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WO2025064567A1 - Tricyclic phenols for inhibition of raf kinases - Google Patents

Tricyclic phenols for inhibition of raf kinases Download PDF

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Publication number
WO2025064567A1
WO2025064567A1 PCT/US2024/047316 US2024047316W WO2025064567A1 WO 2025064567 A1 WO2025064567 A1 WO 2025064567A1 US 2024047316 W US2024047316 W US 2024047316W WO 2025064567 A1 WO2025064567 A1 WO 2025064567A1
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compound
solvate
pharmaceutically acceptable
acceptable salt
alkyl
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PCT/US2024/047316
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French (fr)
Inventor
Joseph P. Lyssikatos
Li Ren
Alex KELLUM
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Enliven Inc.
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Publication of WO2025064567A1 publication Critical patent/WO2025064567A1/en

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  • the mitogen activated kinase (MAPK) pathway 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
  • RAF 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.
  • the primary output of the MAPK pathway is to drive cell growth and proliferation as well as to suppress apoptosis (regulated cell death).
  • 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.
  • J is C(R 3 ) or N; J 1 is N and J 2 is C, or J 1 is C and J 2 is N; X, Y and Z are each independently C(R 7 ), C(O), C(R 7a )(R 7b ), N(R 7c ), or N, wherein at least one of X, Y and Z is C(R 7 ), C(O), or C(R 7a )(R 7b ); X 1 and Z 1 are each independently C(R 7 ), C(O), C(R 7a )(R 7b ), N(R 7c ), N, O, or S; Y 1 is C(R 7 ), C(R 7a )(R 7b ), N(R 7c ), or N; R 1 is selected from hydrogen, -C(O)R 1a
  • the compound is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: Formula (I).
  • the compound of Formula (I) is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: Formula (Ia).
  • the compound of Formula (I) is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof: Formula (Ib).
  • the compound of Formula (I) is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof: Formula (Ic).
  • the compound of Formula (I) is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof: Formula (Id).
  • the compound of Formula (I) is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof: Formula (Ie).
  • the compound is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof: Formula (II).
  • the compound of Formula (II) is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: Formula (IIa).
  • the compound of Formula (II) is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof: Formula (IIb).
  • the compound of Formula (II) is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof: Formula (IIc).
  • R 7a and R 7b are each independently hydrogen or C 1-6 alkyl optionally substituted with 1-5 R 8e groups.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 7a and R 7b are hydrogen.
  • a compound of Formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 7c is C 1-6 alkyl optionally substituted with 1-5 R 8e groups.
  • the compound of Formula (II) is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof: Formula (IId).
  • the compound is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof: Formula (III).
  • each R 7 is independently selected from hydrogen, halogen, -CN, and C 1-6 alkyl optionally substituted with 1-5 R 8d groups.
  • each R 7 is independently selected from hydrogen, halogen, -CN, and unsubstituted C 1- 6alkyl.
  • each R 7 is hydrogen.
  • each R 7 is unsubstituted C 1-6 alkyl.
  • R 1a is selected from C 1- 6alkyl, -N(H)R 10 , C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1- 6 alkyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-5 R 8c groups.
  • R 1a is selected from C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups.
  • R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups.
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • each R 8c is independently selected from halogen.
  • R 1a is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is .
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is unsubstituted C 1-6 alkyl.
  • each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and - N(R 10 )(R 11 ), wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -OR 10 , and -N(R 10 )(R 11 ).
  • n is 0, 1, or 2.
  • n is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
  • n is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
  • n is 0.
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate 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
  • 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, G13R, 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 IIa, Class IIb, Class IIc, 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 P261A, 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 ROS1.
  • the cancer is a refractory cancer.
  • 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 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 L597Q.
  • the refractory cancer is associated with one or more alternative splicing or internal deletion 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 (including, but not limited to, the anti-EGFR inhibitory antibodies cetuximab and panitumumab), ERBB2, LTK, MET, NTRK, RET, ROS1), RAS inhibitors (including, but not limited to, sotorasib and adagrasib), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II) (including, but not limited to, vemurafenib, dabrafenib, encorafenib, exarafenib, tovorafenib, naporafenib, belvarafenib, bri
  • RTK inhibitors including inhibitors against
  • 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., C 1 -C 6 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 C 1 -C 6 alkyl, C 2- C 6 alkyl, C 3 -C 6 alkyl, C 4 -C 6 alkyl, C 5 -C 6 alkyl, C 1- C 5 alkyl, C 2- C 5 alkyl, C 3 -C 5 alkyl, C 4- C 5 alkyl, C 1- C 4 alkyl, C 2- C 4 alkyl, C 3 -C 4 alkyl, C 1- C 3 alkyl, C 2 -C 3 alkyl, or C 1- C 2 alkyl.
  • cycloalkyl 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 C 5-12 alkane, etc.
  • cycloalkyl encompasses C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkyl, C 5 -C 7 cycloalkyl, C 5 -C 7 cycloalkyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkyl, C 5 -C 6 cycloalkyl, C 3 -C 5 cycloalkyl, C 4 -C 5 cycloalkyl, or C 3 -C 4 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.
  • a “heteroalkyl” can contain up to three units of unsaturation, and also include mono- and poly-halogenated variants, or combinations thereof. Examples include: -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CF 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O)2-CH 3 , -CH ⁇ CH-O-CH 3 , -Si(CH 3 ) 3 , -CH 2 -CH ⁇ N-OCH 3 , and -CH ⁇ CH ⁇ N(CH 3 )-CH 3 .
  • 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 polycyclic 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(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran,
  • 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 -CH 2 CH 2 CH 2 CH 2 -.
  • 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.
  • heteroalkylene by itself or as part of another substituent means a divalent radical, saturated or unsaturated or polyunsaturated, derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 CH 2 -, -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -, -O-CH 2 -CH ⁇ CH-, -CH 2 -CH ⁇ C(H)CH 2 -O- CH 2 - and -S-CH 2 -C ⁇ C-.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
  • the term “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.
  • C 1 -C 4 haloalkyl is meant 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 includes -CH(F)OH, -CH 2 CFHCH 2 OH, -CH(OH)CF 3 , and the like.
  • alkyl-OH refers to an alkyl 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.
  • alkyl-OH includes -CH 2 OH, -CH(OH)CH 3 , -CH 2 CH 2 OH, -C(CH 3 )2OH, and the like.
  • 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 includes -CH 2 CN, -CH 2 CH 2 CN, -CH(CN)CH 3 , 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 C6-C14 aryl, C8-C14 aryl, C10-C14 aryl, C 12 -C 14 aryl, C 6 -C 12 aryl, C 8 -C 12 aryl, C 10 -C 12 aryl, C 6 -C 10 aryl, C 8 -C 10 aryl, or C 6 -C 8 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.
  • 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.
  • alkyl e.g., “alkyl,” “aryl” and “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 “ ” 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 ) 0-1 ) means that the group can have the number of occurrences as designated by the integer range.
  • (X a )0-1 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.
  • 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.
  • 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.
  • each R 7 is independently selected from hydrogen, halogen, -CN, and C 1-6 alkyl optionally substituted with 1-5 R 8d groups.
  • each R 7 is independently selected from hydrogen, halogen, -CN, and unsubstituted C 1-6 alkyl.
  • each R 7 is independently selected from hydrogen and unsubstituted C 1- 6alkyl.
  • each R 7 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 is unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 is -CH 3 . [0072] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R 3 ).
  • R 1 is selected from -C(O)R 1a , C 1-6 alkyl, C 3-7 cycloalkyl, C 2- 9heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, are optionally substituted with 1-5 R 8c groups.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is selected from -C(O)R 1a , C 1-6 alkyl, C 3-7 cycloalkyl, and C 2- 9 heterocycloalkyl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1 is selected from -C(O)R 1a and C 1- 6alkyl, wherein C 1-6 alkyl is optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a and R 1a is selected from C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 3- 7cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a and R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is -C(O)R 1a and R 1a is unsubstituted C 3-7 cycloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a , R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2- 9 heterocycloalkyl.
  • R 1 is -C(O)R 1a , R 1a is cyclopropyl optionally substituted with 1-5 R 8b groups, and each R 8c is independently selected from halogen.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is unsubstituted cyclopropyl.
  • R 1 is [0078]
  • R 1 is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a and R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 2- 9 heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 - C 2-9 heterocycloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is -C(O)R 1a and R 1a is unsubstituted C 2-9 heterocycloalkyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein [0079] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a and R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is unsubstituted C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 2-6 heteroalkyl, C 2-6 alkenyl, C 2- 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C 3- 6cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and -N(R 10 )(R 11 ).
  • a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is unsubstituted C 1-6 alkyl.
  • R 1 is hydrogen.
  • each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -N(R 10 )(R 11 ), wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and unsubstituted C 1-6 alkyl.
  • each R 6 is independently selected from halogen.
  • each R 6 is independently selected from unsubstituted C 1-6 alkyl.
  • n is 0, 1, 2, or 3.
  • n is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • each R 7 is independently selected from hydrogen, halogen, -CN, and C 1-6 alkyl optionally substituted with 1-5 R 8d groups.
  • each R 7 is hydrogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 is unsubstituted C 1- 6 alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 is -CH 3 . [0086] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R 3 ).
  • R 1 is selected from -C(O)R 1a , C 1-6 alkyl, C 3-7 cycloalkyl, C 2- 9heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, are optionally substituted with 1-5 R 8c groups.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is selected from -C(O)R 1a , C 1-6 alkyl, C 3-7 cycloalkyl, and C 2- 9 heterocycloalkyl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1 is selected from -C(O)R 1a and C 1- 6alkyl, wherein C 1-6 alkyl is optionally substituted with 1-5 R 8c groups.
  • R 1 is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a .
  • R 1a is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a and R 1a is selected from C 1-6 alkyl, -N(H)R 10 , C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-5 R 8c groups.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is selected from C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 3- 7cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a and R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C3- 7cycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is -C(O)R 1a and R 1a is unsubstituted C 3-7 cycloalkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2- 9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is cyclopropyl optionally substituted with 1-5 R 8b groups
  • each R 8c is independently selected from halogen.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is unsubstituted cyclopropyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is selected from , [0092]
  • R 1 is -C(O)R 1a
  • R 1a is C 2- 9 heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 - C 2-9 heterocycloalkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 2- 9 heterocycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a and R 1a is unsubstituted C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a and R 1a is .
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is -C(O)R 1a and R 1a is unsubstituted C 3-7 cycloalkyl.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 2- 9heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 - C 2-9 heterocycloalkyl.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 2- 9heterocycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is -C(O)R 1a and R 1a is unsubstituted C 2-9 heterocycloalkyl.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is .
  • R 1 is -C(O)R 1a and R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 1- 6alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen.
  • a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is unsubstituted C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 2-6 heteroalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C3- 6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 1 is hydrogen.
  • each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -N(R 10 )(R 11 ), wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and unsubstituted C 1-6 alkyl.
  • each R 6 is independently selected from halogen.
  • each R 6 is independently selected from unsubstituted C 1-6 alkyl.
  • n is 0, 1, 2, or 3.
  • n is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • [0200] is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a and R 7b are each independently hydrogen or C 1-6 alkyl optionally substituted with 1-5 R 8e groups.
  • R 7a and R 7b are each independently unsubstituted C 1-6 alkyl.
  • R 7a and R 7b are -CH 3 .
  • R 7a and R 7b are hydrogen.
  • R 7c is C 1-6 alkyl optionally substituted with 1-5 R 8e groups.
  • R 7c is unsubstituted C 1-6 alkyl.
  • R 7c is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7c is -CH 3 .
  • J is C(R 3 ).
  • R 3 is hydrogen.
  • R 3 is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is halogen.
  • J is N.
  • R 1 is selected from -C(O)R 1a , C 1-6 alkyl, C 3-7 cycloalkyl, C 2- 9heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, are optionally substituted with 1-5 R 8c groups.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is selected from -C(O)R 1a , C 1-6 alkyl, C 3-7 cycloalkyl, and C 2- 9 heterocycloalkyl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1 is selected from -C(O)R 1a and C 1- 6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1-5 R 8c groups.
  • R 1 is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a .
  • R 1a is selected from C 1-6 alkyl, -N(H)R 10 , C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-5 R 8c groups.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is selected from C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 3- 7cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a and R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C3- 7cycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is -C(O)R 1a and R 1a is unsubstituted C 3-7 cycloalkyl.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2- 9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is cyclopropyl optionally substituted with 1-5 R 8b groups
  • each R 8c is independently selected from halogen.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is unsubstituted cyclopropyl.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 [0208]
  • R 1 is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a and R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 2- 9 heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 - C 2-9 heterocycloalkyl.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 2- 9heterocycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is -C(O)R 1a and R 1a is unsubstituted C 2-9 heterocycloalkyl.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is .
  • R 1 is -C(O)R 1a and R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 1- 6alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen.
  • a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is unsubstituted C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 2-6 heteroalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C3- 6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6- 10aryl, C 1-9 heteroaryl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 1 is hydrogen.
  • each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -N(R 10 )(R 11 ), wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and unsubstituted C 1-6 alkyl.
  • each R 6 is independently selected from halogen.
  • each R 6 is independently selected from unsubstituted C 1-6 alkyl.
  • n is 0, 1, 2, or 3.
  • n is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 7 is selected from hydrogen, halogen, -CN, and C 1-6 alkyl optionally substituted with 1-5 R 8d groups.
  • R 7 is selected from hydrogen, halogen, -CN, and unsubstituted C 1-6 alkyl.
  • R 1 is selected from -C(O)R 1a , C 1-6 alkyl, C 3-7 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, C 2- 9heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, are optionally substituted with 1-5 R 8c groups.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is selected from -C(O)R 1a , C 1-6 alkyl, C 3-7 cycloalkyl, and C 2- 9 heterocycloalkyl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1 is selected from -C(O)R 1a and C 1- 6 alkyl, wherein C 1-6 alkyl is optionally substituted with 1-5 R 8c groups.
  • R 1 is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a .
  • R 1a is selected from C 1-6 alkyl, -N(H)R 10 , C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9heteroaryl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-5 R 8c groups.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is selected from C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C3- 7cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a and R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C3- 7 cycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is -C(O)R 1a and R 1a is unsubstituted C 3-7 cycloalkyl.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2- 9heterocycloalkyl.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is cyclopropyl optionally substituted with 1-5 R 8b groups, and each R 8c is independently selected from halogen.
  • R 1 is -C(O)R 1a and R 1a is unsubstituted cyclopropyl.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is selected from , [0222]
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 2- 9 heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 - C 2-9 heterocycloalkyl.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 2- 9heterocycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is -C(O)R 1a and R 1a is unsubstituted C 2-9 heterocycloalkyl.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is .
  • R 1 is -C(O)R 1a and R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 1- 6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen.
  • a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is unsubstituted C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 2-6 heteroalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C3- 6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6- 10aryl, C 1-9 heteroaryl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 1 is hydrogen.
  • each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -N(R 10 )(R 11 ), wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and unsubstituted C 1-6 alkyl.
  • each R 6 is independently selected from halogen.
  • each R 6 is independently selected from unsubstituted C 1-6 alkyl.
  • n is 0, 1, 2, or 3.
  • n is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • J is C(R 3 ) or N;
  • R 1 is selected from hydrogen, -C(O)R 1a , C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 2- 6heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 2-6 heteroalkyl, C 2- 6alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-5 R 8c groups
  • each R 7 is independently selected from hydrogen, halogen, -CN, and C 1-6 alkyl optionally substituted with 1-5 R 8d groups.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein each R 7 is independently selected from hydrogen, halogen, -CN, and unsubstituted C 1-6 alkyl.
  • each R 7 is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 is unsubstituted C 1-6 alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7 is -CH 3 . [0230] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R 3 ).
  • R 1 is selected from -C(O)R 1a , C 1-6 alkyl, C 3-7 cycloalkyl, C 2- 9heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, C 2- 9heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, are optionally substituted with 1-5 R 8c groups.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is selected from -C(O)R 1a , C 1-6 alkyl, C 3-7 cycloalkyl, and C 2- 9heterocycloalkyl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1 is selected from -C(O)R 1a and C 1- 6alkyl, wherein C 1-6 alkyl is optionally substituted with 1-5 R 8c groups.
  • R 1 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a .
  • R 1a is selected from C 1-6 alkyl, -N(H)R 10 , C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1- 9 heteroaryl, wherein C 1-6 alkyl, C 3-7 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a and R 1a is selected from C 1-6 alkyl, C 3-7 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C 1-6 alkyl, C 3- 7 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a and R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 3-7 cycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 3- 7cycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a and R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups.
  • R 1 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a , R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a , R 1a is cyclopropyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2- 9 heterocycloalkyl.
  • R 1 is -C(O)R 1a , R 1a is cyclopropyl optionally substituted with 1-5 R 8b groups, and each R 8c is independently selected from halogen.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is unsubstituted cyclopropyl.
  • R 1 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 [0236]
  • R 1 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a and R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is -C(O)R 1a
  • R 1a is C 2- 9heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 2-9 heterocycloalkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 - C 2-9 heterocycloalkyl.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a , R 1a is C 2- 9heterocycloalkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen.
  • R 1 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a and R 1a is unsubstituted C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a and R 1a is .
  • R 1 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a and R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(O)R 1a , R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, -CN, C 1-6 alkyl, C 1- 6haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 1- 6alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and -CH 2 -C 2-9 heterocycloalkyl.
  • R 1 is -C(O)R 1a
  • R 1a is C 1-6 alkyl optionally substituted with 1-5 R 8c groups
  • each R 8c is independently selected from halogen.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(O)R 1a and R 1a is unsubstituted C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups.
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 2-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl, wherein C 2-6 heteroalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, C 1-9 heteroaryl
  • R 1 is C 1-6 alkyl optionally substituted with 1-5 R 8c groups, and each R 8c is independently selected from halogen, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, wherein C3- 6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6- 10 aryl, C 1-9 heteroaryl, -OR 10 , and -N(R 10 )(R 11 ).
  • R 1 is hydrogen.
  • each R 6 is independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -OR 10 , and -N(R 10 )(R 11 ), wherein C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and C 1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, -OR 10 , and -N(R 10 )(R 11 ).
  • each R 6 is independently selected from halogen and unsubstituted C 1-6 alkyl.
  • each R 6 is independently selected from halogen.
  • each R 6 is independently selected from unsubstituted C 1-6 alkyl.
  • n is 0, 1, 2, or 3.
  • n is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0242] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
  • 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.
  • 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.
  • 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.
  • compositions and Formulations [0250] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition. [0251] 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.
  • 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 described herein intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound described herein.
  • 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 co- crystal 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 co-crystal 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 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 co-crystal 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.
  • 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.
  • routes of delivery e.g., tablet or i.v.
  • Methods of Use 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.
  • 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.
  • RAF Kinase Inhibition 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.
  • 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.
  • RAF function 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.
  • 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.
  • RAF Structure and Regulation [0268] 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).
  • 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.
  • RAF 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.
  • 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/SHOC2/PP1 complex.
  • 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.
  • RAF Mutations and Cancer [0269] 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. [0270] 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).
  • CRC colorectal
  • NSCLC non-small cell lung cancers
  • These mutations can be further subdivided into 3 subclasses according to which region within the kinase domain the alteration occurs (designated as Class IIa and IIb) or the formation of a kinase fusion arising from a chromosome translocation event (designated Class IIc) 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 P261A.
  • the second CRAF mutation type is analogous to the Class II mutations in BRAF.
  • CRAF fusions CRAF fusions
  • RAF Kinase Inhibitors 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.
  • Type 2 inhibitors [0275] 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.
  • 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.
  • Type 1.5 inhibitors 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.
  • 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.
  • Paradoxical activation [0277] 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.
  • 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. [0278] 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).
  • 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 [0279] 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.
  • Type 2 RAF inhibitors 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 [0280] 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.
  • 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 [0281] Paradoxical activation is known to adversely impact the tolerability of these inhibitors in patients, thereby limiting their clinical utility.
  • Type 1.5 inhibitors markedly induce paradoxical activation in normal tissues by binding RAF dimers and transactivating the second unbound protomer.
  • 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.
  • 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, G13R, 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 IIa, Class IIb, Class IIc, 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 P261A, 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 ROS1.
  • the cancer is a refractory cancer.
  • the refractory cancer is associated with a genetic alteration or alterations in KRAS (including mutants G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, 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, G
  • 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 (including, but not limited to, the anti-EGFR inhibitory antibodies cetuximab and panitumumab), ERBB2, LTK, MET, NTRK, RET, ROS1), RAS inhibitors (including, but not limited to, sotorasib and adagrasib), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II) (including, but not limited to, vemurafenib, dabrafenib, encorafenib, exarafenib, tovorafenib
  • RTK inhibitors including inhibitors against ALK, EGFR (including, but not limited to, the anti-EGFR inhibitor
  • 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, G13R, 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, G13R, 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 or internal deletion 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 (including, but not limited to, the anti-EGFR inhibitory antibodies cetuximab and panitumumab), ERBB2, LTK, MET, NTRK, RET, ROS1), RAS inhibitors (including, but not limited to, sotorasib and adagrasib), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II) (including, but not limited to, vemurafenib, dabrafenib, encorafenib, exarafenib, tovorafenib, naporafenib, belvarafenib, bri
  • RTK inhibitors including inhibitors against
  • 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.
  • the present disclosure further provides articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal 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.
  • kits 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, HRAS, ARAF, BRAF or CRAF.
  • 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.
  • 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.
  • 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.
  • 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.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.
  • Example 2 Synthesis of N-(4-(2-chloro-3-hydroxy-6-methylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (Compound 2) [0305] To a solution of 2-(2-chloro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (A-2) (300 mg, 1.06 mmol) in toluene (8.0 mL) was added K3PO4 (676 mg, 3.19 mmol), 4-bromo-8-chloro-[1,2,4]triazolo[1,5-a][1,6]naphthyridine (B-1) (301 mg, 1.06 mmol) and DPEPhos PdCl 2 (76 mg, 0.11 mmol) at room temperature under N2.
  • A-2 2-(2-chloro-3-methoxy-6-
  • Example 4 Synthesis of N-(4-(3-hydroxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3- a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (Compound 4) [0312] To a solution of 4-bromo-8-chloro-[1,2,4]triazolo[4,3-a][1,6]naphthyridine (D-1) (1.0 g, 3.53 mmol) in 1,4-dioxane (20.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (2.7 g, 10.58 mmol), KOAc (1.0 g, 10.58 mmol) and Pd(dppf)Cl 2 .CH 2 Cl 2 (0.3 g, 0.35 mmol) at room temperature under N 2 .
  • Example 5 Synthesis of 3-(8-amino-[1,2,4]triazolo[1,5-a][1,6]naphthyridin-4-yl)-2,4- dimethylphenol (Compound 5) [0316] To a solution of 8-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- [1,2,4]triazolo[1,5-a]1,6-naphthyridine (E-1) (2.0 g, 6.05 mmol) in 1,4-dioxane (20 mL)/H2O (4 mL) were added 2-iodo-4-methoxy-1,3-dimethylbenzene (1.5 g, 6.05 mmol), K 2 CO 3 (2.5 g, 18.15 mmol) and Pd(dppf)Cl 2 (0.4 g, 0.60 mmol) at room temperature under N2.
  • Example 6 Synthesis of N-[1-cyano-4-(3-hydroxy-2,6-dimethylphenyl)imidazo[1,2-a]1,6- naphthyridin-8-yl]cyclopropanecarboxamide (Compound 6) [0320] To a solution of 4-bromo-8-chloroimidazo[1,2-a]1,6-naphthyridine (F-1) (1.5 g, 5.31 mmol) in 1,4-dioxane/H2O (40.0 mL/8.0 mL) was added 3-methoxy-2,6-dimethylphenylboronic acid (1.0 g, 5.57 mmol), Pd(PPh 3 ) 4 (640 mg, 0.55 mmol) and K 2 CO 3 (2.2 g, 15.92 mmol) at room temperature under N 2 .
  • F-1 4-bromo-8-chloroimidazo[1,2-a]1,6-naphthyridine
  • Example 7 Synthesis of 2,4-dimethyl-3-(8-(methylamino)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-4-yl)phenol (Compound 7) [0325] To a mixture of tert-butyl (4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)carbamate (250 mg, 0.59 mmol) (G-1) in DMF (5.0 mL) was added NaH (17 mg, 60%) at 0 o C under N2. The mixture was stirred at 0 o C for 30 min.
  • Example 10 Synthesis of N-(5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3- f]quinoxalin-9-yl)cyclopropanecarboxamide (Compound 10) [0338] To a solution of 5-bromo-9-chloro-2,3-dimethylpyrido[4,3-f]quinoxaline (J-1) (400 mg, 1.24 mmol) in dioxane (14.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (315 mg, 1.24 mmol), Pd(dppf)Cl 2 (182 mg, 0.25 mmol) and KOAc (360 mg, 3.67 mmol) at room temperature under N2.
  • Example 11 Synthesis of 4-methyl-3-(8-(methylamino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3- d]pyrimidin-4-yl)phenol (Compound 11) [0342] To a stirred solution of 4-bromo-8-(methylthio)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3- d]pyrimidine (H-5) (1.0 g, 3.38 mmol) in dioxane (10.0 mL)/H 2 O (2.0 mL) was added 5- methoxy-2-methylphenylboronic acid (1.7 g, 10.13 mmol), K 2 CO 3 (2.8 g, 20.26 mmol) and Pd(PPh 3 ) 4 (395 mg, 0.34 mmol) at room temperature under N 2 .
  • H-5 4-bromo-8-(methylthio)-[1,2,4]triazolo[1'
  • Example 12 Synthesis of 2-chloro-4-methyl-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 12) [0346] To a solution of 2-(2-chloro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (A-2) (480 mg, 1.70 mmol) in 1,4-dioxane/H2O (10.0 mL/2.0 mL) was added 6- bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-1) (503 mg, 1.70 mmol), K2CO3 (695 mg, 5.03 mmol) and Pd(dppf)Cl 2 (124 mg, 0.17 mmol) at room temperature under N2.
  • Example 13 Synthesis of 2,4-dimethyl-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 13) [0350] To a solution of 6-bromo-7-chloro-2-(methylsulfanyl)pyrido[2,3-d]pyrimidine (H-1) (3.0 g, 10.33 mmol) in THF (30.0 mL) was added hydrazine hydrate (6.0 mL, 80%) at room temperature. The resulting mixture was stirred at 80 °C for 2 h.
  • Example 14 Synthesis of 2,4-dimethyl-3-(2-(methylamino)imidazo[1',2':1,6]pyrido[2,3- d]pyrimidin-6-yl)phenol (Compound 14) [0356] A solution of 3-bromo-2-chloro-7-(methylsulfanyl)-1,6-naphthyridine (N-1) (3.0 g, 10.36 mmol) was added NH 3 /dioxane (30.0 mL, 0.4 mol/L in dioxane) was stirred at 80 °C for 2 h.
  • Example 15 Synthesis of 4-methyl-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidin-6-yl)phenol (Compound 15) [0362] To a mixture of 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-1) (500 mg, 1.68 mmol) in 1,4-dioxane/H2O (10.0 mL/2.0 mL) was added 5-methoxy-2- methylphenylboronic acid (850 mg, 5.12 mmol), K 2 CO 3 (1400 mg, 10.13 mmol) and Pd(PPh 3 ) 4 (370 mg, 0.19 mmol) at room temperature under N 2 .
  • L-1 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':
  • Example 16 Synthesis of 4-chloro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidin-6-yl)phenol (Compound 16) [0366] To a mixture of 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-1) (500 mg, 1.68 mmol) in 1,4-dioxane/H2O (10.0 mL/2.0 mL) was added 2-chloro-5- methoxyphenylboronic acid (945 mg, 5.07 mmol), K2CO3 (1400 mg, 10.13 mmol) and Pd(PPh3)4 (370 mg, 0.19 mmol) at room temperature under N 2 .
  • L-1 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3'
  • Example 17 Synthesis of 2-chloro-4-methyl-3-(8-(methylamino)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)phenol (Compound 17) [0370] To a solution of 4-bromo-8-(methylthio)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-5) (400 mg, 1.43 mmol) and 2-(2-chloro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (A-2) (1224 mg, 4.33 mmol) in dioxane (15.0 mL) and H 2 O (5.0 mL) were added K2CO3 (1211 mg, 8.76 mmol) and Pd(PPh3)4 (340 mg, 0.294 mmol) at room temperature under N2.
  • Example 19 Synthesis of 2-chloro-4-methyl-3-[8-(methylamino)-[1,2,4]triazolo[4,3-a]1,6- naphthyridin-4-yl]phenol (Compound 19) [0378] To a stirred solution of 8-chloro-4-(2-chloro-3-methoxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a]1,6-naphthyridine (A-4) (280 mg, 0.78 mmol) in methanamine (10.0 mL, 2.0 M in THF) was stirred at 80 °C for 16 h. The mixture was cooled and concentrated under reduced pressure.
  • Example 20 Synthesis of 2-chloro-4-methyl-3-(8-(methylamino)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-4-yl)phenol (Compound 20) [0380] To a solution of 4-bromo-8-chloro-[1,2,4]triazolo[1,5-a]1,6-naphthyridine (B-1) (500 mg, 1.76 mmol) in 1,4-dioxane (25.0 mL) and H 2 O (5.0 mL) was added 2-(2-chloro-3-methoxy-6- methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (A-2) (717 mg, 3.57 mmol), K2CO3 (735 mg, 5.31 mmol), Pd(PPh3)4 (291 mg, 0.39 mmol) and K2CO3 (735 mg, 5.31 mmol) at room temperature under
  • Example 21 Synthesis of 2,4-dimethyl-3-(8-(pyridin-2-ylamino)-[1,2,4]triazolo[4,3- a][1,6]naphthyridin-4-yl)phenol formate (Compound 21) [0383] To a solution of 4-bromo-8-chloro-[1,2,4]triazolo[4,3-a]1,6-naphthyridine (B-1) (500 mg, 1.76 mmol) in t-amyl alcohol/H 2 O (20 mL/5 mL) was added 3-methoxy-2,6- dimethylphenylboronic acid (320 mg, 1.78 mmol), Pd(dppf)Cl 2 (145 mg, 0.18 mmol) and KOH (300 mg, 5.35 mmol) at room temperature under N2.
  • B-1 4-bromo-8-chloro-[1,2,4]triazolo[4,3-a]1,6-naphthy
  • Example 22 Synthesis of (1S,2S)-N-(4-(2-chloro-3-hydroxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a][1,6]naphthyridin-8-yl)-2-fluorocyclopropane-1-carboxamide (Compound 22) [0386] To a stirred solution of 8-chloro-4-(2-chloro-3-methoxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a]1,6-naphthyridine (170 mg, 0.47 mmol) in dioxane (10 mL) was added (1S,2S)-2-fluorocyclopropane-1-carboxamide (102 mg, 0.99 mmol), Cs 2 CO 3 (477 mg, 1.46 mmol), XantPhos (52 mg, 0.09 mmol) and Pd2(dba) 3 (52 mg, 0.06 mmol) at room temperature
  • Example 23 Synthesis of (1R,2R)-N-(4-(2-chloro-3-hydroxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a][1,6]naphthyridin-8-yl)-2-fluorocyclopropane-1-carboxamide (Compound 23) [0388] Following the same procedure as in Example 22, but using (1R,2R)-2- fluorocyclopropane-1-carboxamide, (1R,2R)-N-(4-(2-chloro-3-hydroxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a][1,6]naphthyridin-8-yl)-2-fluorocyclopropane-1-carboxamide (Compound 23) (6.4 mg) was prepared as a white solid.
  • Example 24 Synthesis of N-(4-(3-hydroxy-2,6-dimethylphenyl)-1-methyl-[1,2,4]triazolo[4,3- a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (Compound 24) [0389] To a solution of 4-bromo-8-chloro-1-methyl-[1,2,4]triazolo[4,3-a][1,6]naphthyridine (X- 1) (500 mg, 1.76 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was added 3-methoxy-2,6- dimethylphenylboronic acid (350 mg, 1.94 mmol), Pd(PPh3)4 (180 mg, 0.16 mmol) and K2CO3 (750 mg, 5.43 mmol) at room temperature under N 2 .
  • X- 1 4-bromo-8-chloro-1-methyl-[1,2,4]
  • Example 25 Synthesis of 2,4-dimethyl-3-(8-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-4-yl)phenol (Compound 25) [0392] To a solution of 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]1,6- naphthyridine (C-2) (172 mg, 0.51 mmol) in dioxane (6 mL) was added 2-aminopyridine (154 mg, 1.64 mmol), BrettPhos (87 mg, 0.16 mmol), BrettPhos Pd G3 (51 mg, 0.06 mmol) and Cs2CO3 (700 mg, 2.15 mmol) at room temperature under N2.
  • Example 26 Synthesis of N-(4-(3-hydroxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)cyclobutanecarboxamide (Compound 26) [0394] To a solution of 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]1,6- naphthyridine (C-2) (270 mg, 0.80 mmol) in dioxane (25.0 mL) was added K 2 CO 3 (387 mg, 2.80 mmol), cyclobutanecarboxamide (135 mg, 1.36 mmol), XPhos (144 mg, 0.30 mmol) and Pd2(dba) 3 (95 mg, 0.10 mmol) at room temperature under N2.
  • Example 27 Synthesis of 2,4-dimethyl-3-(8-(pyridin-2-ylamino)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)phenol (Compound 27) [0396] To a solution of 4-(3-methoxy-2,6-dimethylphenyl)-8-(methylsulfonyl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-8) (120 mg, 0.31 mmol) in DMSO (5 mL) was added pyridin-2-amine (60 mg, 0.63 mmol) and t-BuOK (66 mg, 0.58 mmol) at room temperature under N2.
  • Example 28 Synthesis of 4-chloro-2-methyl-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 28) [0398] To a solution of 3-bromo-2-methylaniline (AB-1) (50.0 g, 268.83 mmol) in DMF (500 mL) was added NCS (36.0 g, 268.83 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 3 h. The reaction mixture was cooled, diluted with H 2 O, and extracted with ethyl acetate.
  • AB-1 3-bromo-2-methylaniline
  • NCS 36.0 g, 268.83 mmol
  • Example 29 Synthesis of 2-chloro-3-(2-((2-(dimethylamino)ethyl)amino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenol (Compound 29) [0405] To a solution of 6-(2-chloro-3-methoxy-6-methylphenyl)-2-(methylsulfonyl)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-3) (70 mg, 0.22 mmol) in THF (2 mL) was added (2-aminoethyl)dimethylamine (70 mg, 0.79 mmol) at room temperature.
  • Example 30 Synthesis of 2-chloro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidin-6-yl)phenol (Compound 30) [0407] 2-Chloro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 30) was prepared by the procedure described in Example 18 using (2-chloro-3- methoxyphenyl)boronic acid in place of (2,6-dichloro-3-methoxyphenyl)boronic acid in Step 1.
  • Example 31 Synthesis of 2-chloro-4-fluoro-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 31) [0408] 2-Chloro-4-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6- yl)phenol (Compound 31) was prepared by the procedure described in Example 18 using (2- chloro-6-fluoro-3-methoxyphenyl)boronic acid in place of (2,6-dichloro-3- methoxyphenyl)boronic acid in Step 1.
  • Example 32 Synthesis of 2-fluoro-4-methyl-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 32) [0409] To a stirred solution of 3-bromo-2-fluorophenol (AF-1) (25.0 g, 130.89 mmol) in DMF (500 mL) was added K 2 CO 3 (54.3 g, 392.67 mmol) and CH 3 I (22.3 g, 157.07 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate.
  • AF-1 3-bromo-2-fluorophenol
  • CH 3 I 22.3 g, 157.07 mmol
  • the reaction mixture was diluted with hexane and the pH of the mixture was adjusted to 7.0 with Na2CO3 (aq).
  • the mixture was extracted with ethyl acetate.
  • the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by flash column chromatography to afford 2-bromo-1-(bromomethyl)-3- fluoro-4-methoxybenzene (AF-3) (6.0 g, 51%) as a white solid.
  • Example 33 Synthesis of N-(5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3- f]quinoxalin-9-yl)cyclobutanecarboxamide (Compound 33) [0417] To a solution of 5-bromo-9-chloro-2,3-dimethylpyrido[4,3-f]quinoxaline (J-1) (180 mg, 0.56 mmol) in dioxane/H 2 O (5.0 mL/1.0 mL) was added (3-methoxy-2,6-dimethylphenyl)boronic acid (150 mg, 0.83 mmol), Pd(dppf)Cl 2 (81.0 mg, 0.11 mmol) and K 2 CO 3 (231 mg, 1.67 mmol) at room temperature under N2.
  • Example 35 Synthesis of 8-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-1H- pyrrolo[3,4-f]isoquinolin-3-one (Compound 35) [0424] To a solution of 4-bromo-2-fluoro-6-methylbenzoic acid (AI-1) (30.0 g, 128.74 mmol) in DMSO (300 mL) was added NaOCH 3 (20.9 g, 386.86 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 16 h. The mixture was cooled to room temperature and diluted with water. The pH value of the mixture was adjusted to 2 with 2 M HCl at 0 °C.
  • AI-1 4-bromo-2-fluoro-6-methylbenzoic acid
  • DMSO 300 mL
  • NaOCH 3 20.9 g, 386.86 mmol
  • Example 36 Synthesis of N-(4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-3-oxo-2,3- dihydro-1H-pyrrolo[3,4-f]isoquinolin-8-yl)cyclopropanecarboxamide (Compound 36) [0438] A solution of N-(4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-f]isoquinolin-8-yl)acetamide (AI-14) (110 mg, 0.28 mmol) in HBr (2.0 mL, 40% in water) was stirred at 50 °C for 1 h.
  • Example 37 Synthesis of N-(4-(2-chloro-3-hydroxy-6-methylphenyl)-2-methyl-3-oxo-2,3- dihydro-1H-pyrrolo[3,4-f]isoquinolin-8-yl)cyclopropanecarboxamide (Compound 37) [0440] To a solution of 8-amino-4-methoxy-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-f]isoquinolin- 3-one (AI-9) (2.0 g, 8.22 mmol) in pyridine (25 mL) was added cyclopropanecarbonyl chloride (4.0 g, 38.23 mmol) at 0 °C under N2.
  • Example 38 Cell Viability Assays [0445] Cell viability was measured in the following MAPK pathway mutant cancer cell lines: A375 (BRAF V600E), HepG2 (NRAS Q61L), SK-MEL-30 (NRAS Q61K), and OCI-AML-2 (MBNL1-CRAF fusion). Cell viability was also measured in K562 cells. [0446] A375, HepG2, SK-MEL-30 and OCI-AML-2 cells were grown in the appropriate growth medium and harvested at 50-80% confluence. Cells were counted and seeded at their appropriate density in a 384-well plate (Corning 3570).
  • Table 1 provides the growth media, number of cells seeded per well and drug treatment times for each cell line.
  • Table 1 [0448] K562 cells, cultured in Iscove's Modified Dulbecco's Media (IMDM) supplemented with 10% FBS, were harvested at 50-80% confluency and plated at 2,000 cells per well in 384-well tissue culture plates.
  • IMDM Iscove's Modified Dulbecco's Media
  • 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.
  • % viability 100 x (LumSample – LumLC) / (LumHC – LumLC).
  • Example 39 Detection of phosphorylated ERK (pERK) [0451] A375 cells were counted and seeded at 10,000 cells/well in 384 well plates (Corning 3764) and allowed to adhere overnight. [0452] Compounds were dissolved and serially diluted in DMSO. The compounds were then added, mixed, and incubated for four hours at 37°C, 5% CO 2 . Compounds were added using four-fold dilutions at final concentrations ranging from 10 ⁇ M to 0.01 nM. DMSO only and 10 ⁇ M staurosporine were added as high and low controls.
  • DMSO only and 10 ⁇ M staurosporine were added as high and low controls.
  • Lysis buffer was made from 1X AlphaLISA SureFire Assay Kit (AlphaLISA SureFire Ultra pERK 1 ⁇ 2 (Thr202/Tyr204) ALSU-PERK-A50K) lysis buffer with protease and phosphatase inhibitors.
  • LC/HC low and high controls

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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.

Description

TRICYCLIC PHENOLS FOR INHIBITION OF RAF KINASES CROSS-REFERENCE [0001] This application claims benefit of U.S. Provisional Patent Application No.63/583,786 filed on September 19, 2023, which is incorporated herein by reference in its entirety. 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. 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 of 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, described herein is a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000003_0001
wherein: J is C(R3) or N; J1 is N and J2 is C, or J1 is C and J2 is N; X, Y and Z are each independently C(R7), C(O), C(R7a)(R7b), N(R7c), or N, wherein at least one of X, Y and Z is C(R7), C(O), or C(R7a)(R7b); X1 and Z1 are each independently C(R7), C(O), C(R7a)(R7b), N(R7c), N, O, or S; Y1 is C(R7), C(R7a)(R7b), N(R7c), or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R7 is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, - N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R7a and R7b is each independently selected from hydrogen, halogen, -CN, -OR10, -SR10, - SF5, -N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; R7c is selected from hydrogen, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; each R8c, R8d, and R8e is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and indicates a single or double bond such that all valences are satisfied. [0007] In some embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000006_0001
Formula (I). [0008] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000006_0002
Formula (Ia). [0009] In some embodiments, the compound of Formula (I) is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000006_0003
Formula (Ib). [0010] In some embodiments, the compound of Formula (I) is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000006_0004
Formula (Ic). [0011] In some embodiments, the compound of Formula (I) is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0001
Formula (Id). [0012] In some embodiments, the compound of Formula (I) is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0002
Formula (Ie). [0013] In some embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0003
Formula (II). [0014] In some embodiments, the compound of Formula (II) is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0004
Formula (IIa). [0015] In some embodiments, the compound of Formula (II) is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000008_0001
Formula (IIb). [0016] In some embodiments, the compound of Formula (II) is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000008_0002
Formula (IIc). [0017] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7a and R7b are each independently hydrogen or C1-6alkyl optionally substituted with 1-5 R8e groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7a and R7b are hydrogen. In some embodiments is a compound of Formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is C1-6alkyl optionally substituted with 1-5 R8e groups. In some embodiments is a compound of Formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is unsubstituted C1-6alkyl. [0018] In some embodiments, the compound of Formula (II) is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000008_0003
Formula (IId). [0019] In some embodiments, the compound is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000009_0001
Formula (III). [0020] In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is hydrogen. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is selected from C1- 6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8c is independently selected from halogen. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is selected from:
Figure imgf000010_0001
Figure imgf000010_0002
. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is
Figure imgf000010_0003
. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and - N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. In some embodiments is a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are each hydrogen. [0021] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. [0022] In 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing. [0023] In 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing. [0024] 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a mixture of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (III), as described herein, or a pharmaceutically acceptable salt or solvate 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, G13R, 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 IIa, Class IIb, Class IIc, 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 P261A, P261L, E478K, R391W, R391S and T491I, or is associated with a CRAF fusion. [0025] In some 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 ROS1. [0026] 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 BRAF selected from the group consisting of gene amplification, point mutation, BRAF fusion, and gene splicing events. In some embodiments, 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 or internal deletion 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 (including, but not limited to, the anti-EGFR inhibitory antibodies cetuximab and panitumumab), ERBB2, LTK, MET, NTRK, RET, ROS1), RAS inhibitors (including, but not limited to, sotorasib and adagrasib), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II) (including, but not limited to, vemurafenib, dabrafenib, encorafenib, exarafenib, tovorafenib, naporafenib, belvarafenib, brimarafenib and lifrafenib), MEK1/2 inhibitors (including, but not limited to, binimetinib, trametinib, pimasertib, mirdametinib, tunlametinib, avutometinib and zapnometinib), ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, SHP2 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation. DETAILED DESCRIPTION [0027] 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 [0028] 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. [0029] 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. [0030] 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. [0031] 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. [0032] “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration. [0033] 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. [0034] 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. [0035] 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(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH═CH-O-CH3, -Si(CH3)3, -CH2-CH═N-OCH3, and -CH═CH═N(CH3)-CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. [0036] 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 polycyclic 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(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, 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. [0037] 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. [0038] 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-C≡C-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). [0039] 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. [0040] 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. [0041] The term “heterocycloalkoxy” refers to a heterocycloalkyl-O- group in which the heterocycloalkyl group is as previously described herein. [0042] 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 meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, difluoromethyl, and the like. [0043] 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. For example, the term “haloalkyl-OH” includes -CH(F)OH, -CH2CFHCH2OH, -CH(OH)CF3, and the like. [0044] The term “alkyl-OH” refers to an alkyl 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. For example, the term “alkyl-OH” includes -CH2OH, -CH(OH)CH3, -CH2CH2OH, -C(CH3)2OH, and the like. [0045] 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. For example, the term “alkyl-CN” includes -CH2CN, -CH2CH2CN, -CH(CN)CH3, and the like. [0046] 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 C6-C14 aryl, C8-C14 aryl, C10-C14 aryl, C12-C14 aryl, C6-C12 aryl, C8-C12 aryl, C10-C12 aryl, C6-C10 aryl, C8-C10 aryl, or C6-C8 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 non-limiting 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. [0047] The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. [0048] As used herein, the term “heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). [0049] 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. [0050] 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. [0051] As used herein, a wavy line “ ” 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. [0052] As used herein, the representation of a group (e.g., Xa) in parenthesis followed by a subscript integer range (e.g., (Xa)0-1) means that the group can have the number of occurrences as designated by the integer range. For example, (Xa)0-1 means the group Xa can be absent or can occur one time. [0053] “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. [0054] “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. [0055] 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, i.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 l or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or l 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. [0056] 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. [0057] 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. [0058] 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. Co-crystals 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. [0059] 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. [0060] 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. [0061] 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. [0062] 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. [0063] 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, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 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 (i.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, 11C, 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. [0064] “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. [0065] “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. [0066] 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. [0067] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. [0068] 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 (i.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. Compounds [0069] In some embodiments, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000023_0001
Formula (I); wherein: J is C(R3) or N; J1 is N and J2 is C, or J1 is C and J2 is N; X, Y and Z are each independently C(R7), C(O), C(R7a)(R7b), N(R7c), or N, wherein at least one of X, Y and Z is C(R7), C(O), or C(R7a)(R7b); X1 and Z1 are each independently C(R7), C(O), C(R7a)(R7b), N(R7c), N, O, or S; Y1 is C(R7), C(R7a)(R7b), N(R7c), or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R7 is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, - N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R7a and R7b is each independently selected from hydrogen, halogen, -CN, -OR10, -SR10, - SF5, -N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; R7c is selected from hydrogen, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; each R8c, R8d, and R8e is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and indicates a single or double bond such that all valences are satisfied. [0070] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J1 is N and J2 is C. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J1 is C and J2 is N. [0071] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N, and X and Y are each C(R7). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R7), and Y and Z are N. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C(R7), and X and Z are N. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R7), and X and Y are N. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N, and Y and Z are each C(R7). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen and unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is -CH3. [0072] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0073] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0074] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0075] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0076] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0077] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Figure imgf000028_0001
[0078] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Figure imgf000028_0002
[0079] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0080] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0081] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0082] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0083] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0084] In some embodiments, described herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000030_0001
Formula (Ia); wherein: J is C(R3) or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R7 is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, - N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R8c and each R8d is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. [0085] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is hydrogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is -CH3. [0086] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0087] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0088] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0089] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0090] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0091] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from
Figure imgf000035_0001
,
Figure imgf000035_0002
[0092] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is
Figure imgf000035_0003
. [0093] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0094] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0095] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0096] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0097] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0098] In some embodiments, described herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000037_0001
Formula (Ib); wherein: J is C(R3) or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C2-6alkenyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); R7 is selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, -N(R10)(R11), C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R8c and each R8d is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. [0099] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3. [0100] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0101] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0102] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0103] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0104] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0105] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from
Figure imgf000041_0001
, , , , ,
Figure imgf000041_0002
[0106] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is
Figure imgf000042_0001
. [0107] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0108] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0109] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0110] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0111] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0112] In some embodiments, described herein is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000044_0001
Formula (Ic); wherein: J is C(R3) or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); R7 is selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, -N(R10)(R11), C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R8c and each R8d is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. [0113] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3. [0114] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0115] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0116] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0117] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0118] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0119] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from
Figure imgf000048_0001
, , , , ,
Figure imgf000048_0002
[0120] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is
Figure imgf000049_0001
. [0121] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0122] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0123] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0124] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0125] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0126] In some embodiments, described herein is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000051_0001
Formula (Id); wherein: J is C(R3) or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R7 is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, - N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R8c and each R8d is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. [0127] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is hydrogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is -CH3. [0128] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0129] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0130] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0131] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0132] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0133] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from
Figure imgf000055_0001
, , , , ,
Figure imgf000055_0002
[0134] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is
Figure imgf000056_0001
. [0135] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0136] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0137] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0138] In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0139] In some embodiments, described herein is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000057_0001
Formula (Ie); wherein: J is C(R3) or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C2-6alkenyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); R7 is selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, -N(R10)(R11), C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R8c and each R8d is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. [0140] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3. [0141] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0142] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0143] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0144] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0145] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0146] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from
Figure imgf000062_0001
, , , , ,
Figure imgf000062_0002
[0147] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is
Figure imgf000062_0003
. [0148] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0149] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0150] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0151] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0152] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0153] In some embodiments, described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000064_0001
Formula (II); wherein: J is C(R3) or N; X1 and Z1 are each independently C(R7), C(O), C(R7a)(R7b), N(R7c), N, O, or S; Y1 is C(R7), C(R7a)(R7b), N(R7c), or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R7 is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, - N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R7a and R7b is each independently selected from hydrogen, halogen, -CN, -OR10, -SR10, - SF5, -N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; R7c is selected from hydrogen, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; each R8c, R8d, and R8e is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and indicates a single or double bond such that all valences are satisfied. [0154] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N(R7c), Y1 is C(R7), and Z1 is N. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N, Y1 is C(R7), and Z1 is N(R7c). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is S, Y1 is C(R7), and Z1 is N. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N, Y1 is C(R7), and Z1 is S. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N(R7c), Y1 is N, and Z1 is N. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N, Y1 is N, and Z1 is N(R7c). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is C(R7a)(R7b), Y1 is N(R7c), and Z1 is C(O). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is CH2, Y1 is N(R7c), and Z1 is C(O). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is C(O), Y1 is N(R7c), and Z1 is C(R7a)(R7b). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is C(O), Y1 is N(R7c), and Z1 is CH2. [0155] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is -CH3. [0156] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is C1-6alkyl optionally substituted with 1-5 R8e groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is hydrogen. [0157] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0158] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0159] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0160] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0161] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0162] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from
Figure imgf000070_0001
, , , , ,
Figure imgf000070_0002
[0163] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein
Figure imgf000070_0003
[0164] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0165] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0166] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0167] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0168] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0169] In some embodiments, described herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000072_0001
Formula (IIa); wherein: J is C(R3) or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); R7 is selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, -N(R10)(R11), C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; R7c is selected from hydrogen, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; each R8c, R8d, and R8e is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. [0170] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3. [0171] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is C1-6alkyl optionally substituted with 1-5 R8e groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is -CH3. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is hydrogen. [0172] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0173] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0174] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0175] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0176] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0177] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from
Figure imgf000077_0001
,
Figure imgf000077_0002
[0178] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is
Figure imgf000077_0003
. [0179] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1- 6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0180] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0181] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0182] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0183] In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0184] In some embodiments, described herein is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000079_0001
Formula (IIb); wherein: J is C(R3) or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); R7 is selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, -N(R10)(R11), C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; R7c is selected from hydrogen, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; each R8c, R8d, and R8e is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. [0185] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3. [0186] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is C1-6alkyl optionally substituted with 1-5 R8e groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is -CH3. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is hydrogen. [0187] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0188] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0189] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0190] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0191] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0192] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
Figure imgf000084_0001
[0193] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is
Figure imgf000085_0001
. [0194] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1- 6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0195] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0196] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0197] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0198] In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0199] In some embodiments, described herein is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000087_0001
Formula (IIc); wherein: J is C(R3) or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); R7a and R7b is each independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, -N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; R7c is selected from hydrogen, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; each R8c and R8e is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and indicates a single or double bond such that all valences are satisfied. [0200] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7a and R7b are each independently hydrogen or C1-6alkyl optionally substituted with 1-5 R8e groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7a and R7b are each independently unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7a and R7b are -CH3. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7a and R7b are hydrogen. [0201] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is C1-6alkyl optionally substituted with 1-5 R8e groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is -CH3. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is hydrogen. [0202] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0203] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0204] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0205] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0206] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0207] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
Figure imgf000091_0001
[0208] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is
Figure imgf000092_0001
. [0209] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1- 6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0210] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0211] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0212] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0213] In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0214] In some embodiments, described herein is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000094_0001
Formula (IId); wherein: J is C(R3) or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); R7 is selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, -N(R10)(R11), C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R8c and R8d is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4. [0215] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3. [0216] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0217] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0218] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0219] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0220] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0221] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from
Figure imgf000098_0001
,
Figure imgf000098_0002
[0222] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is
Figure imgf000099_0001
. [0223] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1- 6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0224] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0225] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0226] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0227] In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0228] In some embodiments, described herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000101_0001
wherein: J is C(R3) or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R7 is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, - N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R8c and R8d is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and indicates a single or double bond such that all valences are satisfied. [0229] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and C1-6alkyl optionally substituted with 1-5 R8d groups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is -CH3. [0230] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3). [0231] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. [0232] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein J is N. [0233] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are hydrogen. [0234] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a, C1-6alkyl, C3-7cycloalkyl, and C2- 9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from -C(O)R1a and C1- 6alkyl, wherein C1-6alkyl is optionally substituted with 1-5 R8c groups. [0235] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3- 7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3- 7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C3-7cycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is cyclopropyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2- 9heterocycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is cyclopropyl optionally substituted with 1-5 R8b groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted cyclopropyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
Figure imgf000105_0001
[0236] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2-9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2- C2-9heterocycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C2- 9heterocycloalkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C2-9heterocycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is
Figure imgf000106_0001
. [0237] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1- 6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -CH2-C2-9heterocycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a, R1a is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a and R1a is unsubstituted C1-6alkyl. [0238] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups, and each R8c is independently selected from halogen, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C3- 6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1- 6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. [0239] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. [0240] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from unsubstituted C1-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is -CH3. [0241] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, 2, or 3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. [0242] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
Figure imgf000108_0001
. [0243] Although certain compounds described herein 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 are herein described. In some embodiments, the compound described herein is selected from a compound described in Examples 1-37. [0244] 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. [0245] 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. 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 Formula (Ia), (Ib), and (Ic), 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. General Synthetic Methods [0246] 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. [0247] 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). [0248] 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). [0249] 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. Pharmaceutical Compositions and Formulations [0250] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition. [0251] 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. [0252] 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 described herein intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound described herein. 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 co- crystal 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 co-crystal 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. [0253] 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. [0254] 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. [0255] 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 co-crystal 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. [0256] 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. [0257] 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. [0258] 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. I n 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. [0259] 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. Methods of Use [0260] 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. [0261] In one aspect, provided herein is 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 [0262] 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. [0263] 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. [0264] 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. [0265] 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 [0266] 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 [0267] 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 [0268] 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/SHOC2/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 [0269] 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. [0270] 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 IIa and IIb) or the formation of a kinase fusion arising from a chromosome translocation event (designated Class IIc) 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. [0271] 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 P261A. 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 IIa and IIb 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 IIc 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. [0272] 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 [0273] 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 1, 1.5 and 2. Type 1 Inhibitors [0274] 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 [0275] 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 [0276] 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 [0277] 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. [0278] 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 [0279] 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 internal deletions or 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 [0280] 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 [0281] 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. [0282] 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. [0283] 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, G13R, 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 IIa, Class IIb, Class IIc, 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 P261A, 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 ROS1. [0284] 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 a genetic alteration or alterations in KRAS (including mutants G12D, G12V, G12C, G12S, G12R, G12A, G13D, G13C, G13R, 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 (including, but not limited to, the anti-EGFR inhibitory antibodies cetuximab and panitumumab), ERBB2, LTK, MET, NTRK, RET, ROS1), RAS inhibitors (including, but not limited to, sotorasib and adagrasib), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II) (including, but not limited to, vemurafenib, dabrafenib, encorafenib, exarafenib, tovorafenib, naporafenib, belvarafenib, brimarafenib and lifrafenib), MEK1/2 inhibitors (including, but not limited to, binimetinib, trametinib, pimasertib, mirdametinib, tunlametinib, avutometinib and zapnometinib), ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, SHP2 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation. [0285] 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, G13R, 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, G13R, 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 or internal deletion 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 (including, but not limited to, the anti-EGFR inhibitory antibodies cetuximab and panitumumab), ERBB2, LTK, MET, NTRK, RET, ROS1), RAS inhibitors (including, but not limited to, sotorasib and adagrasib), RAF inhibitors representing alternative binding modes (such as Type 1.5 or Type II) (including, but not limited to, vemurafenib, dabrafenib, encorafenib, exarafenib, tovorafenib, naporafenib, belvarafenib, brimarafenib and lifrafenib), MEK1/2 inhibitors (including, but not limited to, binimetinib, trametinib, pimasertib, mirdametinib, tunlametinib, avutometinib and zapnometinib), ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, SHP2 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors (including ATM, ATR), PI3K inhibitors and/or radiation. Dosing and Method of Administration [0286] 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. [0287] 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. [0288] 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. [0289] 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. [0290] 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. Articles of Manufacture and Kits [0291] The present disclosure further provides articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal 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. [0292] 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. [0293] 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, HRAS, ARAF, BRAF or CRAF. [0294] 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. [0295] 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. [0296] 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). [0297] 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. EXAMPLES [0298] 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. [0299] 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. [0300] Abbreviations used in the Examples include the following: ACN: acetonitrile; Brettphos: 2-(dicyclohexylphosphino)3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl; dppf: 1,1’- ferrocenediyl-bis(diphenylphosphine); DCM: dichloromethane; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate; EtOH: ethanol or ethyl alcohol; 1H NMR: proton nuclear magnetic resonance; LCMS: liquid chromatography–mass spectrometry; LiHMDS: lithium hexamethyldisilazide; MeOH: methanol or methyl alcohol; NBS: N- bromosuccinimide; OAc: acetate; Py: pyridine; THF: tetrahydrofuran; and TLC: thin-layer chromatography. Example 1: Synthesis of N-[4-(2-chloro-3-hydroxy-6-methylphenyl)-[1,2,4]triazolo[4,3- a]1,6-naphthyridin-8-yl]cyclopropanecarboxamide (Compound 1)
Figure imgf000128_0001
[0301] To a solution of 2-bromo-3-chloro-4-methoxy-1-methylbenzene (A-1) (1.0 g, 4.25 mmol) in dioxane (80.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.6 g, 6.30 mmol), K2CO3 (1.8 g, 13.02 mmol), and Pd(dppf)Cl2 (691 mg, 0.85 mmol) at room temperature under N2. The resulting mixture was stirred at 100 oC for 16 h under N2. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 2-(2-chloro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (A-2) (500.0 mg, 41%) as a white solid. [0302] To a solution of 2-(2-chloro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (A-2) (329 mg, 1.16 mmol) in dioxane/H2O (10.0 mL/2.0 mL) was added 4- bromo-8-chloro-[1,2,4]triazolo[4,3-a]1,6-naphthyridine (A-3) (321 mg, 1.13 mmol), K2CO3 (466 mg, 3.37 mmol), and Pd(PPh3)4 (262 mg, 0.23 mmol) at room temperature under N2. The resulting mixture was stirred at 80 oC for 2 h under N2. The mixture was cooled, 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 to afford 8-chloro-4-(2-chloro-3- methoxy-6-methylphenyl)-[1,2,4]triazolo[4,3-a]1,6-naphthyridine (A-4) (200 mg, 49%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 359.0. [0303] To a solution of 8-chloro-4-(2-chloro-3-methoxy-6-methylphenyl)-[1,2,4]triazolo[4,3- a]1,6-naphthyridine (A-4) (200 mg, 0.56 mmol) in dioxane (8.0 mL) was added cyclopropanecarboxamide (75 mg, 0.88 mmol), K2CO3 (250 mg, 1.81 mmol), XantPhos (67 mg, 0.12 mmol) and Pd2(dba)3 (61 mg, 0.07 mmol) at room temperature under N2. The resulting mixture was stirred at 100 oC for 16 h under N2. The mixture was cooled, 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 to afford N-[4-(2-chloro-3-methoxy-6- methylphenyl)-[1,2,4]triazolo[4,3-a]1,6-naphthyridin-8-yl]cyclopropanecarboxamide (A-5) (100 mg, 44%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 408.1. [0304] To a solution of N-[4-(2-chloro-3-methoxy-6-methylphenyl)-[1,2,4]triazolo[4,3-a]1,6- naphthyridin-8-yl]cyclopropanecarboxamide (A-5) (100 mg, 0.25 mmol) in DCM (5.0 mL) was added BBr3 in DCM (1.0 mL, 1 mol/L) at 0 oC under N2. The resulting mixture was stirred at room temperature for 1 h under N2. The mixture was quenched with methanol. The mixture was diluted with H2O and 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 Prep-HPLC to afford N-[4-(2-chloro-3-hydroxy-6- methylphenyl)-[1,2,4]triazolo[4,3-a]1,6-naphthyridin-8-yl]cyclopropanecarboxamide (Compound 1) (16.3 mg, 16%) as a white solid. LCMS (ESI, m/z): [M+H]+ =394.1.1H NMR (300 MHz, DMSO-d6): δ 11.37 (s, 1H), 10.10 - 9.98 (m, 2H), 9.07 (s, 1H), 8.91 (s, 1H), 7.70 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 2.19 - 2.09 (m, 1H), 1.98 (s, 3H), 1.02 - 0.89 (m, 4H). Example 2: Synthesis of N-(4-(2-chloro-3-hydroxy-6-methylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (Compound 2)
Figure imgf000129_0001
[0305] To a solution of 2-(2-chloro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (A-2) (300 mg, 1.06 mmol) in toluene (8.0 mL) was added K3PO4 (676 mg, 3.19 mmol), 4-bromo-8-chloro-[1,2,4]triazolo[1,5-a][1,6]naphthyridine (B-1) (301 mg, 1.06 mmol) and DPEPhos PdCl2 (76 mg, 0.11 mmol) at room temperature under N2. The resulting mixture was stirred at 120 °C for 2 h under N2. The mixture was cooled, 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. The residue was purified by flash column chromatography to afford 8-chloro-4-(2-chloro-3-methoxy-6- methylphenyl)-[1,2,4]triazolo[1,5-a][1,6]naphthyridine (B-2) (100 mg, 26%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 359.0. [0306] To a solution of 8-chloro-4-(2-chloro-3-methoxy-6-methylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridine (B-2) (90 mg, 0.25 mmol) in dioxane (3.0 mL) was added Cs2CO3 (245 mg, 0.75 mmol), cyclopropanecarboxamide (43 mg, 0.51 mmol), XantPhos (29 mg, 0.05 mmol) and Pd2(dba)3 (23 mg, 0.03 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. The mixture was cooled, 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. The residue was purified by flash column chromatography to afford N-(4-(2-chloro-3-methoxy-6-methylphenyl)- [1,2,4]triazolo[1,5-a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (B-3) (45 mg, 44%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 408.1. [0307] To a solution of N-(4-(2-chloro-3-methoxy-6-methylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (B-3) (30 mg, 0.07 mmol) in DCM (1.0 mL) was added a solution of BBr3 in CH2Cl2 (0.30 mL, 1 mol/L) at 0 oC under N2. The resulting mixture was stirred at room temperature for 2 h. 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 and then further 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: ACN; Flow rate: 60 mL/min; Gradient: isocratic Wavelength: 254 nm/220 nm) to afford N-(4-(2-chloro-3-hydroxy-6-methylphenyl)- [1,2,4]triazolo[1,5-a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (Compound 2) (3 mg, 11%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 394.0.1H NMR (400 MHz, DMSO-d6): δ 11.44 (s, 1H), 10.15 (s, 1H), 9.22 (s, 1H), 9.07 (s, 1H), 8.63 (s, 1H), 8.05 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 2.17 - 2.09 (m, 1H), 1.95 (s, 3H), 0.94 - 0.83 (m, 4H). Example 3: Synthesis of N-(4-(3-hydroxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (Compound 3)
Figure imgf000131_0001
[0308] To a solution of 4-bromo-8-chloro-[1,2,4]triazolo[1,5-a][1,6]naphthyridine (B-1) (2.5 g, 8.82 mmol) in dioxane (25.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (4.5 g, 17.64 mmol), KOAc (2.6 g, 26.45 mmol) and Pd(PPh3)4 (2.0 g, 1.77 mmol) at room temperature under N2. The mixture was stirred at 100 °C for 16 h under N2. The mixture was cooled and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography to afford (8-chloro-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-4-yl)boronic acid (C-1) (0.4 g, 19%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 249.0. [0309] To a solution of (8-chloro-[1,2,4]triazolo[1,5-a][1,6]naphthyridin-4-yl)boronic acid (C-1) (400 mg, 1.61 mmol) in dioxane/H2O (10.0 mL/2.0 mL) was added 2-iodo-4-methoxy-1,3- dimethylbenzene (633 mg, 2.41 mmol), Cs2CO3 (1.5 g, 4.83 mmol) and Pd(dppf)Cl2 (131 mg, 0.16 mmol) at room temperature under N2. The mixture was stirred at 100 °C for 16 h under N2. The mixture was cooled, 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 to afford 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridine (C-2) (180 mg, 32%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 339.1. [0310] To a solution of 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridine (C-2) (150 mg, 0.44 mmol) in dioxane (4.0 mL) was added cyclopropanecarboxamide (38 mg, 0.44 mmol), Cs2CO3 (430 mg, 1.32 mmol), XantPhos (50 mg, 0.09 mmol) and Pd2(dba)3 (48 mg, 0.05 mmol) at room temperature under N2. The mixture was stirred at room temperature for 16 h under N2. The 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. The residue was purified by flash column chromatography to afford N-(4-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (C-3) (50 mg, 30%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 388.2. [0311] To a solution of N-(4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (C-3) (28 mg, 0.07 mmol) in DCM (5.0 mL) was added BBr3 (1.0 mL, 1.00 mmol, 1 mol/L) at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with water and then 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 reverse phase flash column chromatography to afford N-(4-(3-hydroxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (Compound 3) (2.5 mg, 9%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 374.5.1H NMR (400 MHz, DMSO-d6): δ 11.41 (s, 1H), 9.32 (s, 1H), 9.19 (s, 1H), 9.06 (s, 1H), 8.62 (s, 1H), 7.95 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 2.19 - 2.03 (s, 1H), 1.88 (s, 3H), 1.81 (s, 3H), 0.93 - 0.85 (m, 4H). Example 4: Synthesis of N-(4-(3-hydroxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3- a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (Compound 4)
Figure imgf000132_0001
[0312] To a solution of 4-bromo-8-chloro-[1,2,4]triazolo[4,3-a][1,6]naphthyridine (D-1) (1.0 g, 3.53 mmol) in 1,4-dioxane (20.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (2.7 g, 10.58 mmol), KOAc (1.0 g, 10.58 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.3 g, 0.35 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 4 h under N2. The mixture was cooled and concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography to afford (8-chloro-[1,2,4]triazolo[4,3- a][1,6]naphthyridin-4-yl)boronic acid (D-2) (400 mg, 45%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =249.0. [0313] To a solution of 8-chloro-[1,2,4]triazolo[4,3-a]1,6-naphthyridin-4-ylboronic acid (D-2) (400 mg, 1.61 mmol) in dioxane/H2O (10.0 mL/2.0 mL) was added 2-iodo-4-methoxy-1,3- dimethylbenzene (422 mg, 1.61 mmol), K3PO4 (1.0 g, 4.83 mmol) and DPEphos Pd G3 (84 mg, 0.12 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. The mixture was cooled, 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 to afford 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3- a][1,6]naphthyridine (D-3) (174.0 mg, 31%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =339.1. [0314] To a solution of 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3-a]1,6- naphthyridine (D-3) (150 mg, 0.44 mmol) in dioxane (5.0 mL) was added cyclopropanecarboxamide (112 mg, 1.32 mmol), K2CO3 (351 mg, 2.54 mmol), BrettPhos (97 mg, 0.18 mmol) and BrettPhos Pd G3 (102 mg, 0.11 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 4 h under N2. The mixture was cooled, 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 to afford N-(4-(3-methoxy-2,6- dimethylphenyl)-[1,2,4]triazolo[4,3-a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (D-4) (50 mg, 29%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =388.2. [0315] To a solution of N-[4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3-a]1,6- naphthyridin-8-yl]cyclopropanecarboxamide (D-4) (40 mg, 0.10 mmol) in DCM (3.0 mL) was added BBr3 (1.0 mL, 1 mol/L in CH2Cl2) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was quenched with MeOH at room temperature. 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 reverse phase flash column chromatography to afford N-[4-(3-hydroxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3-a]1,6-naphthyridin-8- yl]cyclopropanecarboxamide (Compound 4) (2.7 mg, 7%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 374.1.1H NMR (400 MHz, DMSO-d6): δ 11.35 (s, 1H), 9.97 (s, 1H), 9.34 (s, 1H), 9.04 (s, 1H), 8.90 (s, 1H), 7.60 (s, 1H), 7.02 - 6.97 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), 2.17 - 2.02 (m, 1H), 1.91 (s, 3H), 1.84 (s, 3H), 0.95 - 0.85 (m, 4H). Example 5: Synthesis of 3-(8-amino-[1,2,4]triazolo[1,5-a][1,6]naphthyridin-4-yl)-2,4- dimethylphenol (Compound 5)
Figure imgf000134_0001
[0316] To a solution of 8-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- [1,2,4]triazolo[1,5-a]1,6-naphthyridine (E-1) (2.0 g, 6.05 mmol) in 1,4-dioxane (20 mL)/H2O (4 mL) were added 2-iodo-4-methoxy-1,3-dimethylbenzene (1.5 g, 6.05 mmol), K2CO3 (2.5 g, 18.15 mmol) and Pd(dppf)Cl2 (0.4 g, 0.60 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. 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 to afford 8-chloro-4-(3-methoxy-2,6- dimethylphenyl)-[1,2,4]triazolo[1,5-a]1,6-naphthyridine (C-2) (500 mg, 24%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 339.1. [0317] To a solution of 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]1,6- naphthyridine(C-2) (600 mg, 1.77 mmol) in 1,4-dioxane (10 mL) was added tert-butyl carbamate (599 mg, 5.12 mmol), Cs2CO3 (1.7 g, 5.12 mmol), Pd(OAc)2 (40 mg, 0.17 mmol) and XPhos (163 mg, 0.34 mmol) at room temperature under N2. The mixture was stirred at 100 °C for 2 h under N2. The mixture was cooled, diluted with H2O, 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. The residue was purified by flash column chromatography to afford tert-butyl (4-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a][1,6]naphthyridin-8-yl)carbamate (E-2) (500 mg, 67%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 420.2. [0318] To a solution of tert-butyl (4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)carbamate (E-2) (150 mg, 0.35 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was then basified to pH=7 with saturated NaHCO3 (aq). The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]1,6-naphthyridin-8-amine (E-3) (150 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 320.1. [0319] To a solution of 4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]1,6- naphthyridin-8-amine (E-3) (130 mg, 0.40 mmol) in CH2Cl2 (3 mL) were added BBr3 (0.8 mL, 1 mol/L in CH2Cl2) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with H2O at 0 °C. 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 and then further purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 25% B in 7.8 min; Wavelength: 254 nm/220 nm) to afford 3-(8-amino- [1,2,4]triazolo[1,5-a][1,6]naphthyridin-4-yl)-2,4-dimethylphenol (Compound 5) (34 mg, 26%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 306.0.1H NMR (400 MHz, DMSO-d6): δ 9.18 (s, 1H), 8.81 (s, 1H), 8.47 (s, 1H), 7.69 (s, 1H), 7.19 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.85 - 6.74 (m, 3H), 1.88 (s, 3H), 1.81 (s, 3H). Example 6: Synthesis of N-[1-cyano-4-(3-hydroxy-2,6-dimethylphenyl)imidazo[1,2-a]1,6- naphthyridin-8-yl]cyclopropanecarboxamide (Compound 6)
Figure imgf000135_0001
[0320] To a solution of 4-bromo-8-chloroimidazo[1,2-a]1,6-naphthyridine (F-1) (1.5 g, 5.31 mmol) in 1,4-dioxane/H2O (40.0 mL/8.0 mL) was added 3-methoxy-2,6-dimethylphenylboronic acid (1.0 g, 5.57 mmol), Pd(PPh3)4 (640 mg, 0.55 mmol) and K2CO3 (2.2 g, 15.92 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2-a]1,6- naphthyridine (F-2) (350 mg, 19%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 338.1. [0321] To a solution of 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2-a]1,6- naphthyridine (F-2) (350 mg, 1.04 mmol) in 1,4-dioxane (17.0 mL) was added cyclopropanecarboxamide (450 mg, 5.29 mmol), XPhos (90 mg, 0.19 mmol), K2CO3 (345 mg, 2.50 mmol) and Pd2(dba)3 (75 mg, 0.08 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 4 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford N-[4-(3-methoxy- 2,6-dimethylphenyl)imidazo[1,2-a]1,6-naphthyridin-8-yl]cyclopropanecarboxamide (F-3) (240 mg, 59%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 387.2. [0322] To a solution of N-[4-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2-a]1,6-naphthyridin-8- yl]cyclopropanecarboxamide (F-3) (220 mg, 0.57 mmol) in acetonitrile (10.0 mL) was added NBS (101 mg, 0.57 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The 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 to afford N-[1-bromo-4-(3-methoxy-2,6- dimethylphenyl)imidazo[1,2-a]1,6-naphthyridin-8-yl]cyclopropanecarboxamide (F-4) (350 mg, crude) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 465.1. [0323] To a solution of N-[1-bromo-4-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2-a]1,6- naphthyridin-8-yl]cyclopropanecarboxamide (F-4) (300 mg, crude) in DMF (15.0 mL) was added Zn(CN)2 (150 mg, 1.28 mmol) and Pd(PPh3)4 (150 mg, 0.13 mmol) at room temperature under N2. The resulting mixture was stirred at 120 °C for 16 h under N2. The mixture was cooled, 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 to afford N-[1- cyano-4-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2-a]1,6-naphthyridin-8- yl]cyclopropanecarboxamide (F-5) (74 mg, 27%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 412.2. [0324] To a solution of N-[1-cyano-4-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2-a]1,6- naphthyridin-8-yl]cyclopropanecarboxamide (F-5) (70 mg, 0.17 mmol) in DCM (3.0 mL) was added BBr3 (1.4 mL, 1.0 mol/L in DCM) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with water 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. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column19x250 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 33% B to 43% B in 10 min; Wavelength: 254 nm) to afford N-[1-cyano-4-(3-hydroxy-2,6- dimethylphenyl)imidazo[1,2-a]1,6-naphthyridin-8-yl]cyclopropanecarboxamide (Compound 6) (7.1 mg, 10%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 398.2.1H NMR (400 MHz, DMSO-d6): δ 11.37 (s, 1H), 9.59 (s, 1H), 9.29 - 9.24 (m, 1H), 9.16 (s, 1H), 8.49 (s, 1H), 7.83 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 2.15 - 2.08 (m, 1H), 1.87 (s, 3H), 1.84 (s, 3H), 0.95 - 0.84 (m, 4H). Example 7: Synthesis of 2,4-dimethyl-3-(8-(methylamino)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-4-yl)phenol (Compound 7)
Figure imgf000137_0001
[0325] To a mixture of tert-butyl (4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)carbamate (250 mg, 0.59 mmol) (G-1) in DMF (5.0 mL) was added NaH (17 mg, 60%) at 0 oC under N2. The mixture was stirred at 0 oC for 30 min. Then CH3I (254 mg, 1.78 mmol) was added to the mixture at 0 oC. The resulting mixture was stirred at room temperature for additional 1 h. 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 to afford tert-butyl (4-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a][1,6]naphthyridin-8-yl)(methyl)carbamate (G-2) (140 mg, 54%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 434.2. [0326] To a solution of tert-butyl (4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)(methyl)carbamate (G-2) (100 mg, 0.23 mmol) in CH2Cl2 (3.0 mL) were added BBr3 (2.3 mL, 1 mol/L) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H2O at 0 °C. 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 and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B; Wavelength: 254 nm/220 nm) to afford 2,4-dimethyl-3-(8- (methylamino)-[1,2,4]triazolo[1,5-a][1,6]naphthyridin-4-yl)phenol (Compound 7) (22 mg, 30%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 320.1.1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 8.87 (s, 1H), 8.49 (s, 1H), 7.70 (s, 1H), 7.42 - 7.38 (m, 1H), 7.08 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 2.94 (d, J = 4.8 Hz, 3H), 1.88 (s, 3H), 1.81 (s, 3H). Example 8: Synthesis of 2,4-dimethyl-3-(8-(methylamino)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)phenol (Compound 8)
Figure imgf000138_0001
[0327] A solution of 6-bromo-7-chloro-2-(methylsulfanyl)pyrido[2,3-d]pyrimidine (H-1) (5.0 g, 17.21 mmol) in NH3-dioxane (200.0 mL, 0.4 mol/L) was stirred at 80 °C for 2 h. The mixture was cooled and concentrated under reduced pressure to afford 6-bromo-2- (methylsulfanyl)pyrido[2,3-d]pyrimidin-7-amine (H-2) (5.0 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 271.0. [0328] To a mixture of 6-bromo-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7-amine (H-2) (5.0 g, 18.44 mmol) in 1,4-dioxane (50.0 mL) was added DMF-DMA (6.6 g, 55.32 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 3 h. The mixture was cooled and concentrated under reduced pressure. The residue was washed with Et2O and then filtered. The solid was collected and dried to afford (E)-N'-(6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7- yl)-N,N-dimethylformimidamide (H-3) (5.0 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 326.0. [0329] To a solution of (E)-N'-(6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)-N,N- dimethylformimidamide (H-3) (5.0 g, crude) in methanol (50.0 mL) was added hydroxylamine hydrochloride (3.2 g, 45.98 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 3 h. The mixture was cooled and diluted with H2O and filtered. The solid was washed with Et2O and then collected to afford (E)-N'-(6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7- yl)-N-hydroxyformimidamide (H-4) (5.0 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 314.0. [0330] To a solution of (E)-N'-(6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7-yl)-N- hydroxyformimidamide (H-4) (5.0 g, crude) in THF (50.0 mL) was added TFAA (10.0 mL) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 4-bromo-8-(methylthio)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3- d]pyrimidine (H-5) (3.0 g, 63%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 296.0. [0331] To a solution of 4-bromo-8-(methylthio)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-5) (3.0 g, 10.13 mmol) in 1,4-dioxane (50.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (5.1 g, 20.26 mmol), KOAc (3.0 g, 30.39 mmol) and Pd(dppf)Cl2 (741.2 g, 1.01 mmol) at room temperature under N2. The mixture was stirred at 100 °C for 16 h under N2. The mixture was cooled to room temperature and filtered. The solid was washed with water (5.0 mmol/L TFA) and then collected to afford 8-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-6) (3.0 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 344.1. [0332] To a solution of 8-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-6) (2.0 g, crude) in 1,4-dioxane/H2O (40.0 mL/8.0 mL) was added 2-iodo-4-methoxy-1,3-dimethylbenzene (3.1 g, 11.64 mmol), K2CO3 (2.4 g, 17.48 mmol) and Pd(dppf)Cl2 (426 mg, 0.6 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The mixture was cooled, 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 to afford 4-(3-methoxy-2,6- dimethylphenyl)-8-(methylthio)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-7) (1.4 g, 26%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 352.1. [0333] To a solution of 4-(3-methoxy-2,6-dimethylphenyl)-8-(methylthio)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-7) (1.4 g, 4.00 mmol) in CH2Cl2 (20.0 mL) was added m-CPBA (2.1 g, 11.96 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 h under N2. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 4-(3-methoxy-2,6- dimethylphenyl)-8-(methylsulfonyl)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-8) (200 mg, 13%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 384.1. [0334] A solution of 4-(3-methoxy-2,6-dimethylphenyl)-8-(methylsulfonyl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-8) (100 mg, 0.26 mmol) in CH3NH3-THF (2.0 mL, 1.0 mol/L) was stirred at 80 °C for 2 h. The mixture was cooled and concentrated under reduced pressure to afford 4-(3-methoxy-2,6-dimethylphenyl)-N-methyl- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-8-amine (H-9) (100 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 335.2. [0335] To a solution of 4-(3-methoxy-2,6-dimethylphenyl)-N-methyl- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-8-amine (H-9) (100 mg, 0.30 mmol) in CH2Cl2 (5.0 mL) was added a solution of BBr3 in CH2Cl2 (1.5 mL, 1.0 mol/L) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 3 h under N2. The mixture was quenched with water and then concentrated under vacuum. The residue was purified by flash column chromatography to afford 2,4-dimethyl-3-(8-(methylamino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4- yl)phenol (Compound 8) (19 mg, 19%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 321.1.1H NMR (400 MHz, DMSO-d6): δ 9.20 - 9.10 (m, 2H), 8.50 (s, 1H), 8.25 - 8.16 (m, 1H), 7.71 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 3.03 - 2.99 (m, 3H), 1.87 (s, 3H), 1.80 (s, 3H). Example 9: Synthesis of 3-(8-amino-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)- 2,4-dimethylphenol (Compound 9)
Figure imgf000140_0001
[0336] A solution of 4-(3-methoxy-2,6-dimethylphenyl)-8-(methylsulfonyl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-8) (100 mg, 0.26 mmol) in NH3/dioxane (2.0 mL, 0.4 mol/L) was stirred at 80 °C for 2 h. The mixture was cooled and concentrated under reduced pressure to afford 4-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-8-amine (I-1) (100 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 321.1. [0337] To a solution of 4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3- d]pyrimidin-8-amine (I-1) (100 mg, 0.31 mmol) in CH2Cl2 (10.0 mL) was added a solution of BBr3 in CH2Cl2 (1.6 mL, 1.0 mol/L) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 3 h under N2. The mixture was quenched with water and then concentrated under vacuum. The residue was purified by flash column chromatography to afford 3-(8-amino- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)-2,4-dimethylphenol (Compound 9) (48 mg, 49%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 307.0.1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1H), 9.11 (s, 1H), 8.50 (s, 1H), 7.90 - 7.60 (m, 3H), 6.96 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 1.87 (s, 3H), 1.80 (s, 3H). Example 10: Synthesis of N-(5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3- f]quinoxalin-9-yl)cyclopropanecarboxamide (Compound 10)
Figure imgf000141_0001
[0338] To a solution of 5-bromo-9-chloro-2,3-dimethylpyrido[4,3-f]quinoxaline (J-1) (400 mg, 1.24 mmol) in dioxane (14.0 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (315 mg, 1.24 mmol), Pd(dppf)Cl2 (182 mg, 0.25 mmol) and KOAc (360 mg, 3.67 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 9-chloro-2,3-dimethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrido[4,3-f]quinoxaline (J-2) (270 mg, 55%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =370.1. [0339] To a mixture of 9-chloro-2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrido[4,3-f]quinoxaline (J-2) (200 mg, 0.54 mmol) and 2-iodo-4-methoxy-1,3- dimethylbenzene (201 mg, 0.77 mmol) in dioxane (4.0 mL) and H2O (0.8 mL) were added K2CO3 (288 mg, 2.08 mmol) and Pd(dppf)Cl2 (102 mg, 0.14 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 9-chloro-5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3- f]quinoxaline (J-3) (140 mg, 53%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =378.1. [0340] To a mixture of 9-chloro-5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3- f]quinoxaline (J-3) (140 mg, 0.38 mmol) and cyclopropanecarboxamide (97 mg, 1.14 mmol) in dioxane (5.0 mL) were added Cs2CO3 (372 mg, 1.14 mmol) and Pd-PEPPSI-IPentCl 2- methylpyridine (o-picoline) (64 mg, 0.07 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford N-(5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3-f]quinoxalin-9- yl)cyclopropanecarboxamide (J-4) (85 mg, 53%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =427.2 [0341] To a stirred solution of N-(5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3- f]quinoxalin-9-yl)cyclopropanecarboxamide (J-4) (80 mg, 0.19 mmol) in CH2Cl2 (2.0 mL) was added BBr3 (0.2 mL, 1.0 mol/L in CH2Cl2) at 0 °C under N2. The resulting mixture was stirred at room temperature for 50 min. The mixture 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 vacuum. The residue was purified by flash column chromatography and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 42% B to 52% B in 7.8 min; Wavelength: 254 nm/220 nm) to afford N-[5-(3-hydroxy-2,6-dimethylphenyl)-2,3- dimethylpyrido[4,3-f]quinoxalin-9-yl]cyclopropanecarboxamide (Compound 10) (6 mg, 7%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 413.2. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 9.61 (s, 1H), 9.19 (s, 1H), 9.10 (s, 1H), 7.89 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 2.95 (s, 3H),2.68 (s, 3H),2.13 - 2.08 (m, 1H), 1.93 (s, 3H), 1.86 (s, 3H), 0.93 - 0.88 (m, 4H). Example 11: Synthesis of 4-methyl-3-(8-(methylamino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3- d]pyrimidin-4-yl)phenol (Compound 11)
Figure imgf000142_0001
[0342] To a stirred solution of 4-bromo-8-(methylthio)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3- d]pyrimidine (H-5) (1.0 g, 3.38 mmol) in dioxane (10.0 mL)/H2O (2.0 mL) was added 5- methoxy-2-methylphenylboronic acid (1.7 g, 10.13 mmol), K2CO3 (2.8 g, 20.26 mmol) and Pd(PPh3)4 (395 mg, 0.34 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The mixture was cooled, diluted with H2O, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 4-(5-methoxy-2-methylphenyl)-8-(methylthio)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (K-1) (800 mg, 70%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 338.1. [0343] To a stirred solution of 4-(5-methoxy-2-methylphenyl)-8-(methylthio)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (K-1) (800 mg, 2.37 mmol) in CH2Cl2 (10.0 mL) was added m-CPBA (3.3 g, 18.97 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 16 h. The mixture was concentrated under reduced pressure to afford 4-(5-methoxy-2-methylphenyl)- 8-(methylsulfonyl)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (K-2) (1.0 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 370.1. [0344] To a stirred solution of 4-(5-methoxy-2-methylphenyl)-8-(methylsulfonyl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (K-2) (900 mg, crude) was added methanamine (10.0 mL, 2.0 mol/L in THF) at room temperature. The resulting mixture was stirred at 80 ℃ for 2 h. The mixture was cooled and concentrated under reduced pressure to afford 4-(5-methoxy-2- methylphenyl)-N-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-8-amine (K-3) (1.0 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 321.1 [0345] To a stirred solution of 4-(5-methoxy-2-methylphenyl)-N-methyl- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-8-amine (K-3) (900 mg, crude) in CH2Cl2 (3.0 mL) was added BBr3 (0.5 mL, 1.0 mol/L in CH2Cl2) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with H2O and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography and then purified by Prep-Achiral-SFC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (0.05% NH3 .H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 28% B; Wavelength: 254/220 nm) to afford 4-methyl-3-(8-(methylamino)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)phenol (Compound 11) (21 mg, 2%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 307.0.1H NMR (400 MHz, DMSO-d6): δ 9.34 - 9.12 (m, 2H), 8.55 (s, 1H), 8.27 - 8.19 (m, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.79 - 6.75 (m, 2H), 3.01 - 2.98 (m, 3H), 2.04 (s, 3H). Example 12: Synthesis of 2-chloro-4-methyl-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 12)
Figure imgf000144_0001
[0346] To a solution of 2-(2-chloro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (A-2) (480 mg, 1.70 mmol) in 1,4-dioxane/H2O (10.0 mL/2.0 mL) was added 6- bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-1) (503 mg, 1.70 mmol), K2CO3 (695 mg, 5.03 mmol) and Pd(dppf)Cl2 (124 mg, 0.17 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. The mixture was cooled, 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 to afford 6-(2- chloro-3-methoxy-6-methylphenyl)-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidine (L-2) (320 mg, 50%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 372.1. [0347] To a solution of 6-(2-chloro-3-methoxy-6-methylphenyl)-2-(methylthio)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-2) (300 mg, 0.81 mmol) in CH2Cl2 (10.0 mL) was added m-CPBA (1.1 g, 6.43 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 6-(2-chloro-3-methoxy-6-methylphenyl)- 2-(methylsulfonyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-3) (100 mg, 30%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 404.1. [0348] A solution of 6-(2-chloro-3-methoxy-6-methylphenyl)-2-(methylsulfonyl)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-3) (90 mg, 0.22 mmol) in CH3NH2/THF (3.0 mL, 1.0 mol/L in THF) was stirred at 80 °C for 2 h. The mixture was cooled and concentrated under reduced pressure to afford 6-(2-chloro-3-methoxy-6-methylphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (L-4) (90 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 355.1. [0349] To a solution of 6-(2-chloro-3-methoxy-6-methylphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (L-4) (80 mg, crude) in CH2Cl2 (5.0 mL) was added BBr3 (1.2 mL, 1.0 mol/L in CH2Cl2) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h under N2. The mixture was quenched with water and then concentrated under vacuum. The residue was purified by flash column chromatography to afford 2-chloro-4- methyl-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 12) (13 mg, 16%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 341.1.1H NMR (400 MHz, DMSO-d6): δ 10.01 (d, J = 3.6 Hz, 1H), 9.71 - 9.46 (m, 1H), 9.08 - 9.00 (m, 1H), 8.19 - 8.09 (m, 1H), 7.50 (d, J = 3.2 Hz, 1H), 7.18 - 7.12 (m, 1H), 7.02 - 6.99 (m, 1H), 3.03 - 2.98 (m, 3H), 1.97 (s, 3H). Example 13: Synthesis of 2,4-dimethyl-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 13)
Figure imgf000145_0001
[0350] To a solution of 6-bromo-7-chloro-2-(methylsulfanyl)pyrido[2,3-d]pyrimidine (H-1) (3.0 g, 10.33 mmol) in THF (30.0 mL) was added hydrazine hydrate (6.0 mL, 80%) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The mixture was cooled and concentrated under reduced pressure to afford 6-bromo-7-hydrazinyl-2- (methylsulfanyl)pyrido[2,3-d]pyrimidine (M-1) (3.0 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 286.0. [0351] A solution of 6-bromo-7-hydrazinyl-2-(methylsulfanyl)pyrido[2,3-d]pyrimidine (M-1) (3.0 g, crude) in formic acid (30.0 mL) was stirred at 80 °C for 3 h. The mixture was cooled and concentrated under reduced pressure. The residue diluted with water and then filtered. The solid was collected and dried to afford 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidine (L-1) (3.0 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =296.0. [0352] To a solution of 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-1) (500 mg, crude) in 1,4-dioxane/H2O (10.0 mL/2.0 mL) was added 3-methoxy-2,6- dimethylphenylboronic acid (912 mg, 5.07 mmol), K2CO3 (700 mg, 5.07 mmol) and Pd(dppf)Cl2 (124 mg, 0.17 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. The mixture was cooled, 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 to afford 6-(3-methoxy-2,6-dimethylphenyl)-2-(methylthio)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (M-2) (150 mg, 25%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 352.1. [0353] To a solution of 6-(3-methoxy-2,6-dimethylphenyl)-2-(methylthio)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (M-2) (150 mg, 0.43 mmol) in CH2Cl2 (5.0 mL) was added m-CPBA (589.0 mg, 3.41 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 6-(3-methoxy-2,6-dimethylphenyl)-2- (methylsulfonyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (M-3) (100 mg, 61%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 384.1. [0354] A solution of 6-(3-methoxy-2,6-dimethylphenyl)-2-(methylsulfonyl)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (M-3) (90 mg, 0.24 mmol) in CH3NH2 (2.0 mL, 1.0 mol/L in THF) was stirred at 80 °C for 2 h. The mixture was cooled and concentrated under reduced pressure to afford 6-(3-methoxy-2,6-dimethylphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (M-4) (90 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 335.2. [0355] To a solution of 6-(3-methoxy-2,6-dimethylphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (M-4) (70 mg, crude) in CH2Cl2 (3.0 mL) was added BBr3 (1.1 mL, 1.0 mol/L in CH2Cl2) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h under N2. The mixture was quenched with water and then concentrated under vacuum. The residue was purified by flash column chromatography and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B; Wavelength: 254/220 nm) to afford 2,4-dimethyl-3-(2- (methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 13) (5.7 mg, 8%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 321.2.1H NMR (400 MHz, DMSO-d6): δ 9.70 - 9.44 (m, 1H), 9.20 (s, 1H), 9.05 - 8.97 (m, 1H), 8.14 - 8.03 (m, 1H), 7.40 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 3.03 - 2.98 (m, 3H), 1.91 (s, 3H), 1.83 (s, 3H). Example 14: Synthesis of 2,4-dimethyl-3-(2-(methylamino)imidazo[1',2':1,6]pyrido[2,3- d]pyrimidin-6-yl)phenol (Compound 14)
Figure imgf000147_0001
[0356] A solution of 3-bromo-2-chloro-7-(methylsulfanyl)-1,6-naphthyridine (N-1) (3.0 g, 10.36 mmol) was added NH3/dioxane (30.0 mL, 0.4 mol/L in dioxane) was stirred at 80 °C for 2 h. The mixture was cooled and concentrated under reduced pressure to afford 3-bromo-7- (methylsulfanyl)-1,6-naphthyridin-2-amine (N-2) (3.1 g, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 270.0. [0357] To a stirred solution of 3-bromo-7-(methylsulfanyl)-1,6-naphthyridin-2-amine (N-2) (2.3 g, crude) in EtOH (10.0 mL) was added chloroacetaldehyde (7.5 mL, 40% in water) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The mixture was cooled to 0 °C and then filtered. The solid was washed with EtOH and then collected to afford 4-bromo-8- (methylsulfanyl)imidazo[1,2-a]1,6-naphthyridine (N-3) (2.0 g, 79%) as a brown yellow solid. LCMS (ESI, m/z): [M+H]+ = 294.0. [0358] To a stirred solution of 4-bromo-8-(methylsulfanyl)imidazo[1,2-a]1,6-naphthyridine (N- 3) (300 mg, 1.02 mmol) in dioxane (10.0 mL)/H2O (2.0 mL) was added 3-methoxy-2,6- dimethylphenylboronic acid (276 mg, 1.53 mmol), K2CO3 (423 mg, 3.06 mmol) and Pd(PPh3)4 (118 mg, 0.10 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was cooled, diluted with H2O, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 6-(3-methoxy-2,6-dimethylphenyl)-2- (methylthio)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (N-4) (80 mg, 22%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 351.1. [0359] To a stirred solution of 6-(3-methoxy-2,6-dimethylphenyl)-2- (methylthio)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (N-4) (80 mg, 0.23 mmol) in CH2Cl2 (5.0 mL) was added m-CPBA (320 mg, 1.85 mmol) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 16 h. The mixture was concentrated under reduced pressure to afford 6-(3-methoxy-2,6- dimethylphenyl)-2-(methylsulfonyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (N-5) (90 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 383.1. [0360] A solution of 6-(3-methoxy-2,6-dimethylphenyl)-2- (methylsulfonyl)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidine (N-5) (70 mg, crude) in methanamine/THF (5.0 mL, 2.0 mol/L in THF) was stirred at 80 ℃ for 2 h. The mixture was cooled and concentrated under reduced pressure to afford 6-(3-methoxy-2,6-dimethylphenyl)-N- methylimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (N-6) (80 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 334.2. [0361] To a stirred solution of 6-(3-methoxy-2,6-dimethylphenyl)-N- methylimidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-2-amine (N-6) (50 mg, crude) in CH2Cl2 (5.0 mL) was added BBr3 (0.5 mL, 1.0 mol/L in CH2Cl2) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with H2O and then 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. The residue was purified by flash column chromatography and then 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: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B, 9% B to 19% B; Wavelength: 254/220 nm) to afford 2,4-dimethyl-3-(2- (methylamino)imidazo[1',2':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 14) (8 mg, 20%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 320.1.1H NMR (400 MHz, DMSO-d6): δ 9.13 - 8.96 (m, 2H), 8.35 - 8.19 (m, 1H), 7.93 - 7.81 (m, 1H), 7.51 (s, 1H), 7.28 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 3.00 (s, 3H), 1.87 (s, 3H), 1.80 (s, 3H). Example 15: Synthesis of 4-methyl-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidin-6-yl)phenol (Compound 15)
Figure imgf000148_0001
[0362] To a mixture of 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-1) (500 mg, 1.68 mmol) in 1,4-dioxane/H2O (10.0 mL/2.0 mL) was added 5-methoxy-2- methylphenylboronic acid (850 mg, 5.12 mmol), K2CO3 (1400 mg, 10.13 mmol) and Pd(PPh3)4 (370 mg, 0.19 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The mixture was cooled, 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 to afford 6-(5-methoxy-2-methylphenyl)-2-(methylthio)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (O-1) (300 mg, 52%) as a red solid. LCMS (ESI, m/z): [M+H]+ = 338.1. [0363] To a mixture of 6-(5-methoxy-2-methylphenyl)-2-(methylthio)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (O-1) (300 mg, 0.88 mmol) in CH2Cl2 (10.0 mL) was added m-CPBA (618 mg, 3.58 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 4 h under N2. The mixture was concentrated under reduced pressure to afford 6-(5-methoxy-2-methylphenyl)-2-(methylsulfonyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidine (O-2) (900 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 370.1. [0364] A mixture of 6-(5-methoxy-2-methylphenyl)-2-(methylsulfonyl)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (O-2) (900 mg, crude) in MeNH2 (10.0 mL, 1.0 mol/L in THF) was stirred at 80 °C for 3 h. The mixture was cooled and concentrated under reduced pressure to afford 6-(5-methoxy-2-methylphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (O-3) (1.0 g, crude) as a red solid. LCMS (ESI, m/z): [M+H]+ = 321.1. [0365] To a mixture of 6-(5-methoxy-2-methylphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (O-3) (1.0 g, crude) in CH2Cl2 (5.0 mL) was added boron tribromide (8.0 mL, 1 mol/L in CH2Cl2) at 0 °C. The resulting mixture was stirred at 0 °C for 4 h. The mixture was quenched with water and then concentrated under vacuum. The residue was purified by flash column chromatography and then purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 28% B; Wavelength: 254/220 nm; RT1(min): 9.68) to afford 4- methyl-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 15) (21 mg, 2%) as an off-white solid. LCMS (ESI, m/z): [M+H]+ = 307.0.1H NMR (400 MHz, DMSO-d6): δ 9.71 (s, 1H), 9.45 - 9.31 (m, 1H), 9.07 - 8.99 (m, 1H), 8.15 - 8.03 (m, 1H), 7.51 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.82 - 6.76 (m, 2H), 3.03 - 2.98 (m, 3H), 2.08 (s, 3H). Example 16: Synthesis of 4-chloro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidin-6-yl)phenol (Compound 16)
Figure imgf000150_0001
[0366] To a mixture of 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-1) (500 mg, 1.68 mmol) in 1,4-dioxane/H2O (10.0 mL/2.0 mL) was added 2-chloro-5- methoxyphenylboronic acid (945 mg, 5.07 mmol), K2CO3 (1400 mg, 10.13 mmol) and Pd(PPh3)4 (370 mg, 0.19 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The mixture was cooled, 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 to afford 6-(2-chloro-5-methoxyphenyl)-2-(methylthio)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (P-1) (270 mg, 44%) as a red solid. LCMS (ESI, m/z): [M+H]+ = 358.0. [0367] To a mixture of 6-(2-chloro-5-methoxyphenyl)-2-(methylthio)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (P-1) (270 mg, 0.75 mmol) in CH2Cl2 (10.0 mL) was added m-CPBA (556 mg, 3.22 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 4 h under N2. The mixture was concentrated under reduced pressure to afford 6-(2- chloro-5-methoxyphenyl)-2-(methylsulfonyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (P-2) (850 mg, crude) as a red solid. LCMS (ESI, m/z): [M+H]+ = 390.0. [0368] A mixture of 6-(2-chloro-5-methoxyphenyl)-2-(methylsulfonyl)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (P-2) (800 mg, crude) in MeNH2 (10.0 mL, 1.0 mol/L in THF) was stirred at 80 °C for 3 h. The mixture was cooled and concentrated under reduced pressure to afford 6-(2-chloro-5-methoxyphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (P-3) (900 mg, crude) as a red solid. LCMS (ESI, m/z): [M+H]+ = 341.1. [0369] To a mixture of 6-(2-chloro-5-methoxyphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (P-3) (900 mg, crude) in CH2Cl2 (5.0 mL) was added boron tribromide (8.0 mL, 1 mol/L in CH2Cl2) at 0 °C. The resulting mixture was stirred at 0 °C for 4 h. The mixture was quenched with water and then concentrated under vacuum. The residue was purified by flash column chromatography and then 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: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B, 18% B to 28% B; Wavelength: 254/220 nm) to afford 4-chloro-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 16) (19 mg, 7%) as an off-white solid. LCMS (ESI, m/z): [M+H]+ = 326.9.1H NMR (400 MHz, DMSO-d6): δ 9.89 (s, 1H), 9.72 - 9.46 (m, 1H), 9.10 - 9.02 (m, 1H), 8.21 - 8.10 (m, 1H), 7.64 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.91 - 6.88 (m, 1H), 3.03 - 2.98 (m, 3H). Example 17: Synthesis of 2-chloro-4-methyl-3-(8-(methylamino)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)phenol (Compound 17)
Figure imgf000151_0001
[0370] To a solution of 4-bromo-8-(methylthio)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-5) (400 mg, 1.43 mmol) and 2-(2-chloro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (A-2) (1224 mg, 4.33 mmol) in dioxane (15.0 mL) and H2O (5.0 mL) were added K2CO3 (1211 mg, 8.76 mmol) and Pd(PPh3)4 (340 mg, 0.294 mmol) at room temperature under N2. The resulting mixture was stirred at 85 °C for 16 h under N2. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 4-(2-chloro-3-methoxy-6-methylphenyl)-8- (methylthio)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (Q-1) (281 mg, 55%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =372.1. [0371] To a solution of 4-(2-chloro-3-methoxy-6-methylphenyl)-8-(methylthio)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (Q-1) (400 mg, 1.07 mmol) in CH2Cl2 (15.0 mL) was added m-CPBA (445 mg, 2.44 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with H2O at 0 °C 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 to afford 4-(2-chloro-3-methoxy-6-methylphenyl)-8-(methylsulfonyl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (Q-2) (320 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ =404.1. [0372] To a solution of 4-(2-chloro-3-methoxy-6-methylphenyl)-8-(methylsulfonyl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (320.0 mg, crude) in EtOH (5.0 mL) was added CH3NH2 (4.0 mL, 30% in EtOH) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled, 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 to afford 4-(2-chloro-3-methoxy-6- methylphenyl)-N-methyl-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-8-amine (190.0 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 355.1. [0373] The mixture of 4-(2-chloro-3-methoxy-6-methylphenyl)-N-methyl- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-8-amine (Q-3) (190 mg, crude) in HBr (3.0 mL, 40% in H2O) was stirred at 80 °C for 4 h. The mixture was cooled and the pH value of the mixture was adjusted to 8.0 with saturated NaHCO3 (aq.). The mixture was 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. The residue was purified by reverse phase flash column chromatography and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 35% B; Wavelength: 254/220 nm) to afford 2-chloro-4-methyl-3-(8-(methylamino)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)phenol (Compound 17) (9.6 mg, 2%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 341.1.1H NMR (400 MHz, DMSO-d6): δ 9.71 - 9.54 (m, 1H), 9.08 - 9.00 (m, 1H), 8.19 - 8.09 (m, 1H), 7.50 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 3.03 - 2.99 (m, 3H), 1.97 (s, 3H). Example 18: Synthesis of 2,4-dichloro-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 18)
Figure imgf000153_0001
[0374] To a stirred solution of 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidine (L-1) (500 mg, 1.68 mmol) in dioxane/H2O (60.0 mL/12.0 mL) was added (2,6- dichloro-3-methoxyphenyl)boronic acid (5.5 g, 25.31 mmol), K2CO3 (2.3 g, 16.88 mmol), XPhos (321 mg, 0.67 mmol) and XPhos Pd G3 (285 mg, 0.33 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. The reaction mixture was cooled, diluted with H2O, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 6-(2,6-dichloro-3- methoxyphenyl)-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (R-1) (500 mg, 75%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 392.0. [0375] To a stirred solution of 6-(2,6-dichloro-3-methoxyphenyl)-2-(methylthio)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (R-1) (480 mg, 1.22 mmol) in CH2Cl2 (5.0 mL) was added m-CPBA (1.0 g, 6.12 mmol) at 0 ℃. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 6-(2,6-dichloro-3-methoxyphenyl)-2- (methylsulfonyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (R-2) (180 mg, 34%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 424.0. [0376] A solution of 6-(2,6-dichloro-3-methoxyphenyl)-2-(methylsulfonyl)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (R-2) (170 mg, 0.40 mmol) in CH3NH2 (3.0 mL, 1 M in THF) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to afford 6-(2,6-dichloro-3-methoxyphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (R-3) (200 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 375.0. [0377] To a stirred solution of 6-(2,6-dichloro-3-methoxyphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (R-3) (180 mg, crude) in CH2Cl2 (5.0 mL) was added BBr3 (2.5 mL, 1.0 mol/L in CH2Cl2) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H2O and then 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. The residue was purified by flash column chromatography and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (0.1%, NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 20% B; Wavelength: 254/220 nm) to afford 2,4-dichloro-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 18) (34 mg, 19%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 361.9.1H NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1H), 9.73 - 9.47 (m, 1H), 9.11 - 9.02 (m, 1H), 8.28 - 8.16 (m, 1H), 7.62 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 3.04 - 2.98 (m, 3H). Example 19: Synthesis of 2-chloro-4-methyl-3-[8-(methylamino)-[1,2,4]triazolo[4,3-a]1,6- naphthyridin-4-yl]phenol (Compound 19)
Figure imgf000154_0001
[0378] To a stirred solution of 8-chloro-4-(2-chloro-3-methoxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a]1,6-naphthyridine (A-4) (280 mg, 0.78 mmol) in methanamine (10.0 mL, 2.0 M in THF) was stirred at 80 ℃ for 16 h. The mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 4-(2- chloro-3-methoxy-6-methylphenyl)-N-methyl-[1,2,4]triazolo[4,3-a]1,6-naphthyridin-8-amine (S- 1) (80 mg, 29%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 354.1. [0379] To a stirred solution of 4-(2-chloro-3-methoxy-6-methylphenyl)-N-methyl- [1,2,4]triazolo[4,3-a]1,6-naphthyridin-8-amine (S-1) (70 mg, 0.20 mmol) in CH2Cl2 (2.0 mL) was added BBr3 (1.0 mL, 1.0 mol/L in CH2Cl2) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. The reaction mixture was quenched with H2O and then 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. The residue was purified by flash column chromatography and then purified by Prep-HPLC with the following conditions: (Column: XBridge Prep Phenyl OBD Column 19x250 mm, 5 um; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 18% B to 28% B; Wavelength: 254/220 nm) to afford 2-chloro-4-methyl-3-[8-(methylamino)-[1,2,4]triazolo[4,3- a]1,6-naphthyridin-4-yl]phenol (Compound 19) (25 mg, 36%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 340.0.1H NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 9.90 (s, 1H), 8.72 (s, 1H), 7.47 (s, 1H), 7.35 - 7.31 (m, 1H), 7.16 - 7.11 (m, 2H), 6.99 (d, J = 8.4 Hz, 1H), 2.92 (d, J = 4.8 Hz, 3H), 1.96 (s, 3H). Example 20: Synthesis of 2-chloro-4-methyl-3-(8-(methylamino)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-4-yl)phenol (Compound 20)
Figure imgf000155_0001
[0380] To a solution of 4-bromo-8-chloro-[1,2,4]triazolo[1,5-a]1,6-naphthyridine (B-1) (500 mg, 1.76 mmol) in 1,4-dioxane (25.0 mL) and H2O (5.0 mL) was added 2-(2-chloro-3-methoxy-6- methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (A-2) (717 mg, 3.57 mmol), K2CO3 (735 mg, 5.31 mmol), Pd(PPh3)4 (291 mg, 0.39 mmol) and K2CO3 (735 mg, 5.31 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 8-chloro-4-(2-chloro-3-methoxy- 6-methylphenyl)-[1,2,4]triazolo[1,5-a]1,6-naphthyridine (B-2) (360 mg, 64%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 359.0. [0381] To a solution of 8-chloro-4-(2-chloro-3-methoxy-6-methylphenyl)-[1,2,4]triazolo[1,5- a]1,6-naphthyridine (B-2) (360 mg, 1.01 mmol) in i-PrOH (5.0 mL) was added CH3NH2 (4.0 mL, 30% in EtOH) at room temperature. The resulting mixture was stirred at 85 °C for 16 h. The reaction mixture was cooled, 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 to afford 4-(2-chloro-3-methoxy-6- methylphenyl)-N-methyl-[1,2,4]triazolo[1,5-a]1,6-naphthyridin-8-amine (T-1) (160 mg, crude) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 354.1. [0382] To a solution of 4-(2-chloro-3-methoxy-6-methylphenyl)-N-methyl-[1,2,4]triazolo[1,5- a]1,6-naphthyridin-8-amine (T-1) (160 mg, crude) in CH2Cl2 (3.0 mL) was added BBr3 (0.6 mL, 1.0 mol/L in CH2Cl2) at 0 °C under N2. The resulting mixture was stirred at room temperature for 32 h. The resulting mixture 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. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B; Wavelength: 254/220 nm) to afford 2-chloro-4-methyl-3-(8- (methylamino)-[1,2,4]triazolo[1,5-a][1,6]naphthyridin-4-yl)phenol (Compound 20) (8 mg, 5%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 340.0.1H NMR (400 MHz, DMSO-d6): δ 10.04 - 9.91 (m, 2H), 8.72 (s, 1H), 7.47 (s, 1H), 7.33 - 7.26 (m, 1H), 7.16 - 7.11 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H), 2.92 (s, 3H), 1.96 (s, 3H). Example 21: Synthesis of 2,4-dimethyl-3-(8-(pyridin-2-ylamino)-[1,2,4]triazolo[4,3- a][1,6]naphthyridin-4-yl)phenol formate (Compound 21)
Figure imgf000156_0001
[0383] To a solution of 4-bromo-8-chloro-[1,2,4]triazolo[4,3-a]1,6-naphthyridine (B-1) (500 mg, 1.76 mmol) in t-amyl alcohol/H2O (20 mL/5 mL) was added 3-methoxy-2,6- dimethylphenylboronic acid (320 mg, 1.78 mmol), Pd(dppf)Cl2 (145 mg, 0.18 mmol) and KOH (300 mg, 5.35 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. The mixture was cooled, 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 chromatography to afford 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[4,3-a][1,6]naphthyridine (C-2) (180 mg, 30%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 339.1. [0384] To a solution of 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3- a][1,6]naphthyridine (C-2) (150 mg, 0.44 mmol) in 1,4 dioxane (10 mL) was added 2- aminopyridine (60 mg, 0.64 mmol), Cs2CO3 (450 mg, 1.38 mmol), XantPhos (60 mg, 0.10 mmol) and Pd2(dba)3 (45 mg, 0.05 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The mixture was cooled, 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 to afford 4-(3-methoxy-2,6-dimethylphenyl)-N- (pyridin-2-yl)-[1,2,4]triazolo[4,3-a][1,6]naphthyridin-8-amine (U-1) (200 mg, 79%) as a green solid. LCMS (ESI, m/z): [M+H]+ = 397.2. [0385] To a solution of 4-(3-methoxy-2,6-dimethylphenyl)-N-(pyridin-2-yl)-[1,2,4]triazolo[4,3- a][1,6]naphthyridin-8-amine (U-1) (160 mg, 0.40 mmol) in DCM (15 mL) was added BBr3 (3 mL, 1 mol/L in DCM) at 0 oC under N2. The resulting mixture was stirred at room temperature for 4 h. The pH of the mixture was adjusted to 8 with NaHCO3 (aq.) and 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 reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 5% B to 15% B in 10 min; 254 nm) to afford 2,4-dimethyl-3-(8-(pyridin-2-ylamino)-[1,2,4]triazolo[4,3-a][1,6]naphthyridin-4-yl)phenol formate (Compound 21) (21 mg, 12%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 383.1.1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.89 (s, 1H), 9.24 (s, 1H), 8.95 - 8.94 (m, 2H), 8.42 - 8.40 (m, 1H), 8.16 (s, 1H), 7.76 - 7.72 (m, 1H), 7.54 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.01 - 6.97 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 1.93 (s, 3H), 1.86 (s, 3H). Example 22: Synthesis of (1S,2S)-N-(4-(2-chloro-3-hydroxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a][1,6]naphthyridin-8-yl)-2-fluorocyclopropane-1-carboxamide (Compound 22)
Figure imgf000157_0001
[0386] To a stirred solution of 8-chloro-4-(2-chloro-3-methoxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a]1,6-naphthyridine (170 mg, 0.47 mmol) in dioxane (10 mL) was added (1S,2S)-2-fluorocyclopropane-1-carboxamide (102 mg, 0.99 mmol), Cs2CO3 (477 mg, 1.46 mmol), XantPhos (52 mg, 0.09 mmol) and Pd2(dba)3 (52 mg, 0.06 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The mixture was cooled, diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford (1S,2S)-N- [4-(2-chloro-3-methoxy-6-methylphenyl)-[1,2,4]triazolo[4,3-a]1,6-naphthyridin-8-yl]-2- fluorocyclopropane-1-carboxamide (V-1) (120 mg, 59%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 426.1. [0387] To a stirred solution of (1S,2S)-N-[4-(2-chloro-3-methoxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a]1,6-naphthyridin-8-yl]-2-fluorocyclopropane-1-carboxamide (V-1) (110 mg, 0.26 mmol) in CH2Cl2 (5 mL) was added BBr3 (2 mL, 1.0 mol/L in CH2Cl2) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 0.5 h under N2. The reaction mixture was quenched with H2O and then extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography and then further purified by Prep- HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B in 10 min; Wavelength: 254/220 nm) to afford (1S,2S)-N- (4-(2-chloro-3-hydroxy-6-methylphenyl)-[1,2,4]triazolo[4,3-a][1,6]naphthyridin-8-yl)-2- fluorocyclopropane-1-carboxamide (Compound 22) (5.5 mg, 5%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 412.1.1H NMR (400 MHz, DMSO-d6): δ 11.43 (s, 1H), 10.13 (s, 1H), 10.03 (s, 1H), 9.08 (s, 1H), 8.92 (s, 1H), 7.71 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.12 - 4.91 (m, 1H), 2.34 - 2.27 (m, 1H), 1.98 (s, 3H), 1.78 - 1.69 (m, 1H), 1.32 - 1.24 (m, 1H). Example 23: Synthesis of (1R,2R)-N-(4-(2-chloro-3-hydroxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a][1,6]naphthyridin-8-yl)-2-fluorocyclopropane-1-carboxamide (Compound 23)
Figure imgf000158_0001
[0388] Following the same procedure as in Example 22, but using (1R,2R)-2- fluorocyclopropane-1-carboxamide, (1R,2R)-N-(4-(2-chloro-3-hydroxy-6-methylphenyl)- [1,2,4]triazolo[4,3-a][1,6]naphthyridin-8-yl)-2-fluorocyclopropane-1-carboxamide (Compound 23) (6.4 mg) was prepared as a white solid. LCMS (ESI, m/z): [M+H]+ = 412.1.1H NMR (400 MHz, DMSO-d6): δ 11.43 (s, 1H), 10.05 - 9.95 (m, 2H), 9.08 (s, 1H), 8.92 (s, 1H), 7.71 (s, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.10 - 4.93 (m, 1H), 2.36 - 2.31 (m, 1H), 1.98 (s, 3H), 1.79 - 1.69 (m, 1H), 1.32 - 1.24 (m, 1H). Example 24: Synthesis of N-(4-(3-hydroxy-2,6-dimethylphenyl)-1-methyl-[1,2,4]triazolo[4,3- a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (Compound 24)
Figure imgf000159_0001
[0389] To a solution of 4-bromo-8-chloro-1-methyl-[1,2,4]triazolo[4,3-a][1,6]naphthyridine (X- 1) (500 mg, 1.76 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was added 3-methoxy-2,6- dimethylphenylboronic acid (350 mg, 1.94 mmol), Pd(PPh3)4 (180 mg, 0.16 mmol) and K2CO3 (750 mg, 5.43 mmol) at room temperature under N2. The reaction mixture was stirred at 100 °C for 16 h under N2. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 8-chloro- 4-(3-methoxy-2,6-dimethylphenyl)-1-methyl-[1,2,4]triazolo[4,3-a]1,6-naphthyridine (X-2) (450 mg, 72%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 353.1. [0390] To a solution of 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-1-methyl- [1,2,4]triazolo[4,3-a]1,6-naphthyridine (X-2) (200 mg, 0.57 mmol) in 1,4-dioxane (10.0 mL) was added cyclopropanecarboxamide (50 mg, 0.59 mmol), Cs2CO3 (560 mg, 1.72 mmol), BrettPhos (60 mg, 0.11 mmol) and BrettPhos Pd G3 (60 mg, 0.07 mmol) at room temperature under N2. The reaction mixture was stirred at 100 °C for 16 h under N2. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford N-(4-(3-methoxy-2,6-dimethylphenyl)-1-methyl- [1,2,4]triazolo[4,3-a][1,6]naphthyridin-8-yl)cyclopropanecarboxamide (X-3) (160 mg, 70%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 402.1. [0391] To a solution of N-[4-(3-methoxy-2,6-dimethylphenyl)-1-methyl-[1,2,4]triazolo[4,3- a]1,6-naphthyridin-8-yl]cyclopropanecarboxamide (X-3) (120 mg, 0.33 mmol) in CH2Cl2 (3 mL) was added BBr3 (1.2 mL, 1.0 mol/L in CH2Cl2) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with H2O at 0 °C and then 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. The residue was purified by flash column chromatography and then further purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B in 10 min; Wavelength: 254/220 nm) to afford N-(4-(3-hydroxy-2,6- dimethylphenyl)-1-methyl-[1,2,4]triazolo[4,3-a][1,6]naphthyridin-8- yl)cyclopropanecarboxamide (Compound 24) (18 mg, 30%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 388.1.1H NMR (400 MHz, DMSO-d6): δ 11.37 (s, 1H), 9.25 (s, 2H), 8.99 (s, 1H), 7.52 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.06 (s, 3H), 2.13 - 2.08 (m, 1H), 1.91 (s, 3H), 1.84 (s, 3H), 0.96 - 0.90 (m, 4H). Example 25: Synthesis of 2,4-dimethyl-3-(8-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-4-yl)phenol (Compound 25)
Figure imgf000160_0001
[0392] To a solution of 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]1,6- naphthyridine (C-2) (172 mg, 0.51 mmol) in dioxane (6 mL) was added 2-aminopyridine (154 mg, 1.64 mmol), BrettPhos (87 mg, 0.16 mmol), BrettPhos Pd G3 (51 mg, 0.06 mmol) and Cs2CO3 (700 mg, 2.15 mmol) at room temperature under N2. The mixture was stirred at 100 °C for 16 h under N2. The mixture was cooled, 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 to afford N-[4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a]1,6-naphthyridin-8-yl]pyridin-2-amine (Y-1) (194 mg, 96%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 397.2. [0393] To a solution of N-[4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]1,6- naphthyridin-8-yl]pyridin-2-amine (Y-1) (170 mg, 0.43 mmol) in DCM (4 mL) was added a solution of BBr3 in DCM (2 mL, 1 mol/L) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 0.5 h and then the pH of the mixture was adjusted to 8 with NaHCO3 (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 reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 9% B to 19% B in 10 min; Wavelength: 254/220 nm) to afford 2,4-dimethyl-3-(8-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-4-yl)phenol (Compound 25) (56 mg, 34%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 383.1.1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.40 - 9.11 (m, 3H), 8.59 (s, 1H), 8.41 (d, J = 4.0 Hz, 1H), 7.88 (s, 1H), 7.77 - 7.72 (m, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.00 - 6.97 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 1.98 - 1.90 (m, 6H). Example 26: Synthesis of N-(4-(3-hydroxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a][1,6]naphthyridin-8-yl)cyclobutanecarboxamide (Compound 26)
Figure imgf000161_0001
[0394] To a solution of 8-chloro-4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]1,6- naphthyridine (C-2) (270 mg, 0.80 mmol) in dioxane (25.0 mL) was added K2CO3 (387 mg, 2.80 mmol), cyclobutanecarboxamide (135 mg, 1.36 mmol), XPhos (144 mg, 0.30 mmol) and Pd2(dba)3 (95 mg, 0.10 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was cooled, 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. The residue was purified by flash column chromatography to afford N-[4-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a]1,6-naphthyridin-8-yl]cyclobutanecarboxamide (Z-1) (90 mg, 28%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 402.2. [0395] To a solution of N-[4-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]1,6- naphthyridin-8-yl]cyclobutanecarboxamide (Z-1) (100 mg, 0.25 mmol) in DCM (2.0 mL) was added a solution of BBr3 in DCM (2 mL, 1 mol/L) at 0 oC under N2. The resulting mixture was stirred at room temperature for 1 h and then the pH of the mixture was adjusted to 8 with NaHCO3 (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 reduced pressure. The residue 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: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 5% B in 2 min, 30% B to 40% B in 10 min; Wavelength: 254/220 nm) to afford N-(4-(3-hydroxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a][1,6]naphthyridin-8-yl)cyclobutanecarboxamide (Compound 26) (22 mg, 22%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 388.2.1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H), 9.30 (s, 1H), 9.17 (s, 1H), 9.12 (s, 1H), 8.64 (s, 1H), 7.95 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.53 - 3.45 (m, 1H), 2.35 - 2.25 (m, 2H), 2.21 - 2.13 (m, 2H), 2.08 - 1.94 (m, 1H), 1.90 - 1.86 (m, 4H), 1.81 (s, 3H). Example 27: Synthesis of 2,4-dimethyl-3-(8-(pyridin-2-ylamino)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4-yl)phenol (Compound 27)
Figure imgf000162_0001
[0396] To a solution of 4-(3-methoxy-2,6-dimethylphenyl)-8-(methylsulfonyl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidine (H-8) (120 mg, 0.31 mmol) in DMSO (5 mL) was added pyridin-2-amine (60 mg, 0.63 mmol) and t-BuOK (66 mg, 0.58 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 2 h under N2. 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 to afford 4-(3-methoxy-2,6-dimethylphenyl)-N-(pyridin-2-yl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-8-amine (AA-1) (80 mg, 64%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 398.1. [0397] To a stirred mixture of 4-(3-methoxy-2,6-dimethylphenyl)-N-(pyridin-2-yl)- [1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-8-amine (60 mg, 0.15 mmol) in DCM (2.0 mL) was added BBr3 (0.7 mL, 1 mol/L in DCM) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched with H2O at 0 °C. The pH of the mixture was adjusted to 8 with saturated NaHCO3 (aq). The resulting mixture was extracted with dichloromethane. 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 Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% NH3 .H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 60% B in 10 min; Wavelength: 254/220 nm) to afford 2,4-dimethyl-3-(8-(pyridin-2-ylamino)-[1,2,4]triazolo[1',5':1,6]pyrido[2,3-d]pyrimidin-4- yl)phenol (Compound 27) (3.4 mg, 5%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 384.1.1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 9.40 (s, 1H), 8.74 (d, J = 8.4 Hz, 1H), 8.65 (s, 1H), 8.40 (d, J = 3.6 Hz, 1H), 7.97 - 7.92 (m, 1H), 7.87 (s, 1H), 7.15 - 7.12 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 1.90 (s, 3H), 1.82 (s, 3H). Example 28: Synthesis of 4-chloro-2-methyl-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 28)
Figure imgf000163_0001
[0398] To a solution of 3-bromo-2-methylaniline (AB-1) (50.0 g, 268.83 mmol) in DMF (500 mL) was added NCS (36.0 g, 268.83 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 3 h. The reaction mixture was cooled, diluted with H2O, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 3-bromo-4-chloro-2-methylaniline (AB-2) (20.0 g, 34%) as a black solid. LCMS (ESI, m/z): [M+H]+ = 219.9. [0399] To a solution of 3-bromo-4-chloro-2-methylaniline (AB-2) (8.0 g, 36.36 mmol) in H2SO4 (64 mL, 1.0 mol/L) was added the solution of NaNO2 (4.2 g, 60.32 mmol) in H2O (9.6 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. H2SO4 (21 mL, 18.4 mol/L) was added to the mixture at 0 °C. The resulting mixture was stirred at 100 °C for additional 1 h. The reaction mixture was cooled, diluted with H2O, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 3-bromo-4-chloro-2-methylphenol (AB-3) (3.0 g, 37%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 220.9. [0400] To a solution of 3-bromo-4-chloro-2-methylphenol (3.0 g, 13.52 mmol) in CH2Cl2 (20.0 mL) was added imidazole (AB-3) (9.2 g, 135.32 mmol) and TBSCl (4.1 g, 27.12 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 3- bromo-4-chloro-2-methylphenoxy(tert-butyl)dimethylsilane (AB-4) (2.0 g, 44%) as a colorless oil. LCMS (ESI, m/z): [M+H]+ = 335.0. [0401] To a solution of 3-bromo-4-chloro-2-methylphenoxy(tert-butyl)dimethylsilane (AB-4) (2.0 g, 5.96 mmol) in dioxane (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (4.6 g, 18.11 mmol), KOAc (1.8 g, 18.35 mmol) and Pd(dppf)Cl2 (400 mg, 0.59 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was cooled, diluted with H2O, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford tert-butyl(4-chloro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenoxy)dimethylsilane (AB-5) (900 mg, 39%) as a brown solid. LCMS (ESI, m/z): [M+H]+ = 383.2. [0402] To a solution of tert-butyl(4-chloro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenoxy)dimethylsilane (AB-5) (900 mg, 2.35 mmol) in dioxane (10 mL)/H2O (2 mL) was added 6-bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (250 mg, 0.84 mmol), K2CO3 (1.17 g, 8.47 mmol) and PdAMPHOS (60 mg, 0.09 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was cooled, diluted with H2O, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 6- (3-((tert-butyldimethylsilyl)oxy)-6-chloro-2-methylphenyl)-2-(methylthio)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (AB-6) (120 mg, 9%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 472.1. [0403] To a solution of 6-(3-((tert-butyldimethylsilyl)oxy)-6-chloro-2-methylphenyl)-2- (methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (AB-6) (120 mg, 0.25 mmol) in CH2Cl2 (5 mL) was added m-CPBA (175.4 mg, 1.02 mmol) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 2 h. The mixture was concentrated under reduced pressure to afford 6-(3-((tert- butyldimethylsilyl)oxy)-6-chloro-2-methylphenyl)-2-(methylsulfonyl)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (AB-7) (300 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 504.1. [0404] A mixture of 6-(3-((tert-butyldimethylsilyl)oxy)-6-chloro-2-methylphenyl)-2- (methylsulfonyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (AB-7) (300 mg) in methanamine (5 mL, 2.0 mol/L in THF) was stirred at 80 ℃ for 2 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by flash column chromatography and then further purified by Prep-HPLC with the following conditions: (Column: XBridge Prep Phenyl OBD Column 19ⅹ250 mm, 5 um; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MEOH; Flow rate: 20 mL/min; Gradient: 56% B to 62% B in 10 min; Wavelength: 254/220 nm) to afford 4-chloro-2-methyl-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 28) (28 mg, 13%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 341.0.1H NMR (400 MHz, DMSO-d6): δ 9.82 (s, 1H), 9.72 - 9.46 (m, 1H), 9.08 - 9.00 (m, 1H), 8.22 - 8.11 (m, 1H), 7.50 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 3.03 - 2.98 (m, 3H), 1.88 (s, 3H). Example 29: Synthesis of 2-chloro-3-(2-((2-(dimethylamino)ethyl)amino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenol (Compound 29)
Figure imgf000165_0001
[0405] To a solution of 6-(2-chloro-3-methoxy-6-methylphenyl)-2-(methylsulfonyl)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (L-3) (70 mg, 0.22 mmol) in THF (2 mL) was added (2-aminoethyl)dimethylamine (70 mg, 0.79 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 2 h. The mixture was cooled and concentrated under vacuum. The residue was purified by flash column chromatography to afford N1-(6-(2-chloro-3-methoxy- 6-methylphenyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-yl)-N2,N2-dimethylethane- 1,2-diamine (AC-1) (50 mg, 70%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 412.2. [0406] To a solution of N1-(6-(2-chloro-3-methoxy-6-methylphenyl)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-yl)-N2,N2-dimethylethane-1,2-diamine (AC-1) (45 mg, 0.11 mmol) in CH2Cl2 (2 mL) was added BBr3 (0.6 mL, 1.0 mol/L in CH2Cl2) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 2 h under N2. The mixture was quenched with water and then concentrated under vacuum. The residue was purified by flash column chromatography and then further purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 25% B in 10 min; Wavelength: 254/220 nm) to afford 2-chloro-3-(2-((2-(dimethylamino)ethyl)amino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)-4-methylphenol (Compound 29) (4.3 mg, 9%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 398.1.1H NMR (400 MHz, CD3OD): δ 9.76 - 9.61 (m, 1H), 9.09 - 8.98 (m, 1H), 7.53 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 3.82 - 3.77 (m, 2H), 2.81 - 2.77 (m, 2H), 2.46 (s, 6H), 2.07 (s, 3H). Example 30: Synthesis of 2-chloro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidin-6-yl)phenol (Compound 30)
Figure imgf000166_0001
[0407] 2-Chloro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 30) was prepared by the procedure described in Example 18 using (2-chloro-3- methoxyphenyl)boronic acid in place of (2,6-dichloro-3-methoxyphenyl)boronic acid in Step 1. LCMS (ESI, m/z): [M+H]+ = 327.0.1H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 9.71 - 9.45 (m, 1H), 9.10 - 9.01 (m, 1H), 8.23 - 8.10 (m, 1H), 7.61 (s, 1H), 7.27 - 7.23 (m, 1H), 7.10 - 7.08 (m, 1H), 6.99 (d, J = 7.2 Hz, 1H), 3.02 - 2.96 (m, 3H). Example 31: Synthesis of 2-chloro-4-fluoro-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 31)
Figure imgf000166_0002
[0408] 2-Chloro-4-fluoro-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6- yl)phenol (Compound 31) was prepared by the procedure described in Example 18 using (2- chloro-6-fluoro-3-methoxyphenyl)boronic acid in place of (2,6-dichloro-3- methoxyphenyl)boronic acid in Step 1. LCMS (ESI, m/z): [M+H]+ = 345.0.1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.73 - 9.46 (m, 1H), 9.10 - 9.01 (m, 1H), 8.30 - 8.18 (m, 1H), 7.69 (s, 1H), 7.24 - 7.20 (m, 1H), 7.14 - 7.10 (m, 1H), 3.03 - 2.97 (m, 3H). Example 32: Synthesis of 2-fluoro-4-methyl-3-(2-(methylamino)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 32)
Figure imgf000167_0001
[0409] To a stirred solution of 3-bromo-2-fluorophenol (AF-1) (25.0 g, 130.89 mmol) in DMF (500 mL) was added K2CO3 (54.3 g, 392.67 mmol) and CH3I (22.3 g, 157.07 mmol) at room temperature. The mixture was stirred at room temperature 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 Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 1-bromo-2-fluoro-3-methoxybenzene (AF-2) (21.0 g, 78%) as a colorless oil. [0410] To a solution of 1-bromo-2-fluoro-3-methoxybenzene (AF-2) (8.0 g, 39.02 mmol) in HOAc (30.0 mL) was added POM (1.2 g, 39.97 mmol) and HBr (10 mL, 33% in HOAc) at room temperature. The resulting mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with hexane and the pH of the mixture was adjusted to 7.0 with Na2CO3 (aq). The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 2-bromo-1-(bromomethyl)-3- fluoro-4-methoxybenzene (AF-3) (6.0 g, 51%) as a white solid. [0411] To a solution of 2-bromo-1-(bromomethyl)-3-fluoro-4-methoxybenzene (AF-3) (6.0 g, 20.14 mmol) in THF/MeOH (100 mL/20 mL) was added CaCO3 (10.0 g, 99.91 mmol) and NaBH4 (8.0 g, 211.47 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 2-bromo-3-fluoro-4-methoxy-1-methylbenzene (AF-4) (2.0 g, 45%) as a yellow oil. [0412] To a solution of 2-bromo-3-fluoro-4-methoxy-1-methylbenzene (2.0 g, 9.13 mmol) in 1,4-dioxane (AF-4) (20 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.6 g, 18.12 mmol), K2CO3 (3.8 g, 27.50 mmol) and Pd(dppf)Cl2 (668 mg, 0.91 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled, diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 2- (2-fluoro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (AF-5) (1.0 g, 41%) as a yellow oil. LCMS (ESI, m/z): [M+H]+ = 267.1. [0413] To a stirred solution of 2-(2-fluoro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (AF-5) (1.0 g, 3.75 mmol) in dioxane/H2O (30 mL/6 mL) was added 6- bromo-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (1.1 g, 3.72 mmol), K2CO3 (1.6 g, 11.57 mmol), and PdAMphos (0.2 g, 0.41 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. The reaction mixture was cooled, diluted with H2O, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 6-(2- fluoro-3-methoxy-6-methylphenyl)-2-(methylthio)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3- d]pyrimidine (AF-6) (400 mg, 29%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 356.1. [0414] To a stirred solution of 6-(2-fluoro-3-methoxy-6-methylphenyl)-2-(methylthio)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (AF-6) (380 mg, 1.06 mmol) in CH2Cl2 (5.0 mL) was added m-CPBA (911 mg, 5.27 mmol) at 0 ℃. The resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 6-(2-fluoro-3-methoxy-6-methylphenyl)-2- (methylsulfonyl)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (AF-7) (320 mg, 77%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 388.1. [0415] A solution of 6-(2-fluoro-3-methoxy-6-methylphenyl)-2-(methylsulfonyl)- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidine (AF-7) (300 mg, 0.77 mmol) in CH3NH2 (5 mL, 1 mol/L in THF) was stirred at 80 ℃ for 2 h. The reaction mixture was cooled and concentrated under reduced pressure to afford 6-(2-fluoro-3-methoxy-6-methylphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (AF-8) (320 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 339.1. [0416] To a stirred solution of 6-(2-fluoro-3-methoxy-6-methylphenyl)-N-methyl- [1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-2-amine (AF-8) (130 mg) in CH2Cl2 (5 mL) was added BBr3 (2.5 mL, 1.0 mol/L in CH2Cl2) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with H2O and then 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. The residue was purified by flash column chromatography and then further purified by Prep- HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 35% B in 10 min; Wavelength: 254/220 nm) to afford 2-fluoro-4- methyl-3-(2-(methylamino)-[1,2,4]triazolo[4',3':1,6]pyrido[2,3-d]pyrimidin-6-yl)phenol (Compound 32) (6.3 mg, 5%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 325.1.1H NMR (400 MHz, DMSO-d6): δ 9.72 - 9.45 (m, 2H), 9.07 - 8.99 (m, 1H), 8.22 - 8.13 (m, 1H), 7.59 (s, 1H), 6.99 - 6.94 (m, 2H), 3.03 - 2.98 (m, 3H), 2.01 (s, 3H). Example 33: Synthesis of N-(5-(3-hydroxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3- f]quinoxalin-9-yl)cyclobutanecarboxamide (Compound 33)
Figure imgf000169_0001
[0417] To a solution of 5-bromo-9-chloro-2,3-dimethylpyrido[4,3-f]quinoxaline (J-1) (180 mg, 0.56 mmol) in dioxane/H2O (5.0 mL/1.0 mL) was added (3-methoxy-2,6-dimethylphenyl)boronic acid (150 mg, 0.83 mmol), Pd(dppf)Cl2 (81.0 mg, 0.11 mmol) and K2CO3 (231 mg, 1.67 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was cooled, 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 to afford 9-chloro-5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3- f]quinoxaline (J-3) (40 mg, 18%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 378.1. [0418] To a solution of 9-chloro-5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3- f]quinoxaline (J-3) (40 mg, 0.11 mmol) in dioxane (5 mL) was added cyclobutanecarboxamide (64 mg, 0.65 mmol), XantPhos (24.0 mg, 0.04 mmol), Pd2(dba)3 (20 mg, 0.02 mmol) and K2CO3 (44 mg, 0.32 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was cooled, 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 to afford N-(5-(3-methoxy-2,6-dimethylphenyl)-2,3- dimethylpyrido[4,3-f]quinoxalin-9-yl)cyclobutanecarboxamide (AG-1) (40 mg, 85%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 441.2. [0419] To a solution of N-(5-(3-methoxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3- f]quinoxalin-9-yl)cyclobutanecarboxamide (AG-1) (40 mg, 0.09 mmol) in DCM (4 mL) was added BBr3 (2 mL, 1 mol/L in DCM) at room temperature. The resulting mixture was stirred at room temperature for 3 h and then the pH was adjusted to 8 with NaHCO3 (aq). The mixture was 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 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: ACN; Flow rate: 60 mL/min; Gradient: 45% B to 55% B in 10 min; Wavelength: 254 nm) to afford N-(5-(3- hydroxy-2,6-dimethylphenyl)-2,3-dimethylpyrido[4,3-f]quinoxalin-9-yl)cyclobutanecarboxamide (Compound 33) (15 mg, 37%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 427.3.1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 9.65 (s, 1H), 9.18 - 9.14 (m, 2H), 7.88 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 3.53 - 3.45 (m, 1H), 2.81 (s, 3H), 2.68 (s, 3H), 2.37 - 2.27 (m, 2H), 2.20 - 2.16 (m, 2H), 2.04 - 1.91 (m, 1H), 1.88 - 1.84 (m, 1H), 1.76 (s, 3H), 1.70 (s, 3H). Example 34: Synthesis of N-[5-(3-hydroxy-2,6-dimethylphenyl)pyrido[4,3-f]quinoxalin-9- yl]cyclopropanecarboxamide (Compound 34)
Figure imgf000171_0001
[0420] To a solution of 7-bromo-3-chloroisoquinoline-5,6-diamine (AH-1) (450 mg, 1.65 mmol) in EtOH (10 mL) was added glyoxal (4.5 g, 77.54 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by flash column chromatography to afford 5-bromo-9-chloropyrido[4,3-f]quinoxaline (AH-2) (170 mg, 34%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 293.9. [0421] To a solution of 5-bromo-9-chloropyrido[4,3-f]quinoxaline (AH-2) (130 mg, 0.44 mmol) in dioxane (8 mL) and H2O (2 mL) was added 3-methoxy-2,6-dimethylphenylboronic acid (95 mg, 0.53 mmol), K2CO3 (290 mg, 2.09 mmol) and Pd(dppf)Cl2 (50 mg, 0.09 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column to afford 9-chloro-5-(3-methoxy-2,6- dimethylphenyl)pyrido[4,3-f]quinoxaline (AH-3) (57 mg, 36%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 350.1. [0422] To a mixture of 9-chloro-5-(3-methoxy-2,6-dimethylphenyl)pyrido[4,3-f]quinoxaline (AH-3) (360 mg, 1.02 mmol) and cyclopropanecarboxamide (120 mg, 1.44 mmol) in dioxane (8 mL) was added Cs2CO3 (1.8 g, 5.52 mmol), Pd(OAc)2 (50 mg, 0.22 mmol) and XPhos (202 mg, 0.44 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column to afford N-[5-(3-methoxy-2,6- dimethylphenyl)pyrido[4,3-f]quinoxalin-9-yl]cyclopropanecarboxamide (AH-4) (160 mg, 40%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 399.2. [0423] To a solution of N-[5-(3-methoxy-2,6-dimethylphenyl)pyrido[4,3-f]quinoxalin-9- yl]cyclopropanecarboxamide (AH-4) (155 mg, 0.39 mmol) in DCM (3.0 mL) was added BBr3 (1.2 mL, 1.0 mol/L in CH2Cl2) at 0 °C under N2. The resulting mixture was stirred at room temperature for 24 h. The reaction mixture 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. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (0.05% NH3 H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: isocratic 35% B to 50% B in 10 min; Wavelength: 254/220 nm) to afford N-[5-(3- hydroxy-2,6-dimethylphenyl)pyrido[4,3-f]quinoxalin-9-yl]cyclopropanecarboxamide (Compound 34) (6.2 mg, 11%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ = 385.2.1H NMR (400 MHz, DMSO-d6): δ 11.19 (s, 1H), 9.68 (s, 1H), 9.26 (s, 1H), 9.15 - 9.02 (m, 3H), 8.04 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 2.14 - 2.12 (m, 1H), 1.76 (s, 3H), 1.69 (s, 3H), 0.93 - 0.86 (m, 4H). Example 35: Synthesis of 8-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-1H- pyrrolo[3,4-f]isoquinolin-3-one (Compound 35)
Figure imgf000172_0001
[0424] To a solution of 4-bromo-2-fluoro-6-methylbenzoic acid (AI-1) (30.0 g, 128.74 mmol) in DMSO (300 mL) was added NaOCH3 (20.9 g, 386.86 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 16 h. The mixture was cooled to room temperature and diluted with water. The pH value of the mixture was adjusted to 2 with 2 M HCl at 0 °C. The resulting mixture was filtered. The solid was washed with water and then collected to afford 4-bromo-2- methoxy-6-methylbenzoic acid (AI-2) (28.0 g, 89%) as an off-white solid. LCMS (ESI, m/z): [M+H]+ = 245.0. [0425] To a solution of 4-bromo-2-methoxy-6-methylbenzoic acid (AI-2) (28.0 g, crude) in DMF (300 mL) was added K2CO3 (23.5 g, 170.04 mmol) and CH3I (16.7 g, 117.66 mmol) at room temperature. The resulting mixture was stirred at room temperature for 4 h. The 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 vacuum. The residue was purified by flash column chromatography to afford methyl 4-bromo-2- methoxy-6-methylbenzoate (AI-3) (29.2 g, 98%) as a white solid. LCMS (ESI, m/z): [M+H]+ = 259.0. [0426] To a solution of methyl 4-bromo-2-methoxy-6-methylbenzoate (AI-3) (29.2 g, 111.93 mmol) in CCl4 (300 mL) was added NBS (21.1 g, 118.64 mmol) and BPO (621 mg, 2.42 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 16 h under N2. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to afford methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate (AI-4) (35.0 g) as a white solid. LCMS (ESI, m/z): [M+H]+ = 337.0. [0427] To a solution of methyl 4-bromo-2-(bromomethyl)-6-methoxybenzoate (AI-4) (25.0 g, crude) in ACN (300 mL) was added methylamine hydrochloride (25.0 g, 373.14 mmol) and DIEA (95.4 g, 739.64 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. The mixture was cooled to room temperature and then diluted with water. 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 vacuum. The residue was purified by flash column chromatography to afford 5-bromo-7-methoxy-2- methyl-3H-isoindol-1-one (AI-5) (18.0 g, 95%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 256.0. [0428] To a solution of 5-bromo-7-methoxy-2-methyl-3H-isoindol-1-one (AI-5) (18.0 g, 70.28 mmol) in THF (100 mL) and H2O (100 mL) was added Zn(CN)2 (5.1 g, 43.4 mmol) and t- BuXPhos Pd G3 (2.8 g, 3.50 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under N2. The mixture was cooled to room temperature and then concentrated under vacuum. The residue was purified by flash column chromatography to afford 7-methoxy-2- methyl-1-oxo-3H-isoindole-5-carbonitrile (AI-6) (13.0 g, 91%) as a light yellow solid. LCMS (ESI, m/z): [M+H]+ = 203.1. [0429] To a solution of 7-methoxy-2-methyl-1-oxo-3H-isoindole-5-carbonitrile (AI-6) (13.0 g, 64.29 mmol) in NH3 (g)/MeOH (150 mL, 7 mol/L) was added Raney-Ni (7.0 g, dispersed in H2O) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under H2. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography to afford 5-(aminomethyl)-7-methoxy-2-methyl- 3H-isoindol-1-one (AI-7) (10.0 g, 75%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 207.1. [0430] To a solution of 5-(aminomethyl)-7-methoxy-2-methyl-3H-isoindol-1-one (AI-7) (5.0 g, 24.27 mmol) in methanol (50 mL) was added methyl 2,2-diethoxyethanimidate (4.2 g, 26.21 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 2 h. The mixture was cooled to room temperature and then concentrated under vacuum to afford 2,2-diethoxy-N-[(7- methoxy-2-methyl-1-oxo-3H-isoindol-5-yl)methyl]ethanimidamide (AI-8) (6.0 g) as an off-white solid. LCMS (ESI, m/z): [M+H]+ = 336.2. [0431] To solution of 2,2-diethoxy-N-[(7-methoxy-2-methyl-1-oxo-3H-isoindol-5- yl)methyl]ethanimidamide (AI-8) (6.0 g) in concentrated H2SO4 (30 mL) was stirred at 50 °C for 16 h. The mixture was poured into ice water and then filtered. The solid was washed with water and then collected to afford 8-amino-4-methoxy-2-methyl-1H-pyrrolo[3,4-f]isoquinolin-3-one (AI-9) (8.0 g) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 244.2. [0432] To a solution of 8-amino-4-methoxy-2-methyl-1H-pyrrolo[3,4-f]isoquinolin-3-one (AI-9) (3.0 g) in pyridine (30 mL) was added acetic anhydride (5.4 g, 52.89 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The mixture was diluted with water and then filtered. The solids were washed with water and then collected to afford N-(4-methoxy- 2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-8-yl)acetamide hydrobromide (AI-10) (1.2 g, 34%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 286.1. [0433] To a solution of N-(4-methoxy-2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4- f]isoquinolin-8-yl)acetamide hydrobromide (AI-10) (1.2 g, 4.21 mmol) in DCM (20 mL) was added BBr3 (9.0 mL, 1 mol/L in DCM) at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 h under N2. The reaction mixture was quenched with MeOH at 0 °C and concentrated under vacuum. The residue was purified by flash column chromatography to afford N-(4-hydroxy-2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-8-yl)acetamide (AI-11) (900 mg, 79%) as an orange solid. LCMS (ESI, m/z): [M+H]+ = 272.1. [0434] To a solution of N-(4-hydroxy-2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin- 8-yl)acetamide (AI-11) (300 mg, 1.11 mmol) in CH2Cl2 (15.0 mL) was added TEA (1.1 g, 10.97 mmol) and triflic anhydride (1.6 g, 5.53 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h. The mixture was diluted with water and extracted with CH2Cl2. The 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 to afford 8-acetamido-2-methyl-3-oxo-1H-pyrrolo[3,4-f]isoquinolin-4-yl trifluoromethanesulfonate (AI-12) (410 mg, 92%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 404.0. [0435] To a solution of 8-acetamido-2-methyl-3-oxo-1H-pyrrolo[3,4-f]isoquinolin-4-yl trifluoromethanesulfonate (AI-12) (200 mg, 0.50 mmol) in dioxane (10 mL) and H2O (2 mL) was added 3-methoxy-2,6-dimethylphenylboronic acid (178 mg, 0.90 mmol), Pd(dppf)Cl2 (78 mg, 0.11 mmol) and K2CO3 (212 mg, 1.53 mmol) at room temperature under N2. The resulting mixture was stirred at 70 °C for 16 h under N2. The reaction mixture was cooled to room temperature, 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 vacuum. The residue was purified by flash column chromatography to afford N-[4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-3-oxo-1H-pyrrolo[3,4-f]isoquinolin-8- yl]acetamide (AI-13) (140 mg, 72%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 390.2. [0436] To solution of N-[4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-3-oxo-1H-pyrrolo[3,4- f]isoquinolin-8-yl]acetamide (AI-13) (110 mg, 0.28 mmol) in HBr (2.0 mL, 40% in H2O) was stirred at 50 °C for 2 h. The mixture was concentrated under vacuum to afford 8-amino-4-(3- methoxy-2,6-dimethylphenyl)-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-f]isoquinolin-3-one hydrobromide (AI-14) (100 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 348.2. [0437] To a solution of 8-amino-4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-1,2-dihydro-3H- pyrrolo[3,4-f]isoquinolin-3-one hydrobromide (AI-14) (100 mg) in DCM (2 mL) was added BBr3 (1.2 mL, 1 mol/L in DCM) at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with methanol at room temperature and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: isocratic 20% B to 35% B in 10 min; Wavelength: 254/220 nm) to afford 8-amino-4-(3-hydroxy-2,6-dimethylphenyl)-2-methyl-1H- pyrrolo[3,4-f]isoquinolin-3-one (Compound 35) (26 mg, 27%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 334.2.1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.93 (s, 1H), 7.45 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 6.24 (s, 2H), 4.68 (s, 2H), 3.04 (s, 3H), 1.77 (s, 3H), 1.70 (s, 3H). Example 36: Synthesis of N-(4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-3-oxo-2,3- dihydro-1H-pyrrolo[3,4-f]isoquinolin-8-yl)cyclopropanecarboxamide (Compound 36)
Figure imgf000176_0001
[0438] A solution of N-(4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-f]isoquinolin-8-yl)acetamide (AI-14) (110 mg, 0.28 mmol) in HBr (2.0 mL, 40% in water) was stirred at 50 °C for 1 h. The resulting mixture was cooled to room temperature and then concentrated under vacuum to afford 8-amino-4-(3-methoxy-2,6-dimethylphenyl)-2-methyl- 1,2-dihydro-3H-pyrrolo[3,4-f]isoquinolin-3-one hydrobromide (AJ-1) (81 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 348.2. [0439] To a solution of 8-amino-4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-1,2-dihydro-3H- pyrrolo[3,4-f]isoquinolin-3-one hydrobromide (AJ-1) (71 mg) in pyridine (3 mL) was added cyclopropanecarbonyl chloride (42.5 mg, 0.41 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h under N2. The 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 vacuum. The residue was purified by flash column chromatography to afford N-(4-(3-methoxy-2,6-dimethylphenyl)-2-methyl-3-oxo- 2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-8-yl)cyclopropanecarboxamide (Compound 36) (73 mg, 85%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 416.2. Example 37: Synthesis of N-(4-(2-chloro-3-hydroxy-6-methylphenyl)-2-methyl-3-oxo-2,3- dihydro-1H-pyrrolo[3,4-f]isoquinolin-8-yl)cyclopropanecarboxamide (Compound 37)
Figure imgf000176_0002
[0440] To a solution of 8-amino-4-methoxy-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-f]isoquinolin- 3-one (AI-9) (2.0 g, 8.22 mmol) in pyridine (25 mL) was added cyclopropanecarbonyl chloride (4.0 g, 38.23 mmol) at 0 °C under N2. The resulting mixture was stirred at 40 °C for 8 h under N2. The mixture was cooled to room temperature, diluted with H2O, and filtered. The solid was washed with H2O and then collected to afford N-(4-methoxy-2-methyl-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-f]isoquinolin-8-yl)cyclopropanecarboxamide (AK-1) (800 mg) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 312.1. [0441] To a solution of N-(4-methoxy-2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4- f]isoquinolin-8-yl)cyclopropanecarboxamide (AK-1) (650 mg) in DCM (20 mL) was added BBr3 (4.2 mL, 1.0 mol/L in DCM) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h under N2. The reaction mixture was quenched with CH3OH and concentrated under vacuum. The residue was purified by flash column chromatography and then further purified by reverse phase flash column chromatography to afford N-(4-hydroxy-2-methyl-3-oxo- 2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-8-yl)cyclopropanecarboxamide (AK-2) (300 mg, 48%) as a light brown solid. LCMS (ESI, m/z): [M+H]+ = 298.1. [0442] To a solution of N-(4-hydroxy-2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin- 8-yl)cyclopropanecarboxamide (AK-2) (270 mg, 0.91 mmol) in DCM (8.0 mL) was added pyridine (718 mg, 9.08 mmol) and triflic anhydride (768 mg, 2.72 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h under N2. The reaction mixture was diluted with water and then 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 to afford 8-(cyclopropanecarboxamido)-2- methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-4-yl trifluoromethanesulfonate (AK-3) (250 mg, 64%) as a yellow solid. LCMS (ESI, m/z): [M+H]+ = 430.1. [0443] To a mixture of 8-(cyclopropanecarboxamido)-2-methyl-3-oxo-2,3-dihydro-1H- pyrrolo[3,4-f]isoquinolin-4-yl trifluoromethanesulfonate (AK-3) (90 mg, 0.21 mmol) and 2-(2- chloro-3-methoxy-6-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (90 mg, 0.32 mmol) in dioxane (10 mL) and H2O (2 mL) was added CPhos (38 mg, 0.09 mmol), CPhos Pd G3 (37 mg, 0.04 mmol) and K2CO3 (90 mg, 0.65 mmol) at room temperature under N2. The resulting mixture was stirred at 65 °C for 2 h under N2. The mixture was then cooled to room temperature and diluted with H2O. 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 vacuum. The residue was purified by flash column chromatography to afford N-(4-(2-chloro-3-methoxy-6-methylphenyl)-2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4- f]isoquinolin-8-yl)cyclopropanecarboxamide (AK-4) (40 mg, 43%) as a yellow solid. LCMS (ESI, m/z): [M+H]+= 436.1. [0444] To a solution of N-(4-(2-chloro-3-methoxy-6-methylphenyl)-2-methyl-3-oxo-2,3- dihydro-1H-pyrrolo[3,4-f]isoquinolin-8-yl)cyclopropanecarboxamide (AK-4) (35 mg, 0.08 mmol) in DCM (4 mL) was added a solution of BBr3 (0.2 mL, 1.0 mol/L in DCM) at 0 °C under N2. The resulting mixture was stirred at room temperature for 3 h under N2. The reaction mixture was quenched with CH3OH and concentrated under vacuum. The residue was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 40% B in 10 min; Wavelength: 254/220 nm) to afford N-(4-(2-chloro-3- hydroxy-6-methylphenyl)-2-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-8- yl)cyclopropanecarboxamide (Compound 37) (12 mg, 34%) as an off-white solid. LCMS (ESI, m/z): [M+H]+ = 422.1.1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 9.84 (s, 1H), 9.29 (s, 1H), 8.55 (s, 1H), 7.81 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.88 - 4.77 (m, 2H), 3.06 (s, 3H), 2.12 - 2.08 (m, 1H), 1.83 (s, 3H), 0.90 - 0.84 (m, 4H). Example 38: Cell Viability Assays [0445] Cell viability was measured in the following MAPK pathway mutant cancer cell lines: A375 (BRAF V600E), HepG2 (NRAS Q61L), SK-MEL-30 (NRAS Q61K), and OCI-AML-2 (MBNL1-CRAF fusion). Cell viability was also measured in K562 cells. [0446] A375, HepG2, SK-MEL-30 and OCI-AML-2 cells were grown in the appropriate growth medium and harvested at 50-80% confluence. Cells were counted and seeded at their appropriate density 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 1). [0447] Table 1 provides the growth media, number of cells seeded per well and drug treatment times for each cell line. Table 1
Figure imgf000178_0001
Figure imgf000179_0001
[0448] K562 cells, cultured in Iscove's Modified Dulbecco's Media (IMDM) supplemented with 10% FBS, were harvested at 50-80% confluency and plated at 2,000 cells per well in 384-well tissue culture plates. [0449] 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 µM to 0.51 nM, using three-fold dilutions. The final proportion of DMSO never exceeded 0.1%. [0450] Plates were placed in a 37℃, 5% CO2 incubator for the indicated treatment times (Table 1). Plates were then removed from the incubator and equilibrated for 15 minutes at room temperature.40 µl of CellTiter Glo 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 (LumSample – LumLC) / (LumHC – LumLC). IC50 values were calculated using XLFit software or Prism (GraphPad Software), as shown in Table 2 below (NT = not tested). Graphical curves were fitted using a nonlinear regression model with a sigmoidal dose response. Table 2
Figure imgf000179_0002
Figure imgf000180_0001
Example 39: Detection of phosphorylated ERK (pERK) [0451] A375 cells were counted and seeded at 10,000 cells/well in 384 well plates (Corning 3764) and allowed to adhere overnight. [0452] Compounds were dissolved and serially diluted in DMSO. The compounds were then added, mixed, and incubated for four hours at 37℃, 5% CO2. Compounds were added using four-fold dilutions at final concentrations ranging from 10 µM to 0.01 nM. DMSO only and 10 µM staurosporine were added as high and low controls. [0453] 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 1X AlphaLISA SureFire Assay Kit (AlphaLISA SureFire Ultra pERK ½ (Thr202/Tyr204) ALSU-PERK-A50K) lysis buffer with protease and phosphatase inhibitors. Cells were lysed by adding 10uL to all the wells and mixed for 40 minutes on a plate shaker.10uL cell lysate was transferred to a new Optiplate (PerkinElmer 6007290) and incubated with 5uL 1X acceptor mix for 2 hours in the dark.5uL of 1X donor mix was added to all wells and mixed by shaking followed by overnight incubation in the dark. [0454] 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) were 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 + 10^((LogIC50 - X)*HillSlope)). The IC50 values are shown in Table 3 below (NT = not tested). Table 3
Figure imgf000181_0001
[0455] 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. [0456] 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: 1. A compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000183_0001
wherein: J is C(R3) or N; J1 is N and J2 is C, or J1 is C and J2 is N; X, Y and Z are each independently C(R7), C(O), C(R7a)(R7b), N(R7c), or N, wherein at least one of X, Y and Z is C(R7), C(O), or C(R7a)(R7b); X1 and Z1 are each independently C(R7), C(O), C(R7a)(R7b), N(R7c), N, O, or S; Y1 is C(R7), C(R7a)(R7b), N(R7c), or N; R1 is selected from hydrogen, -C(O)R1a, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2- 6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R1a is selected from C1-6alkyl, C1-6deuteroalkyl, -N(H)R10, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups; R2 is hydrogen; R3, R4, and R5 are independently selected from hydrogen and halogen; each R6 is independently selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6- 10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R7 is independently selected from hydrogen, halogen, -CN, -OR10, -SR10, -SF5, - N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8d groups; each R7a and R7b is each independently selected from hydrogen, halogen, -CN, -OR10, -SR10, - SF5, -N(R10)(R11), C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; R7c is selected from hydrogen, C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C1-6deuteroalkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8e groups; each R8c, R8d, and R8e is each independently selected from halogen, oxo, -CN, C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -SF5, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), - N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, - OC(O)R13, -C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(O)2N(R10)(R11)-, -S(=O)(=NH)N(R10)(R11), -C(=NOR11)R13, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR10, and -N(R10)(R11); each R10 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- 6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; or R10 and R11 taken together with the nitrogen atom to which they are attached independently form a 4-to-7-membered heterocyclic ring, wherein the heterocyclic ring optionally contains an additional 1-2 heteroatoms selected from the group consisting of N, O, and S, and wherein each heterocyclic nitrogen atom, if present, is independently optionally substituted with C1-C3 alkyl, C3-C6 cycloalkyl, C2-C3 haloalkyl, C2-C3 alkylene-CN, or C2-C3 heteroalkyl; each R12 is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl C2-6heteroalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl; each R13 is independently selected C1-6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C2-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, SF5, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1- 6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; n is 0, 1, 2, 3, or 4; and indicates a single or double bond such that all valences are satisfied.
2. The compound of claim 1 having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000186_0001
Formula (I).
3. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):
Figure imgf000186_0002
Formula (Ia).
4. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ib):
Figure imgf000186_0003
Formula (Ib).
5. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ic):
Figure imgf000186_0004
Formula (Ic).
6. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Id):
Figure imgf000187_0001
Formula (Id).
7. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ie):
Figure imgf000187_0002
Formula (Ie).
8. The compound of claim 1 having the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000187_0003
Formula (II).
9. The compound of claim 8 having the structure of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000187_0004
Formula (IIa).
10. The compound of claim 8 having the structure of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000188_0001
Formula (IIb).
11. The compound of claim 8 having the structure of Formula (IIc), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000188_0002
Formula (IIc).
12. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R7a and R7b are each independently hydrogen or C1-6alkyl optionally substituted with 1-5 R8e groups.
13. The compound of claim 11 or claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R7a and R7b are hydrogen.
14. The compound of any one of claims 8-13, or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is C1-6alkyl optionally substituted with 1-5 R8e groups.
15. The compound of any one of claims 8-14, or a pharmaceutically acceptable salt or solvate thereof, wherein R7c is unsubstituted C1-6alkyl.
16. The compound of claim 8 having the structure of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000188_0003
Formula (IId).
17. The compound of claim 1 having the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000189_0001
Formula (III).
18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and C1- 6alkyl optionally substituted with 1-5 R8d groups.
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is independently selected from hydrogen, halogen, -CN, and unsubstituted C1-6alkyl.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is hydrogen.
21. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein each R7 is unsubstituted C1-6alkyl.
22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(O)R1a.
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is selected from C1-6alkyl, -N(H)R10, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-7cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with 1-5 R8c groups.
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is selected from C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C3-7cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with 1-5 R8c groups.
25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is C3-7cycloalkyl optionally substituted with 1-5 R8c groups.
26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is cyclopropyl optionally substituted with 1-5 R8c groups.
27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8c is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, and -CH2-C2-9heterocycloalkyl.
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8c is independently selected from halogen.
29. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein R1a is selected from:
Figure imgf000190_0001
30. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein
Figure imgf000190_0002
.
31. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C1-6alkyl optionally substituted with 1-5 R8c groups.
32. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C1-6alkyl.
33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen, -CN, C1-6alkyl, C1- 6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR10, and -N(R10)(R11), wherein C1- 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, -OR10, and -N(R10)(R11).
34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and C1-6alkyl optionally substituted with one, two, or three groups selected from halogen, -OR10, and -N(R10)(R11).
35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently selected from halogen and unsubstituted C1- 6alkyl.
36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2.
37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
39. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof, wherein J is C(R3).
41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen.
42. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof, wherein J is N.
43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 and R5 are each hydrogen.
44. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
45. A pharmaceutical composition comprising a compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
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, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, or a pharmaceutical composition according to claim 45.
47. A method of treating a cancer or neoplastic disease in a subject in need thereof, comprising administering to the subject a compound of any one of claims 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 claim 45.
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.
49. The method of claim 47 or claim 48, wherein the cancer or neoplastic disease is associated with one or more genetic alterations in KRAS, NRAS, HRAS, ARAF, BRAF or CRAF.
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, G13R, 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 IIa, Class IIb, Class IIc, 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.
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).
52. The method of claim 51, wherein the one or more genetic lesions is a point mutation, a fusion or any combination thereof.
53. The method of claim 51 or claim 52, wherein the one or more receptor tyrosine kinase is selected from the group consisting of ALK, EGFR, ERBB2, LTK, MET, NTRK, RET, and ROS1.
54. The method of any one of claims 47-53, wherein the cancer is a refractory cancer.
55. The method of any one of claims 47-54, 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.
56. The method of any one of claims 47-55, the cancer is a refractory BRAF Class I mutant cancer.
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.
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.
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.
60. The method of claim 58, wherein the refractory cancer is associated with one or more alternative splicing or internal deletion events that result in the loss of BRAF gene exons 4-10, 4-8, 2-8 or 2-10.
61. The method of any one of claims 47-60, 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 (including inhibitors against ALK, EGFR (including, but not limited to, the anti-EGFR inhibitory antibodies cetuximab and panitumumab), ERBB2, LTK, MET, NTRK, RET, ROS1), RAS inhibitors (including, but not limited to, sotorasib and adagrasib), RAF inhibitors representing alternative binding modes (including, but not limited to, vemurafenib, dabrafenib, encorafenib, exarafenib, tovorafenib, naporafenib, belvarafenib, brimarafenib and lifrafenib), MEK1/2 inhibitors (including, but not limited to, binimetinib, trametinib, pimasertib, mirdametinib, tunlametinib, avutometinib and zapnometinib), ERK1/2 inhibitors, RSK1/2/3/4 inhibitors, SHP2 inhibitors, AKT inhibitors, TORC1/2 inhibitors, DNA damage response pathway inhibitors, PI3K inhibitors and/or radiation.
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