounds of formula (1-1), wherein is a single bond and X1 is -OH.
Scheme I.
Figure imgf000072_0003
[0159] Compounds of formula (1-1) may also be prepared according to the general synthetic scheme shown in Scheme J. In Scheme J, compounds of formula (1-2), wherein is a double bond and X1 is =0, are reacted with suitable reducing agent, such as sodium borohydride, to convert the oxo moiety of compounds of formula (1-2) to a hydroxyl
Figure imgf000072_0002
moiety, thereby providing compounds of formula (1-1), wherein is a single bond and X1 is -OH.
Scheme J.
Figure imgf000073_0001
[0160] Compounds of formula (1-13 may also be prepared according to the general synthetic scheme shown in Scheme K. In Scheme K, compounds of formula (1-2), wherein is a double bond and X1 is =0, are reacted with hydroxylamine to convert the oxo moiety of compounds of formula (1-2) to an oxime moiety, thereby providing compounds of formula (1-3), wherein is a double bond and X1 is =N-0H.
Figure imgf000073_0002
1-2 1-3
[0161] It should be recognized that the present disclosure also provides for any intermediates of the compounds and methods for synthesizing the compounds as described herein. In another aspect, provided herein are general intermediates as described in any one of Schemes A through K above, or compound-specific intermediates as described in the examples below. It should be further recognized that the present disclosure also provides for synthetic methods comprising any individual step or combination of individual process steps, or compositions of synthetic intermediates and/or reaction products as described herein.
IV. Pharmaceutical Compositions and Formulations
[0162] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition.
[0163] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
[0164] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein is in substantially pure form. In one variation, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. For example, a composition of a substantially pure compound selected from a compound of Table 1, Table 2 and/or Table 3 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound of Table 1, Table 2 and/or Table 3. In one variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 5% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 3% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 1% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 0.5% impurity. In yet other variations, a composition of substantially pure compound means that the composition contains no more than 15%, no more than 10%, no more than 5%, no more than 3%, or no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, and without limitation, a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.
[0165] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein. In some embodiments, the compounds and compositions as provided herein are sterile. Methods for sterilization known in the art may be suitable for any compounds or form thereof and compositions thereof as detailed herein.
[0166] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
[0167] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, with a pharmaceutically acceptable carrier. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference.
[0168] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
[0169] Any of the compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated as a 10 mg tablet. [0170] Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, provided herein are also described. In one variation, the composition comprises a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.
[0171] Compositions formulated for co-administration of a compound provided herein and one or more additional pharmaceutical agents are also described. The co-administration can be simultaneous or sequential in any order. A compound provided herein may be formulated for co-administration with the one or more additional pharmaceutical agents in the same dosage form (e.g., single tablet or single i.v.) or separate dosage forms (e.g., two separate tablets, two separate i.v., or one tablet and one i.v.). Furthermore, co-administration can be, for example, 1) concurrent delivery, through the same route of delivery (e.g., tablet or i.v.), 2) sequential delivery on the same day, through the same route or different routes of delivery, or 3) delivery on different days, through the same route or different routes of delivery.
V. Methods of Use
[0172] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of formula (I) or any variation thereof provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays. [0173] In one aspect, provided herein are methods of a method of treating a cancer or neoplastic disease in a human in need thereof. In some embodiments, provided herein are methods of treating a disease or disorder mediated by a RAF kinase.
RAF Kinase Inhibition
[0174] In one aspect, provided herein is a method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
[0175] The compounds and compositions described herein may be used in a method of treating a disease or disorder mediated by ARAF, BRAF, or CRAF kinase activity. In some embodiments, the compound or composition is administered according to a dosage described herein.
[0176] In some embodiments, provided herein is a method for treating a disease or disorder mediated by RAF kinase activity comprising administering to an individual in need of treatment an effective amount of a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. In some embodiments, the disease or disorder is a cancer or neoplastic disease.
[0177] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
RAF Kinase Family [0178] In vertebrates, RAF is comprised of a family of three genetically distinct serine/threonine protein kinases designated ARAF, BRAF and CRAF (sometimes referred to as RAF-1). These family members are highly conserved at the primary sequence level (75% amino acid identity across their entire protein sequence and >87% identity within their respective kinase domains) and exhibit the same overall domain architecture. ARAF, BRAF and CRAF are ubiquitously and differentially expressed across all cell and tissue types. As such, they collectively serve as an essential signaling node of the Ras/Raf/MEK/ERK (MAPK) pathway. Importantly, a substantial proportion of all cancers are driven by genetic alterations in either the RTKs or a particular member of the MAPK pathway especially HRAS, KRAS, NRAS and the RAF isoforms, that then drive aberrant activation of the pathway. Therefore, as an essential node in the MAPK pathway, the RAF kinases represent an important therapeutic intervention point for the treatment of a variety of malignancies whose dysregulated growth and survival rely upon MAPK signaling. Accordingly, multiple RAF kinase inhibitors have been approved for specific indications including melanoma and NSCLC and numerous additional inhibitors are currently undergoing clinical investigation for a variety of other malignancies.
RAF function
[0179] Upon ligand binding, RTKs homo- or hetero oligomerize with other receptors and auto-phosphorylate key tyrosine residues in trans. These phosphorylated residues then serve as docking sites for downstream effectors, especially adapter proteins involved in the recruitment and activation of RAS (H-, K- and N-RAS) such as Grb2 and SOS, respectively. Activated GTP -bound RAS now binds and recruits RAF thereby inducing conformational changes in the latter to induce its dimerization and concomitant activation. RAF then binds and phosphorylates /activates MEK which then phosphorylates/activates ERK. Activated ERK then redistributes to the cytoplasm, the cytoskeleton and the nucleus to control cell growth/division, differentiation and survival.
RAF Structure and Regulation
[0180] Grossly, the primary structure of RAF can be divided into two domains; an N- terminal regulatory domain and a C-terminal kinase domain (KD) connected by a linker region. The regulatory domain contains multiple elements including a RAS-binding domain (RBD) followed immediately downstream by a Cysteine-Rich Domain (CRD). A key phosphorylation site resides within the linker region and another at the extreme C-terminus downstream of the KD. In its inactive conformation, RAF is located in the cytoplasm in a monomeric, dual-phosphorylated, autoinhibited state. This autoinhibition is mediated via two cooperative mechanisms: (1) direct interaction between the RBD and the KD and (2) 14-3-3 protein dimers that simultaneously interact with the two phosphorylated residues flanking the KD. The combination of these interactions effectively binds up the KD into the inactive conformation. Upon RAS engagement via interactions with both the RBD and CRD, the RBD-KD interaction is effectively disrupted exposing the phosphorylation site within the linker region to phosphatase action via the MRAS/SH0C2/PP1 complex. Subsequent dephosphorylation of this residue abrogates intramolecular 14-3-3 binding thereby fully relieving autoinhibition and exposing residues critical for interaction with the plasma membrane. RAS-bound hemi-phosphorylated RAF can now dimerize with another RAF protein (homo- or heterodimerization) via intermolecular interactions between their respective KDs as well as 14-3-3 cross-linking between the two adjacent phosphorylated residues at the C-terminus of each protomer. Importantly, this fully active RAF complex functions as an obligate dimer to both bind to and activate MEK, ultimately driving ERK activation to complete the signaling cascade.
RAF Mutations and Cancer
[0181] Given their critical involvement in the RTK/RAS/RAF/MEK/ERK pathway, it should be no surprise each of the RAF isoforms are bona fide proto-oncogenes. Accordingly, a variety of mutations have been identified in ARAF, BRAF and CRAF that have been functionally linked to tumor formation. Importantly, these mutations fall into distinct classes with discrete mechanisms of kinase activation.
[0182] BRAF is the most commonly mutated RAF isoform with alterations reported in approximately 8% of all solid tumors. Melanomas harbor the greatest proportion of BRAF mutations with 40-50% prevalence followed by thyroid, colorectal (CRC) and non-small cell lung cancers (NSCLC). These mutations can be divided into three distinct functional classes based upon how they elicit aberrant activation of RAF kinase activity. Class I mutations render the kinase constitutively active and independent of the requirement for RAS binding or dimerization with another RAF isoform. These mutations are unique to BRAF and are associated with highly specific alterations within the 600th codon leading to the conversion of a valine residue to an aspartate, glutamate, lysine or arginine (V600D/E/K/R). Class II mutations drive aberrant kinase activation by conferring constitutive RAS-independent RAF- dimerization without adversely impacting the intrinsic kinase activity of the mutant. These mutations can be further subdivided into 3 subclasses according to which region within the kinase domain the alteration occurs (designated as Class Ila and lib) or the formation of a kinase fusion arising from a chromosome translocation event (designated Class lie) whereby the negative regulatory RBD and CRD domains are removed by deletion and replaced with the fusion partner. The class II mutations include the following: G464V, G469A, G469V, G469R, E586K, K601E, K601N, L597R, L597S, L597Q) These mutations are most common in NSCLC and CRC. Finally, Class III mutants confer enhanced RAS-dependent RAF dimerization to drive pathway activation. These mutations substantially attenuate the intrinsic kinase activity of the mutant such that transactivation of the wildtype RAF dimerization partner is key to aberrant pathway activation. Accordingly, other genetic alterations leading to RAS activation are often found co-occurring with these Class III mutations to facilitate dimerization. The class III mutations include the following: G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R.
[0183] Compared to BRAF, the prevalence of oncogenic mutations within CRAF are relatively rare and found sporadically across a wide array of cancers including melanoma, NSCLC, pancreatic carcinoma, glioma, colorectal and hematological malignancies. There are two distinct mutation types that have been reported for CRAF. The first mutation type consists of point mutations that reside within the linker region effectively disrupting 14-3-3 binding to the linker domain phosphorylation site and conferring a more open confirmation that is now accessible to phosphatase action and subsequent dimerization/activation. These mutations include P261L and P261 A. The second CRAF mutation type is analogous to the Class II mutations in BRAF. Specifically, there are reports of point mutations found in regions of the kinase domain analogous to the Class Ila and lib BRAF mutants in CRAF across multiple cancer types, especially melanomas. These mutations include E478K, R391W, R391S and T491I as well as certain mutations that are also found in a subset of RASopathies; a cluster of diverse genetic diseases whose underlying etiology appears to derive from chronic MAPK pathway activation. There are also multiple reports of Class lie mutations in RAF (CRAF fusions), which, like the BRAF fusions, possess fusion partners that effectively replace the RBD and CRD domains to relieve autoinhibition and drive dimerization and activation. [0184] To date, only one oncogenic mutation at codon 214 in ARAF has been reported. This mutation results in either a cysteine or phenylalanine for serine substitution (S214C/F) and has been identified in multiple NSCLC patients with an approximate prevalence of 0.5%. Given that no additional oncogenic mutations were identified in these tumors, it is likely that the ARAF mutants are the oncogenic drivers in these cancers. Accordingly, in vitro characterization of cell lines engineered to express an S214F ARAF mutant revealed that the mutant induces MAPK pathway activation and markedly enhances colony formation (a hallmark activity of an oncogene) in a kinase-dependent manner. Given that S214 is the linker region phosphorylation site critical for 14-3-3 binding, it is likely conferring constitutive activation in a manner very similar to the CRAF point mutants described above.
RAF Kinase Inhibitors
[0185] Given the strong link between genetic alterations in components of the MAPK pathway and the development of cancer in a wide array of tumor types, this pathway represents a key opportunity for the development of targeted therapies to control these proliferative diseases. In particular, inhibitors directed against the RAF family should offer an important treatment option for patients harboring RAF kinase activating mutations found in a number of cancer types including those of the skin, thyroid and lung. Accordingly, over the last 2 decades, numerous small molecule RAF inhibitors have been discovered and several of these have advanced into the clinic and gone on to full regulatory approval. The vast majority of these compounds are ATP-competitive small molecule inhibitors and bind in the kinase active site. They are divided into three types, dependent upon the specific structural conformation they induce within the kinase upon binding. These inhibitor types are designated type 1 inhibitors, type 1.5 inhibitors and type 2 inhibitors.
Type 1 Inhibitors
[0186] Type 1 inhibitors bind in the active or ‘closed’ form of the kinase domain which is largely defined by the relative inward orientation of the C-helix and the ‘DFG’ loop which both comprise key structural and functional elements of the active site. This binding mode is designated C-helix-in/DFG-in. These compounds make key interactions with what is known as the hinge (the flexible linker between the amino and carboxyl terminal lobes of the kinase domain) as well as the pocket that normally accommodates the adenine ring of ATP. SB590885 and GDC-0879 are two literature examples of type I RAF inhibitors. Both were demonstrated to be almost exclusively active in BRAF Class 1 mutant cell contexts both in vitro and in vivo. Despite this promising activity, to date, no type I inhibitors have entered clinical development.
Type 2 inhibitors
[0187] Type 2 inhibitors bind to the kinase domain in an open conformation in which the DFG-loop is oriented in an outward or inactive position. This conformation exposes an allosteric, hydrophobic pocket adjacent to the ATP binding site that can be exploited to gain further enhancements in potency and selectivity via hydrogen bonding, Van der Waals and hydrophobic interactions. Accordingly, Type 2 inhibitors consist of functionalities that interact with both the hinge region as well as the allosteric pocket leaving the C-helix in an inward undisturbed orientation. Accordingly, this conformation is denoted as C-helix- in/DFG-out. In the literature, there exist a number of examples of Type 2 RAF inhibitors including several that have undergone clinical evaluation. Unlike the Type 1 inhibitor examples, these molecules as a class are more broadly active, exhibiting activity across a range of mutant contexts including RAS (KRAS, NRAS, HRAS), BRAF (Class 1, II and III) and CRAF. To date, multiple Type 2 inhibitors have entered into clinical development for patients harboring genetic alterations in the MAPK pathway. Importantly, several of these agents have demonstrated clinical activity in both Class I mutant BRAF and RAS mutant contexts. However, the activity has been limited and no Type 2 RAF inhibitor is currently approved for any indication.
Type 1.5 Inhibitors
[0188] Type 1.5 inhibitors bind to both the hinge region as well as the space typically occupied by the adenine moiety of ATP in much the same way as the Type 1 RAF inhibitors. What distinguishes the Type 1.5 inhibitors is that they take advantage of additional interactions at the back of the ATP binding pocket made accessible by the relatively small threonine gatekeeper residue found in all RAF isoforms (T382 in ARAF, T529 in BRAF and T421 in CRAF). Importantly, these back-pocket interactions alter the conformation of the C- helix, forcing it into an outward conformation while the DFG loop is oriented in its active or ‘in’ conformation. This conformation is denoted as C-helix-out/DFG-in. This conformation exerts a significant impact on the affinity of inhibitor for the second protomer of the RAF dimer rendering it markedly less able to bind inhibitor. Consequently, Type 1.5 inhibitors are highly active against BRAF Class I mutants that signal as monomers versus other MAPK pathway mutant contexts and the wildtype state where RAF signals as an obligate dimer. To date, 3 Type 1.5 inhibitors have been approved for the treatment of malignant melanomas harboring Class 1 BRAF mutations: vemurafenib, dabrafenib and encorafenib.
Paradoxical activation
[0189] As described above, ARAF, BRAF and CRAF are primarily regulated at the structural level in which various intra- and inter-molecular protein-protein interactions define both their localization and activity state. Accordingly, the structural changes induced with inhibitor binding exert biological effects beyond simple inhibition of kinase activity and these effects can differ depending upon the genetic context of the cells or tissues being exposed to inhibitor. In addition, dependent upon the inhibitor type, these effects are distinct, having important implications regarding safety as well as sensitivity and resistance to inhibitor treatment.
[0190] In normal cells and tissues in which the RAF isoforms are unmutated, inhibitor binding actually enhances signaling flux through the MAPK pathway in what is known as paradoxical activation. This effect derives from one or more of four distinct yet interdependent mechanisms; (1) attenuation of inhibitory auto-phosphorylation in the linker region, (2) interruption of kinase domain interactions, (3) enhancement of binding to GTP- bound RAS at the plasma membrane and (4) transactivation of the second protomer of the RAF dimer. The first 3 of these mechanisms collectively drive enhanced RAF protomer dimerization and therefore enhance downstream signaling. The fourth mechanism involves inhibitor binding to the first protomer of the RAF dimer to induce a C-helix out conformation that effectively locks the conformation of the active site of the second protomer to the active C-helix-in conformation thereby inducing both its activation and markedly reducing its affinity for inhibitor (negative allostery). The extent and magnitude of activation is dependent upon which of these mechanisms are induced by inhibitor binding and this is ultimately dictated by the binding mode of the inhibitor. Accordingly, Type 1, 2 and 1.5 inhibitors all engage the first 3 mechanisms to induce paradoxical activation. Only the Type 1.5 inhibitors engage the fourth mechanism to further enhance paradoxical activation.
Therapeutic Resistance
[0191] Clinical resistance to Type 1.5 and Type 2 inhibitors has been observed, but with distinct mechanisms of action. Patients with BRAF Class I mutant melanoma that become refractory to or relapse on Type 1.5 inhibitor therapies often exhibit mutations that drive RAF dimerization. These alterations typically involve RAF amplification/overexpression or RAS mutations but can also include aberrant alternative splicing events that remove the RBD and CRD and effectively remove the blockade to dimerization. When the Class I mutant BRAF protomer acts in the context of a dimer rather than its typical monomeric state, it is much less sensitive to Type 1.5 inhibitor treatment. This is due largely to the inhibitor’s impact on the C-helix which, as mentioned in the previous section not only results in transactivation of the unoccupied protomer but it also renders this protomer markedly less able to bind inhibitor such that super-clinical concentrations of inhibitor are required to significantly attenuate MAPK pathway signaling in the resistant tumor. Given the relatively limited clinical data available for the Type 2 RAF inhibitors, only one mechanism of therapeutic resistance has been reported thus far. In the case of belvarafenib, multiple patients that relapsed on therapy exhibited alterations in ARAF. These mutations reside within the kinase domain active site and rendered the kinase resistant not only to belvarafenib but a panel of Type 2 inhibitors.
Mutant coverage
[0192] Because the type 1.5 inhibitors are not effective at inhibiting RAF activity in the context of a dimer, they are only effective at inhibiting Class I BRAF mutants that signal as monomers. Because Type 2 inhibitors can inhibit both monomeric and dimeric RAF, they are able to inhibit Class II and III BRAF mutants that signal as obligate dimers in addition to the Class I mutants.
Clinical Safety
[0193] Paradoxical activation is known to adversely impact the tolerability of these inhibitors in patients, thereby limiting their clinical utility. As mentioned previously, Type 1.5 inhibitors markedly induce paradoxical activation in normal tissues by binding RAF dimers and transactivating the second unbound protomer. Accordingly, in the clinic, Type 1.5 inhibitor treatment is associated with multiple adverse events associated with aberrant MAPK pathway activation particularly involving the skin such as palmoplantar erythrodysaesthesia syndrome and proliferative skin lesions including keratoacanthomas and cutaneous squamous cell carcinomas. MEK inhibitors have been successfully deployed in combination with Type 1.5 RAF inhibitors to effectively manage these toxicities. Specifically, vemurafenib, dabrafenib and encorafenib have been approved in combination with cobimetinib, trametinib and binimetinib, respectively, for patients with BRAF Class I mutant metastatic melanoma. Not only have these combinations improved tolerability by attenuating paradoxical activation in normal tissues but they have also improved therapeutic benefit both in terms of overall response rate and long term survival.
[0194] In contrast, Type 2 inhibitors can bind and inhibit both protomers equally thereby significantly attenuating paradoxical activation and driving full MAPK inhibition, even in normal unmutated tissues. Consequently, the toxicities associated with Type 2 inhibitors are more in keeping with those elicited by MEK inhibitors.
[0195] In still yet another aspect, provided herein is a method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation. In some embodiments, the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in ARAF selected from the group consisting of S214C and S214F. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in BRAF selected from the group consisting of Class I, Class Ila, Class lib, Class lie, and Class III mutations. In some embodiments, the cancer or neoplastic disease is associated with one or more mutations in CRAF selected from the group consisting of P261 A, P261L, E478K, R391W, R391S and T491I, or is associated with a CRAF fusion. In other embodiments, the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs). In some embodiments, the one or more genetic lesions is a point mutation, a fusion or any combination thereof. In some embodiments, the one or more receptor tyrosine kinase is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROSE
[0196] The compounds and compositions of the present disclosure may be suitable for treatment of certain subtypes of cancer or neoplastic diseases, which may also be associated with mutations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF. In some embodiments, the cancer is is a solid tumor or a hematological malignancy. In some embodiments, the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, or colorectal carcinoma. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In one aspect, provided herein is a method of treating a solid tumor or a hematological malignancy, comprising administering to the human a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. In some embodiments, the solid tumor or hematological malignancy is melanoma, lung cancer, pancreatic carcinoma, glioma, or colorectal carcinoma. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC).
[0197] In some embodiments of the present aspect, the cancer is a refractory cancer. In certain embodiments of the foregoing, the refractory cancer is associated with one or more genetic alterations in KRAS, NRAS, HRAS, BRAF, or one or more RTKs. In certain embodiments of the foregoing, the refractory cancer is associated with a genetic alteration or alterations in KRAS (including mutants G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E), NRAS (including mutants G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, G61L), HRAS (including mutants G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, Q61H), BRAF (including gene amplification, class II and III mutants [including G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, L597Q], BRAF fusions or alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10), RTKs (including ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1). In still further embodiments of the foregoing, the refractory cancer may be combined with any preceding embodiments of the present aspect, the method further comprises administering one or more pharmaceutical agents including anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, T0RC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation.
[0198] In some embodiments of the present aspect, the cancer is a refractory BRAF Class I mutant cancer. In some embodiments, the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R. In certain embodiments of the foregoing, the refractory cancer is associated with a genetic alteration in KRAS, NRAS, HRAS or BRAF that drives BRAF dimerization and confers resistance to approved Type 1.5 inhibitors (including vemurafenib, dabrafenib and encorafenib) both alone and in the context of MEK inhibitor (including cobimetinib, trametinib and binimetinib) combinations. In some embodiments, the refractory cancer is associated with one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E. In some embodiments, the refractory cancer is associated with one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L. In some embodiments, the refractory cancer is associated with one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, GBR, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H. In some embodiments, the refractory cancer is associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. In some embodiments, the refractory cancer is associated with one or more Class II or Class III mutations in BRAF. In some embodiments, the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q. In some embodiments, the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10. In still further embodiments of the foregoing, the method further comprises administering one or more pharmaceutical agents including anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors (including inhibitors against ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, ROS1), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II), MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation.
[0199] In some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, dog, cat, rabbit, or rodent. In some embodiments, the individual is a primate. In some embodiments, the individual is a human. In some embodiments, the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old.
[0200] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents. In some embodiments, the method further comprises administering radiation. In some embodiments, the method further comprises administering one or more additional pharmaceutical agents, including anti-microtubular therapies (e.g. paclitaxel, vincristine), topoisomerase inhibitors (e.g. adriamycin), alylating agents (e.g. busulfan, cyclophosphamide), nucleotide synthesis inhibitors (hyroxyurea), DNA synthesis inhibtiors (e.g. cytarabine), protein synthesis inhibitors (e.g. omacetaxine), developmental signaling pathway inhibitors (e.g. sonidegib, Hedgehog pathway), pro-apoptotic agents (e.g. venetoclax), Abl myristoyl-pocket binding inhibitors (e.g. asciminib), MEK1/2 inhibitors (e.g. trametinib, binimetinib), AKT inhibitors (e.g. ipatasertib), PI3K inhibitors (e.g. apelisib)and radiation.
VI. Dosing and Method of Administration
[0201] The dose of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular cancer, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is a therapeutically effective amount.
[0202] The compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal.
[0203] The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight. An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.
[0204] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable excipient.
[0205] A compound or composition provided herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
VII. Articles of Manufacture and Kits
[0206] The present disclosure further provides articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or cocrystal thereof, or a mixture of any of the foregoing, a composition described herein, or one or more unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed.
[0207] The present disclosure further provides kits for carrying out the methods of the present disclosure, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer or neoplastic disease, such as those associated with or mediated by RAF kinase activity.
[0208] In some embodiments, the kit contains instructions for the treatment of a disease or disorder mediated by or associated with RAF kinase activity. In some embodiments, the disease or disorder is associated with one or more genetic alterations in KRAS, NRAS, HR AS, ARAF, BRAF or CRAF.
[0209] The kits optionally further comprise a container comprising one or more additional pharmaceutical agents and which kits further comprise instructions on or in the package insert for treating the subject with an effective amount of the one or more additional pharmaceutical agents.
[0210] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf-life permit.
[0211] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
[0212] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual.
ENUMERATED EMBODIMENTS
[0213] The following enumerated embodiments are representative of some aspects of the invention.
Embodiment 1. A compound of formula (I)
Figure imgf000092_0001
or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein:
Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R4 groups; Y is a bond or -C(=O)-;
Figure imgf000093_0002
is a single or double bond, wherein when is a single bond, then X1 is -OH, and the carbon atom to which X1 is attached is optionally further substituted by R2’; when
Figure imgf000093_0001
double bond, then X1 is =O or =N-OH; R1 is C1-C6 alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups; R2 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R2 is optionally substituted with 1 to 5 R5 groups, R2’ is H or D; and R3 is H or C1-C6 alkyl; each R4 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; each R5 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; and each R6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 10-membered heteroaryl. Embodiment 2. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (I-1),
Figure imgf000094_0001
or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
Embodiment 3. The compound of embodiment 1, wherein the compound of formula (I) is a compound of formula (1-2):
Figure imgf000094_0002
(1-2) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing.
Embodiment 4. The compound of embodiment 1, wherein the compound is a compound of formula (1-3):
Figure imgf000094_0003
(1-3) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Embodiment 5. The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Y is a bond.
Embodiment 6. The compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Y is -C(=O)-.
Embodiment 7. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R1 is Ci-Ce alkyl optionally substituted by one or more R5 groups.
Embodiment 8. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R1 is C3-C7 cycloalkyl optionally substituted by one or more R5 groups.
Embodiment 9. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R1 is 4- to 7-membered heterocycloalkyl optionally substituted by one or more R5 groups.
Embodiment 10. The compound of any one of embodiments 1-4, 6 and 8, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Y is -C(=O)- and R1 is C3-C7 cycloalkyl, optionally substituted by one or more R5 groups.
Embodiment 11. The compound of any one of embodiments 1-4, 6, 8 and 10, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the compound is a compound of formula (I-l-a), (I-l-b), (I-2-a), (I- 2-b), (1-3 -a), or (1-3 -b),
Figure imgf000095_0001
Figure imgf000096_0001
Wherein:
A1 and A5 are each independently C, N, O, or S;
A2-A4 are each independently C-R4, N, N-R4, O, or S; provided that at least one of Ax-A5 is a heteroatom;
A6 and A11 are each independently C, N, O, or S; and
A7-A10 are each independently C-R4, N, N-R4, O, or S.
Embodiment 12. The compound of embodiment 11, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the compound is a compound of formula (I-l-a) or a compound of formula (I-l-b).
Embodiment 13. The compound of embodiment 11, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the compound is a compound of formula (I-2-a) or a compound of formula (I-2-b).
Embodiment 14. The compound of embodiment 11, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein the compound is a compound of formula (I-3-a) or a compound of formula (I-3-b). Embodiment 15. The compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is phenyl optionally substituted with 1 to 4 R4 groups.
Embodiment 16. The compound of any one of embodiments 1-15, wherein Ring A is
*
Figure imgf000097_0001
wherein f indicates the point of attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
Embodiment 17. The compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is 5- to 6-membered heteroaryl optionally substituted with 1 to 4 R4 groups.
Embodiment 18. The compound of any one of embodiments 1-14 and 17, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is an optionally substituted 5-membered heteroaryl.
Embodiment 19. The compound of any one of embodiments 1-14 and 17-18, wherein Ring A is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 3 R4 groups.
Embodiment 20. The compound of any one of embodiments 1-14 and 17-19, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any
Figure imgf000097_0002
t
Figure imgf000098_0001
, wherein f indicates the point of attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
Embodiment 21. The compound of any one of embodiments 1-14 and 17, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is an optionally substituted 6-membered heteroaryl.
Embodiment 22. The compound of any one of embodiments 1-14, 17 and 21, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted.
Embodiment 23. The compound of any one of embodiments 1-14, 17 and 21-22, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any
Figure imgf000098_0002
attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
Embodiment 24. The compound of any one of embodiments 1-14 and 17, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is a 5- to 6-membered heteroaryl comprising at least one nitrogen atom.
Embodiment 25. The compound of any one of embodiments 1-14 and 17, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is a 5- to 6-membered heteroaryl comprising two heteroatoms. Embodiment 26. The compound of any one of embodiments 1-14, 17, and 24-25, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein Ring A is a 5- to 6-membered heteroaryl comprising at least two nitrogen atoms.
Embodiment 27. The compound of any one of embodiments 1-4, 6, 8 and 10-26, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R1 is cyclopropyl optionally substituted by 1-2 R5 groups.
Embodiment 28. The compound of any one of embodiments 1-4, 6, 8 and 10-27, wherein the moiety
Figure imgf000099_0001
Embodiment 29. The compound of any one of embodiments 1-4, 6, 8 and 10-27, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R1 is cyclopropyl substituted by 1-2 fluorine atoms.
Embodiment 30. The compound of any one of embodiments 1-4, 6, 8, 10-27 and 29,
Figure imgf000099_0002
Embodiment 31. The compound of any one of embodiments 1-2, 5-12 and 15-30, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R2’, when present, is H.
Embodiment 32. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R2 is C1-C3 alkyl optionally substituted by 1-5 R5 groups.
Embodiment 33. The compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing,
Figure imgf000100_0001
Embodiment 34. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R2 is C2-C6 alkenyl optionally substituted by 1-5 R5 groups. Embodiment 35. The compound of any one of embodiments 1-31 and 34, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any
Figure imgf000100_0002
Embodiment 36. The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R2 is C3-C7 cycloalkyl optionally substituted by 1-5 R5 groups. Embodiment 37. The compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R3 is H. Embodiment 38. The compound of any one of embodiments 1-36, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R3 is C1-C6 alkyl. Embodiment 39. The compound of any one of embodiments 1-36 and 38, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein R3 is -CH3. Embodiment 40. The compound of any one of embodiments 1-4, 6, 8, 10-14 and 38, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein:
Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the 5- to 6- membered heteroaryl comprises at least one nitrogen atom and is optionally substituted with 1 to 5 R4 groups;
Y is -C(=O)-;
R1 is cyclopropyl optionally substituted with 1 to 2 fluorine atoms;
R2 is C1-C3 alkyl optionally substituted with 1 to 5 R5 groups, and
R2 is H or D;
R3 is independently C1-C3 alkyl; each R4 is independently H, F, Cl, Br, I, -OCF3, -OR6, =0, -N(R6)R6, -OCHF2, -CF3, - CHF2, -CN, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R5 is independently H, F, Cl, Br, I, -OCF3, -OR6, =0, -N(R6)R6, -OCHF2, -CF3, - CHF2, -CN, Ci-Ce alkyl, or Ci-Ce haloalkyl; and each R6 is independently H or Ci-Ce alkyl.
Embodiment 41. The compound of embodiment 40, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, wherein:
Figure imgf000101_0001
Figure imgf000102_0001
attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety;
Y is -C(=0)-; is a single bond, wherein
X1 is -OH;
R1 is cyclopropyl optionally substituted with 1 to 2 fluorine atoms;
R2 is -CH3 or -CH2CH3, and
R2 is H;
R3 is -CH3; each R5 is independently H, F, or -CH3; and each R6 is independently H or -CH3.
Embodiment 42. A compound, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, which is selected from the group consisting of:
Figure imgf000102_0002
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Embodiment 43. A compound, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, which is selected from the group consisting of:
Figure imgf000107_0002
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Embodiment 44. A compound, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, which is selected from the group consisting of:
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Embodiment 45. A pharmaceutical composition comprising the compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable excipients.
Embodiment 46. A method of inhibiting ARAE, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of any one of embodiments 1-44, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition according to embodiment 45.
Embodiment 47. A method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of any one of embodiments 1- 44, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition according to embodiment 45. Embodiment 48. The method of embodiment 47, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation.
Embodiment 49. The method of embodiment 47 or 48, wherein the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF.
Embodiment 50. The method of any one of embodiments 47-49, wherein the cancer or neoplastic disease is associated with: one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E; or one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, GBR, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L; or one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, GBR, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H; or one or more mutations in ARAF selected from the group consisting of S214C and S214F; or one or more mutations in BRAF selected from the group consisting of Class I, Class Ila, Class lib, Class lie, and Class III mutations; or one or more mutations in CRAF selected from the group consisting of P261A, P261L, E478K, R391W, R391S and T491I, or a CRAF fusion.
Embodiment 51. The method of any one of embodiments 47-50, wherein the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs).
Embodiment 52. The method of embodiment 51, wherein the one or more genetic lesions is a point mutation, a fusion or any combination thereof. Embodiment 53. The method of embodiment 51 or 52, wherin the one or more receptor tyrosine kinase is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROSE
Embodiment 54. The method of any one of embodiments 47-53, wherein the cancer is a refractory cancer.
Embodiment 55. The method of any one of embodiments 47-54, wherein the cancer is a refractory cancer associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events.
Embodiment 56. The method of any one of embodiments 47-55, the cancer is a refractory BRAF Class I mutant cancer.
Embodiment 57. The method of embodiment 56, wherein the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R.
Embodiment 58. The method of any one of embodiments 47-55, wherein the refractory cancer is associated with one or more Class II or Class III mutations in BRAF.
Embodiment 59. The method of embodiment 58, wherein the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q.
Embodiment 60. The method of embodiment 58, wherein the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10.
Embodiment 61. The method of any one of embodiments 47-60, wherein the cancer is a solid tumor or a hematological malignancy.
Embodiment 62. The method of embodiment 61, wherein the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, or colorectal carcinoma. Embodiment 63. The method of embodiment 62, wherein the lung cancer is non-small cell lung cancer (NSCLC).
Embodiment 64. The method of any one of embodiments 47-63, further comprising administering one or more pharmaceutical agents including anti -microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro- apoptotic agents, RTK inhibitors, RAF inhibitors representing alternative binding modes, MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, T0RC1/2 inhibitors, DNA damage response pathway inhibitors, PI3K inhibitors and/or radiation.
EXAMPLES
[0214] It is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of present disclosure.
Synthetic Examples
[0215] The chemical reactions in the Examples described can be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds of this disclosure are deemed to be within the scope of this disclosure. For example, the synthesis of non-exemplified compounds according to the present disclosure can be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions, reagents, and starting materials. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.
[0216] Abbreviations used in the Examples include the following: ACN: acetonitrile; Brettphos: 2-(dicyclohexylphosphino)3,6-dimethoxy-2’,4’,6’-triisopropyl-l,r-biphenyl; dba: dibenzylideneacetone; DPPA: diphenylphosphoryl azide; dppf: 1,1’ -ferrocenediyl - bis(diphenylphosphine); DCM: dichloromethane; DIEA: diisopropylethylamine; DMAP: 4- dimethylaminopyridine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EDCI: 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide; EtOAc: ethyl acetate; Ephos: Dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[l,l'-biphenyl]-2-yl)phosphane; EtOH: ethanol or ethyl alcohol; 'H NMR: proton nuclear magnetic resonance; IBA: Isobutanol; LCMS: liquid chromatography -mass spectrometry; LiHMDS: lithium hexamethyldisilazide; MeOH: methanol or methyl alcohol; NBS: N-bromosuccinimide; NIS: N-iodosuccinimide;
AcO or OAc: acetate; Py: pyridine; rt or RT: room temperature; t-BuOH: Zc/V-butanol or tertbutyl alcohol; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TLC: thin-layer chromatography; Xantphos: (9,9-Dimethyl-9J/-xanthene-4,5-diyl)bis(diphenylphosphane); and Xphos: Dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2-yl]phosphane.
Example 1. Synthesis of (lR,2R)-2-fluoro-N-{6-[2-({6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide (Compound 1.1) and (lR,2R)-2-fluoro-N-{6-[2-({6-[(lS)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide (Compound 1.2)
Step 1. Synthesis of (lR,2R)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-l- carboxamide
Figure imgf000118_0001
Cs2CO3, dioxane
[0217] To a solution of 4,6-dichloropyrimidine (1.0 g, 6.71 mmol) in dioxane (20.0 mL) was added (lR,2R)-2-fluorocyclopropane-l-carboxamide (692.1 mg, 6.71 mmol), CS2CO3 (6.6 g, 20.14 mmol), XantPhos (252.5 mg, 0.44 mmol) and Pd(dba)2 (193.0 mg, 0.34 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (46/54, v/v) to afford (lR,2R)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-l-carboxamide (600.0 mg, 41%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 216.0.
Step 2. Synthesis of (lR,2R)-N-[6-(2-aminopyridin-3-yl)pyrimidin-4-yl]-2- fluorocyclopropane-l-carboxamide
Figure imgf000119_0001
dioxane, H2O
[0218] To a solution of (lR,2R)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-l- carboxamide (540.0 mg, 2.51 mmol) in dioxane/ELO (10.0 mL/2.0 mL) was added 3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (551.2 mg, 2.51 mmol), CS2CO3 (1.6 g, 5.01 mmol) and Pd(PPh3)4 (289.4 mg, 0.25 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride/methanol (95/5, v/v) to afford (lR,2R)-N-[6-(2- aminopyridin-3-yl)pyrimidin-4-yl]-2-fluorocyclopropane-l-carboxamide (400.0 mg, 58%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ = 274.1.
Step 3. Synthesis of (lR,2R)-2-fluoro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyridin-3-yl}pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.1)
Figure imgf000119_0002
[0219] To a solution of (lR,2R)-N-[6-(2-aminopyridin-3-yl)pyrimidin-4-yl]-2- fluorocyclopropane-1 -carboxamide (400.0 mg, 1.46 mmol) in dioxane (10.0 mL) was added l-(5-bromo-4-methylpyridin-2-yl)propan-l-one (333.9 mg, 1.46 mmol), CS2CO3 (1.4 g, 4.39 mmol) and XantPhos Pd G3 (208.2 mg, 0.22 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride/methanol (95/4, v/v) to afford (lR,2R)-2- fluoro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3-yl)amino]pyridin-3-yl}pyrimidin-4- yl)cy cl opropane-1 -carboxamide (Compound 2.1, 400.0 mg, 65%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 421.2.
Step 4. Synthesis of (lR,2R)-2-fluoro-N-[6-(2-{[6-(l-hydroxypropyl)-4-methylpyridin-3- yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-l-carboxamide
Figure imgf000120_0001
[0220] To a solution of (lR,2R)-2-fluoro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyri din-3 -yl}pyrimidin-4-yl)cy cl opropane-1 -carboxamide (Compound 2.1, 400.0 mg, 0.95 mmol) in THF/MeOH (5.0 mL/5.0 mL) was added NaBH4 (36.0 mg, 0.95 mmol) at
0 °C under N2. The mixture was then warmed to room temperature and stirred for 1 h under
N2. After the reaction was completed, the reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure The residue was purified by silica gel chromatography eluting with methylene chloride/methanol (94/6, v/v) to afford (lR,2R)-2-fluoro-N-[6-(2-{[6-(l-hydroxypropyl)-4- methylpyridin-3-yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-l-carboxamide (60.0 mg, 14%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 423.2.
Step 5. Chiral Separation of (lR,2R)-2-fluoro-N-{6-[2-({6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide
(Compound 1.1) and (lR,2R)-2-fluoro-N-{6-[2-({6-[(lS)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide
(Compound 1.2)
Figure imgf000120_0002
[0221] The product of (lR,2R)-2-fluoro-N-[6-(2-{[6-(l-hydroxypropyl)-4-methylpyridin- 3-yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-l-carboxamide (60.0 mg, 0.14 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRALPAK AD-H, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 12 min; Wavelength: 254/220 nm; RT1(min): 7.43; RT2(min): 9.99) to afford (1R,2R)-2-fluoro-N-{6-[2-({6-[1- hydroxypropyl]-4-methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1- carboxamide Isomer A (retention time 7.43 minutes, 23.5 mg, 78%) as a yellow solid and (1R,2R)-2-fluoro-N-{6-[2-({6-[(1-hydroxypropyl]-4-methylpyridin-3-yl}amino)pyridin-3- yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B (retention time 9.99 minutes, 21.6 mg, 72%) as a yellow solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.1 and 1.2 in Table 1. [0222] (1R,2R)-2-fluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer A: RT1(min): 7.43; LCMS (ESI, m/z): [M+H]+ = 423.1. 1H NMR (400 MHz, DMSO-d6^^^į 11.47 (s, 1H), 11.37 (s, 1H), 9.13 - 9.08 (m, 2H), 8.67 (s, 1H), 8.30 (d, J = 4.0 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H), 7.35 (s, 1H), 6.98 - 6.95 (m, 1H), 5.18 (d, J = 4.8 Hz, 1H), 5.10 - 4.93 (m, 1H), 4.49 - 4.45 (m, 1H), 2.37 (s, 3H), 2.35 - 2.31 (m, 1H), 1.80 - 1.62 (m, 3H), 1.32 - 1.21 (m, 1H), 0.90 - 0.80 (m, 3H)濁 [0223] (1R,2R)-2-fluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B: RT2 (min): 9.99; LCMS (ESI, m/z): [M+H]+ = 423.2. 1H NMR (400 MHz, DMSO-d6): į 11.48 (s, 1H), 11.37 (s, 1H), 9.12 - 9.08 (m, 2H), 8.67 (s, 1H), 8.31 - 8.29 (m, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 6.99 - 6.96 (m, 1H), 5.17 (d, J = 4.8 Hz, 1H), 5.10 - 4.90 (m, 1H), 4.49 - 4.45 (m, 1H), 2.37 (s, 3H), 2.35 - 2.26 (m, 1H), 1.80 - 1.62 (m, 3H), 1.31 - 1.23 (m, 1H), 0.88 - 0.85 (m, 3H)濁 Example 2. Synthesis of (1R)-2,2-difluoro-N-{6-[2-({6-[(1R)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.3) and (1R)-2,2-difluoro-N-{6-[2-({6-[(1S)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.4) Step 1. Synthesis of tert-butyl N-(6-chloropyrimidin-4-yl)carbamate
Figure imgf000121_0001
[0224] To a solution of 4,6-dichloropyrimidine (5.0 g, 33.56 mmol) in dioxane (20.0 mL) was added tert-butyl carbamate (3.9 g, 33.56 mmol), Cs2CO3 (21.9 g, 67.13 mmol), XantPhos (1.3 g, 2.18 mmol) and Pd(dba)2 (1.0 g, 1.68 mmol) at room temperature under N2. The resulting mixture was then stirred at 70 °C for 16 h under N2. After the reaction was completed, the reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (1/1, v/v) to afford tert- butyl N-(6-chloropyrimidin-4-yl)carbamate (7.0 g, 64%) as a yellow solid LCMS (ESI, m/z): [M+H]+ =230.1. Step 2. Synthesis of tert-butyl N-[6-(2-aminopyridin-3-yl)pyrimidin-4-yl]carbamate
Figure imgf000122_0001
[0225] To a solution of tert-butyl N-(6-chloropyrimidin-4-yl)carbamate (2.0 g, 8.71 mmol) in dioxane/H2O (20.0 mL/4.0 mL) was added 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2-amine (1.9 g, 8.71 mmol), Cs2CO3 (8.5 g, 26.13mmol) and Pd(PPh3)4 (1.0 g, 0.87 mmol) at room temperature under N2. The resulting mixture was then stirred at 100 °C for 1 h under N2. After the reaction was completed, the reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) to afford tert-butyl N-[6-(2- aminopyridin-3-yl)pyrimidin-4-yl]carbamate (950.0 mg, 38%) as an orange solid. LCMS (ESI, m/z): [M+H]+ =288.1. Step 3. Synthesis of tert-butyl N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyridin-3-yl}pyrimidin-4-yl)carbamate
Figure imgf000122_0002
[0226] To a solution of tert-butyl N-[6-(2-aminopyridin-3-yl)pyrimidin-4-yl]carbamate (380.0 mg, 1.32 mmol) in dioxane (5.0 mL) was added 1-(5-bromo-4-methylpyridin-2- yl)propan-1-one (301.7 mg, 1.32 mmol), Cs2CO3 (68.0 mg, 0.21 mmol) and XantPhos Pd G3 (125.4 mg, 0.13 mmol) at room temperature under N2. The resulting mixture was then stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with methylene chloride/methanol (20/1, v/v) to afford tert-butyl N-(6-{2-[(4-methyl-6- propanoylpyridin-3-yl)amino]pyridin-3-yl}pyrimidin-4-yl)carbamate (360.0 mg, 63%) as a brown solid. LCMS (ESI, m/z): [M+H]+ =435.2. Step 4. Synthesis of 1-(5-{[3-(6-aminopyrimidin-4-yl)pyridin-2-yl]amino}-4- methylpyridin-2-yl)propan-1-one
Figure imgf000123_0001
[0227] To a solution of tert-butyl N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyridin-3-yl}pyrimidin-4-yl)carbamate (430.0 mg, 0.99 mmol) in DCM (4.0 mL) was added TFA (1.0 mL) at 0 oC. The resulting mixture was then warmed to room temperature and stirred for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7 with NaHCO3 (aq.) and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 1-(5-{[3-(6- aminopyrimidin-4-yl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)propan-1-one (330.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =335.2. Step 5. Synthesis of (1R)-2,2-difluoro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyridin-3-yl}pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 2.2)
Figure imgf000123_0002
[0228] To a solution of 1-(5-{[3-(6-aminopyrimidin-4-yl)pyridin-2-yl]amino}-4- methylpyridin-2-yl)propan-1-one (140.0 mg, 0.42 mmol) in Pyridine (5.0 mL) was added (1R)-2,2-difluorocyclopropane-1-carboxylic acid (51.1 mg, 0.42 mmol) and POCl3 (0.14 mL) at 0 °C and the resulting mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (3/1, v/v) to afford (lR)-2,2-difluoro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3-yl)amino]pyridin-3- yl}pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.2, 40.0 mg, 22%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =439.2.
Step 6. Synthesis of (lR)-2,2-difluoro-N-[6-(2-{[6-(l-hydroxypropyl)-4-methylpyridin-3- yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-l-carboxamide
Figure imgf000124_0001
[0229] To a solution of (lR)-2,2-difluoro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyri din-3 -yl}pyrimidin-4-yl)cy cl opropane-1 -carboxamide (Compound 2.2, 60.0 mg, 0.14 mmol) in MeOH/THF (2.0 mL/2.0 mL) was added NaBH4 (10.4 mg, 0.27 mmol) at 0 °C. The resulting mixture was then warmed to room temperature and stirred for 1 h. After the reaction was completed, the reaction mixture was quenched with water and then extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with methylene chloride/methanol (10/1, v/v) to afford (lR)-2,2-difluoro-N-[6-(2-{[6-(l-hydroxypropyl)-4-methylpyridin-3- yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-l-carboxamide (50.0 mg, 83%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =441.2.
Step 7. Chiral Separation of (lR)-2,2-difluoro-N-{6-[2-({6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide (Compound 1.3) and (lR)-2,2-difluoro-N-{6-[2-({6-[(lS)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide (Compound 1.4)
Figure imgf000125_0001
methylpyridin-3-yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-1-carboxamide (50.0 mg, 0.11 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SC, 2x^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[ (0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 25 min; Wavelength: 254/220 nm; RT1(min): 17.22; RT2(min): 22.05) to afford (1R)-2,2-difluoro-N-{6-[2-({6-[1-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer A (retention time 17.22 minUTES, 22.6 mg, 75%) as a yellow solid and (1R)-2,2-difluoro-N- {6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4- yl}cyclopropane-1-carboxamide Isomer B (retention time 22.05 minUTS, 14.8 mg, 49%) as a yellow solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.3 and 1.4 in Table 1. [0231] (1R)-2,2-difluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer A: RT1(min): 17.22. LCMS (ESI, m/z): [M+H]+ =441.2. 1H NMR (400 MHz, DMSO-d6): į^ 11.63 (s, 1H), 11.35 (s, 1H), 9.12 (s, 2H), 8.64 (s, 1H), 8.31 - 8.29 (m, 1H), 8.22 - 8.20 (m, 1H), 7.36 (s, 1H), 7.00 - 6.96 (m, 1H), 5.20 (d, J = 4.8 Hz, 1H), 4.50 - 4.47 (m, 1H), 3.13 - 3.05 (m, 1H), 2.37 (s, 3H), 2.14 - 2.07 (m, 2H), 1.81 - 1.75 (m, 1H), 1.67 - 1.60 (m, 1H), 0.88 - 0.85 (m, 3H). [0232] (1R)-2,2-difluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B: RT2(min): 22.05. LCMS (ESI, m/z): [M+H]+ =441.1. 1H NMR (400 MHz, DMSO-d6): į^ 11.62 (s, 1H), 11.34 (s, 1H), 9.11 (s, 2H), 8.64 (s, 1H), 8.31 - 8.29 (m, 1H), 8.22 - 8.20 (m, 1H), 7.35 (s, 1H), 7.00 - 6.96 (m, 1H), 5.19 (d, J = 4.8 Hz, 1H), 4.50 - 4.45 (m, 1H), 3.13 - 3.05 (m, 1H), 2.37 (s, 3H), 2.14 - 2.07 (m, 2H), 1.82 - 1.75 (m, 1H), 1.67 - 1.60 (m, 1H), 0.88 - 0.85 (m, 3H). Example 3. Synthesis of (1R)-2,2-difluoro-N-{6-[2-({6-[(1R)-1-hydroxybutyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.5) and (1R)-2,2-difluoro-N-{6-[2-({6-[(1S)-1-hydroxybutyl]-4-methylpyridin- 3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.6) Step 1. Synthesis of tert-butyl N-(6-{2-[(6-butanoyl-4-methylpyridin-3- yl)amino]pyridin-3-yl}pyrimidin-4-yl)carbamate
Figure imgf000126_0001
[0233] To a solution of tert-butyl N-[6-(2-aminopyridin-3-yl)pyrimidin-4-yl]carbamate (570.0 mg, 1.98 mmol) in dioxane (20.0 mL) was added 1-(5-bromo-4-methylpyridin-2- yl)butan-1-one (480.3 mg, 1.98 mmol), Cs2CO3 (1.9 g, 5.95 mmol), BrettPhos (213.0 mg, 0.40 mmol) and BrettPhos Pd G3 (179.8 mg, 0.20 mmol) at room temperature under N2. The resulting mixture was then stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was then purified by silica gel chromatography eluting with methylene chloride/methanol (10/1, v/v) to afford tert-butyl N-(6-{2-[(6- butanoyl-4-methylpyridin-3-yl)amino]pyridin-3-yl}pyrimidin-4-yl)carbamate (520.0 mg, 58%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =449.2. Step 2. Synthesis of 1-(5-{[3-(6-aminopyrimidin-4-yl)pyridin-2-yl]amino}-4-
Figure imgf000126_0002
[0234] To a solution of tert-butyl N-(6-{2-[(6-butanoyl-4-methylpyridin-3- yl)amino]pyridin-3-yl}pyrimidin-4-yl)carbamate (630.0 mg, 1.41 mmol) in DCM (4.0 mL) was added TFA (1.0 mL) at 0 oC. The resulting mixture was then warmed to room temperature and stirred for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7 with NaHCO3 (aq) and the mixture was extracted with ethyl acetate. The combined organic layer was then washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 1-(5-{[3-(6- aminopyrimidin-4-yl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)butan-l-one (290.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =349.2.
Step 3. Synthesis of (lR)-N-(6-{2-[(6-butanoyl-4-methylpyridin-3-yl)amino]pyridin-3- yl}pyrimidin-4-yl)-2,2-difluorocyclopropane-l-carboxamide (Compound 2.3)
Figure imgf000127_0001
[0235] To a solution of l-(5-{[3-(6-aminopyrimidin-4-yl)pyridin-2-yl]amino}-4- methylpyridin-2-yl)butan-l-one (290.0 mg, 0.83 mmol) in Pyridine (5.0 mL) was added (lR)-2,2-difluorocyclopropane-l-carboxylic acid (101.6 mg, 0.83 mmol) and POCh (0.29 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with methylene chloride/methanol (20/1, v/v) to afford (lR)-N-(6-{2-[(6-butanoyl-4-methylpyridin-3-yl)amino]pyridin-3-yl}pyrimidin-4-yl)-2,2- difluorocyclopropane- 1 -carboxamide (Compound 2.3, 70.0 mg, 19%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =453.2.
Step 4. Synthesis of (lR)-2,2-difluoro-N-[6-(2-{[6-(l-hydroxybutyl)-4-methylpyridin-3- yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-l-carboxamide
Figure imgf000127_0002
[0236] To a solution of (lR)-N-(6-{2-[(6-butanoyl-4-methylpyridin-3-yl)amino]pyridin- 3 -yl}pyrimidin-4-yl)-2,2-difluorocyclopropane-l -carboxamide (Compound 2.3, 75.0 mg, 0.17 mmol) in MeOH/THF (2.0 mL/2.0 mL) was added NaBEL (12.5 mg, 0.33 mmol) at 0 °C. The resulting mixture was then warmed to room temperature and stirred for 1 h. After the reaction was completed, the reaction mixture was quenched with water and then extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrousanhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure and the residue was purified by reverse phase Cl 8 chromatography eluting with acetonitrile/water (2/3, v/v) to afford (1R)-2,2-difluoro-N-[6-(2-{[6-(1-hydroxybutyl)-4- methylpyridin-3-yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-1-carboxamide (20.0 mg, 27%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =455.2. Step 5. Chiral Separation of (1R)-2,2-difluoro-N-{6-[2-({6-[(1R)-1-hydroxybutyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.5) and (1R)-2,2-difluoro-N-{6-[2-({6-[(1S)-1-hydroxybutyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.6)
Figure imgf000128_0001
[0237] The product of (1R)-2,2-difluoro-N-[6-(2-{[6-(1-hydroxybutyl)-4-methylpyridin- 3-yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-1-carboxamide (20.0 mg, 0.04 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-6&^^^[^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^^0^1+^-MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 19 min; Wavelength: 254/220 nm; RT1(min): 13.91; RT2(min): 17.12) to afford (1R)-2,2- difluoro-N-{6-[2-({6-[1-hydroxybutyl]-4-methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin- 4-yl}cyclopropane-1-carboxamide Isomer A (retention time 13.91 minutes, 5.9 mg, 59%) as a yellow solid and (1R)-2,2-difluoro-N-{6-[2-({6-[1-hydroxybutyl]-4-methylpyridin-3- yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B (retention time 17.12 minutes, 5.3 mg, 53%) as a yellow solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixtures as described above are shown as Compounds 1.5 and 1.6 in Table 1. [0238] (1R)-2,2-difluoro-N-{6-[2-({6-[1-hydroxybutyl]-4-methylpyridin-3- yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer A: RT1(min): 13.91. LCMS (ESI, m/z): [M+H]+ =455.2. 1H NMR (400 MHz, DMSO-d6): į^ 11.64 (s, 1H), 11.33 (s, 1H), 9.11 - 9.09 (m, 2H), 8.63 (s, 1H), 8.30 - 8.19 (m, 2H), 7.35 (s, 1H), 6.98 - 6.95 (m, 1H), 5.19 (d, J = 4.8 Hz, 1H), 4.55 - 4.51 (m, 1H), 3.12 - 3.04 (m, 1H), 2.36 (s, 3H), 2.14 - 2.07 (m, 2H), 1.71 - 1.58 (m, 2H), 1.38 - 1.23 (m, 2H), 0.90 - 0.86 (m, 3H). [0239] (1R)-2,2-difluoro-N-{6-[2-({6-[1-hydroxybutyl]-4-methylpyridin-3- yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B: RT2(min): 17.12. LCMS (ESI, m/z): [M+H]+ =455.3. 1H NMR (400 MHz, DMSO-d6): į^ 11.62 (s, 1H), 11.32 (s, 1H), 9.10 - 9.08 (m, 2H), 8.63 (s, 1H), 8.30 - 8.28 (m, 1H), 8.21 - 8.19 (m, 1H), 7.35 (s, 1H), 6.98 - 6.95 (m, 1H), 5.17 (s, 1H), 4.56 - 4.53 (m, 1H), 3.13 - 3.05 (m, 1H), 2.36 (s, 3H), 2.14 - 2.08 (m, 2H), 1.74 - 1.67 (m, 1H), 1.65 - 1.51 (m, 1H), 1.44 - 1.29 (m, 2H), 0.92 - 0.85 (m, 3H). Example 4. Synthesis of (1R,2R)-2-fluoro-N-(6-(2-((6-((R)-1-hydroxybutyl)-4- methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.7) and (1R,2R)-2-fluoro-N-(6-(2-((6-((S)-1-hydroxybutyl)-4-methylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.8) Step 1. Synthesis of (1R,2R)-N-(6-(2-((6-butyryl-4-methylpyridin-3-yl)amino)pyridin-3- yl)pyrimidin-4-yl)-2-fluorocyclopropane-1-carboxamide (Compound 2.4)
Figure imgf000129_0001
. [0240] To a solution of (1R,2R)-N-(6-(2-aminopyridin-3-yl)pyrimidin-4-yl)-2- fluorocyclopropane-1-carboxamide (500.0 mg, 1.83 mmol) in dioxane (10.0 mL) was added 1-(5-bromo-4-methylpyridin-2-yl)butan-1-one (443.0 mg, 1.83 mmol), XantPhos Pd G3 (260.3 mg, 0.28 mmol ) and Cs2CO3 (1.8 g, 5.49 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (1/1, v/v) to afford (1R,2R)-N-(6- (2-((6-butyryl-4-methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)-2- fluorocyclopropane-1-carboxamide (Compound 2.4, 250.0 mg, 31%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 435.2. Step 2. Synthesis of (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxybutyl)-4-methylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide
Figure imgf000130_0001
[0241] To a solution of (lR,2R)-N-(6-(2-((6-butyryl-4-methylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)-2-fluorocyclopropane-l -carboxamide (Compound 2.4, 150.0 mg, 0.33 mmol) in THF/CH3OH (5.0 mL/1.0 mL) was added NaBH4 (39.1 mg, 1.04 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was quenched with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase C18 chromatography eluting with water/acetonitrile (3/7, v/v) to afford (lR,2R)-2-fluoro-N-(6-(2-((6-(l-hydroxybutyl)-4- m ethylpyri din-3 -yl)amino)pyri din-3 -yl)pyrimidin-4-yl)cy cl opropane-1 -carboxamide (80.0 mg, 53%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 437.2.
Step 3. Chiral Separation of (lR,2R)-2-fluoro-N-(6-(2-((6-((R)-l-hydroxybutyl)-4- methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
(Compound 1.7) and (lR,2R)-2-fluoro-N-(6-(2-((6-((S)-l-hydroxybutyl)-4- methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
(Compound 1.8)
OH OH OH
Figure imgf000130_0002
[0242] The product of (lR,2R)-2-fluoro-N-(6-(2-((6-(l-hydroxybutyl)-4-methylpyridin- 3 -yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (80.0 mg, 0.18 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 15 min; Wavelength: 254/220 nm; RTl(min): 11.42; RT2(min): 13.44) to afford (lR,2R)-2- fluoro-N-(6-(2-((6-(l-hydroxybutyl)-4-methylpyri din-3 -yl)amino)pyri din-3 -yl)pyrimidin-4- yl)cyclopropane-l -carboxamide Isomer A (retention time 11.42 minutes, 17.3 mg, 43%) as a yellow solid and (lR,2R)-2-fluoro-N-(6-(2-((6-(l-hydroxybutyl)-4-methylpyridin-3- yl)amino)pyri din-3 -yl)pyrimi din-4-yl)cy cl opropane-1 -carboxamide Isomer B (retention time 13.44 minutes, 12.8 mg, 32%) as a yellow solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.7 and 1.8 in Table 1. [0243] (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxybutyl)-4-methylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A: RT1 (min): 11.42; LCMS (ESI, m/z): [M+H]+ = 437.2. 1H NMR (400 MHz, DMSO-d6): į 11.50 (s, 1H), 11.37 (s, 1H), 9.12 – 9.08 (m, 2H), 8.67 (s, 1H), 8.30 – 8.28 (m, 1H), 8.21 – 8.19 (m, 1H), 7.35 (s, 1H), 6.98 – 6.95 (m, 1H), 5.17 (d, J = 4.8 Hz, 1H), 5.11 – 4.90 (m, 1H), 4.55 – 4.52 (m, 1H), 2.37 (s, 3H), 2.35 – 2.30 (m, 1H), 1.74 – 1.67 (m, 2H), 1.65 – 1.59 (m, 1H), 1.39 – 1.23 (m, 3H), 0.91 – 0.87 (m, 3H). [0244] (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxybutyl)-4-methylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B: RT2 (min): 13.44; LCMS (ESI, m/z): [M+H]+ = 437.2. 1H NMR (400 MHz, DMSO-d6): į 11.50 (s, 1H), 11.37 (s, 1H), 9.12 – 9.08 (m, 2H), 8.67 (s, 1H), 8.30 – 8.28 (m, 1H), 8.21 – 8.19 (m, 1H), 7.35 (s, 1H), 6.98 – 6.95 (m, 1H), 5.18 (d, J = 4.8 Hz, 1H), 5.11 – 4.90 (m, 1H), 4.55 – 4.52 (m, 1H), 2.37 (s, 3H), 2.35 – 2.30 (m, 1H), 1.74 – 1.69 (m, 2H), 1.68 – 1.59 (m, 1H), 1.39 – 1.25 (m, 3H), 0.91 – 0.87 (m, 3H). Example 5. Synthesis of (1R,2R)-2-fluoro-N-(6-(3-((6-((R)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.9) and (1R,2R)-2-fluoro-N-(6-(3-((6-((S)-1-hydroxypropyl)-4-methylpyridin- 3-yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.10) Step 1. Synthesis of 6-(3-aminopyrazin-2-yl)-N,N-bis(4-methoxybenzyl)pyrimidin-4- amine
Figure imgf000131_0001
[0245] To a solution of N,N-bis(4-methoxybenzyl)-6-(tributylstannyl)pyrimidin-4-amine (1.5 g, 2.57 mmol) in dioxane (60.0 mL) was added 3-bromopyrazin-2-amine (535.9 mg, 3.08 mmol), CuI (97.8 mg, 0.51 mmol) and Pd(PPh3)2Cl2 (360.3 mg, 0.51 mmol) at room temperature under N2. The resulting mixture was stirred at 100 ^ for 2 h under N2. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (83/17, v/v) to afford 6-(3-aminopyrazin-2-yl)-N,N-bis(4-methoxybenzyl)pyrimidin-4-amine (300.0 mg, 30%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 429.2.
Step 2. Synthesis of l-(5-((3-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)pyrazin-2- yl)amino)-4-methylpyridin-2-yl)propan-l-one
Figure imgf000132_0001
[0246] To a solution of 6-(3-aminopyrazin-2-yl)-N,N-bis(4-methoxybenzyl)pyrimidin-4- amine (300.0 mg, 0.77 mmol) in dioxane (10.0 mL) was added l-(5-bromo-4-methylpyridin- 2-yl)propan-l-one (211.4 mg, 0.93 mmol), CS2CO3 (754.9 mg, 2.32 mmol), BrettPhos (165.8 mg, 0.31 mmol) and BrettPhos Pd G3 (140.0 mg, 0.15 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (84/16, v/v) to afford 1- (5-((3-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)pyrazin-2-yl)amino)-4-methylpyridin- 2-yl)propan-l-one (400.0 mg, 96%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 576.3.
Step 3. Synthesis of l-(5-((3-(6-aminopyrimidin-4-yl)pyrazin-2-yl)amino)-4- methylpyridin-2-yl)propan-l-one
Figure imgf000132_0002
[0247] The solution of l-(5-((3-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)pyrazin- 2-yl)amino)-4-methylpyridin-2-yl)propan-l-one (500.0 mg, 0.93 mmol) in TFA (15.0 mL) was stirred at 80 °C for 1 h. After the reaction was completed, the resulting mixture was cooled to room temperature and then concentrated under reduced pressure. The pH value of the residue was adjusted to 7 with NaHCCh (aq.) and the mixture was filtered. The resulting solid was washed with water and collected to afford l-(5-((3-(6-aminopyrimidin-4- yl)pyrazin-2-yl)amino)-4-methylpyridin-2-yl)propan-l-one (300.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 336.1.
Step 4. Synthesis of (lR,2R)-2-fluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3- yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.5)
Figure imgf000133_0001
[0248] To a solution of (lR,2R)-2-fluorocyclopropane-l-carboxylic acid (93.1 mg, crude) in pyridine (9.0 mL) was added l-(5-((3-(6-aminopyrimidin-4-yl)pyrazin-2-yl)amino)-4- methylpyridin-2-yl)propan-l-one (300.0 mg, 0.90 mmol) and POCh (489.4 mg, 3.22 mmol) at 0 °C under N2. The resulting mixture was then warmed to room temperature and stirred for 1 h under N2. After the reaction was completed, the reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gelchromatography eluting with petroleum ether/ethyl acetate (44/56, v/v) to afford (lR,2R)-2-fluoro-N-(6-(3-((4-methyl-6- propionylpyri din-3 -yl)amino)pyrazin-2 -yl)pyrimidin-4-yl)cy cl opropane-1 -carboxamide (Compound 2.5, 200.0 mg, 53%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 422.2.
Step 5. Synthesis of (lR,2R)-2-fluoro-N-(6-(3-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
Figure imgf000133_0002
[0249] To a solution of (lR,2R)-2-fluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3- yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.5, 170.0 mg, 0.40 mmol) in THF/MeOH (6.0 mL/1.2 mL) was added NaBEL (30.5 mg, 0.81 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gelchromatography with dichloromethane/methanol (98/2, v/v) to afford (1R,2R)-2-fluoro-N-(6-(3-((6-(1- hydroxypropyl)-4-methylpyridin-3-yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-1- carboxamide (50.0 mg, 29%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 424.2. Step 6. Chiral Separation of (1R,2R)-2-fluoro-N-(6-(3-((6-((R)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.9) and (1R,2R)-2-fluoro-N-(6-(3-((6-((S)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.10)
Figure imgf000134_0001
[0250] The product of (1R,2R)-2-fluoro-N-(6-(3-((6-(1-hydroxypropyl)-4-methylpyridin- 3-yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (50.0 mg, 0.12 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRALPAK IC, 2x^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[ (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 13 min; Wavelength: 220/254 nm; RT1(min): 7.19; RT2(min): 11.15) to afford (1R,2R)-2-fluoro-N- (6-(3-((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)pyrazin-2-yl)pyrimidin-4- yl)cyclopropane-1-carboxamide Isomer A (retention time 7.19 minutes, 6.2 mg, 24%) as a yellow solid and (1R,2R)-2-fluoro-N-(6-(3-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B (retention time 11.15 minutes, 10.3 mg, 41%) as a yellow solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.9 and 1.10 in Table 1. [0251] (1R,2R)-2-fluoro-N-(6-(3-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A: RT1(min): 7.19; LCMS (ESI, m/z): [M+H]+ = 424.1. 1H NMR (300 MHz, DMSO-d6^^^į 11.88 (s, 1H), 11.48 (s, 1H), 9.20 - 9.11 (m, 3H), 8.35 - 8.20 (m, 2H), 7.40 (s, 1H), 5.21 - 4.87 (m, 2H), 4.51 - 4.47 (m, 1H), 2.41 (s, 3H), 2.37 - 2.28 (m, 1H), 1.84 - 1.60 (m, 3H), 1.33 - 1.22 (m, 1H), 0.90 - 0.85 (m, 3H). [0252] (1R,2R)-2-fluoro-N-(6-(3-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyrazin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B: RT2(min): 11.15; LCMS (ESI, m/z): [M+H]+ = 424.3. 1H NMR (400 MHz, DMSO-d6^^^į 11.89 (s, 1H), 11.48 (s, 1H), 9.20 - 9.11 (m, 3H), 8.35 (s, 1H), 8.21 (s, 1H), 7.41 (s, 1H), 5.21 (d, J = 4.8 Hz, 1H), 5.10 - 4.92 (m, 1H), 4.51 - 4.47 (m, 1H), 2.42 (s, 3H), 2.34 - 2.30 (m, 1H) 1.82 - 1.61 (m, 3H), 1.30 - 1.25 (m, 1H), 0.89 - 0.85 (m, 3H). Example 6. Synthesis of (1R,2R)-2-fluoro-N-[5'-({6-[(1R)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)-[4,4'-bipyrimidin]-6-yl]cyclopropane-1-carboxamide (Compound 1.11) and (1R,2R)-2-fluoro-N-[5'-({6-[(1S)-1-hydroxypropyl]-4-methylpyridin- 3-yl}amino)-[4,4'-bipyrimidin]-6-yl]cyclopropane-1-carboxamide (Compound 1.12) Step 1. Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-(6-chloropyrimidin-4- yl)carbamate
Figure imgf000135_0001
[0253] To a solution of 6-chloropyrimidin-4-amine (5.0 g, 38.60 mmol) in THF (120.0 mL) was added DMAP (0.9 g, 7.72 mmol) and Boc2O (16.9 g, 77.19 mmol) and the resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gelchromatography eluting with petroleum ether/ethyl acetate (74/26, v/v) to afford tert-butyl N-(tert-butoxycarbonyl)-N-(6-chloropyrimidin-4-yl)carbamate (9.0 g, 70%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 330.1. Step 2. Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-[6-(tributylstannyl)pyrimidin- 4-yl]carbamate
Figure imgf000135_0002
[0254] To a solution of tert-butyl N-(tert-butoxycarbonyl)-N-(6-chloropyrimidin-4- yl)carbamate (2.0 g, 6.07 mmol) in dioxane (80.0 mL) was added hexabutyldistannane (10.6 g, 18.20 mmol) and Pd(PPh3)4 (350.4 mg, 0.30 mmol) at room temperature under N2. The resulting mixture was stirred at 110 oC for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase C18chromatography eluting with acetonitrile/water (98/2, v/v) to afford tert-butyl N- (tert-butoxycarbonyl)-N-[6-(tributylstannyl)pyrimidin-4-yl]carbamate (576.0 mg, 16%) as a light yellow oil. LCMS (ESI, m/z): [M+H]+ = 586.3.
Step 3. Synthesis of tert-butyl N-{5'-amino-[4,4'-bipyrimidin]-6-yl}-N-(tert- butoxycarbonyl)carbamate
Figure imgf000136_0001
[0255] To a solution of tert-butyl N-(tert-butoxycarbonyl)-N-[6- (tributylstannyl)pyrimidin-4-yl]carbamate (500.0 mg, 0.86 mmol) in dioxane (16.0 mL) was added 4-iodopyrimidin-5-amine (189.1 mg, 0.86 mmol), Cui (16.3 mg, 0.09 mmol) and Pd(PPh3)2C12 (60.1 mg, 0.09 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase C18chromatography eluting with methanol/water (95/5, v/v) to afford tert-butyl N-{5'-amino- [4,4'-bipyrimidin]-6-yl}-N-(tert-butoxycarbonyl)carbamate (90.0 mg, 27%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 389.2.
Step 4. Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-{5'-[(4-methyl-6- propa
Figure imgf000136_0002
[0256] To a solution of tert-butyl N-{5'-amino-[4,4'-bipyrimidin]-6-yl}-N-(tert- butoxycarbonyl)carbamate (90.0 mg, 0.23 mmol) in dioxane (3.0 mL) was added l-(5- bromo-4-methylpyridin-2-yl)propan-l-one (52.9 mg, 0.23 mmol), CS2CO3 (151.0 mg, 0.46 mmol), XantPhos (26.8 mg, 0.05 mmol), and Pd(dba)2 (13.3 mg, 0.02 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 4 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gelchromatography eluting with petroleum ether/ethyl acetate (40/60, v/v) to afford tert-butyl N-(tert-butoxycarbonyl)-N-{5'-[(4-methyl-6-propanoylpyridin-3- yl)amino]-[4,4'-bipyrimidin]-6-yl}carbamate (80.0 mg, 64%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 536.3.
Step 5. Synthesis of l-[5-({6'-amino-[4,4'-bipyrimidin]-5-yl}amino)-4-methylpyridin-2- yl]propan-l-one
Figure imgf000137_0001
[0257] To a solution of tert-butyl N-(tert-butoxycarbonyl)-N-{5'-[(4-methyl-6- propanoylpyridin-3-yl)amino]-[4,4'-bipyrimidin]-6-yl}carbamate (60.0 mg, 0.11 mmol) in CH2CI2 (2.0 mL) was added TFA (2.0 mL) and the resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 7 with NaHCCh (aq.) and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford l-[5-({6'-amino-[4,4'-bipyrimidin]-5-yl}amino)-4- methylpyridin-2-yl]propan-l-one (50.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 336.2.
Step 6. Synthesis of (lR,2R)-2-fluoro-N-{5'-[(4-methyl-6-propanoylpyridin-3-yl)amino]- [4,4'-bipyrimidin]-6-yl}cyclopropane-l-carboxamide (Compound 2.6)
Figure imgf000137_0002
[0258] To a solution of l-[5-({6'-amino-[4,4'-bipyrimidin]-5-yl}amino)-4-methylpyridin- 2-yl]propan-l-one (50.0 mg, crude) in pyridine (4.0 mL) was added (lR,2R)-2- fluorocyclopropane-1 -carboxylic acid (15.5 mg, 0.15 mmol) and POCI3 (0.1 mL) at 0 °C. The resulting mixture was then warmed to room temperature and stirred for 1 h. After the reaction was completed, the reaction mixture was quenched with H2O and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gelchromatography eluting with dichloromethane/methanol (95/5, v/v) to afford (lR,2R)-2-fluoro-N-{5'-[(4-methyl-6-propanoylpyridin-3-yl)amino]-[4,4'- bipyrimidin]-6-yl} cyclopropane- 1 -carboxamide (Compound 2.6, 45.0 mg, 71%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 422.2.
Step 7. Synthesis of (lR,2R)-2-fluoro-N-(5'-{[6-(l-hydroxypropyl)-4-methylpyridin-3- yl]amino}-[4,4'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide
Figure imgf000138_0001
[0259] To a solution of (lR,2R)-2-fluoro-N-{5'-[(4-methyl-6-propanoylpyridin-3- yl)amino]-[4,4'-bipyrimidin]-6-yl}cyclopropane-l-carboxamide (Compound 2.6, 45.0 mg, 0.11 mmol) in THF/MeOH (1.0 mL/1.0 mL) was added NaBEL (4.9 mg, 0.13 mmol) at 0 °C under N2. The mixture was then warmed to room temperature and stirred for 1 h under N2.
After the reaction was completed, the reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gelchromatography eluting with dichloromethane/methanol (90/10, v/v) to afford (lR,2R)-2-fhioro-N-(5'-{[6-(l- hydroxypropyl)-4-methylpyridin-3-yl]amino}-[4,4'-bipyrimidin]-6-yl)cyclopropane-l- carboxamide (40.0 mg, 88%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 424.2.
Step 8. Chiral Separation of (!R,2R)-2-fluoro-N-[5'-({6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)-[4,4'-bipyrimidin]-6-yl]cyclopropane-l-carboxamide (Compound 1.11) and (lR,2R)-2-fluoro-N-[5'-({6-[(lS)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)-[4,4'-bipyrimidin]-6-yl]cyclopropane-l-carboxamide (Compound 1.12)
Figure imgf000138_0002
[0260] The product of (lR,2R)-2-fluoro-N-(5'-{[6-(l-hydroxypropyl)-4-methylpyridin-3- yl]amino}-[4,4'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide (40.0 mg, 0.09 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SC, 2x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1— HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 11.5 min; Wavelength: 220/254 nm; RTl(min): 8.80; RT2(min): 10.55) to afford (lR,2R)-2- fluoro-N-[5'-({6-[l-hydroxypropyl]-4-methylpyridin-3-yl}amino)-[4,4'-bipyrimidin]-6- yl]cyclopropane-l-carboxamide Isomer A (retention time 8.80 minutes, 5.3 mg, 27%) as a yellow solid and (lR,2R)-2-fluoro-N-[5'-({6-[l-hydroxypropyl]-4-methylpyridin-3- yl}amino)-[4,4'-bipyrimidin]-6-yl]cyclopropane-l-carboxamide Isomer B (retention time 10.55 minutes, 5.0 mg, 25%) as a yellow solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.11 and 1.12 in Table 1.
[0261] (lR,2R)-2-fluoro-N-[5'-({6-[l-hydroxypropyl]-4-methylpyridin-3-yl}amino)- [4,4'-bipyrimidin]-6-yl]cyclopropane-l-carboxamide Isomer A: RTl(min): 8.80; LCMS (ESI, m/z): [M+H]+ = 424.2. ’H NMR (400 MHz, DMSO-t/e): 5 11.50 (s, 1H), 10.72 (s, 1H), 9.24 (s, 1H), 9.10 (s, 1H), 8.74 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 7.47 (s, 1H), 5.30 (d, J = 4.8 Hz, 1H), 5.12 - 4.91 (m, 1H), 4.54 - 4.50 (m, 1H), 2.32 - 2.29 (m, 4H), 1.84 - 1.62 (m, 3H), 1.32 - 1.23 (m, 1H), 0.89 - 0.86 (m, 3H).
[0262] (lR,2R)-2-fluoro-N-[5*-({6-[l-hydroxypropyl]-4-methylpyridin-3-yl} amino)-
[4,4*-bipyrimidin]-6-yl]cyclopropane-l-carboxamide Isomer B: RT2 (min): 10.55; LCMS (ESI, m/z): [M+H]+ = 424.2. 1HNMR (400 MHz, DMSO-t/e): 5 11.51 (s, 1H), 10.72 (s, 1H), 9.24 (s, 1H), 9.10 (s, 1H), 8.74 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 7.47 (s, 1H), 5.29 (d, J = 4.8 Hz, 1H), 5.12 - 4.91 (m, 1H), 4.54 - 4.50 (m, 1H), 2.32 - 2.29 (m, 4H), 1.84 - 1.66 (m, 3H), 1.32 - 1.23 (m, 1H), 0.90 - 0.85 (m, 3H).
Example 7. Synthesis of (lR,2R)-2-fluoro-N-{6-[5-({6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)-l,3-thiazol-4-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide (Compound 1.13) and (lR,2R)-2-fluoro-N-{6-[5-({6-[(lS)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)-l,3-thiazol-4-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide (Compound 1.14)
Step 1. Synthesis of tert-butyl N-(l,3-thiazol-5-yl)carbamate oc
Figure imgf000140_0001
[0263] To a solution of l,3-thiazole-5-carboxylic acid (4.0 g, 30.98 mmol) in t-BuOH (20.0 mL) was added DPPA (17.1 g, 61.95 mmol) and TEA (6.3 g, 61.95 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (2/1, v/v) to afford tertbutyl N-(l,3-thiazol-5-yl)carbamate (4.0 g, 64%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =201.1.
Step 2. Synthesis of tert-butyl (4-iodothiazol-5-yl)carbamate
Boc Boc
HNX HhL
Figure imgf000140_0002
[0264] To a solution of tert-butyl N-(l,3-thiazol-5-yl)carbamate (4.0 g, 19.97 mmol) in DMF (20.0 mL) was added NIS (4.5 g, 19.97 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gelchromatography with petroleum ether/ethyl acetate (3/1, v/v) to afford tert-butyl (4-iodothiazol-5-yl)carbamate (2.2 g, 34%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ =327.0.
Step 3. Synthesis of (lR,2R)-2-fluoro-N-[6-(tributylstannyl)pyrimidin-4- yl]cyclopropane-l-carboxamide
Figure imgf000140_0003
[0265] To a solution of (lR,2R)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-l- carboxamide (1.0 g, 4.64 mmol) in dioxane (10.0 mL) was added Sn2(n-Bu)e (8.1 g, 13.91 mmol) and Pd(PPhs)4 (268.0 mg, 0.23 mmol) at room temperature. The resulting mixture was stirred at 110 °C for 16 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gelchromatography eluting with petroleum ether/ethyl acetate (1/1, v/v) to afford (lR,2R)-2- fluoro-N-[6-(tributylstannyl)pyrimidin-4-yl]cyclopropane-1-carboxamide (500.0 mg, 23%) as a light yellow oil. LCMS (ESI, m/z): [M+H]+ =472.2. Step 4. Synthesis of tert-butyl N-(4-{6-[(1R,2R)-2-fluorocyclopropaneamido]pyrimidin- 4-yl}-1,3-thiazol-5-yl)carbamate
Figure imgf000141_0001
[0266] To a solution of (1R,2R)-2-fluoro-N-[6-(tributylstannyl)pyrimidin-4- yl]cyclopropane-1-carboxamide (300.0 mg, 0.64 mmol) in dioxane (5.0 mL) was added tert- butyl (4-iodothiazol-5-yl)carbamate (207.6 mg, 0.64 mmol), CuI (24.3 mg, 0.13 mmol) and Pd(PPh3)2Cl2 (89.6 mg, 0.13 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gelchromatography eluting with petroleum ether/ethyl acetate (1/1, v/v) to afford tert-butyl N-(4-{6-[(1R,2R)-2- fluorocyclopropaneamido]pyrimidin-4-yl}-1,3-thiazol-5-yl)carbamate (95.0 mg, 39%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =380.1. Step 5. Synthesis of (1R,2R)-N-[6-(5-amino-1,3-thiazol-4-yl)pyrimidin-4-yl]-2- fluorocyclopropane-1-carboxamide
Figure imgf000141_0002
[0267] To a solution of tert-butyl N-(4-{6-[(1R,2R)-2- fluorocyclopropaneamido]pyrimidin-4-yl}-1,3-thiazol-5-yl)carbamate (155.0 mg, 0.41 mmol) in DCM (4.0 mL) was added TFA (1.0 mL) at 0 °C. The resulting mixture was then warmed to room temperature and stirred for 1 h. After the reaction was completed, the pH value of the mixture was adjusted to 7 with NaHCO3 (aq.) and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (1R,2R)- N-[6-(5-amino-1,3-thiazol-4-yl)pyrimidin-4-yl]-2-fluorocyclopropane-1-carboxamide (95.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =280.1. Step 6. Synthesis of (lR,2R)-2-fluoro-N-(6-{5-[(4-methyl-6-propanoylpyridin-3- yl)amino]-l,3-thiazol-4-yl}pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.7)
Figure imgf000142_0001
[0268] To a solution of (lR,2R)-N-[6-(5-amino-l,3-thiazol-4-yl)pyrimidin-4-yl]-2- fluorocyclopropane-1 -carboxamide (95.0 mg, 0.34 mmol) in dioxane (5.0 mL) was added 1- (5-bromo-4-methylpyridin-2-yl)propan-l-one (77.6 mg, 0.34 mmolv), CS2CO3 (332.5 mg, 1.02 mmol), BrettPhos (36.5 mg, 0.07 mmol) and BrettPhos Pd G3 (30.8 mg, 0.03 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gelchromatography eluting with petroleum ether/ethyl acetate (2/1, v/v) to afford (lR,2R)-2-fluoro-N-(6-{5-[(4-methyl-6-propanoylpyridin-3- yl)amino]- 1 ,3 -thiazol-4-yl }pyrimidin-4-yl)cyclopropane- 1 -carboxamide (Compound 2.7, 45.0 mg, 31%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =427.1.
Step 7. Synthesis of (lR,2R)-2-fluoro-N-[6-(5-{[6-(l-hydroxypropyl)-4-methylpyridin-3- yl]amino}-l,3-thiazol-4-yl)pyrimidin-4-yl]cyclopropane-l-carboxamide
Figure imgf000142_0002
[0269] To a solution of (lR,2R)-2-fluoro-N-(6-{5-[(4-methyl-6-propanoylpyridin-3- yl)amino]- 1 ,3 -thiazol-4-yl }pyrimidin-4-yl)cyclopropane- 1 -carboxamide (Compound 2.7, 40.0 mg, 0.09 mmol) in MeOH/THF (2.0 mL/2.0 mL) was added NaBEL (7.1 mg, 0.19 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction mixture was quenched with water and then extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gelchromatography eluting with dichloromethane/methanol (15/1, v/v) to afford ( lR,2R)-2-fluoro-N- [6-(5 - { [6-( 1 -hy droxypropyl)-4-methylpyri din-3 -yl] amino } - 1 ,3 - thiazol-4-yl)pyrimidin-4-yl]cyclopropane-1-carboxamide (35.0 mg, 87%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =429.1. Step 8. Chiral Separation of (1R,2R)-2-fluoro-N-{6-[5-({6-[(1R)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)-1,3-thiazol-4-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.13) and (1R,2R)-2-fluoro-N-{6-[5-({6-[(1S)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)-1,3-thiazol-4-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.14)
Figure imgf000143_0001
1.13 1.14 [0270] The product of (1R,2R)-2-fluoro-N-[6-(5-{[6-(1-hydroxypropyl)-4-methylpyridin- 3-yl]amino}-1,3-thiazol-4-yl)pyrimidin-4-yl]cyclopropane-1-carboxamide (35.0 mg, 0.08 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-6&^^^[^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^0^1+3-MeOH)-- HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 12.5 min; Wavelength: 220/254 nm; RT1(min): 9.20; RT2(min): 14.66) to afford (1R,2R)-2-fluoro-N-{6-[5-({6-[1-hydroxypropyl]-4-methylpyridin-3-yl}amino)-1,3-thiazol- 4-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer A (retention time 9.20 minutes, 6.9 mg, 39%) as a yellow solid and (1R,2R)-2-fluoro-N-{6-[5-({6-[1-hydroxypropyl]-4- methylpyridin-3-yl}amino)-1,3-thiazol-4-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B (retention time 14.66 minutes, 6.7 mg, 38%) as a yellow solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.13 and 1.14 in Table 1. [0271] (1R,2R)-2-fluoro-N-{6-[5-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)-1,3-thiazol-4-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer A: RT1(min): 9.20; LCMS (ESI, m/z): [M+H]+ =429.1. 1H NMR (400 MHz, DMSO-d6): į^ 11.31 (s, 1H), 11.26 (s, 1H), 8.93 (s, 1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 7.45 (s, 1H), 5.30 (s, 1H), 5.09 - 4.90 (m, 1H), 4.51 - 4.48 (m, 1H), 2.43 (s, 3H), 2.32 - 2.25 (m, 1H), 1.82 - 1.61 (m, 3H), 1.29 - 1.22 (m, 1H), 0.88 - 0.84 (m, 3H). [0272] (1R,2R)-2-fluoro-N-{6-[5-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)-1,3-thiazol-4-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B: RT2(min): 14.66; LCMS (ESI, m/z): [M+H]+ =429.1. 1H NMR (400 MHz, DMSO-d6): į^ 11.30 (s, 1H), 11.25 (s, 1H), 8.93 (s, 1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 7.45 (s, 1H), 5.28 (d, J = 4.8 Hz, 1H), 5.09 - 4.90 (m, 1H), 4.51 - 4.47 (m, 1H), 2.42 (s, 3H), 2.32 - 2.27 (m, 1H), 1.82 - 1.61 (m, 3H), 1.28 - 1.20 (m, 1H), 0.88 - 0.84 (m, 3H). Example 8. Synthesis of (1R,2R)-2-fluoro-N-(5'-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)-1'-methyl-6'-oxo-1',6'-dihydro-[4,4'-bipyrimidin]-6-yl)cyclopropane-1- carboxamide (Compound 1.15) Step 1. Synthesis of 6-chloro-5-nitropyrimidin-4(1H)-one
Figure imgf000144_0001
[0273] To a solution of 5-nitropyrimidine-4,6-diol(1.0 g, 7.86 mmol) in POCl3 (12.0 mL) was added DMF (0.1 mL) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford 6-chloro-5-nitropyrimidin-4(1H)-one (1.1 g, crude) as a light yellow solid. Step 2. Synthesis of 5-amino-6-chloro-3H-pyrimidin-4-one
Figure imgf000144_0002
[0274] To a solution of 6-chloro-5-nitropyrimidin-4(1H)-one (1.0 g, crude) in EtOH (10.0 mL) and H2O (2.0 mL) was added Fe (1.9 g, 34.35 mmol) and NH4Cl (1.1 g, 20.61 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 5-amino-6-chloro-3H-pyrimidin-4-one (630.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 146.2. Step 3. Synthesis of 5-amino-6-iodopyrimidin-4(3H)-one
Figure imgf000145_0001
[0275] To a solution of 5-amino-6-chloropyrimidin-4(3H)-one (600.0 mg, crude) in ACN (10.0 mL) was added Nal (650.6 mg, 4.23 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 5-amino-6-iodopyrimidin-4(3H)-one (600.0 mg, crude) as a purple solid. LCMS (ESI, m/z): [M+H]+ = 237.9.
Step 4. Synthesis of 5-amino-6-iodo-3-methylpyrimidin-4(3H)-one
Figure imgf000145_0002
[0276] To a solution of 5-amino-6-iodopyrimidin-4(3H)-one (630.0 mg, crude) in acetone (15.0 mL) was added dimethyl sulfate (545.9 mg, 4.33 mmol) and K2CO3 (1196.4 mg, 8.65 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase Cl 8 chromatography eluting with acetonitrile/water (65/35, v/v) to afford 5-amino-6-iodo-3-methylpyrimidin-4(3H)-one (400.0 mg, 58%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 252.1.
Step 5. Synthesis of tert-butyl N-{5'-amino-l'-methyl-6'-oxo-[4,4'-bipyrimidin]-6-yl}-N-
(tert-butoxycarbonyl)carbamate
N^N )
Figure imgf000145_0003
ZnCI2, DMF
[0277] To a solution of 5-amino-6-iodo-3-methylpyrimidin-4(3H)-one (500.0 mg, 3.13 mmol) in DMF (15.0 mL) was added tert-butyl N-(tert-butoxycarbonyl)-N-[6-
(tributylstannyl)pyrimidin-4-yl]carbamate (1.8 g, 3.13 mmol), BrettPhos Pd G3 (284.0 mg, 0.31 mmol), BrettPhos (336.3 mg, 0.62 mmol) and ZnCh (427.0 mg, 3.13 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane/methanol (95/5, v/v) to afford tert-butyl N- { 5'-amino- 1 '-methyl-6'-oxo-[4,4'-bipyrimidin]-6-yl } -N-(tert- butoxycarbonyl)carbamate (300.0 mg, 23%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 419.2.
Step 6. Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-{l'-methyl-5'-[(4-methyl-6- propanoylpyridin-3-yl)amino]-6'-oxo-[4,4'-bipyrimidin]-6-yl}carbamate
Figure imgf000146_0001
[0278] To a stirred solution of tert-butyl N-{5'-amino-l'-methyl-6'-oxo-[4,4'- bipyrimidin]-6-yl]-N-(tert-butoxycarbonyl)carbamate (300.0 mg, 0.72 mmol) in DMF (9.0 mL) was added l-(5-bromo-4-methylpyridin-2-yl)propan-l-one (196.2 mg, 0.86 mmol), Pd2(dba)3 (65.6 mg, 0.07 mmol), XantPhos (82.9 mg, 0.14 mmol) and CS2CO3 (583.9 mg, 1.79 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane/methanol (93/7, v/v) to afford tert-butyl N-(tert-butoxycarbonyl)-N-{ l'- methyl-5'-[(4-methyl-6-propanoylpyridin-3-yl)amino]-6'-oxo-[4,4'-bipyrimidin]-6- yljcarbamate (80.0 mg, 19%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 566.1.
Step 7. Synthesis of 6'-amino-l-methyl-5-((4-methyl-6-propionylpyridin-3-yl)amino)-
[4,4'-bipyrimidin]-6(lH)-one
Figure imgf000146_0002
[0279] To a solution of tert-butyl N-(tert-butoxycarbonyl)-N-{ l'-methyl-5'-[(4-methyl-6- propanoylpyridin-3-yl)amino]-6'-oxo-[4,4'-bipyrimidin]-6-yl}carbamate (140.0 mg, 0.25 mmol) in CH2CI2 (5.0 mL) was added TFA (1.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8.0 with saturated NaHCCh (aq.) and the mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 6'-amino-l-methyl-5- ((4-methyl-6-propionylpyridin-3-yl)amino)-[4,4'-bipyrimidin]-6(lH)-one (110.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 366.2.
Step 8. Synthesis of (lR,2R)-2-fluoro-N-{l'-methyl-5'-[(4-methyl-6-propanoylpyridin-3- yl)amino]-6'-oxo-[4,4'-bipyrimidin]-6-yl}cyclopropane-l-carboxamide (Compound 2.8)
Figure imgf000147_0001
[0280] To a solution of 6'-amino-l-methyl-5-[(4-methyl-6-propanoylpyridin-3-yl)amino]- [4,4'-bipyrimidin]-6-one (40.0 mg, crude) in pyridine (2.0 mL) was added (lR,2R)-2- fluorocyclopropane-1 -carboxylic acid (11.4 mg, 0.11 mmol) and POCh (0.1 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane/methanol (90/10, v/v) to afford (lR,2R)-2-fluoro-N-{ T-methyl-5'-[(4-methyl-6-propanoylpyridin-3-yl)amino]-6'-oxo-[4,4'- bipyrimidin]-6-yl} cyclopropane- 1 -carboxamide (Compound 2.8, 25.0 mg, 51%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 452.2.
Step 9. Synthesis of (lR,2R)-2-fluoro-N-(5'-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-l'-methyl-6'-oxo-l',6'-dihydro-[4,4'-bipyrimidin]-6-yl)cyclopropane-l- carboxamide (Compound 1.15)
Figure imgf000148_0001
1.15 [0281] To a solution of (1R,2R)-2-fluoro-N-{1'-methyl-5'-[(4-methyl-6- propanoylpyridin-3-yl)amino]-6'-oxo-[4,4'-bipyrimidin]-6-yl}cyclopropane-1-carboxamide (Compound 2.8, 45.0 mg, 0.10 mmol) in THF (2 mL) and MeOH (0.4 mL) was added NaBH4 (7.5 mg, 0.20 mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane/methanol (88/12, v/v) and then purified by Prep-HPLC with the following conditions: (Xselect CSH OBD Column 19x250 mm, 5 umn; Mobile Phase A: Water (0.1% FA), Mobile Phase B: 20 mm NaOH+10%ACN; Flow rate: 20 mL/min mL/min; Gradient: 25% B to 35% B in 9 min; Wavelength: 254nm/220 nm) to afford (1R,2R)-2-fluoro-N-(5'- ((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)-1'-methyl-6'-oxo-1',6'-dihydro-[4,4'- bipyrimidin]-6-yl)cyclopropane-1-carboxamide (Compound 1.15, 11.2 mg, 20%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 454.2. 1H NMR (400 MHz, DMSO-d6^^^į^^^^^^^- 11.26 (m, 2H), 8.93 (s, 1H), 8.66 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 7.45 (s, 1H), 5.28 (d, J = 4.8 Hz, 1H), 5.09 - 4.90 (m, 1H), 4.51 - 4.47 (m, 1H), 3.53 (s, 3H), 2.42 (s, 3H), 2.33 - 2.27 (m, 1H), 1.82 - 1.61 (m, 3H), 1.28 - 1.20 (m, 1H), 0.88 - 0.84 (m, 3H). Example 9. Synthesis of (1S,2S)-2-fluoro-N-{6-[2-({6-[(1S)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.16) and (1S,2S)-2-fluoro-N-{6-[2-({6-[(1R)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.17) Step 1. Synthesis of (1S,2S)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-1- carboxamide
Figure imgf000148_0002
[0282] To a solution of (lS,2S)-2-fluorocyclopropane-l-carboxamide (1.5 g, 14.77 mmol) in dioxane (20.0 mL) was added 4,6-dichloropyrimidine (2.2 g, 14.77 mmol), K2CO3 (6.1 g, 44.30 mmol), XantPhos (1.7 g, 2.95 mmol) and Pd(dba)2 (849.2 mg, 1.48 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (22/78, v/v) to afford (lS,2S)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-l- carboxamide (1.1 g, 34%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 216.0.
Step 2. Synthesis of (lS,2S)-N-[6-(2-aminopyridin-3-yl)pyrimidin-4-yl]-2- fluorocyclopropane-l-carboxamide
Figure imgf000149_0001
[0283] To a solution of (lS,2S)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-l- carboxamide (550.0 mg, 2.55 mmol) in dioxane/ELO (10.0 mL/2.0 mL) was added 3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (561.4 mg, 2.55 mmol), CS2CO3 (1.7 g, 5.10 mmol) and Pd(dppf)C12 (207.8 mg, 0.26 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane/methanol (95/5, v/v) to afford (lS,2S)-N-[6- (2-aminopyridin-3-yl)pyrimidin-4-yl]-2-fluorocyclopropane-l-carboxamide (368.0 mg, 52%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ = 274.1.
Step 3. Synthesis of (2S)-2-fluoro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyridin-3-yl}pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.9)
Figure imgf000149_0002
[0284] To a solution of (lS,2S)-N-[6-(2-aminopyridin-3-yl)pyrimidin-4-yl]-2- fluorocyclopropane-1 -carboxamide (300.0 mg, 1.10 mmol) in dioxane (10.0 mL) was added l-(5-bromo-4-methylpyridin-2-yl)propan-l-one (250.4 mg, 1.10 mmol), CS2CO3 (1.1 g, 3.29 mmol) and XantPhos Pd G3 (156.2 mg, 0.17 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane/methanol (95/5, v/v) to afford (2S)-2-fluoro- N-(6-{2-[(4-methyl-6-propanoylpyridin-3-yl)amino]pyridin-3-yl}pyrimi din-4- yl)cyclopropane-l -carboxamide (Compound 2.9, 251.0 mg, 54%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 421.2.
Step 4. Synthesis of (lS,2S)-2-fluoro-N-[6-(2-{[6-(l-hydroxypropyl)-4-methylpyridin-3- yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-l-carboxamide
Figure imgf000150_0001
[0285] To a solution of (2S)-2-fluoro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyri din-3 -yl}pyrimidin-4-yl)cy cl opropane-1 -carboxamide (Compound 2.9, 230.0 mg, 0.55 mmol) in THF/MeOH (5.0 mL/5.0 mL) was added NaBEL (31.0 mg, 0.82 mmol) at 0 °C under N2. The mixture was then warmed to room temperature and stirred for 1 h under N2. After the reaction was completed, the reaction mixture was diluted with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with dichloromethane/methanol (93/7, v/v) to afford (lS,2S)-2-fhioro-N-[6-(2-{[6-(l- hydroxypropyl)-4-methylpyridin-3-yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-l- carboxamide (100.0 mg, 43%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 423.2.
Step 5. Chiral Separation of (!S,2S)-2-fluoro-N-{6-[2-({6-[(lS)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide (Compound 1.16) and (lS,2S)-2-fluoro-N-{6-[2-({6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.17)
Figure imgf000151_0001
[0286] The product of (1S,2S)-2-fluoro-N-[6-(2-{[6-(1-hydroxypropyl)-4-methylpyridin- 3-yl]amino}pyridin-3-yl)pyrimidin-4-yl]cyclopropane-1-carboxamide (100.0 mg, 0.23 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-4, 2.12×^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^,3$PLQH^--HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 12.5 min; Wavelength: 220/254 nm; RT1(min): 9.17; RT2(min): 12.01) to afford (1S,2S)-2- fluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3-yl}amino)pyridin-3-yl]pyrimidin- 4-yl}cyclopropane-1-carboxamide Isomer A (retention time 9.17 minutes, 24.3 mg, 48%) as a yellow solid and (1S,2S)-2-fluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B (retention time 12.01 minutes, 24.0 mg, 48%) as a yellow solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.16 and 1.17 in Table 1. [0287] (1S,2S)-2-fluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer A: RT1(min): 9.17; LCMS (ESI, m/z): [M+H]+ = 423.2. 1H NMR (400 MHz, DMSO-d6): į 11.47 (s, 1H), 11.37 (s, 1H), 9.13 - 9.08 (m, 2H), 8.67 (d, J = 1.2 Hz, 1H), 8.30 - 8.28 (m, 1H), 8.21 - 8.19 (m, 1H), 7.35 (s, 1H), 6.98 - 6.95 (m, 1H), 5.18 (d, J = 4.8 Hz, 1H), 5.09 - 4.93 (m, 1H), 4.49 - 4.46 (m, 1H), 2.37 (s, 3H), 2.33 - 2.29 (m, 1H), 1.79 - 1.62 (m, 3H), 1.30 - 1.25 (m, 1H), 0.88 - 0.85 (m, 3H)濁 [0288] (1S,2S)-2-fluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)pyridin-3-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B: RT2 (min): 12.01; LCMS (ESI, m/z): [M+H]+ = 423.2. 1H NMR (400 MHz, DMSO-d6^^^į 11.48 (s, 1H), 11.37 (s, 1H), 9.13 - 9.08 (m, 2H), 8.67 (d, J = 0.8 Hz, 1H), 8.30 - 8.28 (m, 1H), 8.21 - 8.19 (m, 1H), 7.35 (s, 1H), 6.98 - 6.95 (m, 1H), 5.18 (d, J = 4.8 Hz, 1H), 5.10 - 4.93 (m, 1H), 4.48 - 4.46 (m, 1H), 2.37 (s, 3H), 2.33 - 2.29 (m, 1H), 1.79 - 1.62 (m, 3H), 1.30 - 1.25 (m, 1H), 0.88 - 0.85 (m, 3H).
Example 10. Synthesis of (R)-2,2-difluoro-N-(6-(2-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.18) and (R)-2,2-difluoro-N-(6-(2-((6-((S)-l-hydroxypropyl)-4-niethylpyridin- 3-yl) amino)-lH-imidazol-l -yl)pyrimidin-4-yl) cyclopropane-1 -carboxamide ( Compound 1.19)
Step 1. Synthesis of 6-chloro-N,N-bis(4-methoxybenzyl)pyrimidin-4-amine
Figure imgf000152_0001
[0289] To a solution of 6-chloropyrimidin-4-amine (5.0 g, 38.59 mmol) in DMF (30.0 mL) was added NaH (3.1 g, 77.19 mmol) and l-(chloromethyl)-4-methoxybenzene (18.0 g, 115.78 mmol) at 0 °C. The resulting mixture was then warmed to room temperature and stirred for 4 h. After the reaction was completed, the resulting mixture was quenched with H2O and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (20/80, v/v) to afford 6-chloro-N,N-bis(4- methoxybenzyl)pyrimidin-4-amine (5.0 g, 35%) as a white solid. LCMS (ESI, m/z): [M+H]+ =370.1.
Step 2. Synthesis of 6-(2-amino-lH-imidazol-l-yl)-N,N-bis(4-methoxybenzyl)pyrimidin- 4-amine
Figure imgf000152_0002
[0290] To a solution of 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]pyrimidin-4-amine (4.0 g, 10.81 mmol) in DMSO (15.0 mL) was added lH-imidazol-2-amine (2.7 g, 32.44 mmol) and CS2CO3 (10.6 g, 32.44mmol) at room temperature. The resulting mixture was stirred at 110 °C for 14 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (50/50, v/v) to afford 6-(2-aminoimidazol-l-yl)-N,N-bis[(4- methoxyphenyl)methyl]pyrimidin-4-amine (2.0 g, 44%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =417.2.
Step 3. Synthesis of l-(5-((l-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-lH- imidazol-2-yl)amino)-4-methylpyridin-2-yl)propan-l-one
Figure imgf000153_0001
[0291] To a solution of 6-(2-aminoimidazol-l-yl)-N,N-bis[(4- methoxyphenyl)methyl]pyrimidin-4-amine (1.5 g, 3.60 mmol) in 1,4-dioxane (15.0 ml) was added l-(5-bromo-4-methylpyridin-2-yl)propan-l-one (821.4 mg, 3.60 mmol), Pd2(dba)3 (659.6 mg, 0.72 mmol), Xantphos (833.6 mg, 1.44 mmol) and K2CO3 (1.5 g, 10.80 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 14 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (50/50, v/v) to afford l-(5-{[l-(6-{bis[(4-methoxyphenyl)methyl]amino}pyrimidin-4- yl)imidazol-2-yl]amino}-4-methylpyridin-2-yl)propan-l-one (1.5 g, 73%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =564.3.
Step 4. Synthesis of l-(5-((l-(6-aminopyrimidin-4-yl)-lH-imidazol-2-yl)amino)-4- methylpyridin-2-yl)propan-l-one
Figure imgf000153_0002
[0292] A solution of l-(5-{[l-(6-{bis[(4-methoxyphenyl)methyl]amino}pyrimidin-4- yl)imidazol-2-yl]amino}-4-methylpyridin-2-yl)propan-l-one (800.0 mg, 1.41 mmol) in TFA (10.0 mL) was stirred at 80 °C for 2 h. After the reaction was completed, the pH value of the mixture was adjusted to 7 with aq. NaHCOi and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford l-(5-{[l-(6- aminopyrimidin-4-yl)imidazol-2-yl]amino}-4-methylpyridin-2-yl)propan-l-one (300.0 mg, crude) as a white solid. LCMS (ESI, m/z): [M+H]+ =324.1.
Step 5. Synthesis of (R)-2,2-difluoro-N-(6-(2-((4-methyl-6-propionylpyridin-3-yl)amino)- lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.10)
Figure imgf000154_0001
[0293] To a solution of l-(5-{[l-(6-aminopyrimidin-4-yl)imidazol-2-yl]amino}-4- methylpyridin-2-yl)propan-l-one (360.0 mg, crude) in pyridine (15.0 mL) was added (1R)- 2,2-difluorocyclopropane-l -carboxylic acid (203.8 mg, 1.66 mmol) and POCI3 (170.6 mg, 1.11 mmol) at 0 °C. The resulting mixture was then warmed to room temperature and stirred for 4 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (50/50, v/v) to afford (R)-2,2-difluoro-N-(6-(2-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (Compound 2.10, 30.0mg, 6%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =428.1.
Step 6. Synthesis of (lR)-2,2-difluoro-N-(6-(2-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
Figure imgf000154_0002
[0294] To a solution of (R)-2,2-difluoro-N-(6-(2-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (Compound 2.10, 80.0 mg, 0.18 mmol) in MeOH/THF (30.0 mL/12.0 mL) was added NaBH4 (8.5 mg, 0.22 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (50/50, v/v) to afford (lR)-2,2-difluoro-N-[6-(2-{[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]amino}imidazol-l- yl)pyrimidin-4-yl]cyclopropane-1-carboxamide (30.0 mg, 37%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ =430.2. Step 7. Chiral Separation of (R)-2,2-difluoro-N-(6-(2-((6-((R)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1- carboxamide (Compound 1.18) and (R)-2,2-difluoro-N-(6-(2-((6-((S)-1-hydroxypropyl)- 4-methylpyridin-3-yl)amino)-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1- carboxamide (Compound 1.19)
Figure imgf000155_0001
[0295] The product of (1R)-2,2-difluoro-N-(6-(2-((6-(1-hydroxypropyl)-4-methylpyridin- 3-yl)amino)-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (30.0 mg, 0.07 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-^^^^^^^[^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^0^1+3-MeOH)--HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 20 min; Wavelength: 220/254 nm; RT1(min): 6.74; RT2(min): 8.02) to afford (R)- 2,2-difluoro-N-(6-(2-((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)-1H-imidazol-1- yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A (retention time 6.74 minutes, 6.7 mg, 44%) as an off-white solid and (R)-2,2-difluoro-N-(6-(2-((6-(1-hydroxypropyl)-4- methylpyridin-3-yl) amino)-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B (retention time 8.02 minutes, 2.7 mg, 18%) as a white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.18 and 1.19 in Table 1. [0296] (R)-2,2-difluoro-N-(6-(2-((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)- 1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A: RT1(min): 6.74. LCMS (ESI, m/z): [M+H]+ =430.1.1H NMR (400 MHz, DMSO-d6): į^^^^^^^^V^^^+^^^ 9.45 (s, 1H), 8.98 (s, 1H), 8.17 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.33 (s, 1H), 6.91 (d, J = 1.6 Hz, 1H), 5.18 (d, J = 4.4 Hz, 1H), 4.47 - 4.44 (m, 1H), 3.11 - 3.03 (m, 1H), 2.40 (s, 3H), 2.14 - 2.07 (m, 2H), 1.78 - 1.72 (m, 1H), 1.65 - 1.58 (m, 1H), 0.86 - 0.82 (m, 3H). [0297] (R)-2,2-difluoro-N-(6-(2-((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)- 1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B: RT2(min): 8.02. LCMS (ESI, m/z): [M+H]+ =430.2.1H NMR (300 MHz, DMSO-d6): į^^^^^^^^V^^^+^^^ 10.73 (s, 1H), 9.44 (s, 1H), 8.97 (s, 1H), 8.17 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 6.91 (s, 1H), 5.13 (d, J = 4.5 Hz, 1H), 4.47 - 4.44 (m, 1H), 3.20 - 3.02 (m, 1H), 2.40 (s, 3H), 2.14 - 2.07 (m, 2H), 1.78 - 1.60 (m, 2H), 0.87 - 0.82 (m, 3H). Example 11. Synthesis of (1R,2R)-2-fluoro-N-(6-(2-((6-((R)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.20) and (1R,2R)-2-fluoro-N-(6-(2-((6-((S)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.21) Step 1. Synthesis of (1R,2R)-N-(6-(2-amino-1H-imidazol-1-yl)pyrimidin-4-yl)-2- fluorocyclopropane-1-carboxamide
Figure imgf000156_0001
[0298] To a solution of (1R,2R)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-1- carboxamide (2.2 g, 10.20 mmol) in isobutanol (30.0 mL) was added TEA (3.1 g, 30.61 mmol) and 1H-imidazol-2-amine (1.7 g, 20.41 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase C18 chromatography eluting with acetonitrile/water (5 mmol/L NH4HCO3) (1/ 5, v/ v) to afford (1R,2R)-N-(6-(2-amino-1H-imidazol-1-yl)pyrimidin-4-yl)-2-fluorocyclopropane-1- carboxamide (500.0 mg, 18%) as an off-white solid. LCMS (ESI, m/z): [M+H]+ =263.1. Step 2. Synthesis of (1R,2R)-2-fluoro-N-(6-(2-((4-methyl-6-propionylpyridin-3- yl)amino)-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound
Figure imgf000156_0002
, . [0299] To a solution of (1R,2R)-N-(6-(2-amino-1H-imidazol-1-yl)pyrimidin-4-yl)-2- fluorocyclopropane-1-carboxamide (500.0 mg, 1.91 mmol) in dioxane (20.0 mL) was added 1-(5-bromo-4-methylpyridin-2-yl)propan-1-one (521.9 mg, 2.29 mmol), K2CO3 (790.5 mg, 5.72 mmol), XantPhos (220.6 mg, 0.38 mmol) and Pd2(dba)3 (174.6 mg, 0.19 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 3 h under N2. After the reaction was completed, the resulting mixture diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (1/2, v/v) to afford (lR,2R)-2-fluoro-N-(6-(2-((4-methyl-6-propionylpyridin-3-yl)amino)-lH-imidazol-l- yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (Compound 2.11, 220.0 mg, 28%) as a white solid. LCMS (ESI, m/z): [M+H]+ =410.2.
Step 3. Synthesis of (lR,2R)-2-fluoro-N-(6-(2-(6-(l-hydroxypropyl)-4-methylpyridin-3- ylamino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropanecarboxamide
Figure imgf000157_0001
[0300] To a solution of (lR,2R)-2-fluoro-N-(6-(2-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (Compound 2.11, 110.0 mg, 0.27 mmol) in MeOH/THF (2.0 mL/2.0 mL) was added NaBH4 (12.2 mg, 0.32 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 0.5 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure and the residue was purified by reverse phase C18 chromatography eluting with acetonitrile/water (5 mmol/L NH4HCO3) (1/5, v/v) to afford (lR,2R)-2-fluoro-N-(6-(2-(6-(l- hydroxypropyl)-4-methylpyridin-3-ylamino)-lH-imidazol-l-yl)pyrimidin-4- yl)cyclopropanecarboxamide (80.0 mg, 72%) as a white solid. LCMS (ESI, m/z): [M+H]+ =412.2.
Step 4. Chiral Separation of (lR,2R)-2-fluoro-N-(6-(2-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.20) and (lR,2R)-2-fluoro-N-(6-(2-((6-((S)-l-hydroxypropyl)- 4-methylpyridin-3-yl)amino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.21)
Figure imgf000157_0002
[0301] The product of (lR,2R)-2-fluoro-N-(6-(2-(6-(l-hydroxypropyl)-4-methylpyridin-
3-ylamino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropanecarboxamide (70.0 mg, 0.17 mmol) was separated by Prep-chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-^^^^^^^[^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^0^1+3-MeOH)--HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 9 min; Wavelength: 254/220 nm; RT1(min): 6.89; RT2(min): 8.42) to afford (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)-1H-imidazol- 1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A (retention time 6.89 minutes, 25.4 mg, 73%) as a white solid and (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxypropyl)-4- methylpyridin-3-yl)amino)-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B (retention time 8.42 minutes, 23.1 mg, 66%) as a white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.20 and 1.21 in Table 1. [0302] (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A: RT1(min): 6.89; LCMS (ESI, m/z): [M+H]+ =412.21H NMR (400 MHz, DMSO-d6^^^į 11.63 (s, 1H), 10.74 (s, 1H), 9.46 (s, 1H), 8.95 (s, 1H), 8.20 (s, 1H), 7.47 (d, J = 1.6 Hz, 1H), 7.33 (s, 1H), 6.91 (d, J =1.6 Hz, 1H), 5.15 - 4.91 (m, 2H), 4.47 - 4.44 (m, 1H), 2.39 (s, 3H), 2.34 - 2.30 (m, 1H), 1.79 - 1.59 (m, 3H), 1.32 - 1.24 (m, 1H), 0.87 - 0.83 (m, 3H). [0303] (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B: RT2(min): 8.42; LCMS (ESI, m/z): [M+H]+ =412.1. 1H NMR (400 MHz, DMSO- d6^^^į 11.63 (s, 1H), 10.73 (s, 1H), 9.46 (s, 1H), 8.95 (s, 1H), 8.21 (s, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.33 (s, 1H), 6.91 (d, J = 2.4 Hz, 1H), 5.15 - 4.89 (m, 2H), 4.48 - 4.44 (m, 1H), 2.40 (s, 3H), 2.36 - 2.28 (m, 1H), 1.78 - 1.58 (m, 3H), 1.36 - 1.24 (m, 1H), 0.87 - 0.82 (m, 3H). Example 12. Synthesis of (1S,2S)-2-fluoro-N-{6-[2-({6-[(1R)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)imidazol-1-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.22) and (1S,2S)-2-fluoro-N-{6-[2-({6-[(1S)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)imidazol-1-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide (Compound 1.23) Step 1. Synthesis of (1S,2S)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-1- carboxamide
Figure imgf000159_0001
POCI3
[0304] To a solution of (lS,2S)-2-fluorocyclopropane-l-carboxylicacid (2.0 g, 19 mmol) in pyridine (40.0 ml) was added POCI3 (2.9 g, 19 mmol) and 6-chloropyrimidin-4-amine (2.4 g, 19 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the resulting mixture was quenched with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with petroleum ether/ethyl acetate (50/50, v/v) to afford (lS,2S)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-l- carboxamide (2.4 g, 57%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =216.0.
Step 2. Synthesis of (lS,2S)-N-[6-(2-aminoimidazol-l-yl)pyrimidin-4-yl]-2- fluorocyclopropane-l-carboxamide
Figure imgf000159_0002
[0305] To a solution of (lS,2S)-N-(6-chloropyrimidin-4-yl)-2-fluorocyclopropane-l- carboxamide (2.4 g, 11 mmol) in IBA (15.0 mL) was added lH-imidazol-2-amine (1.1 g, 13 mmol) and DIEA (4.3 g, 33 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 14 h. The reaction was then cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with petroleum ether/ethyl acetate (60/40, v/v) to afford (lS,2S)-N-[6-(2-aminoimidazol-l- yl)pyrimidin-4-yl]-2-fluorocyclopropane-l -carboxamide (500.0 mg, 17%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ =263.1.
Step 3. Synthesis of (lS,2S)-2-fluoro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]imidazol-l-yl}pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.12)
Figure imgf000159_0003
[0306] To a solution of (lS,2S)-N-[6-(2-aminoimidazol-l-yl)pyrimidin-4-yl]-2- fluorocyclopropane- 1 -carboxamide (460.0 mg, 1.75 mmol) in 1,4-dioxane (15.0 ml) was added l-(5-bromo-4-methylpyridin-2-yl)propan-l-one (400.0 mg, 1.75 mmol), K2CO3 (727.2 mg, 5.26 mmol), Brettphos Pd G3 (159.0 mg, 0.17 mmol) and Brettphos (188.3 mg, 0.35 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 14 h. The reaction was then cooled to ambient temperature, diluted with H2O, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with petroleum ether/ethyl acetate (55/45, v/v) to afford (lS,2S)-2-fhioro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]imidazol- 1 -yl }pyrimidin-4-yl)cyclopropane- 1 -carboxamide (Compound 2.12, 300.0 mg, 41%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =410.2.
Step 4. Synthesis of (lS,2S)-2-fluoro-N-(6-(2-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
Figure imgf000160_0001
[0307] To a solution of (lS,2S)-2-fluoro-N-(6-{2-[(4-methyl-6-propanoylpyridin-3- yl)amino]imidazol- 1 -yl }pyrimidin-4-yl)cyclopropane- 1 -carboxamide (Compound 2.12,
150.0 mg, 0.36 mmol) in THF/MeOH (8.0 mL/2.0 mL) was added NaBEU (16.6 mg, 0.44 mmol) at -40 °C. The resulting mixture was stirred at 0 °C for 3 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with CELCh/MeOH (5/1, v/v) to afford (lS,2S)-2- fluoro-N-[6-(2-{[6-(l-hydroxypropyl)-4-methylpyridin-3-yl]amino}imidazol-l-yl)pyrimidin- d-yljcyclopropane-l -carboxamide (120.0 mg, 80%) as a white solid. LCMS (ESI, m/z): [M+H]+ =412.2.
Step 5. Chiral Separation of (lS,2S)-2-fluoro-N-{6-[2-({6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)imidazol-l-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide (Compound 1.22) and (lS,2S)-2-fluoro-N-{6-[2-({6-[(lS)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)imidazol-l-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide (Compound 1.23)
Figure imgf000161_0001
[0308] The product of (1S,2S)-2-fluoro-N-[6-(2-{[6-(1-hydroxypropyl)-4-methylpyridin- 3-yl]amino}imidazol-1-yl)pyrimidin-4-yl]cyclopropane-1-carboxamide (100.0 mg, 0.24 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-4, 2.12x^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[ (0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 20 min; Wavelength: 220/254 nm; RT1(min): 6.74; RT2(min): 8.02) to afford (1S,2S)-2-fluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3-yl}amino)imidazol-1- yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer A (retention time 6.74 minutes, 19.0 mg, 38%) as an off-white solid and (1S,2S)-2-fluoro-N-{6-[2-({6-[1-hydroxypropyl]-4- methylpyridin-3-yl}amino)imidazol-1-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B (retention time 8.02 minutes, 14.5 mg, 29%) as an off-white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.22 and 1.23 in Table 1. [0309] (1S,2S)-2-fluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)imidazol-1-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer A: RT1(min): 6.74; LCMS (ESI, m/z): [M+H]+ =412.2. 1H NMR (300 MHz, DMSO-d6): į^ 11.57 (s, 1H), 10.73 (s, 1H), 9.46 (s, 1H), 8.95 (s, 1H), 8.21 (s, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.33 (s, 1H), 6.91 (d, J = 1.8 Hz, 1H), 5.14 - 4.89 (m, 2H), 4.49 - 4.43 (m, 1H), 2.40 (s, 3H), 2.33 - 2.28 (m, 1H), 1.87 - 1.58 (m, 3H), 1.32 - 1.23 (m, 1H), 0.87 - 0.82 (m, 3H). [0310] (1S,2S)-2-fluoro-N-{6-[2-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)imidazol-1-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B: RT1(min): 8.02; LCMS (ESI, m/z): [M+H]+ =412.2. 1H NMR (300 MHz, DMSO-d6): į^ 11.57 (s, 1H), 10.73 (s, 1H), 9.45 (s, 1H), 8.95 (s, 1H), 8.21 (s, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.33 (s, 1H), 6.91 (d, J = 1.5 Hz, 1H), 5.15 - 4.87 (m, 2H), 4.49 - 4.43 (m, 1H), 2.40 (s, 3H), 2.35 - 2.28 (m, 1H), 1.80 - 1.57 (m, 3H), 1.32 - 1.24 (m, 1H), 0.87 - 0.82 (m, 3H). Example 13. Synthesis of (1R,2R)-2-fluoro-N-(6-(3-((6-((S)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.24) and (1R,2R)-2-fluoro-N-(6-(3-((6-((R)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.25)
Step 1. Synthesis of tert-butyl N-[6-(3-aminopyridin-2-yl)pyrimidin-4-yl]-N-(tert- butoxycarbonyl)carbamate
B c B
Figure imgf000162_0001
[0311] To a mixture of tert-butyl N-(tert-butoxycarbonyl)-N-[6-(tributylstannyl)- pyrimidin-4-yl]carbamate (1.5 g, 2.6 mmol) and 2-iodopyridin-3 -amine (0.56 g, 2.6 mmol) in NMP (15.0 mL) were added Cui (0.05 g, 0.25 mmol) and Pd(PPh3)2Ch (0.18 g, 0.25 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2.
The reaction was then allowed to cool to ambient temperature and the resulting mixture diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (50/50, v/v) to afford tert-butyl N-[6-(3-aminopyridin-2- yl)pyrimidin-4-yl]-N-(tert-butoxycarbonyl)carbamate (600.0 mg, 60%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 388.2.
Step 2. Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-(6-{3-[(4-methyl-6- propanoylpyridin-3-yl)amino]pyridin-2-yl}pyrimidin-4-yl)carbamate
Figure imgf000162_0002
[0312] To a mixture of tert-butyl N-[6-(3-aminopyridin-2-yl)pyrimidin-4-yl]-N-(tert- butoxycarbonyl)carbamate (460.0 mg, 1.18 mmol) and l-(5-bromo-4-methylpyridin-2- yl)propan-l-one (270.8 mg, 1.18 mmol) in dioxane (6.0 mL) were added CS2CO3 (492.2 mg, 3.56 mmol), XantPhos (45.2 mg, 0.23 mmol) and Pd2(dba)3 (108.7 mg, 0.11 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 12 h under N2. The reaction was then allowed to cool to ambient temperature and the resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with petroleum ether/ethyl acetate (50/50, v/v) to afford tert-butyl N-(tert-butoxycarbonyl)-N-(6-{3-[(4-methyl-6-propanoylpyridin-3-yl)amino]pyridin-2- yl}pyrimidin-4-yl)carbamate (300.0 mg, 47%) as a yellow solid. LCMS (ESI, m/z): [M+H] = 535.3.
Step 3. Synthesis of l-(5-((2-(6-aminopyrimidin-4-yl)pyridin-3-yl)amino)-4-
Figure imgf000163_0001
[0313] To a mixture of tert-butyl N-(tert-butoxycarbonyl)-N-(6-{3-[(4-methyl-6- propanoylpyridin-3-yl)amino]pyridin-2-yl}pyrimidin-4-yl)carbamate (280.0 mg, 0.52 mmol) in DCM (1.5 mL) was added TFA (3.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. After the reaction was completed, the resulting mixture was neutralized to pH = 8 with saturated aqueous NaHCCh. The resulting mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with petroleum ether/ethyl acetate (30/70, v/v) to afford l-(5-((2-(6-aminopyrimidin-4-yl)pyridin-3-yl)amino)-4- methylpyridin-2-yl)propan-l-one (160.0 mg, 91%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 335.2.
Step 4. Synthesis of (lR,2R)-2-fluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3- yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.13)
Figure imgf000163_0002
[0314] To a mixture of l-(5-((2-(6-aminopyrimidin-4-yl)pyridin-3-yl)amino)-4- methylpyridin-2-yl)propan-l-one (160.0 mg, 0.47 mmol) and (lR,2R)-2-fluorocyclopropane- 1-carboxylic acid (49.8 mg, 0.47 mmol) in pyridine (3.0 mL) was added POCh (0.2 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with C^Ch/MeOH (10/1, v/v) to afford (lR,2R)-2-fluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3- yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.13, 140.0 mg, 69%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ = 421.2.
Step 5. Synthesis of (lR,2R)-2-fluoro-N-(6-(3-((6-(l-hydroxypropyl)-4-methylpyridin-3-
Figure imgf000164_0001
[0315] To a solution of (lR,2R)-2-fluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3- yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.13, 140.0 mg, 0.33 mmol) in THF (3.0 mL) and MeOH (0.3 mL) was added NaBTU (25.1 mg, 0.66 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h under N2. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with petroleum ether/ethyl acetate (20/80, v/v) to afford (lR,2R)-2-fluoro-N-(6-(3-((6-(l-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (120.0 mg, 88%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 423.2.
Step 6. Chiral Separation of (lR,2R)-2-fluoro-N-(6-(3-((6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.24) and (lR,2R)-2-fluoro-N-(6-(3-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.25)
Figure imgf000164_0002
[0316] The product of (lR,2R)-2-fluoro-N-(6-(3-((6-(l-hydroxypropyl)-4-methylpyridin- 3 -yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (120.0 mg, 0.26 mmol) was separated by Prep-HPLC with the following conditions: (Column: CHIRALPAK IC, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NHs-MeOH), Mobile Phase B: MEOH: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 28 min; Wavelength: 220/254 nm; RT1(min): 17.75; RT2(min): 21.5) to afford (1R,2R)-2-fluoro-N- (6-(3-((6-((1-hydroxypropyl)-4-methylpyridin-3-yl)amino)pyridin-2-yl)pyrimidin-4- yl)cyclopropane-1-carboxamide Isomer A (retention time 17.75 minutes, 47.6 mg, 79%) as a white solid and (1R,2R)-2-fluoro-N-{6-[3-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)pyridin-2-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B (retention time 21.5 minutes, 52.8 mg, 88%) as a white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.24 and 1.25 in Table 1. [0317] (1R,2R)-2-fluoro-N-(6-(3-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A: RT1(min): 17.75; LCMS (ESI, m/z): [M+H]+ = 423.1. 1H NMR (400 MHz, DMSO-d6^^^į 11.36 (s, 1H), 11.11 (s, 1H), 9.17 (d, J = 1.2 Hz, 1H), 9.02 (d, J = 1.2 Hz, 1H), 8.42 (s, 1H), 8.16 - 8.14 (m, 1H), 7.45 (s, 1H), 7.35 - 7.32 (m, 1H), 7.26 - 7.23 (m, 1H), 5.27 (d, J = 4.4 Hz, 1H), 5.08 - 4.91 (m, 1H), 4.51 - 4.49 (m, 1H), 2.34 - 2.26 (m, 4H), 1.82 -1.63 (m, 3H), 1.28 - 1.23 (m, 1H), 0.89 - 0.85 (s, 3H). [0318] (1R,2R)-2-fluoro-N-(6-(3-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyridin-2-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B: RT2(min): 21.5; LCMS (ESI, m/z): [M+H]+ = 423.2. 1H NMR (400 MHz, DMSO-d6): į^11.37 (s, 1H), 11.11 (s, 1H), 9.17 (d, J = 1.2 Hz, 1H), 9.02 (d, J = 0.8 Hz, 1H), 8.42 (s, 1H), 8.16 - 8.14 (m, 1H), 7.45 (s, 1H), 7.35 - 7.32 (m, 1H), 7.26 - 7.23 (m, 1H), 5.28 (d, J = 4.0 Hz, 1H), 5.09 - 4.91 (m, 1H), 4.51 - 4.48 (m, 1H), 2.32 - 2.27 (m, 4H), 1.81 -1.63 (m, 3H), 1.28 - 1.23 (m, 1H), 0.89 - 0.85 (s, 3H). Example 14. Synthesis of (1R)-2,2-difluoro-N-{6-[3-({6-[(1R)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)-1-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-1- carboxamide (Compound 1.26) and (1R)-2,2-difluoro-N-{6-[3-({6-[(1S)-1-hydroxypropyl]- 4-methylpyridin-3-yl}amino)-1-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-1- carboxamide (Compound 1.27) Step 1. Synthesis of 1-{4-methyl-5-[(1-methylpyrazol-3-yl)amino]pyridin-2-yl}propan-1- one
Figure imgf000166_0001
[0319] To a solution of 1 -methylpyrazol-3 -amine (2.6 g, 26 mmol) in dioxane (40.0 mL) was added l-(5-bromo-4-methylpyridin-2-yl)propan-l-one (6.0 g, 26 mmol), CS2CO3 (25.8 g, 79.1 mmol) and XantPhos Pd G3 (2.5 g, 2.6 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 1 h under N2. The reaction was then allowed to cool to ambient temperature, diluted with H2O, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (2/1, v/v) to afford l-{4-methyl-5-[(l-methylpyrazol-3-yl)amino]pyridin-2-yl}propan-l-one (5.3 g, 82%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 245.1.
Step 2. Synthesis of l-{5-[(4-iodo-l-methylpyrazol-3-yl)amino]-4-methylpyridin-2- yl}propan-l-one
Figure imgf000166_0002
[0320] To a solution of l-{4-methyl-5-[(l-methylpyrazol-3-yl)amino]pyridin-2- yl } propan- 1 -one (5.3 g, 22 mmol) in acetonitrile (80.0 mL) was added NIS (5.9 g, 26 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 0.5 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (2/1, v/v) to afford 1 - { 5 - [(4-iodo- 1 -methylpyrazol-3 -yl)amino] -4-methylpyri din-2 -yl } propan- 1 -one (6.0 g, 75%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 371.0.
Step 3. Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-(6-{l-methyl-3-[(4-methyl-6- propanoylpyridin-3-yl)amino]pyrazol-4-yl}pyrimidin-4-yl)carbamate
Figure imgf000167_0001
[0321] To a solution of l-{5-[(4-iodo-l-methylpyrazol-3-yl)amino]-4-methylpyridin-2- yl] propan- 1 -one (1.8 g, 4.9 mmol) in dioxane (30.0 mL) was added tert-butyl N-(tert- butoxycarbonyl)-N-[6-(tributylstannyl)pyrimidin-4-yl]carbamate (3.1 g, 5.4 mmol), Cui (92.6 mg, 0.47 mmol) and Pd(PPh3)2Ch (341.3 mg, 0.49 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 3 h under N2. The reaction was then allowed to cool to ambient temperature, diluted with H2O, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (2/1, v/v) to afford tert-butyl N-(tert-butoxycarbonyl)-N-(6-{ l-methyl-3-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyrazol-4-yl}pyrimidin-4-yl)carbamate (490.0 mg, 19%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 538.3.
Step 4. Synthesis of l-(5-{[4-(6-aminopyrimidin-4-yl)-l-methylpyrazol-3-yl]amino}-4- methylpyridin-2-yl)propan-l-one
Figure imgf000167_0002
[0322] To a solution of tert-butyl N-(tert-butoxycarbonyl)-N-(6-{ l-methyl-3-[(4-methyl- 6-propanoylpyridin-3-yl)amino]pyrazol-4-yl}pyrimidin-4-yl)carbamate (490.0 mg, 0.91 mmol) in DCM (6.0 mL) was added TFA (2.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was adjusted to pH = 8 with aqueous NaHCCh. The mixture was filtered. The solid was washed with water and collected to afford l-(5-{[4-(6-aminopyrimidin-4-yl)-l- methylpyrazol-3-yl]amino}-4-methylpyridin-2-yl)propan-l-one (260.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 338.2. Step 5. Synthesis of (1R)-2,2-difluoro-N-(6-{1-methyl-3-[(4-methyl-6-propanoylpyridin- 3-yl)amino]pyrazol-4-yl}pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 2.14)
Figure imgf000168_0001
[0323] To a solution of 1-(5-{[4-(6-aminopyrimidin-4-yl)-1-methylpyrazol-3-yl]amino}- 4-methylpyridin-2-yl)propan-1-one (300.0 mg, crude) in pyridine (5.0 mL) was added (1R)- 2,2-difluorocyclopropane-1-carboxylic acid (108.5 mg, 0.89 mmol) and POCl3 (0.45 mL) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h under N2. After the reaction was completed, the reaction mixture was quenched with ice water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with CH2Cl2 /MeOH (25/1, v/v) to afford (1R)-2,2-difluoro-N-(6-{1-methyl-3-[(4-methyl-6-propanoylpyridin-3- yl)amino]pyrazol-4-yl}pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 2.14, 130.0 mg, 33%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 442.2. Step 6. Synthesis of (1R)-2,2-difluoro-N-[6-(3-{[6-(1-hydroxypropyl)-4-methylpyridin-3- yl]amino}-1-methylpyrazol-4-yl)pyrimidin-4-yl]cyclopropane-1-carboxamide
Figure imgf000168_0002
[0324] To a solution of (1R)-2,2-difluoro-N-(6-{1-methyl-3-[(4-methyl-6- propanoylpyridin-3-yl)amino]pyrazol-4-yl}pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 2.14, 130.0 mg, 0.29 mmol) in MeOH/THF (3.0 mL/3.0 mL) was added NaBH4 (22.3 mg, 0.59 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h under N2. After the reaction was completed, the reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with CH2Cl2/MeOH (20/1, v/v) to afford (1R)-2,2-difluoro-N-[6-(3-{[6-(1-hydroxypropyl)-4-methylpyridin-3- yl]amino}-1-methylpyrazol-4-yl)pyrimidin-4-yl]cyclopropane-1-carboxamide (50.0 mg, 38%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 444.2. Step 7. Chiral Separation of (1R)-2,2-difluoro-N-{6-[3-({6-[(1R)-1-hydroxypropyl]-4- methylpyridin-3-yl}amino)-1-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-1- carboxamide (Compound 1.26) and (1R)-2,2-difluoro-N-{6-[3-({6-[(1S)-1- hydroxypropyl]-4-methylpyridin-3-yl}amino)-1-methylpyrazol-4-yl]pyrimidin-4- yl}cyclopropane-1-carboxamide (Compound 1.27)
Figure imgf000169_0001
[0325] The product of (1R)-2,2-difluoro-N-[6-(3-{[6-(1-hydroxypropyl)-4- methylpyridin-3-yl]amino}-1-methylpyrazol-4-yl)pyrimidin-4-yl]cyclopropane-1- carboxamide (50.0 mg, 0.11 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-SC, 2x^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[ (0.5% 2M NH3-MeOH)-HPLC, Mobile Phase B: IPA: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 40% B to 40% B in 16 min; Wavelength: 220/254 nm; RT1(min): 10.83; RT2(min): 14.37) to afford (1R)-2,2-difluoro-N-{6-[3-({6-[1-hydroxypropyl]-4- methylpyridin-3-yl}amino)-1-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-1- carboxamide Isomer A (retention time 10.83 minutes, 15.3 mg, 61%) as a white solid and (1R)-2,2-difluoro-N-{6-[3-({6-[1-hydroxypropyl]-4-methylpyridin-3-yl}amino)-1- methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B (retention time 14.37 minutes, 15.8 mg, 63%) as a white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.26 and 1.27 in Table 1. [0326] (1R)-2,2-difluoro-N-{6-[3-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)-1-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer A: RT1(min): 10.83; LCMS (ESI, m/z): [M+H]+ = 444.1. 1H NMR (400 MHz, DMSO-d6): į^ 11.38 (s, 1H), 9.91 (s, 1H), 9.35 (s, 1H), 8.90 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 7.29 (s, 1H), 5.11 (d, J = 4.0 Hz, 1H), 4.46 - 4.41 (m, 1H), 3.85 (s, 3H), 3.10 - 2.85 (m, 1H), 2.40 (s, 3H), 2.17 - 2.00 (m, 2H), 1.78 - 1.70 (m, 1H), 1.67 - 1.58 (m, 1H), 0.86 - 0.82 (m, 3H). [0327] (1R)-2,2-difluoro-N-{6-[3-({6-[1-hydroxypropyl]-4-methylpyridin-3- yl}amino)-1-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-1-carboxamide Isomer B: RT2(min): 14.37; LCMS (ESI, m/z): [M+H]+ = 444.1. 'HNMR (400 MHz, DMSO-fifc): 5 11.38 (s, 1H), 9.93 (s, 1H), 9.35 (s, 1H), 8.90 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 7.30 (s, 1H), 5.13 (d, J= 4.4 Hz, 1H), 4.47 - 4.42 (m, 1H), 3.86 (s, 3H), 3.10 - 2.93 (m, 1H), 2.41 (s, 3H), 2.15 - 2.00 (m, 2H), 1.79 - 1.70 (m, 1H), 1.68 - 1.57 (m, 1H), 0.86 - 0.82 (m, 3H).
Example 15. Synthesis of (lR,2R)-2-fluoro-N-{6-[3-({6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)-l-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-l- carboxamide (Compound 1.28) and (lR,2R)-2-fluoro-N-{6-[3-({6-[(lS)-l-hydroxypropyl]- 4-methylpyridin-3-yl}amino)-l-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-l- carboxamide (Compound 1.29)
Step 1. Synthesis of (lR,2R)-2-fluoro-N-(6-{l-methyl-3-[(4-methyl-6-propanoylpyridin-
3-yl)amino]pyrazol-4-yl}pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.15)
Figure imgf000170_0001
[0328] To a solution of l-(5-{[4-(6-aminopyrimidin-4-yl)-l-methylpyrazol-3-yl]amino}- 4-methylpyridin-2-yl)propan-l-one (200.0 mg, 0.59 mmol) in pyridine (5.0 mL) was added (lR,2R)-2-fluorocyclopropane-l-carboxylic acid (61.7 mg, 0.59 mmol) and POCh (0.3 mL) at 0° C. The resulting mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure The residue was purified by flash column chromatography, eluting with CJLCh/MeOH (20/1, v/v) to afford (lR,2R)-2- fluoro-N-(6-{ l-methyl-3-[(4-methyl-6-propanoylpyridin-3-yl)amino]pyrazol-4-yl}pyrimidin- 4-yl)cyclopropane-l -carboxamide (Compound 2.15, 160.0 mg, 64%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =424.2.
Step 2. Synthesis of (lR,2R)-2-fluoro-N-[6-(3-{[6-(l-hydroxypropyl)-4-methylpyridin-3- yl]amino}-l-methylpyrazol-4-yl)pyrimidin-4-yl]cyclopropane-l-carboxamide
Figure imgf000170_0002
[0329] To a solution of (lR,2R)-2-fluoro-N-(6-{ l-methyl-3-[(4-methyl-6- propanoylpyridin-3-yl)amino]pyrazol-4-yl}pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.15, 150.0 mg, 0.35 mmol) in MeOH/THF (3.0 mL/3.0 mL) was added NaBEL (26.8 mg, 0.71 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. After the reaction was completed, the reaction mixture was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with CEECh/MeOH (15/1, v/v) to afford (lR,2R)-2-fhioro-N-[6-(3-{[6-(l-hydroxypropyl)-4- methylpyridin-3-yl]amino}-l-methylpyrazol-4-yl)pyrimidin-4-yl]cyclopropane-l- carboxamide (85.0 mg, 56%) as a white solid. LCMS (ESI, m/z): [M+H]+ =426.2.
Step 3. Chiral Separation of (lR,2R)-2-fluoro-N-{6-[3-({6-[(lR)-l-hydroxypropyl]-4- methylpyridin-3-yl}amino)-l-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-l- carboxamide (Compound 1.28) and (lR,2R)-2-fluoro-N-{6-[3-({6-[(lS)-l- hydroxypropyl]-4-methylpyridin-3-yl}amino)-l-methylpyrazol-4-yl]pyrimidin-4- yl}cyclopropane-l-carboxamide (Compound 1.29)
Figure imgf000171_0001
[0330] The product of (lR,2R)-2-fluoro-N-[6-(3-{[6-(l-hydroxypropyl)-4-methylpyridin- 3-yl]amino}-l-methylpyrazol-4-yl)pyrimidin-4-yl]cyclopropane-l -carboxamide (85.0 mg, 0.20 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-4, 2.12x25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NFh-MeOH)- HPLC, Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 30 min; Wavelength: 220/254 nm; RTl(min): 19.501; RT2(min): 25.714) to afford (1R,2R)- 2-fluoro-N-{6-[3-({6-[l-hydroxypropyl]-4-methylpyridin-3-yl}amino)-l-methylpyrazol-4- yl]pyrimidin-4-yl} cyclopropane- 1 -carboxamide Isomer A (retention time 19.501 minutes, 12.7 mg, 30%) as a white solid and (lR,2R)-2-fluoro-N-{6-[3-({6-[l-hydroxypropyl]-4- methylpyri din-3 -yl } amino)- l-methylpyrazol-4-yl]pyrimidin-4-yl (cyclopropane- 1- carboxamide Isomer B (retention time 25.714 minutes, 12.4 mg, 30%) as a white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.28 and 1.29 in Table 1.
[0331] (lR,2R)-2-fluoro-N-{6-[3-({6-[l-hydroxypropyl]-4-methylpyridin-3- yl}amino)-l-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide Isomer A:
RTl(min): 19.501; LCMS (ESI, m/z): [M+H]+ =426.1. 'H NMR (400 MHz, DMSO-t/e): 5
11.23 (s, 1H), 9.94 (s, 1H), 9.35 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 7.29 (s, 1H),
5.10 - 4.87 (m, 2H), 4.47 - 4.41 (m, 1H), 3.85 (s, 3H), 2.40 (s, 3H), 2.31 - 2.24 (m, 1H), 1.79
- 1.59 (m, 3H), 1.29 - 1.21 (m, 1H), 0.86 - 0.82 (m, 3H).
[0332] (lR,2R)-2-fluoro-N-{6-[3-({6-[l-hydroxypropyl]-4-methylpyridin-3- yl}amino)-l-methylpyrazol-4-yl]pyrimidin-4-yl}cyclopropane-l-carboxamide Isomer B:
RT2(min): 25.714; LCMS (ESI, m/z): [M+H]+ =426.1. 'H NMR (400 MHz, DMSO-t/e): 5
11.23 (s, 1H), 9.94 (s, 1H), 9.35 (s, 1H), 8.88 (d, J= 0.8 Hz, 1H), 8.52 (s, 1H), 8.23 (d, J= 0.8 Hz, 1H), 7.29 (s, 1H), 5.09 - 4.90 (m, 2H), 4.46 - 4.42 (m, 1H), 3.85 (s, 3H), 2.40 (s, 3H),
2.30 - 2.24 (m, 1H), 1.79 - 1.59 (m, 3H), 1.28 - 1.23 (m, 1H), 0.86 - 0.82 (m, 3H).
Example 16. Synthesis of (lR,2R)-2-fluoro-N-(6-(4-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-l-methyl-lH-pyrazol-3-yl)pyrinndin-4-yl)cyclopropane-l- carboxamide (Compound 1.30) and (lR,2R)-2-fluoro-N-(6-(4-((6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-l-methyl-lH-pyrazol-3-yl)pyrinndin-4-yl)cyclopropane-l- carboxamide (Compound 1.31)
Step 1. Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-[6-(l-methylpyrazol-3- yl)pyrimidin-4-yl]carbamate
Figure imgf000172_0001
[0333] To a solution of tert-butyl N-(6-bromopyrimidin-4-yl)-N-(tert- butoxycarbonyl)carbamate (800.0 mg, 2.13 mmol) in dioxane (20.0 mL) and H2O (4.0 mL) was added K2CO3 (886.3 mg, 6.41 mmol), l-methyl-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazole (444.7 mg, 2.14 mmol) and Pd(dppf)C12 (348.28 mg, 0.43 mmol) at room temperature under N2. The reaction mixture was stirred at 80 °C for 2 h under N2. The reaction was then allowed to cool to ambient temperature, diluted with H2O, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (40/60, v/v) to afford tert-butyl N-(tert-butoxycarbonyl)-N-[6-(l-methylpyrazol-3- yl)pyrimidin-4-yl]carbamate (400.0 mg, 49%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 376.1.
Step 2. Synthesis of tert-butyl (6-(4-bromo-l-methyl-lH-pyrazol-3-yl)pyrimidin-4- yl)carbamate
Figure imgf000173_0001
[0334] To a solution of tert-butyl N-(tert-butoxycarbonyl)-N-[6-(l-methylpyrazol-3- yl)pyrimidin-4-yl]carbamate (500.0 mg, 1.33 mmol) in acetonitrile (10.0 mL) was added NBS (237.0 mg, 1.33 mmol) at room temperature. The reaction mixture was stirred at 40 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (50/50, v/v) to afford tert-butyl (6-(4-bromo-l-methyl-lH-pyrazol-3-yl)pyrimidin-4- yl)carbamate (200.0 mg, 33%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 354.1.
Step 3. Synthesis of tert-butyl (6-(l-methyl-4-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-pyrazol-3-yl)pyrimidin-4-yl)carbamate
Figure imgf000173_0002
[0335] To a solution of tert-butyl (6-(4-bromo-l-methyl-lH-pyrazol-3-yl)pyrimidin-4- yl)carbamate (764.0 mg, 1.72 mmol) in 1,4-dioxane (15.0 mL) was added l-(5-amino-4- methylpyridin-2-yl)propan-l-one (2.9 g, 1.88 mmol), Cs2CO3 (2.1 g, 6.44 mmol), Pd(OAc)2 (96.5 mg, 0.43 mmol) and XPhos (409.7 mg, 0.86 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature and then filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography, eluting with petroleum ether/ethyl acetate (30/70, v/v) to afford tert-butyl (6-(l -methyl -4-((4-methyl-6- propionylpyridin-3-yl)amino)-lH-pyrazol-3-yl)pyrimidin-4-yl)carbamate (314.0 mg, 41%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 438.3.
Step 4. Synthesis of l-(5-((3-(6-aminopyrimidin-4-yl)-l-methyl-lH-pyrazol-4-yl)amino)- 4-methylpyridin-2-yl)propan-l-one
Figure imgf000174_0001
[0336] To a solution of tert-butyl (6-(l-methyl-4-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-pyrazol-3-yl)pyrimidin-4-yl)carbamate (300.0 mg, 0.68 mmol) in CH2CI2 (8.0 mL) was added TFA (4.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The pH of the residue was adjusted to 8.0 with sat. aq. NaHCCh. The mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford l-(5-((3-(6-aminopyrimidin-4-yl)-l-methyl-lH-pyrazol-4-yl)amino)-4-methylpyri din-2- yl)propan-l-one (260.0 mg, crude) as a white solid. LCMS (ESI, m/z): [M+H]+ = 338.1.
Step 5. Synthesis of (lR,2R)-2-fluoro-N-(6-(l-methyl-4-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound
Figure imgf000174_0002
[0337] To a solution of l-(5-((3-(6-aminopyrimidin-4-yl)-l-methyl-lH-pyrazol-4- yl)amino)-4-methylpyridin-2-yl)propan-l-one (300.0 mg, crude) in pyridine (8.0 mL) was added (lR,2R)-2-fhiorocyclopropane-l-carboxylic acid (108.0 mg, 0.89 mmol) and POCI3 (0.2 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography, eluting with CEECh/MeOH (90/10, v/v) to afford (1R,2R)- 2-fluoro-N-(6-(l-methyl-4-((4-methyl-6-propionylpyridin-3-yl)amino)-lH-pyrazol-3- yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (Compound 2.16, 148.0 mg, 40%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 424.1.
Step 6. Synthesis of (lR,2R)-2-fluoro-N-(6-(4-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-l-methyl-lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
Figure imgf000175_0001
[0338] To a solution of (lR,2R)-2-fluoro-N-(6-(l-methyl-4-((4-methyl-6- propionylpyridin-3-yl)amino)-lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.16, 150.0 mg, 0.33 mmol) in MeOH (1.0 mL) and THF (5.0 mL) was added NaBH4 (19.4 mg, 0.47 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with CELCh/MeOH (91/9, v/v) to afford (lR,2R)-2-fhioro-N-(6-(4-((6-(l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-l-methyl-lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (84.0 mg, 56%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 426.1.
Step 7. Chiral Separation of (lR,2R)-2-fluoro-N-(6-(4-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-l-methyl-lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.30) and (lR,2R)-2-fluoro-N-(6-(4-((6-((S)-l-hydroxypropyl)- 4-methylpyridin-3-yl)amino)-l-methyl-lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.31)
Figure imgf000175_0002
1.30 1.31
[0339] The product of (lR,2R)-2-fluoro-N-(6-(4-((6-(l-hydroxypropyl)-4-methylpyridin- 3-yl)amino)-l -methyl- lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (84.0 mg, 0.19 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRALPAK IH, 2x25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NHs-MeOH)— HPLC, Mobile Phase B: IPA: DCM=1 : 1— HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 18 min; Wavelength: 254/220 nm; RTl(min): 6.25; RT2(min): 13.14) to afford (1R, 2R)-2-fluoro-N-(6-(4-((6-(l-hydroxypropyl)-4-methylpyridin-3-yl)amino)-l -methyl- 1H- pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide Isomer A (retention time 6.25 minutes, 21.2 mg, 51%) as a white solid and (lR,2R)-2-fluoro-N-(6-(4-((6-(l- hydroxypropyl)-4-methylpyridin-3-yl)amino)-l -methyl- lH-pyrazol-3-yl)pyrimidin-4- yl)cyclopropane-l -carboxamide Isomer B (retention time 13.14 minutes, 18.4 mg, 44%) as a white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.30 and 1.31 in Table 1.
[0340] (lR,2R)-2-fluoro-N-(6-(4-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-l-methyl-lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide Isomer A: RTl(min): 6.25; LCMS (ESI, m/z): [M+H]+ = 426.2. 'HNMR (400 MHz, DMSO-tA): 5 11.35 (s, IH), 8.93 (s, IH), 8.58 (s, IH), 8.14 (s, IH), 7.92 (s, IH), 7.30 (s, IH), 5.24 (d, J= 4.8 Hz, IH), 5.08 - 4.89 (m, IH), 4.43 - 4.39 (m, IH), 3.88 (s, 3H), 2.34 - 2.24 (m, 4H), 1.75 - 1.64 (m, 2H), 1.60 - 1.53 (m, IH), 1.27 - 1.17 (m, IH), 0.83 - 0.79 (m, 3H).
[0341] (lR,2R)-2-fluoro-N-(6-(4-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-l-methyl-lH-pyrazol-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide Isomer B: RT2(min): 13.14; LCMS (ESI, m/z): [M+H]+ = 426.2. 'HNMR (400 MHz, DMSO-tA): 5 11.34 (s, IH), 8.93 (s, IH), 8.58 (s, IH), 8.14 (s, IH), 7.92 (s, IH), 7.30 (s, IH), 5.24 (d, J= 4.8 Hz, IH), 5.06 - 4.89 (m, IH), 4.43 - 4.39 (m, IH), 3.88 (s, 3H), 2.34 - 2.24 (m, 4H), 1.75 - 1.64 (m, 2H), 1.60 - 1.53 (m, IH), 1.27 - 1.17 (m, IH), 0.83 - 0.79 (m, 3H).
Example 17. Synthesis of (lR,2R)-2-fluoro-N-(6-(4-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-l-methyl-lH-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.32) and (lR,2R)-2-fluoro-N-(6-(4-((6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-l-methyl-lH-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.33)
Step 1. Synthesis of tert-butyl (6-(l-methyl-4-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-imidazol-5-yl)pyrimidin-4-yl)carbamate
Figure imgf000177_0001
[0342] To a solution of tert-butyl N-[6-(5-bromo-3-methylimidazol-4-yl)pyrimidin-4- yl]carbamate (250.0 mg, 0.70 mmol) in dioxane (8.0 mL) was added l-(5-amino-4- methylpyridin-2-yl)propan-l-one (126.0 mg, 0.77 mmol), Pd(OAc)2 (24.3 mg, 0.11 mmol), XPhos (103.1 mg, 0.22 mmol) and CS2CO3 (557.2 mg, 1.71 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. The reaction was then allowed to cool to ambient temperature and the resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (25/75, v/v) to afford tert-butyl (6-(l-methyl-4-((4-methyl-6- propionylpyridin-3-yl)amino)-lH-imidazol-5-yl)pyrimidin-4-yl)carbamate (150.0 mg, 46%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 438.1.
Step 2. Synthesis of l-(5-((5-(6-aminopyrimidin-4-yl)-l-methyl-lH-imidazol-4- yl)amino)-4-methylpyridin-2-yl)propan-l-one
Figure imgf000177_0002
[0343] To a solution of tert-butyl (6-(l-methyl-4-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-imidazol-5-yl)pyrimidin-4-yl)carbamate (400.0 mg, 0.90 mmol) in CH2CI2 (8.0 mL) was added TFA (4.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The pH value of the residue was adjusted to 8.0 with sat. aq. NaHCCh. The mixture was extracted with CH2CI2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford l-(5-((5-(6-aminopyrimidin-4-yl)-l -methyl- IH-imidazol -4-yl)amino)-4- methylpyridin-2-yl)propan-l-one (300.0 mg, crude) as a white solid. LCMS (ESI, m/z): [M+H]+ = 338.1.
Step 3. Synthesis of (lR,2R)-2-fluoro-N-(6-(l-methyl-4-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.17)
Figure imgf000178_0001
2.17
[0344] To a solution of l-(5-((5-(6-aminopyrimidin-4-yl)-l -methyl- lELimidazol-4- yl)amino)-4-methylpyridin-2-yl)propan-l-one (300.0 mg, crude) in pyridine (8.0 mL) was added (lR,2R)-2-fhiorocyclopropane-l-carboxylic acid (108.1 mg, 0.88 mmol) and EDCI (826.5 mg, 4.32 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with CEECh/MeOH (95/5, v/v) to afford (lR,2R)-2-fhioro-N-(6-(l-methyl-4-((4-methyl-6- propionylpyridin-3-yl)amino)-lH-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.17, 170.0 mg, 46%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 424.1.
Step 4. Synthesis of (lR,2R)-2-fluoro-N-(6-(4-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-l-methyl-lH-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
Figure imgf000178_0002
[0345] To a solution of (lR,2R)-2-fluoro-N-(6-(l-methyl-4-((4-methyl-6- propionylpyridin-3-yl)amino)-lH-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.17, 200.0 mg, 0.47 mmol) in THF (5.0 mL) and MeOH (1.0 mL) was added NaBH4 (26.0 mg, 0.68 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with CELCh/MeOH (90/10, v/v) to afford (lR,2R)-2-fluoro-N-(6-(4-((6-(l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-l-methyl-lH-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (60.0 mg, 30%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =426.2. Step 5. Chiral Separation of (1R,2R)-2-fluoro-N-(6-(4-((6-((R)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)-1-methyl-1H-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-1- carboxamide (Compound 1.32) and (1R,2R)-2-fluoro-N-(6-(4-((6-((S)-1-hydroxypropyl)- 4-methylpyridin-3-yl)amino)-1-methyl-1H-imidazol-5-yl)pyrimidin-4-yl)cyclopropane- 1-carboxamide (Compound 1.33)
Figure imgf000179_0001
1.32 1.33 [0346] The product of (1R,2R)-2-fluoro-N-(6-(4-((6-(1-hydroxypropyl)-4-methylpyridin- 3-yl)amino)-1-methyl-1H-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (80.0 mg, 0.19 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-4, 2.12 x ^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[ (0.5% 2M NH3- MeOH)--HPLC, Mobile Phase B: MeOH: EtOH=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 13 min; Wavelength: 254/220 nm; RT1(min): 8.49; RT2(min): 11.01) to afford (1R,2R)-2-fluoro-N-(6-(4-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)-1-methyl-1H-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A (retention time 8.49 minutes, 11.2 mg, 28%) as a white solid and (1R,2R)-2-fluoro-N-(6-(4- ((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)-1-methyl-1H-imidazol-5-yl)pyrimidin-4- yl)cyclopropane-1-carboxamide Isomer B (retention time 11.01 minutes, 12.4 mg, 31%) as a white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.32 and 1.33 in Table 1. [0347] (1R,2R)-2-fluoro-N-(6-(4-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)-1-methyl-1H-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A: RT1(min): 8.49; LCMS (ESI, m/z): [M+H]+ = 426.2. 1H NMR (400 MHz, DMSO-d6): į 11.46 - 11.44 (m, 2H), 9.07 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.51 (s, 1H), 5.37 (d, J = 4.8 Hz, 1H), 5.10 - 4.93 (m, 1H), 4.59 - 4.55 (m, 1H), 3.92 (s, 3H), 2.36 - 2.33 (m, 1H), 2.28 (s, 3H), 1.88 - 1.84 (m, 1H), 1.78 - 1.68 (m, 2H), 1.29 - 1.24 (m, 1H), 0.95 - 0.91 (m, 3H). [0348] (1R,2R)-2-fluoro-N-(6-(4-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)-1-methyl-1H-imidazol-5-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B: RT2(min): 11.01; LCMS (ESI, m/z): [M+H]+ = 426.2. 1H NMR (400 MHz, DMSO-d6): į 11.48 - 11.45 (m, 2H), 9.07 (s, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.51 (s, 1H), 5.37 (d, J = 4.8 Hz, 1H), 5.12 - 4.92 (m, 1H), 4.59 - 4.55 (m, 1H), 3.92 (s, 3H), 2.38 - 2.31 (m, 1H), 2.28 (s, 3H), 1.90 - 1.84 (m, 1H), 1.78 - 1.68 (m, 2H), 1.29 - 1.24 (m, 1H), 0.95 - 0.86 (m, 3H). Example 18. Synthesis of (1R,2R)-2-fluoro-N-(6-(2-((6-((S)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)-4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1- carboxamide (Compound 1.34) and (1R,2R)-2-fluoro-N-(6-(2-((6-((R)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)-4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1- carboxamide (Compound 1.35) Step 1. Synthesis of N-(4-methyl-1H-imidazol-2-yl)acetamide
Figure imgf000180_0001
[0349] To a solution of 1-chloropropan-2-one (15.0 g, 162 mmol) in acetonitrile (300.0 mL) was added N-carbamimidoylacetamide (3.3 g, 32 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 12 h. The reaction was then allowed to cool to ambient temperature and the resulting mixture was concentrated under reduced pressure. The residue was washed with water and then filtered. The solid was collected and dried to afford N-(4-methyl-1H-imidazol-2-yl)acetamide (1.0 g, crude) as a white solid. LCMS (ESI, m/z): [M+H]+ =140.1 Step 2. Synthesis of N-(1-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-4-methyl-1H- imidazol-2-yl)acetamide
Figure imgf000180_0002
[0350] To a solution of 6-chloro-N,N-bis(4-methoxybenzyl)pyrimidin-4-amine (2.5 g, 6.8 mmol) in DMSO (15.0 mL) was added N-(4-methyl-1H-imidazol-2-yl)acetamide (2.5 g, crude) and Cs2CO3 (6.6 g, 20mmol) at room temperature. The resulting mixture was stirred at 110 °C for 36 h. The reaction was then allowed to cool to ambient temperature, diluted with H2O, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (10/90, v/v) to afford N-(l-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4- yl)-4-methyl-lH-imidazol-2-yl)acetamide (1.1 g, 35%) as a white solid. LCMS (ESI, m/z): [M+H]+ =473.2.
Step 3. Synthesis of 6-(2-amino-4-methyl-lH-imidazol-l-yl)-N,N-bis(4- methoxybenzyl)pyrimidin-4-amine
Figure imgf000181_0001
[0351] To a solution of N-(l-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-4-methyl- lH-imidazol-2-yl)acetamide (1.1 g, 2.3 mmol) in EtOH/ H2O (16.0 mL/4.0 mL) was added LiOH (300.0 mg, 11.64 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The reaction was then allowed to cool to ambient temperature, diluted with H2O, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with dichloromethane/methanol (96/4, v/v) to afford 6-(2-amino-4-methyl-lH-imidazol-l-yl)- N,N-bis(4-methoxybenzyl)pyrimidin-4-amine (810.0 mg, 80%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ =431.2.
Step 4. Synthesis of l-(5-((l-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-4-methyl- lH-imidazol-2-yl)amino)-4-methylpyridin-2-yl)propan-l-one
Figure imgf000181_0002
[0352] To a solution of 6-(2-amino-4-methyl-lH-imidazol-l-yl)-N,N-bis(4- methoxybenzyl)pyrimidin-4-amine (230.0 mg, 0.53 mmol) in dioxane (15.0 mL) were added l-(5-bromo-4-methylpyridin-2-yl)propan-l-one (121.8 mg, 0.53 mmol), CS2CO3 (122.0 mg, 1.60 mmol), XantPhos (101.2 mg, 0.10 mmol) and Pd2(dba)3 (48.9 mg, 0.05 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The reaction was then allowed to cool to ambient temperature, diluted with H2O, extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (75/25, v/v) to afford l-(5-((l-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-4-methyl-lH- imidazol-2-yl)amino)-4-methylpyridin-2-yl)propan-l-one (200.0 mg, 64%) as an orange solid. LCMS (ESI, m/z): [M+H]+ =578.3.
Step 5. Synthesis of l-(5-((l-(6-aminopyrimidin-4-yl)-4-methyl-lH-imidazol-2- yl)amino)-4-methylpyridin-2-yl)propan-l-one
Figure imgf000182_0001
[0353] A solution of l-(5-((l-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-4-methyl- lH-imidazol-2-yl)amino)-4-methylpyridin-2-yl)propan-l-one (200.0 mg, 0.34 mmol) in TFA (15.0 ml) was stirred at 100 °C for 2 h. The reaction was then allowed to cool to ambient temperature, then the mixture was concentrated under reduced pressure. The residue was washed with saturated aqueous NaHCCh and then filtered. The solid was collected and dried to afford l-(5-((l-(6-aminopyrimidin-4-yl)-4-methyl-lH-imidazol-2-yl)amino)-4- methylpyridin-2-yl)propan-l-one (150.0 mg, crude) as a white solid. LCMS (ESI, m/z): [M+H]+ =338.2.
Step 6. Synthesis of (lR,2R)-2-fluoro-N-(6-(4-methyl-2-((4-methyl-6-propionylpyridin-3- yl)amino)-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound
2.18)
Figure imgf000182_0002
[0354] To a solution of l-(5-((l-(6-aminopyrimidin-4-yl)-4-methyl-lH-imidazol-2- yl)amino)-4-methylpyridin-2-yl)propan-l-one (200.0 mg, crude) in pyridine (16.0 mL) was added (lR,2R)-2-fhiorocyclopropane-l-carboxylic acid (123.4 mg, 1.18 mmol) at room temperature. The resulting mixture was stirred at 0 °C for 0.5 h. Then POCI3 (2.0 mL) was added to the mixture at 0 °C under N2. The resulting mixture was stirred at room temperature for an additional 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (60/40, v/v) to afford (lR,2R)-2-fluoro-N-(6-(4-methyl-2-((4-methyl-6- propionylpyri din-3 -yl)amino)- IH-imidazol- 1 -yl)pyrimidin-4-yl)cyclopropane- 1 -carboxamide (Compound 2.18, 30.0 mg, 11%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =424.2.
Step 7. Synthesis of (lR,2R)-2-fluoro-N-(6-(2-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-4-methyl-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
Figure imgf000183_0001
[0355] To a solution of (lR,2R)-2-fluoro-N-(6-(4-methyl-2-((4-methyl-6- propionylpyri din-3 -yl)amino)- IH-imidazol- 1 -yl)pyrimidin-4-yl)cyclopropane- 1 -carboxamide (Compound 2.18, 50.0 mg, 0.12 mmol) in MeOH/THF (1.0 mL/4.0 mL) was added NaBTU (4.5 mg, 0.12 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with dichloromethane/methanol (90/10, v/v) to afford (lR,2R)-2-fluoro-N-(6-(2-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-4-m ethyl- IH-imidazol- 1 -yl)pyrimidin-4-yl)cyclopropane- 1 -carboxamide (40.0 mg, 80%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =426.2
Step 8. Chiral Separation of (lR,2R)-2-fluoro-N-(6-(2-((6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-4-methyl-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.34) and (lR,2R)-2-fluoro-N-(6-(2-((6-((R)-l- hydroxypropyl)-4-methylpyridin-3-yl)amino)-4-methyl-lH-imidazol-l-yl)pyrimidin-4- yl)cyclopropane-l-carboxamide (Compound 1.35)
Figure imgf000183_0002
[0356] The product of (lR,2R)-2-fluoro-N-(6-(2-((6-(l-hydroxypropyl)-4-methylpyridin-
3 -yl)amino)-4-methyl-lH-imidazol-l-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (50.0 mg, 0.12 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: Lux 5um Cellulose-42.12x25 cm, 5 um; Mobile Phase A: Hex (0.5% 2M NH3- MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 15 min; Wavelength: 220/254 nm; RT1(min): 18.11; RT2(min): 22.37) to afford (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)-4-methyl-1H- imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A (retention time 18.11 minutes, 2.4 mg, 9%) as a white solid and (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxypropyl)- 4-methylpyridin-3-yl)amino)-4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1- carboxamide Isomer B (retention time 22.37 minutes, 2.8 mg, 11%) as a white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.34 and 1.35 in Table 1. [0357] (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)-4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A: RT1(min): 18.11; LCMS (ESI, m/z): [M+H]+ = 426.3. 1H NMR (300 MHz, DMSO-d6^^^į^^^^^^^^V^^^+^^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^V^^^+^^^^^^^^^V^^ 1H), 7.15 (s, 1H), 5.14 - 4.90 (m, 2H), 4.49 - 4.44 (m, 1H), 2.39 (s, 3H), 2.37 - 2.29 (m, 1H), 2.14 (s, 3H), 1.81 - 1.73 (m, 1H), 1.70 - 1.61 (m, 2H), 1.28 - 1.17 (m, 1H), 0.92 - 0.88 (m, 3H). [0358] (1R,2R)-2-fluoro-N-(6-(2-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)-4-methyl-1H-imidazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B: RT2 (min): 22.37; LCMS (ESI, m/z): [M+H]+ = 426.3. 1H NMR (300 MHz, DMSO-d6): į^^^^^^^^V^^^+^^^^^^^^^^V^^^+^^^^^50 (s, 1H), 8.91 (s, 1H), 8.12 (s, 1H), 7.33 (s, 1H), 7.16 (s, 1H), 5.14 - 4.90 (m, 2H), 4.49 - 4.42 (m, 1H), 2.40 (s, 3H), 2.37 - 2.29 (m, 1H), 2.14 (s, 3H), 1.81 - 1.65 (m, 3H), 1.25 - 1.19 (m, 1H), 0.92 - 0.86 (m, 3H). Example 19. Synthesis of 1R,2R)-2-fluoro-N-(4'-((6-((S)-1-hydroxypropyl)-4- methylpyridin-3-yl)amino)-[4,5'-bipyrimidin]-6-yl)cyclopropane-1-carboxamide (Compound 1.36) and (1R,2R)-2-fluoro-N-(4'-((6-((R)-1-hydroxypropyl)-4-methylpyridin- 3-yl)amino)-[4,5'-bipyrimidin]-6-yl)cyclopropane-1-carboxamide (Compound 1.37) Step 1. Synthesis of tert-butyl N-{4'-amino-[4,5'-bipyrimidin]-6-yl}-N-(tert- butoxycarbonyl)carbamate
Figure imgf000185_0001
[0359] To a solution of tert-butyl N-(tert-butoxycarbonyl)-N-[6- (tributylstannyl)pyrimidin-4-yl]carbamate (2.4 g, 4.1 mmol) in NMP (30.0 mL) was added 5- iodopyrimidin-4-amine (907.6 mg, 4.11 mmol), Cui (78.1 mg, 0.41 mmol) and Pd(PPh3)2Ch (288.2 mg, 0.41 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The reaction was then allowed to cool to ambient temperature and the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography eluting with methanol/water (88/12, v/v) to afford tert-butyl N- {4'-amino-[4,5'-bipyrimidin]-6-yl}-N-(tert-butoxycarbonyl)carbamate (800.0 mg, 50%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 389.2.
Step 2. Synthesis of tert-butyl N-(tert-butoxycarbonyl)-N-{4'-[(4-methyl-6- propano
Figure imgf000185_0002
[0360] To a solution of tert-butyl N-{4'-amino-[4,5'-bipyrimidin]-6-yl}-N-(tert- butoxycarbonyl)carbamate (800.0 mg, 2.06 mmol) in dioxane (20.0 mL) was added l-(5- bromo-4-methylpyridin-2-yl)propan-l-one (467.6 mg, 2.06 mmol), CS2CO3 (2.1 g, 6.18 mmol), XantPhos (238.3 mg, 0.41 mmol) and Pd(dba)2 (188.6 mg, 0.21 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 4 h under N2. The reaction was then allowed to cool to ambient temperature and the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (65/35, v/v) to afford tert-butyl N-(tert-butoxycarbonyl)-N- {4'-[(4-methyl-6-propanoylpyridin-3-yl)amino]-[4,5'-bipyrimidin]-6-yl}carbamate (551.5 mg, 50%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 536.3. Step 3. Synthesis of l-(5-((6-amino-[4,5'-bipyrimidin]-4'-yl)amino)-4-methylpyridin-2- yl)propan-l-one
Figure imgf000186_0001
[0361] To a solution of tert-butyl N-(tert-butoxycarbonyl)-N-{4'-[(4-methyl-6- propanoylpyridin-3-yl)amino]-[4,5'-bipyrimidin]-6-yl}carbamate (551.5 mg, 1.03 mmol) in CH2CI2 (5.0 mL) was added TFA (5.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 8 with saturated aqueous NaHCCh. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford l-(5-((6-amino-[4,5'-bipyrimidin]-4'- yl)amino)-4-methylpyridin-2-yl)propan-l-one (400.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 336.2.
Step 4. Synthesis of (lR,2R)-2-fluoro-N-(4'-((4-methyl-6-propionylpyridin-3-yl)amino)- [4,5'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide (Compound 2.19)
Figure imgf000186_0002
[0362] To a solution of l-(5-((6-amino-[4,5'-bipyrimidin]-4'-yl)amino)-4-methylpyridin- 2-yl)propan-l-one (400.0 mg, 1.19 mmol) in pyridine (20.0 mL) was added (lR,2R)-2- fluorocyclopropane-1 -carboxylic acid (124.2 mg, 1.19 mmol) and POCI3 (1.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with H2O and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with CH2CI2/CH3OH (95/5, v/v) to afford (lR,2R)-2-fluoro-N-(4'-((4-methyl-6-propionylpyridin-3-yl)amino)-[4,5'-bipyrimidin]-6- yl)cyclopropane-l -carboxamide (Compound 2.19, 100.0 mg, 20%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 422.2. Step 5. Synthesis of (lR,2R)-2-fluoro-N-(4'-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-[4,5'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide
Figure imgf000187_0001
[0363] To a solution of (lR,2R)-2-fluoro-N-(4'-((4-methyl-6-propionylpyridin-3- yl)amino)-[4,5'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide (Compound 2.19, 100.0 mg, 0.23 mmol) in THF/MeOH (2.0 mL/2.0 mL) was added NaBEU (10.0 mg, 0.26 mmol) at 0 °C under N2. The mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with CH2CI2/CH3OH (90/10, v/v) to afford (lR,2R)-2- fluoro-N-(4'-((6-(l-hydroxypropyl)-4-methylpyridin-3-yl)amino)-[4,5'-bipyrimidin]-6- yl)cyclopropane-l -carboxamide (70.0 mg, 72%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 424.2.
Step 6. Chiral Separation of (lR,2R)-2-fluoro-N-(4'-((6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-[4,5'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide (Compound 1.36) and (lR,2R)-2-fluoro-N-(4'-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-[4,5'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide (Compound 1.37)
Figure imgf000187_0002
1.36 1.37
[0364] The product of (lR,2R)-2-fluoro-N-(4'-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-[4,5'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide (70.0 mg, 0.16 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRALPAK H4 2x25 cm, 5 um; Mobile Phase A: Hex(0.5% 2M NHs-MeOH)— HPLC, Mobile Phase B: MeOH: EtOH=l : 1-HPILC; Flow rate: 20 mL/min; Gradient: 15% B to 15% B in 28 min;
Wavelength: 220/254 nm; RTl(min): 19.94; RT2(min): 23.88) to afford (lR,2R)-2-fluoro-N- (4'-((6-(l-hydroxypropyl)-4-methylpyridin-3-yl)amino)-[4,5'-bipyrimidin]-6- yl)cyclopropane-l -carboxamide Isomer B (retention time 19.94 minutes, 1.5 mg, 4%) as a white solid and (lR,2R)-2-fluoro-N-(4'-((6-(l-hydroxypropyl)-4-methylpyridin-3-yl)amino)- [4,5'-bipyrimidin]-6-yl)cyclopropane-l -carboxamide Isomer B (retention time 23.88 minutes, 1.2 mg, 3%) as a white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.36 and 1.37 in Table 1.
[0365] (lR,2R)-2-fluoro-N-(4'-((6-(l-hydroxypropyl)-4-methylpyridin-3-yl)amino)- [4,5'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide Isomer A: RTl(min): 19.94; LCMS (ESI, m/z): [M+H]+ = 424.1. *H NMR (400 MHz, DMSO-t/e): 5 11.47 (s, 1H), 9.08 (s, 1H), 8.89 - 8.87 (m, 2H), 8.69 (s, 1H), 8.64 (s, 1H), 7.41 (s, 1H), 5.24 (d, J= 4.4 Hz, 1H), 5.11 - 4.91 (m, 1H), 4.53 - 4.48 (m, 1H), 2.35 - 2.30 (m, 4H), 1.84 - 1.62 (m, 3H), 1.32 - 1.23 (m, 1H), 0.89 - 0.80 (m, 3H).
[0366] (lR,2R)-2-fluoro-N-(4'-((6-(l-hydroxypropyl)-4-methylpyridin-3-yl)amino)- [4,5'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide Isomer B: RT2(min): 23.88; LCMS (ESI, m/z): [M+H]+ = 424.2. 'H NMR (400 MHz, DMSO-t/e): 5 11.53 - 11.47 (m, 2H), 9.08 (s, 1H), 8.89 - 8.87 (m, 2H), 8.68 - 8.64 (m, 2H), 7.41 (s, 1H), 5.27 - 4.93 (m, 2H), 4.51 - 4.46 (m, 1H), 2.39 - 2.30 (m, 4H), 1.84 - 1.55 (m, 3H), 1.35 - 1.21 (m, 1H), 0.92 - 0.82 (m, 3H).
Example 20. Synthesis of (lR,2R)-2-fluoro-N-(6-(4-((6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)anuno)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.38) and (lR,2R)-2-fluoro-N-(6-(4-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.39)
Step 1. Synthesis of (lR,2R)-N-(6-bromopyrimidin-4-yl)-2-fluorocyclopropane-l- carboxamide
Figure imgf000188_0001
[0367] To a mixture of 6-bromopyrimidin-4-amine (3.0 g, 17.24 mmol) and (lR,2R)-2- fluorocyclopropane-1 -carboxylic acid (0.9 g, 8.62 mmol) in pyridine (30.0 mL) was added POCh (2.2 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography, eluting with petroleum ether/ethyl acetate (45/55, v/v) to afford (lR,2R)-N-(6-bromopyrimidin-4-yl)-2-fluorocyclopropane-l-carboxamide (1.5 g, 66%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 260.0.
Step 2. Synthesis of (lR,2R)-N-(6-(4-chloropyridin-3-yl)pyrimidin-4-yl)-2- fluorocyclopropane-l-carboxamide
Figure imgf000189_0001
[0368] To a mixture of 4-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.5 g, 6.26 mmol) and (lR,2R)-N-(6-bromopyrimidin-4-yl)-2-fluorocyclopropane-l- carboxamide (1.4 g, 5.22 mmol) in dioxane (30.0 mL) and H2O (6.0 mL) was added K2CO3 (1.2 g, 8.66 mmol) and Pd(PPhs)4 (603.0 mg, 0.52 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with H2O. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography eluting with CH2CI2/CH3OH (94/6, v/v) to afford (lR,2R)-N-(6-(4-chloropyridin-3-yl)pyrimidin-4-yl)-2-fluorocyclopropane-l- carboxamide (1.5 g, 98%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 293.0
Step 3. Synthesis of tert-butyl (3-(6-((lR,2R)-2-fluorocyclopropane-l- carboxamido)pyrimidin-4-yl)pyridin-4-yl)carbamate
Figure imgf000189_0002
[0369] To a mixture of (lR,2R)-N-(6-(4-chloropyridin-3-yl)pyrimidin-4-yl)-2- fluorocyclopropane-1 -carboxamide (1.5 g, 5.1 mmol) and tert-butyl carbamate (1.8 g, 15 mmol) in dioxane (20.0 mL) was added K2CO3 (1.4 g, 10 mmol), XantPhos (593.7 mg, 1.03 mmol) and Pd2(dba)3 (469.2 mg, 0.51 mmol) at room temperature under N2. The resulting mixture was stirred at 115 °C for 10 h under N2. After the reaction was completed, the resulting mixture was cooled to room temperature and diluted with H2O. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (2/98, v/v) to afford tert-butyl (3-(6-((lR,2R)-2-fluorocyclopropane-l- carboxamido)pyrimidin-4-yl)pyridin-4-yl)carbamate (900.0 mg, 47%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 374.1.
Step 4. Synthesis of (lR,2R)-N-(6-(4-aminopyridin-3-yl)pyrimidin-4-yl)-2- fluorocyclopropane-l-carboxamide
Figure imgf000190_0001
[0370] To a solution of tert-butyl (3-(6-((lR,2R)-2-fluorocyclopropane-l- carboxamido)pyrimidin-4-yl)pyridin-4-yl)carbamate (900.0 mg, 2.40 mmol) in DCM (8.0 mL) was added TFA (5.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 5 h. After the reaction was completed, the resulting mixture was adjusted to pH = 7.0 with NaHCCh (aq.). The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography, eluting with CH3OH/CH2CI2 (12/88, v/v) to afford (lR,2R)-N-(6-(4-aminopyridin-3- yl)pyrimidin-4-yl)-2-fluorocyclopropane-l -carboxamide (440.0 mg, 66%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ = 274.1.
Step 5. Synthesis of (lR,2R)-2-fluoro-N-(6-(4-((4-methyl-6-propionylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 2.20)
Figure imgf000190_0002
[0371] To a solution of (lR,2R)-N-(6-(4-aminopyridin-3-yl)pyrimidin-4-yl)-2- fluorocyclopropane- 1 -carboxamide (390.0 mg, 1.43 mmol) in dioxane (10.0 mL) was added l-(5-bromo-4-methylpyridin-2-yl)propan-l-one (320.0 mg, 1.40 mmol), EPhos (150.0 mg, 0.28 mmol), EPhos Pd G4 (130.0 mg, 0.14 mmol) and K2CO3 (400.0 mg, 2.89 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 20 h under N2.
After the reaction was completed, the resulting mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography, eluting with CH3OH/CH2CI2 (9/91, v/v) to afford (lR,2R)-2-fluoro- N-(6-(4-((4-methyl-6-propionylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4- yl)cyclopropane-l -carboxamide (Compound 2.20, 75.0 mg, 12%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ = 421.1.
Step 6. Synthesis of (lR,2R)-2-fluoro-N-(6-(4-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
Figure imgf000191_0001
[0372] To a solution of (lR,2R)-2-fluoro-N-(6-(4-((4-methyl-6-propionylpyridin-3- yl)amino)pyri din-3 -yl)pyrimi din-4-yl)cy cl opropane-1 -carboxamide (Compound 2.20, 75.0 mg, 0.18 mmol) in THF (2.0 mL) and CH3OH (0.2 mL) was added NaBEU (13.0 mg, 0.34 mmol) at 0 °C under N2. The resulting mixture was stirred at 10 °C for 2 h under N2. After the reaction was completed, the resulting mixture was quenched with H2O at 0 °C. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford (lR,2R)-2-fluoro-N-(6-(4-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyri din-3 -yl)pyrimidin-4-yl)cy cl opropane-1 -carboxamide (50.0 mg, crude) as a white solid. LCMS (ESI, m/z): [M+H]+ = 423.1.
Step 7. Chiral Separation of (lR,2R)-2-fluoro-N-(6-(4-((6-((S)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.38) and (lR,2R)-2-fluoro-N-(6-(4-((6-((R)-l-hydroxypropyl)-4- methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.39)
Figure imgf000191_0002
[0373] The product of (lR,2R)-2-fluoro-N-(6-(4-((6-(l-hydroxypropyl)-4-methylpyridin- 3 -yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (50.0 mg, 0.12 mmol) was separated by Prep-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Cellulose-6&^^^î^^^FP^^^^^P^^0RELOH^3KDVH^$^^+H[^^^^^^^^0^1+3-MeOH)-HPLC, Mobile Phase B: EtOH: DCM=1: 1-HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 10 min; Wavelength: 220/254 nm; RT1(min): 6.53; RT2(min): 8.55) to afford (1R,2R)-2-fluoro- N-(6-(4-((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4- yl)cyclopropane-1-carboxamide Isomer A (retention time 6.53 minutes, 13.2 mg, 52%) as a white solid and (1R,2R)-2-fluoro-N-(6-(4-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B (retention time 8.55 minutes, 13.2 mg, 52%) as a white solid. The absolute stereochemistry of Isomers A and B was not assigned. The two isomeric structures that could be obtained from chiral separation of the isomeric mixture as described above are shown as Compounds 1.38 and 39 in Table 1. [0374] (1R,2R)-2-fluoro-N-(6-(4-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer A: RT1 (min): 6.53; LCMS (ESI, m/z): [M+H]+ = 423.1. 1H NMR (400 MHz, DMSO-d6^^^į 11.42 (s, 1H), 10.60 (s, 1H), 9.01 (s, 1H), 8.72 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 8.19 (d, J = 6.0 Hz, 1H), 7.47 (s, 1H), 6.55 (d, J = 5.6 Hz, 1H), 5.29 (d, J = 4.0 Hz, 1H), 5.10 - 4.92 (m, 1H), 4.54 - 4.50 (m, 1H), 2.33 - 2.30 (m, 1H), 2.26 (s, 3H), 1.84 - 1.62 (m, 3H), 1.31 - 1.24 (m, 1H), 0.89 - 0.85 (m, 3H). [0375] (1R,2R)-2-fluoro-N-(6-(4-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide Isomer B: RT2 (min): 8.55; LCMS (ESI, m/z): [M+H]+ = 423.1. 1H NMR (400 MHz, DMSO-d6^^^į 11.41 (s, 1H), 10.56 (s, 1H), 9.01 (s, 1H), 8.71 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.46 (s, 1H), 6.54 (d, J = 6.0 Hz, 1H), 5.28 (d, J = 4.8 Hz, 1H), 5.11 - 4.90 (m, 1H), 4.54 - 4.49 (m, 1H), 2.33 - 2.29 (m, 1H), 2.26 (s, 3H), 1.84 - 1.62 (m, 3H), 1.30 - 1.23 (m, 1H), 0.89 - 0.85 (m, 3H). Example 21. Synthesis of (1S,2R)-2-fluoro-N-(6-(5-((6-(1-hydroxypropyl)-4-methylpyridin- 3-yl)amino)-1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.40) and (1S,2R)-2-fluoro-N-(6-(3-((6-(1-hydroxypropyl)-4-methylpyridin-3-yl)amino)- 4H-1,2,4-triazol-4-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.41) Step 1. Synthesis of tert-butyl (6-(1-((tert-butyldimethylsilyl)oxy)propyl)-4- methylpyridin-3-yl)carbamate NH2Boc Brettphos, Brettphos Pd G3,
Figure imgf000193_0001
Cs2CO3, dioxane
Figure imgf000193_0002
[0376] To a solution of 5-bromo-2-(1-((tert-butyldimethylsilyl)oxy)propyl)-4- methylpyridine (5.0 g, 15 mmol) in dioxane (50.0 mL) was added NH2Boc (8.5 g, 73 mmol), Cs2CO3 (14.2 g, 44 mmol), Brettphos (1.6 g, 2.9 mmol) and Brettphos Pd G3 (1.3 g, 1.5 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. The reaction was then allowed to cool to ambient temperature and the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (4/1, v/v) to afford tert-butyl (6-(1-((tert- butyldimethylsilyl)oxy)propyl)-4-methylpyridin-3-yl)carbamate (3.7 g, 66%) as a brown oil. LCMS (ESI, m/z): [M+H]+ = 381.3. Step 2. Synthesis of 6-(1-((tert-butyldimethylsilyl)oxy)propyl)-4-methylpyridin-3-amine
Figure imgf000193_0003
[0377] To a solution of tert-butyl (6-(1-((tert-butyldimethylsilyl)oxy)propyl)-4- methylpyridin-3-yl)carbamate (3.7 g, 9.7 mmol) in DCM (15.0 mL) was added TFA (15.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The mixture was neutralized to pH=8 with saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (56/44, v/v) to afford 6-(1-((tert-butyldimethylsilyl)oxy)propyl)-4-methylpyridin-3-amine (2.0 g, 73%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 281.2. Step 3. Synthesis of 5-chloro-1-(4-methoxybenzyl)-1H-1,2,4-triazole and 3-chloro-1-(4- methoxybenzyl)-1H-1,2,4-triazole
Figure imgf000194_0003
[0378] To a solution of 3-chloro-2H-1,2,4-triazole (3.0 g, 29 mmol) in acetonitrile (30.0 mL) was added 4-methoxybenzyl chloride (4.5 g, 29 mmol), KI (2.4 g, 14 mmol) and DIEA (7.5 g, 58 mmol) at room temperature. The resulting mixture was stirred at 85 °C for 2 h. The reaction was then allowed to cool to ambient temperature and the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with dichloromethane/methanol (90/10, v/v) to afford a mixture of (5-chloro-1-(4- methoxybenzyl)-1H-1,2,4-triazole and 3-chloro-1-(4-methoxybenzyl)-1H-1,2,4-triazole) (3.8 g, 58%) as a yellow liquid. LCMS (ESI, m/z): [M+H]+ = 224.1. Step 4. Synthesis of a mixture of 6-(1-((tert-butyldimethylsilyl)oxy)propyl)-N-(1-(4- methoxybenzyl)-1H-1,2,4-triazol-5-yl)-4-methylpyridin-3-amine and 6-(1-((tert- butyldimethylsilyl)oxy)propyl)-N-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)-4- methylpyridin-3-amine
Figure imgf000194_0001
Figure imgf000194_0002
o a solution of 6-(1-((tert-butyldimethylsilyl)oxy)propyl)-4-methylpyridin-3- amine (2.0 g, 7.1 mmol) in dioxane (20.0 mL) was added a mixture of (5-chloro-1-(4- methoxybenzyl)-1H-1,2,4-triazole and 3-chloro-1-(4-methoxybenzyl)-1H-1,2,4-triazole) (1.6 g, 7.1 mmol), Cs2CO3 (7.0 g, 21 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]- 4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (1612891-29-8, 0.6 g, 1.25 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. The reaction was then allowed to cool to ambient temperature and the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether/ethyl acetate (1/99, v/v) to afford a mixture of 6-(l -((tert-butyl dimethyl silyl)oxy)propyl)-N-( 1 -(4-methoxybenzyl)- 1H- 1 ,2,4- triazol-5-yl)-4-methylpyridin-3-amine and 6-(l-((tert-butyldimethylsilyl)oxy)propyl)-N-(l- (4-methoxybenzyl)-lH-l,2,4-triazol-3-yl)-4-methylpyridin-3-amine (1.7 g, 50%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 468.3.
Step 5. Synthesis of l-(5-((lH-l,2,4-triazol-5-yl)amino)-4-methylpyridin-2-yl)propan-l- ol
Figure imgf000195_0001
[0380] A mixture 6-(l-((tert-butyldimethylsilyl)oxy)propyl)-N-(l-(4-methoxybenzyl)- lH-l,2,4-triazol-5-yl)-4-methylpyridin-3-amine and 6-(l-((tert- butyldimethylsilyl)oxy)propyl)-N-( 1 -(4-methoxybenzyl)- 1H- 1 ,2,4-triazol-3 -yl)-4- methylpyridin-3 -amine (1.7 g, 3.6 mmol) in TFA (20.0 mL) was stirred at 80 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting mixture was adjusted pH to 8.0 with aq. NaHCCh. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography, eluting with Me0H/H20 (99/1, v/v) to afford l-(5-((lH-l,2,4-triazol-5-yl)amino)-4-methylpyridin-2- yl)propan-l-ol (430.0 mg, 50%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 234.1.
Step 6. Chiral Separation of (lS,2R)-2-fluoro-N-(6-(5-((6-(l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-lH-l,2,4-triazol-l-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.40) and (lS,2R)-2-fluoro-N-(6-(3-((6-(l-hydroxypropyl)-4- methylpyridin-3-yl)amino)-4H-l,2,4-triazol-4-yl)pyrimidin-4-yl)cyclopropane-l- carboxamide (Compound 1.41)
Figure imgf000195_0002
[0381] To a solution of l-(5-((lH-l,2,4-triazol-5-yl)amino)-4-methylpyridin-2-yl)propan- l-ol (360.0 mg, 1.54 mmol) in DMA (10.0 mL) was added (lR,2R)-N-(6-chloropyrimidin-4- yl)-2-fluorocyclopropane-1-carboxamide (332.7 mg, 1.54 mmol) and K2CO3 (639.9 mg, 4.63 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The reaction was then allowed to cool to ambient temperature and the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with dichloromethane/methanol (82/18, v/v) afford Isomer A (crude) and Isomer B (crude). The crude product of Isomer A was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH OBD Column 30x150mm, 5umn; Mobile Phase A: Water(0.1% FA), Mobile Phase B: MeCN; Flow rate: 60 mL/min mL/min; Gradient: 10% B to 20% B in 10 min; Wavelength: 254 nm/220nm; RT1(min): 8.7) to afford Isomer A (retention time 8.7 minutes, 2.2 mg, 0.6%) as a white solid. The crude product of Isomer B was purified by Prep- HPLC with the following conditions: (Column: Xselect CSH OBD Column 30x150 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: 20mm NaOH+10% MeCN; Flow rate: 60 mL/min mL/min; Gradient: 10% B to 20% B in 10 min; Wavelength: 254 nm/220 nm nm; RT1(min): 7.17, RT2(min): 9.22) to afford Isomer B (retention time 9.22 minutes, 3.0 mg, 0.8%) as a white solid. The absolute stereochemistry and bonding configuration of Isomers A and B were not assigned. The two isomeric structures that could be obtained from HPLC separation of the isomeric mixture as described above are shown as Compounds 1.40 and 1.41 in Table 1. [0382] Isomer A: Xselect CSH OBD Column 30*150mm, RT1(min): 8.7; LCMS (ESI, m/z): [M+H]+ = 413.1. 1H NMR (400 MHz, DMSO-d6): į 11.51 (s, 1H), 9.23 (s, 1H), 8.83 - 8.79 (m, 3H), 8.33 (s, 1H), 7.29 (s, 1H), 5.10 - 4.90 (m, 1H), 4.48 - 4.45 (m, 1H), 2.32 - 2.28 (m, 4H), 1.80 - 1.59 (m, 3H), 1.28 - 1.23 (m, 1H), 0.88 - 0.84 (m, 3H). [0383] Isomer B: CSH OBD Column 30*150mm, RT2(min): 9.22; LCMS (ESI, m/z): [M+H]+ = 413.2. 1H NMR (400 MHz, DMSO-d6): 1H), 8.96 (s, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.40 (s, 1H), 5.30 - 5.23 (m, 1H), 5.05 - 4.88 (m, 1H), 4.50 - 4.47 (m, 1H), 2.68 - 2.59 (m, 1H), 2.42 (s, 3H), 1.83 - 1.73 (m, 1H), 1.69 - 1.59 (m, 2H), 1.38 - 1.30 (m, 1H), 0.88 - 0.84 (m, 3H). Example 22. Synthesis of (1R,2R)-2-fluoro-N-(6-(2-((6-((Z)-1-(hydroxyimino)propyl)-4- methylpyridin-3-yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 3.1)
Figure imgf000197_0001
. [0384] To a solution of (1R,2R)-2-fluoro-N-(6-(2-((4-methyl-6-propionylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 2.1, 120.0 mg, 0.29 mmol) in EtOH (5.0 mL) was added NH2OH.HCl (19.8 mg, 0.29 mmol) and pyridine (67.7 mg, 0.86 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The reaction was then allowed to cool to ambient temperature and the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (30/70, v/v) and then purified by Prep-HPLC with the following conditions: (Column: XSelect CSH Prep C18 OBD Column, , Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 51% B to 56% B in 8 min; Wavelength: 254 nm) to afford (1R,2R)-2-fluoro-N-(6-(2-((6-((Z)-1-(hydroxyimino)propyl)-4-methylpyridin-3- yl)amino)pyridin-3-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 3.1, 4.0 mg, 3%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 436.2. 1H NMR (400 MHz, DMSO-d6): , 1H), 11.13 (s, 1H), 9.46 (s, 1H), 9.11 (s, 1H), 8.69 (s, 1H), 8.37 (d, J = 3.6 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.05 - 7.02 (m, 1H), 5.10 - 4.94 (m, 1H), 2.87 - 2.82 (m, 2H), 2.42 (s, 3H), 2.33 - 2.30 (m, 1H), 1.75 - 1.61 (m, 1H), 1.28 - 1.20 (m, 1H), 1.07 - 1.04 (m, 3H). Example 23. Synthesis of (1R,2R)-2-fluoro-N-(4'-{[6-(1-hydroxypropyl)-4-methylpyridin-3- yl]amino}-1'-methyl-2'-oxo-[4,5'-bipyrimidin]-6-yl)cyclopropane-1-carboxamide (Compound 1.42) Step 1. Synthesis of 4-[(6-{1-[(tert-butyldimethylsilyl)oxy]propyl}-4-methylpyridin-3- yl)amino]-1-methylpyrimidin-2-one
Figure imgf000198_0001
[0385] To a solution of 5-bromo-2-{ l-[(tert-butyldimethylsilyl)oxy]propyl}-4- methylpyridine (500.0 mg, 1.45 mmol) in dioxane (15.0 mL) was added 1 -methylcytosine
(181.0 mg, 1.45 mmol), CS2CO3 (1.4 g, 4.30 mmol), EPhos (310.0 mg, 0.58 mmol) and EPhos Pd G4 (266.0 mg, 0.29 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluted with CH2CI2/CH3OH (93/7, v/v) to afford 4-[(6-{ l-[(tert- butyldimethylsilyl)oxy]propyl}-4-methylpyridin-3-yl)amino]-l-methylpyrimidin-2-one (342.0 mg, 60%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ = 389.2.
Step 2. Synthesis of 4-[(6-{l-[(tert-butyldimethylsilyl)oxy]propyl}-4-methylpyridin-3- yl)amino]-5-iodo-l-methylpyrimidin-2-one
[0386]
Figure imgf000198_0002
ethylpyridin- 3-yl)amino]-l-methylpyrimidin-2-one (342.0 mg, 0.88 mmol) in AcOH (10.0 mL) was added NIS (217.0 mg, 0.97 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and then filtered. The solid was washed with water and collected to afford 4-[(6-{ 1- [(tert-butyldimethylsilyl)oxy]propyl}-4-methylpyridin-3-yl)amino]-5-iodo-l- methylpyrimidin-2-one (190.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =
515.1. Step 3. Synthesis of (lR,2R)-N-{4'-[(6-{l-[(tert-butyldimethylsilyl)oxy]propyl}-4- methylpyridin-3-yl)amino]-l'-methyl-2'-oxo-[4,5'-bipyrimidin]-6-yl}-2- fluorocyclopropane-l-carboxamide
Figure imgf000199_0001
[0387] To a solution of 4-[(6-{l-[(tert-butyldimethylsilyl)oxy]propyl}-4-methylpyridin- 3-yl)amino]-5-iodo-l-methylpyrimidin-2-one (160.0 mg, 0.31 mmol) in dioxane (10.0 mL) was added (lR,2R)-2-fluoro-N-[6-(tributylstannyl)pyrimidin-4-yl]cyclopropane-l- carboxamide (146.0 mg, 0.31 mmol), Cui (6.5 mg, 0.03 mmol) and Pd(PPh3)2Ch (24.0 mg, 0.03 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluted with CH2CI2/CH3OH (94/6, v/v) to afford (lR,2R)-N-{4'-[(6-{ l-[(tert-butyldimethylsilyl)oxy]propyl}-4- methylpyridin-3-yl)amino]-T-methyl-2'-oxo-[4,5'-bipyrimidin]-6-yl}-2-fluorocyclopropane- 1-carboxamide (150.0 mg, 67%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 568.3.
Step 4. Synthesis of (lR,2R)-2-fluoro-N-(4'-{[6-(l-hydroxypropyl)-4-methylpyridin-3- yl]amino}-l'-methyl-2'-oxo-[4,5'-bipyrimidin]-6-yl)cyclopropane-l-carboxamide
Figure imgf000199_0002
[0388] To a a solution of (lR,2R)-N-{4'-[(6-{ l-[(tert-butyldimethylsilyl)oxy]propyl}-4- methylpyridin-3-yl)amino]-T-methyl-2'-oxo-[4,5'-bipyrimidin]-6-yl}-2-fluorocyclopropane-
1-carboxamide (150.0 mg, 0.26 mmol) in THF (15.0 mL) was added TBAF (134.0 mg, 0.51 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with acetonitrile/water (32/68, v/v) to afford (1R,2R)-2-fluoro-N-(4'-{[6-(1-hydroxypropyl)-4-methylpyridin-3-yl]amino}- 1'-methyl-2'-oxo-[4,5'-bipyrimidin]-6-yl)cyclopropane-1-carboxamide (Compound 1.42, 6.5 mg, 5%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 454.2. 1H NMR (400 MHz, DMSO- d6): į 11.94 (s, 1H), 11.37 (s, 1H), 9.05 - 8.95 (m, 2H), 8.71 (s, 1H), 8.46 (s, 1H), 7.39 (s, 1H), 5.24 (d, J = 4.4 Hz, 1H), 5.10 - 4.92 (m, 1H), 4.52 - 4.43 (m, 1H), 3.48 (s, 3H), 2.40 - 2.22 (m, 4H), 1.80 - 1.71 (m, 1H), 1.69 - 1.60 (m, 1H), 1.28 - 1.18 (m, 2H), 0.94 - 0.86 (m, 3H). Example 24. Synthesis of (1R,2R)-2-fluoro-N-(6-(3-((6-(1-hydroxypropyl)-4-methylpyridin- 3-yl)amino)-4H-1,2,4-triazol-4-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 1.43) Step 1. Synthesis of 6-chloro-N,N-bis(4-methoxybenzyl)pyrimidin-4-amine
Figure imgf000200_0001
[0389] To a solution of 4,6-dichloropyrimidine (10.0 g, 67.13 mmol) in NMP (100.0 mL) was added bis(4-methoxybenzyl)amine (17.3 g, 67.13 mmol) and K2CO3 (27.8 g, 201.38 mmol) at room temperature. The resulting mixture was stirred at 80 oC for 16 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluted with petroleum ether/ethyl acetate (71/29, v/v) to afford 6-chloro-N,N-bis(4-methoxybenzyl)pyrimidin-4-amine (15.0 g, 60%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 370.1濁 Step 2. Synthesis of 6-(3-amino-4H-1,2,4-triazol-4-yl)-N,N-bis(4- methoxybenzyl)pyrimidin-4-amine and 6-(3-amino-1H-1,2,4-triazol-1-yl)-N,N-bis(4- methoxybenzyl)pyrimidin-4-amine
Figure imgf000200_0002
[0390] To a solution of 6-chloro-N,N-bis(4-methoxybenzyl)pyrimidin-4-amine (15.0 g, 40.56 mmol) in DMA (150.0 mL) was added 4H-l,2,4-triazol-3-amine (6.8 g, 81.11 mmol) and CS2CO3 (39.6 g, 121.67 mmol) at room temperature. The resulting mixture was stirred at 120 °C for 16 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluted with petroleum ether/ethyl acetate (48/52, v/v) and then separated by Prep-Achiral-SFC with the following conditions: (Column: YMC-Actus Triart Diol-HILIC 3x25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MEOH(0.1% 2M NH3-MEOH); Flow rate: 75 mL/min; Gradient: isocratic 15% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wavelength: 220 nm; RTl(min): 6.37; RT2(min): 8.68) to afford 6-(3-amino-4H-l,2,4-triazol-4-yl)-N,N-bis(4- methoxybenzyl)pyrimidin-4-amine (RTl(min): 6.37, 2.0 g, 11%) as a white solid.
Step 3. Synthesis of l-(5-((4-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-4H-l,2,4- triazol-3-yl)amino)-4-methylpyridin-2-yl)propan-l-one
Figure imgf000201_0001
[0391] To a solution of 6-(3-amino-4H-l,2,4-triazol-4-yl)-N,N-bis(4- methoxybenzyl)pyrimidin-4-amine (1.5 g, 3.63 mmol) in dioxane (30.0 mL) was added l-(5- bromo-4-methylpyridin-2-yl)propan-l-one (1.0 g, 4.39 mmol), CS2CO3 (3.5 g, 10.69 mmol), Xantphos (562.8 mg, 0.97 mmol) and Pd(dba)2 (454.9 mg, 0.79 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O and then filtered. The solid was washed with MeOH and collected to afford l-(5-((4-(6-(bis(4- methoxybenzyl)amino)pyrimidin-4-yl)-4H-l,2,4-triazol-3-yl)amino)-4-methylpyridin-2- yl)propan-l-one (1.4 g, 68%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 565.3.
Step 4. Synthesis of l-(5-((4-(6-aminopyrimidin-4-yl)-4H-l,2,4-triazol-3-yl)amino)-4- methylpyridin-2-yl)propan-l-one
Figure imgf000202_0001
[0392] The solution of l-(5-((4-(6-(bis(4-methoxybenzyl)amino)pyrimidin-4-yl)-4H- l,2,4-triazol-3-yl)amino)-4-methylpyridin-2-yl)propan-l-one (1.4 g, crude) in TFA (15.0 mL) was stirred at 60 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 7 with NaHCCh (aq.). The mixture was filtered. The solid was washed with ethanol and then collected to afford l-(5-((4-(6-aminopyrimidin-4-yl)-4H-l,2,4-triazol-3-yl)amino)-4- methylpyridin-2-yl)propan-l-one (1.0 g, crude) as a white solid. LCMS (ESI, m/z): [M+H]+ = 325.1.
Step 5. Synthesis of (lR,2R)-2-fluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3- yl)amino)-4H-l,2,4-triazol-4-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (
Figure imgf000202_0002
[0393] To a solution of l-(5-((4-(6-aminopyrimidin-4-yl)-4H-l,2,4-triazol-3-yl)amino)-4- methylpyridin-2-yl)propan-l-one (401.2 mg, 1.23 mmol) in Pyridine (20.0 mL) was added (lR,2R)-2-fluorocyclopropane-l-carboxylic acid (148.1 mg, 1.42 mmol) and POCh (1.0 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with H2O at 0 °C. The resulting mixture was diluted with water and then filtered. The solids were washed with water and collected to afford (lR,2R)-2-fluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3-yl)amino)-4H-l,2,4- triazol-4-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (Compound 2.24, 200.0 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 411.2.
Step 6. Synthesis of (lR,2R)-2-fluoro-N-(6-(3-((6-(l-hydroxypropyl)-4-methylpyridin-3- yl)amino)-4H-l,2,4-triazol-4-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide (Compound 1.43)
Figure imgf000203_0001
[0394] To a solution of (lR,2R)-2-fluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3- yl)amino)-4H- 1 ,2,4-triazol-4-yl)pyrimidin-4-yl)cyclopropane- 1 -carboxamide (assumed, Compound 2.24, 180.0 mg, crude) in THF/MeOH (10.0 mL/10.0 mL) was added NaBTU (19.1 mg, 0.51 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was quenched with water at 0 °C and then extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluted with dichloromethane/methanol (93/7, v/v) to afford (lR,2R)-2- fluoro-N-(6-(3-((6-(l-hydroxypropyl)-4-methylpyridin-3-yl)amino)-4H-l,2,4-triazol-4- yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (Compound 1.43, 52.3 mg, 27%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 413.2. 'HNMR (400 MHz, DMSO-t/e): 5 11.59 (s, 1H), 10.77 (s, 1H), 9.25 (s, 1H), 8.95 (s, 1H), 8.51 (s, 1H), 8.00 (s, 1H), 7.40 (s, 1H), 5.24 (d, J= 4.4 Hz, 1H), 5.15 - 4.92 (m, 1H), 4.55 - 4.48 (m, 1H), 2.43 (s, 3H), 2.35 - 2.25 (m, 1H), 1.90 - 1.60 (m, 3H), 1.35 - 1.24 (m, 1H), 0.88 - 0.70 (m, 3H).
Example 25. Synthesis of (lR)-2,2-difluoro-N-(6-(3-((6-(l-hydroxypropyl)-4-methylpyridin- 3-yl)amino)-4H-l, 2, 4-tria~,ol-4-yl)pyrimidin-4-yl)cyclopropane-l -carboxamide (Compound 1.44)
Step 1. Synthesis of (R)-2,2-difluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3-yl)amino)-
4H-l,2,4-triazol-4-yl)pyrimidin-4-yl)cyclopropane-l-carboxamide
Figure imgf000203_0002
[0395] To a solution of l-(5-((4-(6-aminopyrimidin-4-yl)-4H-l,2,4-triazol-3-yl)amino)-4- methylpyridin-2-yl)propan-l-one (Example 24, step 4, 406.4 mg, 1.25 mmol) in pyridine (20.0 mL) was added (R)-2,2-difluorocyclopropane-l -carboxylic acid (181.1 mg, 1.48 mmol) and POCI3 (1.6 g, 10.73 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h under N2. After the reaction was completed, the reaction mixture was quenched with water at 0 °C and then extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluted with dichloromethane/methanol (96/4, v/v) to afford (R)-2,2- difluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3-yl)amino)-4H-1,2,4-triazol-4-yl)pyrimidin- 4-yl)cyclopropane-1-carboxamide (Compound 2.25, 110.0 mg, 20%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 429.2. Step 2. Synthesis of (1R)-2,2-difluoro-N-(6-(3-((6-(1-hydroxypropyl)-4-methylpyridin-3- yl)amino)-4H-1,2,4-triazol-4-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (C
Figure imgf000204_0001
1.44 [0396] To a solution of (R)-2,2-difluoro-N-(6-(3-((4-methyl-6-propionylpyridin-3- yl)amino)-4H-1,2,4-triazol-4-yl)pyrimidin-4-yl)cyclopropane-1-carboxamide (Compound 2.25¸80.0 mg, 0.19 mmol) in THF/MeOH (2.0 mL/2.0 mL) was added NaBH4 (7.1 mg, 0.19 mmol) at 0 oC under N2. The resulting mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was quenched with water at 0 °C and then extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography, eluted with dichloromethane/methanol (94/6, v/v) and then purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30x150 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 10% B to 20% B in 10min; Wavelength: 254 nm/220 nm) to afford (1R)-2,2-difluoro-N-(6-(3-((6-(1- hydroxypropyl)-4-methylpyridin-3-yl)amino)-4H-1,2,4-triazol-4-yl)pyrimidin-4- yl)cyclopropane-1-carboxamide (Compound 1.44, 2.5 mg, 3%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 431.2. 1H NMR (400 MHz, DMSO-d6 9.23 (s, 1H), 8.98 (s, 1H), 8.48 (s, 1H), 8.09 (s, 1H), 7.40 (s, 1H), 5.25 (s, 1H), 4.61 - 4.49 (m, 1H), 3.18 - 3.07 (m, 1H), 2.43 (s, 3H), 2.19 - 2.05 (m, 2H), 1.85 - 1.77 (m, 1H), 1.70 - 1.55 (m, 1H), 0.95 - 0.75 (m, 3H). Example 26. Synthesis ofN-(6-(2-((6-(l-hydroxybutyl)-4-methylpyridin-3- yl)amino)phenyl)pyrimidin-4-yl)cyclopropanecarboxamide (Compound 1.45)
Step 1. Synthesis of N-(6-chloropyrimidin-4-yl)cyclopropanecarboxamide
Figure imgf000205_0001
Cs2CO3, dioxane
[0397] Cyclopropanecarboxamide (286 mg, 3.36 mmol), 4,6-dichloropyrimidine (0.5 g, 3.36 mmol), cesium carbonate (2.19 g, 2 eq., 6.71 mmol), and XantPhos Pd G3 (127 mg, 0.04 eq., 0.134 mmol) were added to a 100 mL round bottom flask and 1,4-dioxane (30 mL) was added. The reaction was heated at 70 °C under an atmosphere of nitrogen overnight. The reaction was then cooled to ambient temperature and the solvent was stripped in vacuo. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The EtOAc was collected and washed with brine (lx 25 mL), dried over magnesium sulfate and concentrated. The crude mixture was purified via normal phase flash column chromatography, eluting with a gradient of 0-40% EtOAc in heptane to provide N-(6-chloropyrimidin-4- yl)cyclopropanecarboxamide (239 mg, 36%). LCMS (APCI, m/z): [M+l] = 198.1.
Step 2. Synthesis of N-[6-(2-aminophenyl)pyrimidin-4-yl]cyclopropanecarboxamide
Figure imgf000205_0002
[0398] 2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (111 mg, 506 pmol), N-(6- chloropyrimidin-4-yl)cyclopropanecarboxamide (0.1 g, 506 pmol), and tetrakis(triphenylphosphine) palladium (117 mg, 0.2 eq., 101 pmol) were added to a 20 mL vial with septum and dissolved in DMF (5.1 mL). A IN solution of disodium carbonate (215 mg, 4 eq., 2.02 mmol) was added. The reaction was heated at 120 °C in the sealed vial for 1 h. The residue was then allowed to cool to ambient temperature, poured into brine (20 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organics were dried over magnesium sulfate and concentrated. The crude mixture was purified via normal phase flash column chromatography, eluting with a gradient of 0-55% EtOAc in heptane to provide N-[6- (2-aminophenyl)pyrimidin-4-yl]cyclopropanecarboxamide (97.2 mg, 75%). LCMS (APCI, m/z): [M+l] = 255.1.
Step 3. Synthesis of N-(6-{2-[(6-butanoyl-4-methylpyridin-3- yl)amino]phenyl}pyrimidin-4-yl)cyclopropanecarboxamide (Compound 2.26)
Figure imgf000206_0001
[0399] N-[6-(2-aminophenyl)pyrimidin-4-yl]cyclopropanecarboxamide (48.8 mg, 192 pmol), l-(5-bromo-4-methylpyridin-2-yl)butan-l-one (46.5 mg, 192 pmol), cesium carbonate (188 mg, 3 eq., 576 pmol), and XantPhos Pd G3 (27.3 mg, 0.15 eq., 28.8 pmol) were added to a 20 mL vial, to which toluene (1.96 mL) was added. The reaction was heated to 100 °C overnight. The reaction was then allowed to cool to ambient temperature. The crude reaction was diluted with DCM (10 mL), filtered, and concentrated. The crude residue was dissolved methanol and purified via reverse phase HPLC, eluting with a gradient of 0-100% MeCN in water (w/ 0.1% TFA buffer). The desired fractions were diluted with DCM and washed with sat. aq. NaHCCh. The organics were collected, dried over mag sulfate, and concentrated to provide N-(6-{2-[(6-butanoyl-4-methylpyridin-3-yl)amino]phenyl}pyrimidin-4- yl)cyclopropanecarboxamide (Compound 2.26, 33.6 mg, 42%). LCMS (APCI, m/z): [M+l] = 416.3.
Step 4. Synthesis of N-(6-(2-((6-(l-hydroxybutyl)-4-methylpyridin-3- yl)amino)phenyl)pyrimidin-4-yl)cyclopropanecarboxamide (Compound 1.45)
Figure imgf000206_0002
1.45
[0400] N-(6-{2-[(6-butanoyl-4-methylpyridin-3-yl)amino]phenyl}pyrimidin-4- yl)cyclopropanecarboxamide (Compound 2.26, 30 mg, 72.2 pmol) was dissolved in 1.4 mL of 1 : 1 THF/methanol and sodium borohydride (4.1 mg, 1.5 eq., 108 pmol) was added at ambient temperature. The reaction was left for 20 minutes. The reaction was then partitioned between sat. aq. NaHCCh (10 mL) and ethyl acetate (10 mL). The water layer was extracted 2x more with EtOAc (10 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified via normal phase flash column chromatography, eluting with 35-100% gradient of EtOAc in heptane to provide N- [6-(2-{[6-(l-hydroxybutyl)-4-methylpyridin-3-yl]amino}phenyl)pyrimidin-4- yl]cyclopropanecarboxamide (Compound 1.45, 3.3 mg, 11%). LCMS (APCI, m/z): [M+l] = 418.3. 1H NMR (300 MHz, CDCh): 5 10.52 (s, 1H), 8.86 (s, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 7.85 (d, J = 9 Hz, 1H), 7.30 (t, J = 9 Hz, 1H), 7.17 (s, 1H), 7.06 (d, J= 9 Hz, 1H), 6.91 (t, J = 9 Hz, 1H), 4.72-4.76 (m, 1H), 2.36 (s, 3H), 2.03 (s, 1H), 1.84-1.61 (m, 3H), 1.65-1.43 (m, 2H), 1.21-0.98 (m, 6H).
Biological Examples
Example Bl. Cell Viability Assays
[0401] Cell viability was measured in the following MAPK pathway mutant cancer cell lines: A375 (BRAF V600E), HepG2 (NRAS Q61L), SK-MEL-30 (NBAS Q61K), OCI- AML-2 (MBNL1-CRAF fusion), and K562.
[0402] A375, HepG2, SK-MEL-30, OCI-AML-2 and K562 cells were grown in the appropriate growth medium as described in Table 2 below, and harvested at 50-80% confluence. Cells were counted and seeded at their appropriate density (see Table 2) in a 384- well plate (Corning 3570). A375, HepG2 and SK-MEL-30 were allowed to adhere overnight prior to treatment and the OCI-AML-2 were treated immediately for the indicated drug treatment times (Table 4). Table 4 provides the growth media, number of cells seeded per well and drug treatment times for each cell line.
Table 4.
Figure imgf000207_0001
[0403] Compounds were dissolved in DMSO and serially diluted. Serially-diluted compound or a DMSO only control (high control, “HC”) was added to the plated cells in each well. Compounds were tested at concentrations of about 10 pM to 0.51 nM, using threefold dilutions. The final proportion of DMSO never exceeded 0.1%.
[0404] Plates were placed in a 37°C, 5% CO2 incubator for the indicated treatment times (Table Bl). Plates were then removed from the incubator and equilibrated for 15 minutes at room temperature. 40 pl of CellTiter Gio reagent (Promega) was added to measure the relative level of metabolically active cells by quantifying intracellular ATP concentrations. Plates were incubated for 30 minutes at room temperature, and luminescence was measured. Percent viability was normalized to a vehicle control only using the following formula: % viability = 100 x (Lumsampie - Lumi.c) / (Lumnc - Lumrc). IC50 values were calculated using XLFit software or Prism (GraphPad Software), as shown in Table 5, below. Graphical curves were fitted using a nonlinear regression model with a sigmoidal dose response.
Table 5.
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Example B2. Detection of phosphorylated ERK (pERK)
[0405] A375 cells were counted and seeded at 10,000 cells/well in 384 well plates
(Corning 3764) and allowed to adhere overnight.
[0406] Compounds were dissolved and serially diluted in DMSO. The compounds were then added, mixed, and incubated for four hours at 37°C, 5% CO2. Compounds were added using four-fold dilutions at final concentrations ranging from 10 pM to 0.01 nM. DMSO only and lOuM staurosporine were added as high and low controls.
[0407] Following the four-hour incubation with compounds, cell lysates were prepared and AlphaLISA assay measuring phosphorylated ERK was performed. Media was removed using the Apricot Designs pipettor. Lysis buffer was made from IX AlphaLISA SureFire Assay Kit (AlphaLISA SureFire Ultra pERK U (Thr202/Tyr204) ALSU-PERK-A50K) lysis buffer with protease and phosphatase inhibitors. Cells were lysed by adding lOuL to all the wells and mixed for 40 minutes on a plate shaker. lOuL cell lysate was transferred to a new Optiplate (PerkinElmer 6007290) and incubated with 5uL IX acceptor mix for 2 hours in the dark. 5uL of IX donor mix was added to all wells and mixed by shaking followed by overnight incubation in the dark.
[0408] pERK AlphaLISA signal was read on the Envision using standard AlphaLISA settings. Percent inhibition of ERK phosphorylation was calculated by %Inhibition = 100 x (LumHC - LumSample) / (LumHC -LumLC). The low and high controls (LC/HC) are generated from lysate from wells with cells treated with DMSO or 10 mM Staurosporine (BioAustralis, cat # BIA-S1086), respectively. IC50 values were calculated by fitting the Curve using XLfit (v5.3.1.3), equation 201 : Y = Bottom + (Top - Bottom)/(1 + 10A((LogIC50 - X)*HillSlope)). The ICso values are shown in Table 6 below.
Table 6.
Figure imgf000211_0001
Figure imgf000211_0002
Figure imgf000212_0002
Figure imgf000212_0001
[0409] All publications, including patents, patent applications, and scientific articles, mentioned in this specification are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, including patent, patent application, or scientific article, were specifically and individually indicated to be incorporated by reference.
[0410] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced in light of the above teaching. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

CLAIMS What is claimed is:
Claim 1. A compound of formula (I)
Figure imgf000213_0001
or a pharmaceutically acceptable salt, wherein:
Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl or 5- to 6- membered heteroaryl is optionally substituted with 1 to 4 R4 groups;
Y is a bond or -C(=O)-; is a single or double bond, wherein when is a single bond, then X1 is -OH, and the carbon atom to which X1 is attached is optionally further substituted by R2 ; when ■■■■■■■■■" is a double bond, then X1 is =0 or =N-0H;
R1 is Ci-Ce alkyl, C3-C7 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein R1 is optionally substituted with 1 to 5 R5 groups;
R2 is Ci-Ce alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, wherein R2 is optionally substituted with 1 to 5 R5 groups,
R2 is H or D; and
R3 is H or Ci-Ce alkyl; each R4 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, =O, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; each R5 is independently H, F, Cl, Br, I, -SCF3, -SCHF2, -SF5, -OCF3, -OR6, -N(R6)R6, -OCHF2, -CF3, -CHF2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkyl-OH, C1-C6 alkyl-OH, C1-C6 alkyl-CN, C1-C6 heteroalkyl, or C3-C7 cycloalkyl; and each R6 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C7 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 10-membered heteroaryl.
Claim 2. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-1),
Figure imgf000214_0001
(I-1) or a pharmaceutically acceptable salt thereof.
Claim 3. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (I-2):
Figure imgf000214_0002
(I-2) or a pharmaceutically acceptable salt thereof.
Claim 4. The compound of claim 1, wherein the compound is a compound of formula (I-3):
Figure imgf000215_0001
(I-3) or a pharmaceutically acceptable salt thereof.
Claim 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Y is a bond.
Claim 6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Y is -C(=O)-.
Claim 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-C6 alkyl optionally substituted by one or more R5 groups.
Claim 8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1 is C3-C7 cycloalkyl optionally substituted by one or more R5 groups.
Claim 9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1 is 4- to 7-membered heterocycloalkyl optionally substituted by one or more R5 groups.
Claim 10. The compound of any one of claims 1-4, 6 and 8, or a pharmaceutically acceptable salt thereof, wherein Y is -C(=O)- and R1 is C3-C7 cycloalkyl, optionally substituted by one or more R5 groups.
Claim 11. The compound of any one of claims 1-4, 6, 8 and 10, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-1-a), (I-1-b), (I-2- a), (I-2-b), (I-3-a), or (I-3-b),
Figure imgf000216_0001
wherein: A1 and A5 are each independently C, N, O, or S; A2-A4 are each independently C-R4, N, N-R4, O, or S; provided that at least one of A1-A5 is a heteroatom; A6 and A11 are each independently C, N, O, or S; and A7-A10 are each independently C-R4, N, N-R4, O, or S.
Claim 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-1-a) or a compound of formula (I-1-b).
Claim 13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-2-a) or a compound of formula (I-2-b).
Claim 14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I-3-a) or a compound of formula (I-3-b).
Claim 15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl optionally substituted with 1 to 4 R4 groups.
Claim 16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein Ring
Figure imgf000217_0001
wherein f indicates the point of attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
Claim 17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 6-membered heteroaryl optionally substituted with 1 to 4 R4 groups.
Claim 18. The compound of any one of claims 1-14 and 17, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 5-membered heteroaryl.
Claim 19. The compound of any one of claims 1-14 and 17-18, or a pharmaceutically acceptable salt thereof, wherein Ring A is furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 3 R4 groups.
Claim 20. The compound of any one of claims 1-14 and 17-19, or a pharmaceutically
Figure imgf000217_0002
Figure imgf000218_0001
, wherein f indicates the point of attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
Claim 21. The compound of any one of claims 1-14 and 17, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted 6-membered heteroaryl.
Claim 22. The compound of any one of claims 1-14, 17 and 21, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, each of which is optionally substituted.
Claim 23. The compound of any one of claims 1-14, 17 and 21-22, or a pharmaceutically
Figure imgf000218_0002
point of attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety.
Claim 24. The compound of any one of claims 1-14 and 17, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- to 6-membered heteroaryl comprising at least one nitrogen atom.
Claim 25. The compound of any one of claims 1-14 and 17, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- to 6-membered heteroaryl comprising two heteroatoms.
Claim 26. The compound of any one of claims 1-14, 17, and 24-25, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- to 6-membered heteroaryl comprising at least two nitrogen atoms.
Claim 27. The compound of any one of claims 1-4, 6, 8 and 10-26, or a pharmaceutically acceptable salt thereof, wherein R1 is cyclopropyl optionally substituted by 1-2 R5 groups.
Claim 28. The compound of any one of claims 1-4, 6, 8 and 10-27, or a pharmaceutically
O acceptable salt thereof, wherein the moiety
Figure imgf000219_0001
Claim 29. The compound of any one of claims 1-4, 6, 8 and 10-27, or a pharmaceutically acceptable salt thereof, wherein R1 is cyclopropyl substituted by 1-2 fluorine atoms.
Claim 30. The compound of any one of claims 1-4, 6, 8, 10-27 and 29, or a
Figure imgf000219_0002
Claim 31. The compound of any one of claims 1-2, 5-12 and 15-30, or a pharmaceutically acceptable salt thereof, wherein R2’, when present, is H.
Claim 32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-C3 alkyl optionally substituted by 1-5 R5 groups.
Claim 33. The compound of any one of claims 1-32, or a pharmaceutically acceptable
Figure imgf000219_0003
Claim 34. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R2 is C2-C6 alkenyl optionally substituted by 1-5 R5 groups.
Claim 35. The compound of any one of claims 1-31 and 34, or a pharmaceutically
Figure imgf000220_0001
Claim 36. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R2 is C3-C7 cycloalkyl optionally substituted by 1-5 R5 groups.
Claim 37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R3 is H.
Claim 38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R3 is Ci-Ce alkyl.
Claim 39. The compound of any one of claims 1-36 and 38, or a pharmaceutically acceptable salt thereof, wherein R3 is -CH3.
Claim 40. The compound of any one of claims 1-4, 6, 8, 10-14 and 38, or a pharmaceutically acceptable salt thereof, wherein:
Ring A is phenyl or 5- to 6- membered heteroaryl, wherein the 5- to 6- membered heteroaryl comprises at least one nitrogen atom and is optionally substituted with 1 to 5 R4 groups;
Y is -C(=O)-;
R1 is cyclopropyl optionally substituted with 1 to 2 fluorine atoms;
R2 is C1-C3 alkyl optionally substituted with 1 to 5 R5 groups, and
R2 is H or D;
R3 is independently C1-C3 alkyl; each R4 is independently H, F, Cl, Br, I, -OCF3, -OR6, =0, -N(R6)R6, -OCHF2, -CF3, - CHF2, -CN, Ci-Ce alkyl, or Ci-Ce haloalkyl; each R5 is independently H, F, Cl, Br, I, -OCF3, -OR6, =0, -N(R6)R6, -OCHF2, -CF3, - CHF2, -CN, Ci-Ce alkyl, or Ci-Ce haloalkyl; and each R6 is independently H or Ci-Ce alkyl.
Claim 41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, wherein:
Ring A
Figure imgf000221_0001
Figure imgf000221_0002
attachment to the pyrimidinyl ring and { indicates the point of attachment to the amino moiety; is -C(=0)-; is a single bond, wherein
X1 is -OH;
R1 is cyclopropyl optionally substituted with 1 to 2 fluorine atoms;
R2 is -CH3 or -CH2CH3, and R2 is H;
R3 is -CEE; each R5 is independently H, F, or -CH3; and each R6 is independently H or -CH3.
Claim 42. The compound of claim 1 or 2, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 1.
Claim 43. The compound of claim 1 or 3, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 2.
Claim 44. The compound of claim 1 or 4, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 3.
Claim 45. A pharmaceutical composition comprising the compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
Claim 46. A method of inhibiting ARAF, BRAF and CRAF enzymatic activity in a cell, comprising exposing the cell with an effective amount of a compound of any one of claims 1-
44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 45.
Claim 47. A method of treating a cancer or neoplastic disease in a human in need thereof, comprising administering to the human a compound of any one of claims 1-44, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim
45.
Claim 48. The method of claim 47, wherein the cancer or neoplastic disease is associated with one or more genetic alterations that engender elevated RAS/RAF/MEK/ERK pathway activation.
Claim 49. The method of claim 47 or 48, wherein the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF.
Claim 50. The method of any one of claims 47-49, wherein the cancer or neoplastic disease is associated with: one or more mutations in KRAS selected from the group consisting of G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, GBR, Q61H, Q61K, Q61L, Q61P, Q61R and Q61E; or one or more mutations in NRAS selected from the group consisting of G12D, G12S, G12C, G12V, G12A, G13D, G13R, G13V, G13C, G13A, G13S, G61R, Q61K Q61H, and G61L; or one or more mutations in HRAS selected from the group consisting of G12V, G12S, G12D, G12C, G12R, G12A, G13R, G13V, G13D, G13S, G13C, Q61R, Q61L, Q61K, and Q61H; or one or more mutations in ARAF selected from the group consisting of S214C and S214F; or one or more mutations in BRAF selected from the group consisting of Class I, Class Ila, Class lib, Class lie, and Class III mutations; or one or more mutations in CRAF selected from the group consisting of P261A, P261L, E478K, R391W, R391S and T491I, or a CRAF fusion.
Claim 51. The method of any one of claims 47-50, wherein the cancer or neoplastic disease is associated with one or more genetic lesions resulting in the activation of one or more receptor tyrosine kinases (RTKs).
Claim 52. The method of claim 51, wherein the one or more genetic lesions is a point mutation, a fusion or any combination thereof.
Claim 53. The method of claim 51 or 52, wherin the one or more receptor tyrosine kinase is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROSE
Claim 54. The method of any one of claims 47-53, wherein the cancer is a refractory cancer.
Claim 55. The method of any one of claims 47-54, wherein the cancer is a refractory cancer associated with one or more genetic alterations in BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events.
Claim 56. The method of any one of claims 47-55, the cancer is a refractory BRAF Class I mutant cancer.
Claim 57. The method of claim 56, wherein the refractory BRAF Class I mutant cancer is associated with a point mutation selected from the group consisting of V600D, V600E, V600K, and V600R.
Claim 58. The method of any one of claims 47-55, wherein the refractory cancer is associated with one or more Class II or Class III mutations in BRAF.
Claim 59. The method of claim 58, wherein the refractory cancer is associated with one or more mutations in BRAF selected from the group consisting of G464V, G469A, G469V, G469R, E586K, K601E, K601N, G466R, G466A, G466E, G466V, N581I, N581S, D594E, D594G, D594N, G596C, G596R, L597R, L597S, and L597Q.
Claim 60. The method of claim 58, wherein the refractory cancer is associated with one or more alternative splicing events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10.
Claim 61. The method of any one of claims 47-60, wherein the cancer is a solid tumor or a hematological malignancy.
Claim 62. The method of claim 61, wherein the cancer is melanoma, lung cancer, pancreatic carcinoma, glioma, or colorectal carcinoma.
Claim 63. The method of claim 62, wherein the lung cancer is non-small cell lung cancer (NSCLC).
Claim 64. The method of any one of claims 47-63, further comprising administering one or more pharmaceutical agents including anti-microtubular therapies, topoisomerase inhibitors, alkylating agents, nucleotide synthesis inhibitors, DNA synthesis inhibitors, protein synthesis inhibitors, developmental signaling pathway inhibitors, pro-apoptotic agents, RTK inhibitors, RAF inhibitors representing alternative binding modes, MEK1/2 inhibitors, ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors, PI3K inhibitors and/or radiation.
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