Method for preparing tyrosine receptor kinase inhibitors

Abstract

This disclosure relates to pyrazolo[1,5-α]pyrimidine compounds useful as TRK inhibitors, and compounds useful for preparing pyrazolo[1,5-α]pyrimidine compounds, as well as methods of making and using same. This Abstract is intended as a scanning tool for searching particular areas and is not intended to limit the invention. TIFF2023522841000243.tif107170

Description

[Background technology]

[0001] background Growth factors are important signaling molecules that promote the growth, development, and homeostasis of many cell systems. Neurotrophins are growth factors involved in the growth, maturation, and death of central and peripheral neurons. Neurotrophins activate cell surface receptors called tropomyosin-like receptors, which in turn regulate intracellular kinases called tropomyosin receptor kinases (TRKs). The TRK family of receptors includes TRKA, TRKB, and TRKC, which function as high-affinity cell surface receptors for the growth factors NGF, BDNF, and NT3, respectively. Inhibition of these receptors can lead to modulation or inhibition of intracellular signaling cascades that regulate cell growth and proliferation, intercellular communication that regulates signal transduction, feedback mechanisms, and homeostasis. These growth factors have been implicated in the growth and proliferation of both neuronal and non-neuronal cells.

[0002] TRK inhibitors may be used in the treatment or prevention of a variety of diseases, including inflammatory diseases, infectious diseases, autoimmune disorders, stroke, ischemia, cardiac dysfunction, neurological disorders, fibrotic disorders, proliferative disorders, hyperproliferative disorders, non-cancerous hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, malignant diseases, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic pain, neuropathic pain, and other disorders. Despite the broad therapeutic utility of TRK inhibitors, methods for making these compounds suitable for scaling up to large-scale manufacturing processes have been elusive. Thus, there remains a need for compounds useful as intermediates in preparing TRK inhibitors, methods for making these intermediate compounds, and methods for making TRK inhibitors. These and other needs are met by the present invention. Summary of the Invention

[0003] overview In accordance with the object(s) of the invention as embodied and broadly described herein, the present invention relates, in some embodiments, to pyrazolo[1,5-α]pyrimidine compounds useful as TRK inhibitors, and compounds useful in the preparation of pyrazolo[1,5-α]pyrimidine compounds, and methods of making and using the same.

[0004] Thus, in some embodiments, the present disclosure provides a compound of formula (XXV):

[0010] The present invention provides a method for making a compound having a structure represented by the formula: TIFF0007767301000001.tif35128, or a pharmaceutically acceptable salt thereof, the method comprising: Formula (XXVI): TIFF0007767301000002.tif26128 and a compound having the structure represented by the formula: coupling a compound having a structure represented by the formula: TIFF0007767301000003.tif26128; As a result, TIFF0007767301000004.tif25128 is X 1 In the formula, X 1 is a leaving group.

[0005] In some embodiments, the present disclosure provides a compound having the structure: TIFF0007767301000005.tif35128, or a pharmaceutically acceptable salt thereof, the method comprising: (a) Structure: TIFF0007767301000006.tif18128 to form a nitrile having the structure: TIFF0007767301000007.tif15128 and a heteroaryl having formula (XXIV): TIFF0007767301000008.tif6128, (b) Structure: TIFF0007767301000009.tif29128 by reacting the nitrile with formamidine acetal; (c) Structure: preparing an amine having TIFF0007767301000010.tif25128 by reacting acrylonitrile with hydrazine; (d) Structure: TIFF0007767301000011.tif25128 to form an amide having the structure: TIFF0007767301000012.tif17128 by reacting uracil with (e) Formula (XXVI): preparing a compound having a structure represented by the formula: TIFF0007767301000013.tif26128 by reacting an amide with a halogenating agent; and (f) reacting a compound of formula (XXV) with a compound of formula (XXVI) having the structure: TIFF0007767301000014.tif23128, wherein X 1 is a leaving group and X 2 is a halogen.

[0006] In some embodiments, the present disclosure provides a compound of formula (XV): TIFF0007767301000015.tif25128, or a pharmaceutically acceptable salt thereof, the method comprising: TIFF0007767301000016.tif25128 and a compound of formula (XVII): TIFF0007767301000017.tif15128, whereby TIFF0007767301000018.tif14128 is X 1 In the formula, X 1 is a leaving group and R 10is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; Ar 2is a C6-C10 aryl or 5-6 membered heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0007] In some embodiments, the present disclosure provides a compound of formula (XV): TIFF0007767301000019.tif25128, or a pharmaceutically acceptable salt thereof, the method comprising: (a) Formula (XXII): TIFF0007767301000020.tif19128, by reacting a nitrile having a structure represented by formula (XXIII): TIFF0007767301000021.tif16128 and a heteroaryl having a structure represented by formula (XXIV): TIFF0007767301000022.tif6128, (b) Formula (XXI): preparing an acrylonitrile having a structure represented by TIFF0007767301000023.tif30128 by reacting a nitrile of formula (XXII) with formamidine acetal; (c) Formula (XIX): preparing an amine having a structure represented by TIFF0007767301000024.tif25128 by cyclizing an acrylonitrile of formula (XXI) with hydrazine; (d) Formula (XVIII): TIFF0007767301000025.tif26128, by reacting an amine of formula (XIX) with an amide of formula (XX): with uracil having the structure represented by TIFF0007767301000026.tif18128; (e) Formula (XVI): preparing a compound having a structure represented by the formula (XVIII) by reacting an amide of formula (XVIII) with a halogenating agent; and (f) reacting a compound of formula (XV) with a compound of formula (XVI) and a compound of formula (XVII): TIFF0007767301000028.tif15128, In the formula, X 1 is a leaving group and X 2 is a halogen, and X 1 is a leaving group and R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; Ar 2 is a C6-C10 aryl or 5- to 6-membered heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; R 31a and R 31b are each independently C1 to C4 alkyl.

[0008] In some embodiments, the disclosure provides compounds prepared by the disclosed methods.

[0009] In some embodiments, the present disclosure provides a compound of formula (XVI): TIFF0007767301000029.tif26128, or a pharmaceutically acceptable salt thereof, wherein X 1 is a leaving group and R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl.

[0010] In some embodiments, the present disclosure provides a compound of formula (XVI): TIFF0007767301000030.tif26128, or a pharmaceutically acceptable salt thereof, the method comprising producing a compound having a structure represented by formula (XVIII): TIFF0007767301000031.tif26128 with an activating agent, wherein X 1 is a leaving group and R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl.

[0011] In some embodiments, the present disclosure provides a compound of formula (XVIII): TIFF0007767301000032.tif26128, or a pharmaceutically acceptable salt thereof, wherein R 10is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl.

[0012] In some embodiments, the present disclosure provides a compound of formula (XVIII): TIFF0007767301000033.tif26128, or a pharmaceutically acceptable salt thereof, the method comprising: Formula (XIX): TIFF0007767301000034.tif25128 and an amine having a structure represented by formula (XX): TIFF0007767301000035.tif18128, In the formula, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl.

[0013] In some embodiments, the present disclosure provides a compound having the structure: The present invention provides a compound having the formula TIFF0007767301000036.tif25128, or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the present disclosure provides a compound having the structure: The present invention provides a compound having the formula TIFF0007767301000037.tif29128, or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the present disclosure provides a compound of formula (X): TIFF0007767301000038.tif26128, or a salt thereof, the method comprising steps (i-1) to (i-3), i.e., (i-1) Formula (VII): TIFF0007767301000039.tif17128 is contacted with an acetonitrile addition agent, thereby producing a compound of formula (VIII): forming the compound TIFF0007767301000040.tif19128, (i-2) contacting a compound of formula (VIII) with N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof, thereby producing a compound of formula (IX): forming a compound of TIFF0007767301000041.tif29128, or (i-3) Contacting the compound of formula (IX) with hydrazine to obtain a compound of formula (X): TIFF0007767301000042.tif26128, or a salt thereof, wherein R 10 is as above.

[0016] In some embodiments, the present disclosure provides use of a compound of Formula (VII) in the preparation of a compound of Formula (X) or a salt thereof, comprising one or more of steps (i-1) to (i-3).

[0017] In some embodiments, the present disclosure provides a compound of formula (XIV): TIFF0007767301000043.tif34128 or a salt thereof, the method comprising the following steps (f-1) to (f-3): (f-1) Formula (X): The compound of TIFF0007767301000044.tif26128 or its salt is used as compound No. 11: TIFF0007767301000045.tif19128 or a synthetic equivalent thereof, thereby forming a compound of formula (XII): forming a compound of TIFF0007767301000046.tif25128, (f-2) The compound of formula (XII) is contacted with a chlorinating agent, thereby obtaining a compound of formula (XIII): forming a compound of TIFF0007767301000047.tif25128, or (f-3) The compound of formula (XIII) is reacted with Compound No. 6: TIFF0007767301000048.tif18128 or a salt thereof, thereby producing a compound of formula (XIV): TIFF0007767301000049.tif34128, or a salt thereof, wherein R 10 is as above.

[0018] In some embodiments, the present disclosure provides use of a compound of formula (X) or a salt thereof in the preparation of a compound of formula (XIV) or a salt thereof, comprising one or more of steps (f-1) to (f-3).

[0019] In some embodiments, the present disclosure provides a combination comprising a compound of formula (VII) and an acetonitrile addition agent. In these types of reactions, a suitable acetonitrile addition agent is a haloacetonitrile, such as bromoacetonitrile.

[0020] In some embodiments, the present disclosure provides a combination comprising a compound of formula (VII) and an acetonitrile addition agent for preparing a compound of formula (X) or a salt thereof.

[0021] In some embodiments, the present disclosure provides a combination comprising a compound of Formula (VIII) and N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof. The term "formamidine acetal" is used in this context to refer to N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof.

[0022] In some embodiments, the present disclosure provides a combination comprising a compound of formula (VIII) and N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof for preparing a compound of formula (X) or a salt thereof.

[0023] In some embodiments, the present disclosure provides a combination comprising a compound of formula (IX) and hydrazine.

[0024] In some embodiments, the present disclosure provides a combination comprising a compound of formula (IX) and hydrazine, useful for preparing a compound of formula (X) or a salt thereof.

[0025] In some embodiments, the present disclosure provides a combination comprising a compound of formula (X) or a salt thereof and Compound No. 11 or a synthetic equivalent thereof.

[0026] In some embodiments, the present disclosure provides a combination comprising a compound of formula (X), or a salt thereof, and compound number 11, or a synthetic equivalent thereof, useful for preparing a compound of formula (XIV), or a salt thereof.

[0027] In some embodiments, the present disclosure provides a combination comprising a compound of formula (XII) and a chlorinating agent.

[0028] In some embodiments, the present disclosure provides a combination comprising a compound of formula (XII) and a chlorinating agent useful for preparing a compound of formula (XIV) or a salt thereof.

[0029] In some embodiments, the present disclosure provides a combination comprising a compound of formula (XIII) and compound number 6, or a salt thereof.

[0030] In some embodiments, the present disclosure provides a combination comprising a compound of formula (XIII) and compound number 6, or a salt thereof, useful for preparing a compound of formula (XIV), or a salt thereof.

[0031] In some embodiments, the present disclosure provides a compound of any of formulas (VII)-(X) and (XII)-(XIV), wherein R 10 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 An aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be one or more R 1S and each R 1S are independently halogen, —O—(C1-C6 alkyl), or —N(R 1Sa )2.

[0032] In some embodiments, the present disclosure provides a compound of any of formulas (X) and (XIV) or a salt thereof, wherein R10 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 An aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be one or more R 1S and each R 1S are independently halogen, —O—(C1-C6 alkyl), or —N(R 1Sa )2.

[0033] In some embodiments, the disclosure provides compounds prepared by the methods described herein.

[0034] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients.

[0035] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound prepared by a method described herein and one or more pharmaceutically acceptable carriers or excipients.

[0036] In some embodiments, the disclosure provides a method for inhibiting tyrosine receptor kinase (TRK) in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound described herein.

[0037] In some embodiments, the disclosure provides the use of a compound described herein in the manufacture of a medicament for inhibiting tyrosine receptor kinase (TRK) in a subject.

[0038] In some embodiments, the disclosure provides a method of preventing or treating a disease or disorder in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound described herein.

[0039] In some embodiments, the disclosure provides the use of a compound described herein in the manufacture of a medicament for preventing or treating a disease or disorder in a subject.

[0040] The structures of Formulas (VII)-(X) and (XII)-(XIV), and the structures of Compounds Nos. 1-14, are as set forth in Table 1 below, where all variables are as described elsewhere herein.

[0041] [Table 1] TIFF0007767301000051.tif212152TIFF0007767301000052.tif219152TIFF00077673010 00053.tif204152TIFF0007767301000054.tif211152TIFF0007767301000055.tif129152

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular also includes the plural unless the context clearly dictates otherwise. In practicing or testing this disclosure, methods and materials similar or equivalent to those described herein may be used, and suitable methods and materials are described below. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0043] [The present invention 1001] Formula (XXV): TIFF0007767301000056.tif35128 or a pharmaceutically acceptable salt thereof, said method comprising: Formula (XXVI): TIFF0007767301000057.tif26128 and a compound having a structure represented by the formula: TIFF0007767301000058.tif26128 whereby TIFF0007767301000059.tif25128 is X 1 is replaced by In the formula, X 1 is a leaving group, The method. [The present invention 1002] X 1 1001. The method of claim 1001, wherein is a halogen. [The present invention 1003] 1001. The process of claim 10, wherein the coupling reaction is carried out in the presence of a base. [The present invention 1004] 1004. The process of claim 1003, wherein the base is an amine base. [The present invention 1005] 1005. The process of claim 1004, wherein said amine base is a trialkylamine or pyridine. [The present invention 1006] 1001. The process of claim 1001, wherein said coupling reaction is carried out at an elevated temperature, said temperature being within the range of about 70°C to about 110°C. [The present invention 1007] A compound prepared by the method of the present invention. [The present invention 1008] Formula (XV): TIFF0007767301000060.tif25128 or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound having a structure represented by formula (XVI): TIFF0007767301000061.tif25128 with a compound of formula (XVII): TIFF0007767301000062.tif15128 whereby TIFF0007767301000063.tif14128 is X 1 is replaced by In the formula, X 1 is a leaving group, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R20 , -S(O) 2 R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O) 2 R 20 , -NR 21 C(O)R 20 , -NR 21 S(O) 2 R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 is selected from where R 20 、R 21 、R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 is, when present, selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is selected from halogen, —CN, —NH 2 , -OH, -NO 2 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; Ar 2 is a C6-C10 aryl or 5-6 membered heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; The method. [The present invention 1009] R 10 Ga-CF 3 The method of the present invention 1008. [The present invention 1010] Ar2 The process of claim 1008, wherein is phenyl having two halogen groups. [The present invention 1011] The compound of formula (XV) has the formula: TIFF0007767301000064.tif24128 The method of the present invention 1008 has a structure represented by: [The present invention 1012] wherein said compound of formula (XV) TIFF0007767301000065.tif34128 The method of the present invention 1008. [The present invention 1013] Formula (XVI): TIFF0007767301000066.tif26128 or a pharmaceutically acceptable salt thereof, In the formula, X 1 is a leaving group, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O) 2 R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O) 2 R 20 , -NR 21 C(O)R 20 , -NR 21 S(O) 2 R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22aR 22b , and Cy 1 is selected from where R 20 、R 21 、R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 is, when present, selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is selected from halogen, —CN, —NH 2 , -OH, -NO 2 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; The compound or a pharmaceutically acceptable salt thereof. [The present invention 1014] The compound of formula (XVI) has the structure TIFF0007767301000067.tif25128 The compound of the present invention 1013, having the formula: [The present invention 1015] Formula (XVI): TIFF0007767301000068.tif25128 or a salt thereof, said method comprising reacting a compound having a structure represented by formula (XVIII): TIFF0007767301000069.tif26128 with an activating agent, In the formula, X 1 is a leaving group, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O) 2 R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O) 2 R 20 , -NR 21 C(O)R 20 , -NR 21 S(O) 2 R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 is selected from where R 20 、R 21 、R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 is, when present, selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is selected from halogen, —CN, —NH 2 , -OH, -NO 2 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; The method. [The present invention 1016] A compound prepared by the method of the present invention. [The present invention 1017] Formula (XVIII): TIFF0007767301000070.tif26128 or a salt thereof, In the formula, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O) 2 R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O) 2 R 20 , -NR21 C(O)R 20 , -NR 21 S(O) 2 R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 is selected from where R 20 、R 21 、R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 is, when present, selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is selected from halogen, —CN, —NH 2 , -OH, -NO 2 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; The compound or a salt thereof. [The present invention 1018] The compound TIFF0007767301000071.tif26128 The compound of the present invention 1017, [The present invention 1019] Formula (XVIII): TIFF0007767301000072.tif26128 or a salt thereof, said method comprising: TIFF0007767301000073.tif25128 and an amine having a structure represented by formula (XX): TIFF0007767301000074.tif18128 and reacting a uracil having a structure represented by In the formula, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O) 2 R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O) 2 R 20 , -NR 21 C(O)R 20 , -NR 21 S(O) 2 R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 is selected from where R 20 、R 21 、R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 is, when present, selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is selected from halogen, —CN, —NH 2 , -OH, -NO 2 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; The method. [The present invention 1020] A compound prepared by the method of the present invention. [The present invention 1021] structure: TIFF0007767301000075.tif25128 or a salt thereof. [The present invention 1022] structure: TIFF0007767301000076.tif29128 or a salt thereof. Other features and advantages of the present disclosure will become apparent from the following detailed description and claims. [Brief explanation of the drawings]

[0044] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects and, together with the description, serve to explain the principles of the invention.

[0045] [Figure 1A] Representative ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) spectral data of compound No. 14R is shown. [Figure 1B] Representative ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) spectral data of compound No. 14R is shown. [Figure 1C] Representative ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) spectral data of compound No. 14R is shown. [Figure 1D] Representative ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) spectral data of compound No. 14R is shown. [Figure 2A-1] Representative 1H NMR spectrum data of compound No. 14R is shown. [Figure 2A-2] See legend to Figure 2A-1. [Figure 2A-3] See legend to Figure 2A-1. [Figure 2B-1] Representative 1H NMR spectrum data of compound No. 14R is shown. [Figure 2B-2] See legend to Figure 2B-1. [Figure 2B-3] See legend to Figure 2B-1. [Figure 2C-1] Representative 1H NMR spectrum data of compound No. 14R is shown. [Figure 2C-2]See legend to Figure 2C-1. [Figure 2C-3] See legend to Figure 2C-1. [Figure 2D-1] Representative 1H NMR spectrum data of compound No. 14R is shown. [Figure 2D-2] See legend to Figure 2D-1. [Figure 2D-3] See legend to Figure 2D-1. [Figure 3A] Representative high performance liquid chromatography (HPLC) data for compound No. 14R is shown. [Figure 3B] Representative high performance liquid chromatography (HPLC) data for compound No. 14R is shown. DETAILED DESCRIPTION OF THE INVENTION

[0046] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description or may be learned by the practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0047] Detailed Description The present invention may be understood more readily by reference to the following detailed description of the invention and the examples included therein.

[0048] Before the present compounds, compositions, articles, systems, means, and / or methods are disclosed and described, it is to be understood that they are not limited to particular synthetic methods, unless otherwise specified, or to particular reagents, unless otherwise specified, as these may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described.

[0049] Although embodiments of the present invention may be described and claimed in a particular legal classification, such as a systems legal classification, this is merely for convenience, and one of ordinary skill in the art will understand that embodiments of the present invention may be described and claimed in any legal classification. Unless expressly stated otherwise, it is in no way intended that any method or embodiment described herein be construed as requiring that its steps be performed in a particular order. Thus, unless the claims or specification expressly state that the steps of a method claim are limited to a particular order, no order is intended to be inferred in any respect. This holds true over all possible implicit grounds of interpretation, including simple interpretations arising from logical matters regarding the organization or flow of steps, grammatical organization or punctuation, or the number or type of embodiments described herein.

[0050] A. Definition Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, whether individually or as part of a larger group, unless otherwise limited in specific instances.

[0051] As used herein, the terms "a" or "an" mean "at least one" or "one or more," unless the context indicates otherwise. The term "and / or," as used in the description and claims of this specification, should be understood to mean "either or both" of the elements so conjuncted, i.e., elements that are conjunctive in some cases and disjunctive in other cases. Unless clearly indicated to the contrary, other elements other than the elements specifically identified by the "and / or" clause may optionally be present, whether related or unrelated to the elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in various embodiments to A without B (optionally including elements other than B); in other embodiments to B without A (optionally including elements other than A); in yet other embodiments to both A and B (optionally including other elements); etc.

[0052] The term "or" as used herein shall be construed as indicating exclusive alternatives (i.e., "one or the other, but not both") only when preceded by terms of exclusivity, i.e., "either," "one of," "only one of," or "exactly one of."

[0053] As used herein, the terms "comprising" (and any form of comprising, e.g., "comprise," "comprises," and "comprised"), "having" (and any form of having, e.g., "have" and "has"), "including" (and any form of including, e.g., "includes" and "include"), or "containing" (and any form of containing, e.g., "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0054] As used herein, the term "about" refers to a range that encompasses all normal variations understood by those of ordinary skill in the art. In some embodiments, the term "about" refers to a range of values ​​that is within (greater than or less than) 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction from the stated reference value, unless otherwise specified or the context clearly dictates otherwise (except where such number exceeds 100% of the possible values).

[0055] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0056] References in this specification and in the concluding claims to parts by weight of a particular element or component in a composition refer to the weight relationship of that element or component to any other element or component expressed in parts by weight in the composition or article. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, regardless of whether additional components are included in the compound.

[0057] Weight percent (wt %) of an ingredient is based on the total weight of the formulation or composition in which it is included, unless otherwise specified to the contrary.

[0058] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0059] As used herein, the term "high temperature" refers to a temperature greater than 25°C. Thus, for example, high temperature can refer to a temperature of at least about 30°C, at least about 40°C, at least about 50°C, at least about 60°C, at least about 70°C, at least about 80°C, at least about 90°C, at least about 100°C, or at least about 110°C. In some embodiments, high temperature is within the range of about 70°C to about 110°C, about 70°C to about 100°C, about 70°C to about 90°C, about 70°C to about 80°C, about 80°C to about 110°C, about 90°C to about 110°C, about 110°C to about 110°C, about 80°C to about 100°C, or about 85°C to about 95°C. In further embodiments, the elevated temperature is within the range of about 80°C to about 120°C, about 80°C to about 110°C, about 80°C to about 100°C, about 80°C to about 90°C, about 90°C to about 120°C, about 100°C to about 120°C, about 110°C to about 120°C, about 90°C to about 110°C, or about 95°C to about 105°C.

[0060] As used herein, the term "diagnosed" means having been examined by a skilled artisan, e.g., a physician, and known to have a disease, disorder, or condition that can be treated by the compounds, compositions, or methods disclosed herein. In some embodiments of the disclosed methods, the subject has been diagnosed with a disorder associated with aberrant TRK activity prior to the administering step, such as, for example, an inflammatory disease, an infectious disease, an autoimmune disorder, stroke, ischemia, cardiac dysfunction, a neurological disorder, a fibrotic disorder, a proliferative disorder, a hyperproliferative disorder, a non-cancerous hyperproliferative disorder, a tumor, leukemia, a neoplasm, cancer, carcinoma, a metabolic disease, a malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic pain, and neuropathic pain. As used herein, phrases such as "identified as being in need of treatment for a disorder" refer to selection of a subject based on need for treatment for the disorder. It is contemplated that the identification, in some embodiments, may be performed by an individual different from the individual making the diagnosis. It is also contemplated that in further embodiments, the administration may be performed by the person who subsequently administers the administration.

[0061] As used herein, the terms "administer" and "administration" refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral, transdermal, inhalation, nasal, topical, vaginal, ocular, aural, intracerebral, rectal, and parenteral administration, including injection, such as intravenous, intraarterial, intramuscular, and subcutaneous administration. Administration can be continuous or intermittent. In various embodiments, the preparation can be administered therapeutically, i.e., administered to treat an existing disease or condition. In further various embodiments, the preparation can be administered prophylactically, i.e., administered to prevent a disease or condition.

[0062] The compounds of the present disclosure may be administered singly or co-administered to a patient. Co-administration is intended to include simultaneous or sequential administration of individual or combined compounds (more than one compound or agent). Thus, the preparations can be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols, and can be delivered transdermally or topically. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by a patient. Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. The compositions of the present disclosure may further comprise ingredients for sustained release and / or comfort. Such ingredients include high molecular weight anionic mucus-like polymers, gelling polysaccharides, and micronized drug carrier substrates. These ingredients are described in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference for all purposes. The compositions of the present disclosure may also be delivered as microspheres that are slowly released in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995), or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997).In various embodiments, the formulation of the composition of the present disclosure can be delivered by using liposomes that fuse with or are incorporated into cell membranes, i.e., by using receptor ligands that are added to liposomes and bind to cell surface membrane protein receptors to induce endocytosis.By using liposomes, the delivery of the composition of the present disclosure can be focused to target cells in vivo, especially when the liposome surface carries receptor ligands specific to the target cells or is otherwise preferentially directed to a specific organ. (See, for example, Al-Muhammed, J. Microencapsul. 13: 293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6: 698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46: 1576-1587, 1989).The composition of the present disclosure can also be delivered as nanoparticles.

[0063] Pharmaceutical compositions provided by the present disclosure include compositions in which the active ingredient (e.g., a compound described herein, including any embodiment or example) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in a method of treating a disease, such compositions contain an amount of active ingredient effective to achieve a desired result, e.g., modulating the activity of a target molecule (e.g., TRK) and / or reducing, eliminating, or slowing the progression of disease symptoms (e.g., symptoms of inflammatory disease, infectious disease, autoimmune disorder, stroke, ischemia, cardiac dysfunction, neurological disorder, fibrotic disorder, proliferative disorder, hyperproliferative disorder, non-cancerous hyperproliferative disorder, tumor, leukemia, neoplasm, cancer, carcinoma, metabolic disease, malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic pain, and / or neuropathic pain). Determination of a therapeutically effective amount of a compound of the present disclosure is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0064] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending on a variety of factors, including whether the mammal is suffering from another disease and the route of administration; the recipient's size, age, sex, health, weight, body mass index, and diet; the nature and extent of the symptoms of the disease being treated (e.g., inflammatory disease, infection, autoimmune disorder, stroke, ischemia, cardiac dysfunction, neurological disorder, fibrotic disorder, proliferative disorder, hyperproliferative disorder, non-cancerous hyperproliferative disorder, tumor, leukemia, neoplasm, cancer, carcinoma, metabolic disease, malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic pain, and / or neuropathic pain symptoms, and the severity of such symptoms); the type of concurrent treatment; complications resulting from the disease being treated, or other health-related problems. Other therapeutic regimens or agents may also be used in conjunction with the methods and compounds of Applicant's disclosure. Adjustment and manipulation of established dosages (e.g., frequency and duration) is well within the capabilities of one of ordinary skill in the art. In various embodiments, the disclosed compounds may be administered in doses ranging from about 10 mg / day to about 1000 mg / day, from about 10 mg / day to about 900 mg / day, from about 10 mg / day to about 800 mg / day, from about 10 mg / day to about 700 mg / day, from about 10 mg / day to about 600 mg / day, from about 10 mg / day to about 500 mg / day, from about 10 mg / day to about 400 mg / day, from about 10 mg / day to about 300 mg / day, from about 10 mg / day to about 200 mg / day, from about 10 mg / day to about 100 mg / day, from about 10 mg / day to about 50 mg / day, from about 50 mg / day to about 1000 mg / day, from about 100 mg / day to about 1000 mg / day, or from about 200 mg / day. The compounds may be administered at dosages of about 1000 mg / day, about 300 mg / day to about 1000 mg / day, about 400 mg / day to about 1000 mg / day, about 500 mg / day to about 1000 mg / day, about 600 mg / day to about 1000 mg / day, about 700 mg / day to about 1000 mg / day, about 800 mg / day to about 1000 mg / day, about 900 mg / day to about 1000 mg / day, about 50 mg / day to about 900 mg / day, about 100 mg / day to about 800 mg / day, about 200 mg / day to about 700 mg / day, about 300 mg / day to about 600 mg / day, or about 400 mg / day to about 500 mg / day. In various further embodiments, the disclosed compounds can be administered more than once daily, such as twice daily.Thus, in various embodiments, the disclosed compounds can be administered in dosages of about 10 mg to about 500 mg, with each dosage administered twice daily.

[0065] For any compound described herein, the therapeutically effective dose can be determined from cell culture assays, animal studies, and / or human clinical trials. The target concentration will be the concentration of active compound(s) that can achieve the methods described herein, as measured using methods described herein or known in the art.

[0066] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be determined to achieve a concentration known to be effective in animals. The dosage in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward as described above. It is well within the capabilities of a person skilled in the art to adjust the dosage to achieve maximum efficacy in humans based on the above and other methods.

[0067] Dosage may vary depending on the requirements of the patient and the compound used. The dose administered to a patient, in the context of the present disclosure, should be sufficient to affect a beneficial therapeutic response in the patient over time. The amount of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of a physician. Generally, treatment is initiated with small dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.

[0068] Dosage amount and interval can be adjusted individually to provide levels of the administered compound that are effective for the particular clinical indication being treated, thereby providing a treatment regimen commensurate with the severity of the particular disease state.

[0069] Using the teachings provided herein, one can design an effective prophylactic or therapeutic treatment regimen that produces little toxicity while still being effective in treating the clinical symptoms exhibited by a particular patient. This design should involve careful selection of an active compound by considering factors such as the compound's potency, relative bioavailability, the patient's weight, the presence and severity of adverse side effects, the preferred mode of administration and toxicity profile of the selected agent, etc.

[0070] "Derivatives" of the compounds disclosed herein include pharmaceutically acceptable salts, prodrugs, deuterated forms, radiolabeled forms, isomers, solvates, and combinations thereof. A "combination" referred to in this context refers to derivatives that belong to at least two of the following groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radiolabeled forms, isomers, and solvates. Examples of radiolabeled forms include compounds labeled with tritium, phosphorus-32, iodine-129, carbon-11, fluorine-18, and the like.

[0071] As used herein, the term "synthetic equivalent" refers to an agent (e.g., a compound) that is suitable to replace a reference agent (e.g., a reference compound) in a method or use disclosed herein. It is known in the art that suitable synthetic equivalents of a reference agent (e.g., a reference compound) are readily recognizable or can be assessed by routine experimentation by a person skilled in the art (e.g., a synthetic chemist).

[0072] The term "leaving group" refers to an atom (or group of atoms) that moves away from the rest of a molecule, removing a bonding electron. Examples of suitable leaving groups include sulfonate esters, such as triflate, mesylate, tosylate, brosylate, and the like, and halides.

[0073] As used herein, the term "substituted" is intended to include only permissible substituents of chemically stable organic compounds. In a broad embodiment, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. It is not intended that the disclosure be limited in any manner by the permissible substituents of organic compounds. The terms "substituted" or "substituted with" also include the implicit proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound, e.g., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, and the like. In certain embodiments, unless expressly stated otherwise, it is also contemplated that individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0074] In the definition of various terms, "A 1 ","A 2 ","A 3 " and "A 4 " is used herein as a generic symbol to represent various specific substituents. These symbols are not limited to those disclosed herein and may be any substituent, which may be defined as a specific substituent in one instance and some other substituent in another instance.

[0075] The terms "halo" and "halogen," as used herein, refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0076] As used herein, the term "aliphatic" or "aliphatic group" refers to a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclics), may be fully saturated, or may contain one or more units of unsaturation, but is not aromatic. Unless otherwise specified, an aliphatic group contains 1 to 20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched alkyl, alkenyl, and alkynyl groups, as well as hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0077] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups, and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, or C6 alkyl groups. Examples of alkyl include moieties having 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, or n-hexyl. In certain embodiments, a straight-chain or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight-chain and C3-C6 for branched-chain), and in other embodiments, a straight-chain or branched alkyl has 4 or fewer carbon atoms.

[0078] Throughout this specification, "alkyl" is used generally to refer to both unsubstituted and substituted alkyl groups, although substituted alkyl groups may be specifically indicated herein by identifying the particular substituent(s) on the alkyl group. For example, the term "halogenated alkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halides, such as fluorine, chlorine, bromine, or iodine. Alternatively, the term "monohaloalkyl" specifically refers to an alkyl group substituted with a single halide, such as fluorine, chlorine, bromine, or iodine. The term "polyhaloalkyl" specifically refers to an alkyl group independently substituted with two or more halides. In other words, each halide substituent need not be the same halide as another halide substituent, nor need multiple instances of a halide substituent be on the same carbon. The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "aminoalkyl" specifically refers to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl" specifically refers to an alkyl group substituted with one or more hydroxy groups. If "alkyl" is used in one instance and a specific term such as "hydroxyalkyl" is used in another instance, this does not imply that the term "alkyl" does not also refer to the specific term such as "hydroxyalkyl."

[0079] This convention is also used for other groups described herein. That is, a term such as "cycloalkyl" refers to both unsubstituted and substituted cycloalkyl moieties, although substituted moieties may also be specifically identified herein. For example, a particular substituted cycloalkyl may be designated as an "alkylcycloalkyl." Similarly, a substituted alkoxy may be specifically designated as, e.g., a "halogenated alkoxy," and a particular substituted alkenyl may be, e.g., an "alkenylalcohol," etc. Again, the convention for using a general term such as "cycloalkyl" and a specific term such as "alkylcycloalkyl" does not imply that the general term does not also include the specific term.

[0080] The term "alkenyl," as used herein, refers to a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon double bond. 1 A 2 )C=C(A 3 A 4 ), are intended to include both the E and Z isomers. This can be inferred herein in structural formulae where an asymmetric alkene is present in the formula, or can be shown explicitly by the bond symbol C=C. Alkenyl groups can be optionally substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0081] The term "alkynyl," as used herein, refers to a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. Alkynyl groups can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol.

[0082] As used herein, the term "heteroalkyl" refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, where the nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls may be substituted as defined above for alkyl groups.

[0083] The term "haloalkyl" includes mono-, poly-, and perhaloalkyl groups, where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0084] "Alkoxy" is an alkyl group attached to another moiety via an oxygen linker (-O(alkyl)). Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy.

[0085] A "haloalkoxy" is a haloalkyl group that is attached to another moiety via an oxygen atom, for example, but not limited to, -OCHCF2 or -OCF3.

[0086] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3-C 12 , C3~C 10, or C3-C8), saturated or unsaturated non-aromatic hydrocarbon mono- or polycyclic (e.g., fused, bridged, or spirocyclic) systems. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.

[0087] The term "cycloalkenyl," as used herein, refers to a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bond, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term "heterocycloalkenyl" refers to a type of cycloalkenyl group, as defined above, within the meaning of the term "cycloalkenyl," except that at least one of the ring carbon atoms is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups can be substituted or unsubstituted. The cycloalkenyl and heterocycloalkenyl groups may be optionally substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0088] The term "cycloalkynyl" as used herein refers to a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bond. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, etc. The term "heterocycloalkynyl" refers to a type of cycloalkenyl group as defined above, within the meaning of the term "cycloalkynyl," but in which at least one carbon atom in the ring is replaced with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkynyl and heterocycloalkynyl groups can be substituted or unsubstituted. The cycloalkynyl and heterocycloalkynyl groups may be optionally substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0089] As used herein, the terms "heterocycle" and "heterocyclyl" can be used interchangeably and refer to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term includes, but is not limited to, "heterocycloalkyl," "heteroaryl," "bicyclic heterocycle," and "polycyclic heterocycle." Heterocycles can be saturated or partially saturated, monocyclic, bicyclic (e.g., spiro or bridged), polycyclic, or fused systems. Heterocycles include pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole (including 1,2,3-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole), thiadiazole (including 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole), triazole (1,2, 3-triazole, including 1,3,4-triazole), tetrazole (including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole), pyridazine, pyrazine, triazine (including 1,2,4-triazine and 1,3,5-triazine), tetrazine (including 1,2,4,5-tetrazine), pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can be C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, etc., up to and including C2-C18 heterocyclyl. For example, C2 heterocyclyl includes groups having two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, etc.Alternatively, for example, C5 heterocyclyl includes groups having 5 carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, etc. It is understood that heterocyclyl groups can be attached, if chemically possible, through a heteroatom in the ring or through one of the carbons that make up the heterocyclyl ring.

[0090] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclyl" refers to a ring system in which at least one ring member is other than carbon. Bicyclic heterocyclyl includes ring systems in which an aromatic ring is fused to another aromatic ring, or in which an aromatic ring is fused to a non-aromatic ring. Bicyclic heterocyclyl includes ring systems in which a benzene ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, or a pyridine ring is fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0091] As used herein, unless otherwise specified, the term "heterocycloalkyl" refers to a saturated or unsaturated non-aromatic 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (fused, bridged, or spirocyclic), or 11- to 14-membered tricyclic ring system (fused, bridged, or spirocyclic) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.Examples of heterocycloalkyl groups are piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1, 4-Oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl , 7'H-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl dinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, etc. In the case of polycyclic non-aromatic rings, only one of the rings need be non-aromatic (e.g., 1,2,3,4-tetrahydronaphthalenyl or 2,3-dihydroindole).

[0092] As used herein, the term "aromatic group" refers to a ring structure having a cyclic cloud of delocalized π electrons above and below the plane of the molecule, the π cloud containing (4n+2) π electrons. Further discussion of aromaticity can be found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled "Aromaticity," pp. 477-497, which is incorporated herein by reference in its entirety. The term "aromatic group" includes both aryl and heteroaryl groups.

[0093] As used herein, the term "aryl" includes groups with aromatic character, including "conjugated" or polycyclic ring systems having one or more aromatic rings, and no heteroatoms in the ring structure. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In some embodiments, the aryl is phenyl. The aryl group may be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. The term "biaryl" is a specific type of aryl group and is included in the definition of "aryl." Furthermore, aryl groups may be single ring structures or may contain multiple ring structures that are fused ring structures or joined through one or more bridging groups, such as carbon-carbon bonds. For example, a biaryl can be two aryl groups joined together through a fused ring structure, as in naphthalene, or joined through one or more carbon-carbon bonds, as in biphenyl.

[0094] As used herein, the term "heteroaryl" is intended to include stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocyclic rings consisting of carbon atoms and one or more heteroatoms, e.g., 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR, where R is H or other defined substituent). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O)). p (where p=1 or 2). Note that the total number of S and O atoms in the aromatic heterocycle is 1 or less. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

[0095] The terms "aryl" and "heteroaryl" are understood to include polycyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0096] The term "aldehyde" as used herein is represented by the formula -C(O)H. Throughout this specification, "C(O)" is a shorthand notation for a carbonyl group, i.e., C=O.

[0097] As used herein, the term "amine" or "amino" refers to a group of the formula -NA 1 A 2 wherein A1 and A 2 can independently be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A particular example of amino is -NH.

[0098] The term "alkylamino" as used herein is represented by the formula -NH(-alkyl), where alkyl is as defined herein. Representative examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, (sec-butyl)amino, (tert-butyl)amino, pentylamino, isopentylamino, (tert-pentyl)amino, hexylamino, and the like.

[0099] The term "dialkylamino" as used herein is represented by the formula -N(-alkyl), where alkyl is as defined herein. Representative examples include, but are not limited to, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(sec-butyl)amino, di(tert-butyl)amino, dipentylamino, diisopentylamino, di(tert-pentyl)amino, dihexylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, and the like.

[0100] The term "carboxylic acid" as used herein is represented by the formula --C(O)OH.

[0101] As used herein, the term "ester" refers to an ester of the formula -OC(O)A 1 or -C(O)OA 1 wherein A 1can be an alkyl group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, cycloalkynyl group, aryl group, or heteroaryl group as described herein.

[0102] As used herein, the term "ether" refers to a group of the formula A 1 Office Automation 2 wherein A 1 and A 2 can independently be an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, a cycloalkynyl group, an aryl group, or a heteroaryl group as described herein.

[0103] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when multiple positions in any given structure are substitutable with multiple substituents selected from a specified group, the substituents can be the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. In certain embodiments, unless explicitly stated to the contrary, it is also contemplated that individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0104] In some embodiments, the structure of the compound has the formula: TIFF0007767301000077.tif13128, which has the formula: TIFF0007767301000078.tif22128, where n is typically an integer, i.e., R nis five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) In each such case, the five R n Each R can be hydrogen or a listed substituent. "Independent substituents" means that each R substituent can be defined independently. For example, in one example, R n(a) is a halogen, R n(b) is not necessarily a halogen in that example.

[0105] In still some further embodiments, the structure of the compound has the formula: It can be represented by TIFF0007767301000079.tif16128, In the formula, R y For example, A 1 , A 2 , and A 3 and represents 0 to 2 independent substituents selected from the following formula: TIFF0007767301000080.tif165151

[0106] Again, "independent substituents" means that each R substituent can be independently defined. For example, in one example, R y1 A 1 If R y2 In that example, 1 This is not necessarily the case.

[0107] In some further embodiments, the structure of the compound is of the formula It can be represented by TIFF0007767301000081.tif21128, wherein, for example, Q includes three substituents independently selected from hydrogen and A, which corresponds to the formula: It is understood to be equivalent to TIFF0007767301000082.tif21128.

[0108] Again, "independent substituents" means that each Q substituent is independently defined as hydrogen or A, which is understood to be equivalent to the group of formulae below: TIFF0007767301000083.tif56151

[0109] In some embodiments, the disclosed compounds exist as geometric isomers. "Geometric isomer" refers to isomers that differ in the orientation of substituent atoms relative to the cycloalkyl ring, i.e., cis isomers or trans isomers. When the disclosed compounds are named or shown by structure without showing a specific cis or trans geometric isomer, it is understood that the name or structure encompasses one geometric isomer free of the other, a mixture of geometric isomers, or a mixture enriched in one geometric isomer relative to the corresponding geometric isomer. When a specific geometric isomer, i.e., cis or trans, is shown, the isomer shown is at least about 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to the other geometric isomer.

[0110] Unless expressly stated to the contrary, formulas having chemical bonds shown only with solid lines, rather than wedges or dotted lines, contemplate each possible isomer, e.g., each enantiomer and diastereomer, as well as mixtures of isomers, such as racemic or scalemic mixtures. The compounds described herein may contain one or more asymmetric centers and thus may give rise to diastereomers and optical isomers. Unless expressly stated to the contrary, the present invention includes all such possible diastereomers, as well as their racemic mixtures, their substantially pure separated enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of synthetic procedures used to prepare such compounds, or in the use of racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0111] The compounds of the present invention can exist in optically active forms that have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center(s). The prefixes d and l or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. Many of the compounds described herein can have one or more chiral centers and therefore can exist in various enantiomeric forms. If desired, a chiral carbon can be identified by an asterisk ( *) in a disclosed formula. When a bond to a chiral carbon is depicted as a straight line, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof, are encompassed by the formula. As used in the art, when it is desired to designate the absolute configuration to a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (the bond to the atom is above the plane) and the other as a series of short parallel lines or a wedge therefrom (the bond to the atom is below the plane). The Cahn-Ingold-Prelog rules can be used to assign the (R) or (S) configuration to a chiral carbon.

[0112] When a disclosed compound contains one chiral center, the compound can exist in two enantiomeric forms. Unless specifically stated to the contrary, the disclosed compounds include both enantiomers and mixtures of enantiomers, such as a particular 50:50 mixture, referred to as a racemic mixture. Enantiomers can be resolved by methods known to those skilled in the art, such as the formation of diastereomeric salts, which can be separated, for example, by crystallization (see CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)), the formation of diastereomeric derivatives or complexes, which can be separated, for example, by crystallization, gas-liquid, or liquid chromatography, the selective reaction of one enantiomer with an enantiospecific reagent, for example, enzymatic esterification, or gas-liquid or liquid chromatography in a chiral environment, for example, in the presence of a chiral support, for example, silica bonded to a chiral ligand, or a chiral solvent. It will be appreciated that when the desired enantiomer is converted to a separate chemical entity by one of the above separation procedures, a further step may be performed to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0113] When a disclosed compound has two or more chiral carbons, the compound can have more than two optical isomers and can exist in diastereoisomeric forms. For example, if two chiral carbons are present, the compound can have up to four optical isomers and two enantiomeric pairs ((S,S) / (R,R) and (R,S) / (S,R)). Enantiomeric pairs (e.g., (S,S) / (R,R)) are stereoisomers that are mirror images of each other. Stereoisomers that are not mirror images (e.g., (S,S) and (R,S)) are diastereomers. Diastereoisomeric pairs can be separated by methods known to those skilled in the art, such as chromatography or crystallization, and the individual enantiomers within each pair can be separated as described above. Unless otherwise specifically excluded, the disclosed compounds include each diastereoisomeric form of such a compound and mixtures thereof.

[0114] As used herein, the term "purified" means that the isolate, when isolated, contains at least about 90%, at least about 95%, at least about 98%, or at least about 99% by weight of the compound described herein.

[0115] As used herein, the term "solution / suspension" refers to a liquid composition in which a first portion of the active agent is present in solution and a second portion of the active agent is present in particulate form suspended in a liquid matrix.

[0116] As used herein, the phrase "substantially isolated" refers to a compound that is at least partially or substantially separated from the environment in which it was formed or detected.

[0117] It is further understood that certain features described herein, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0118] It should be noted that any embodiment of the present invention may optionally exclude one or more embodiments for purposes of claiming subject matter.

[0119] In some embodiments, the compound or salt thereof is substantially isolated. Partial isolation can include, for example, a composition enriched in the compound of the present disclosure. Substantial isolation can include a composition comprising at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present disclosure or a salt thereof. Methods for isolating compounds and salts thereof are routine in the art.

[0120] As used herein, the terms "subject" and "patient" may be used interchangeably, and are also synonymous with the term "subject in need thereof," all of which refer to a subject having a disease or at risk of developing a disease. A "subject" includes a mammal. A mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. A subject can also be a bird or poultry. In some embodiments, the mammal is a human.

[0121] As used herein, the term "treat" or "treatment" refers to the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treatment" can also include treatment of cells in vitro or in animal models.

[0122] As used herein, the terms "prevent" or "prevention" refer to reducing or eliminating the occurrence of symptoms or complications of such disease, condition, or disorder.

[0123] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0124] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is useful in preparing formulations that are generally safe, non-toxic, and not biologically or otherwise unsuitable, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0125] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, saturated vegetable fatty acids such as glycine, sorbic acid, potassium sorbate, and protamine sulfate, water, partial glyceride mixtures of salts or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0126] As used herein, the term "salt" or "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure where the parent compound is modified by making an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolariolsanilic acid, hexylresorcinol acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl stearate, and the like. These include, but are not limited to, those derived from inorganic and organic acids selected from sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, and the like. Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butyl acetate, muconic acid, and the like.The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs), as defined herein, of the same salt.

[0127] The term "effective amount" or "therapeutically effective amount" refers to an amount sufficient to achieve a desired result (e.g., an amount that elicits a biological or medical response in the subject, e.g., a dosage of 0.5 to 1000 mg / kg body weight / day) or to have an effect on an undesired condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or to have an effect on an undesired symptom, but generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the particular composition used, the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration, the rate of excretion of the particular compound used, the duration of treatment, drugs used in combination with or concomitantly with the particular compound used, and similar factors well known in the medical arts. For example, it is well within the skill of one of ordinary skill in the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If desired, the effective daily amount can be divided into multiple doses for purposes of administration. As a result, a single dose of the composition can contain such an amount, i.e., a submultiple thereof that constitutes a daily dose. The dosage can be adjusted by an individual physician in the event of any contraindications. The dosage can be varied and can be administered in one or more doses per day for one or several days. Guidance on the dosage appropriate for a given class of pharmaceutical product can be found in the literature. In further various embodiments, the preparation can be administered in a "prophylactically effective amount," i.e., an amount effective for preventing a disease or condition.

[0128] As used herein, the term "salt" refers to an acid or base salt of a compound used in the method of the present disclosure. Specific examples of acceptable salts include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, and phosphoric acid), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, and citric acid), and salts of quaternary ammonium salts (such as methyl iodide and ethyl iodide).

[0129] The terms "associated with" or "associated with" in the context of a substance or the activity or function of a substance that is associated with a disease (e.g., a protein-related disease, a condition associated with an inflammatory disease, an infectious disease, an autoimmune disorder, stroke, ischemia, cardiac dysfunction, a neurological disorder, a fibrotic disorder, a proliferative disorder, a hyperproliferative disorder, a non-cancerous hyperproliferative disorder, a tumor, leukemia, a neoplasm, cancer, carcinoma, a metabolic disease, a malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic pain, or neuropathic pain) refer to a substance or an activity or function of a substance that is associated with a disease (e.g., a protein-related disease, a condition associated with an inflammatory disease, an infectious disease, an autoimmune disorder, stroke, ischemia, cardiac dysfunction, a neurological disorder, a fibrotic disorder, a proliferative disorder, a hyperproliferative disorder, a non-cancerous hyperproliferative disorder, a tumor, leukemia, a neoplasm, cancer, carcinoma, a metabolic disease, a malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic pain, or neuropathic pain). "Targeted" means that a disease, infectious disease, autoimmune disorder, stroke, ischemia, cardiac dysfunction, neurological disorder, fibrotic disorder, proliferative disorder, hyperproliferative disorder, non-cancerous hyperproliferative disorder, tumor, leukemia, neoplasm, cancer, carcinoma, metabolic disease, malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic pain, or neuropathic pain is caused (in whole or in part) by a substance or the activity or function of a substance, or that a symptom of a disease is caused (in whole or in part) by a substance or the activity or function of a substance. For example, a symptom of a disease or condition associated with an elevated level of TRK activity can be a symptom attributable (in whole or in part) to an elevated level of TRK activity (e.g., gain-of-function mutation, gene deletion, gene fusion, or modulation of the TRK signaling pathway). As used herein, something described as being associated with a disease, if it is a causative agent, can be a target for treating the disease. For example, diseases associated with TRK can be treated with agents (eg, compounds described herein) that are effective in reducing the level of activity of TRK.

[0130] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subject or agent is treated as in a parallel experiment, except for the omission of an experimental procedure, agent, or variable. In some instances, a control is used as a standard of comparison in evaluating the effectiveness of an experiment.

[0131] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to the interaction of a protein and an inhibitor (e.g., an antagonist), refer to negatively affecting (e.g., decreasing) the activity or function of a protein (e.g., TRK) compared to the activity or function of the protein in the absence of the inhibitor (e.g., a compound described herein). In various embodiments, inhibition refers to a reduction in a disease or disease symptom. In various embodiments, inhibition refers to a reduction in the activity of a signal transduction pathway or a signal pathway (e.g., the TRK pathway). Thus, inhibition includes, at least in part, partially or completely blocking stimulation, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity or the amount of a protein.

[0132] symbol TIFF0007767301000084.tif7137 indicates the point of attachment of a chemical moiety to the rest of a molecule or chemical formula.

[0133] As defined herein, the terms "activation," "activate," "activating," and the like, with respect to the interaction of a protein and an activator (e.g., an agonist), refer to positively affecting (e.g., increasing) the activity or function of a protein compared to the activity or function of the protein in the absence of the activator. In various embodiments, activation refers to an increase in the activity of a signaling pathway or signal pathway. Thus, activation can include, at least in part, partially or fully increasing a stimulus, increasing or enabling activation, or activating, sensitizing, or upregulating signal transduction or enzymatic activity or the amount of a protein.

[0134] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule. In embodiments, the modulator is a modulator of TRK. In embodiments, the modulator is a compound that is a modulator of TRK and reduces the severity of one or more symptoms of a disease associated with TRK (e.g., decreases TRK activity or protein levels associated with an inflammatory disease, an infectious disease, an autoimmune disorder, stroke, ischemia, cardiac dysfunction, a neurological disorder, a fibrotic disorder, a proliferative disorder, a hyperproliferative disorder, a non-cancerous hyperproliferative disorder, a tumor, leukemia, a neoplasm, cancer, carcinoma, a metabolic disease, a malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic pain, or neuropathic pain). In various embodiments, the modulator is a compound that reduces the severity of one or more symptoms of a disease or disorder selected from inflammatory diseases, infectious diseases, autoimmune disorders, stroke, ischemia, cardiac dysfunction, neurological disorders, fibrotic disorders, proliferative disorders, hyperproliferative disorders, non-cancerous hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, malignant diseases, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic pain, and neuropathic pain, which disease or disorder is not caused or characterized by TRK (e.g., TRK gain of function), but which may benefit from modulation of TRK activity (e.g., decreasing TRK levels or TRK activity).

[0135] "Disease," "condition," or "disorder" refers to an existence or state of health in a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In embodiments, the disease is a disease associated with (e.g., characterized by) elevated levels of TRK. In embodiments, the disease is an inflammatory disease, an infectious disease, an autoimmune disorder, stroke, ischemia, cardiac dysfunction, a neurological disorder, a fibrotic disorder, a proliferative disorder, a hyperproliferative disorder, a non-cancerous hyperproliferative disorder, a tumor, leukemia, a neoplasm, cancer, carcinoma, a metabolic disease, a malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, chronic pain, or neuropathic pain.

[0136] As used herein, the term "signal pathway" refers to a series of interactions between cellular and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that communicate a change in one component to one or more other components, which can then communicate the change to additional components, which are optionally propagated to other signal pathway components.

[0137] Unless otherwise specified, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure will be apparent from the various examples. The examples provided illustrate various components and methods useful in practicing the present disclosure. These examples do not limit the claimed disclosure. Based on the present disclosure, one of ordinary skill in the art will be able to identify and use other components and methodologies useful in practicing the present disclosure.

[0138] B. Compound In various embodiments, pyrazolo[1,5-α]pyrimidine compounds are disclosed that can be prepared by the disclosed methods (e.g., compounds prepared by coupling a compound of formula (XVI) with a compound of formula XVII). It is understood that the disclosed compounds can be provided by the disclosed methods.

[0139] In various embodiments, the disclosed pyrazolo[1,5-α]pyrimidine compounds are useful as TRK inhibitors.

[0140] In various embodiments, the disclosed pyrazolo[1,5-α]pyrimidine compounds are useful for treating disorders associated with TRK activity in mammals. In further embodiments, the disclosed pyrazolo[1,5-α]pyrimidine compounds are useful for treating TRK activity in humans.

[0141] In some embodiments, the present disclosure provides a compound of any of formulas (VII)-(X) and (XII)-(XIV), wherein R 10 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 An aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be one or more R 1S and each R 1S are independently halogen, —O—(C1-C6 alkyl), or —N(C1-C6 alkyl)2.

[0142] In some embodiments, the present disclosure provides a compound of any of formulas (X) and (XIV) or a salt thereof, wherein R 10 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C1-C6 alkyl, C3-C8 cycloalkyl, C6-C 10 An aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be one or more R 1S and each R 1S are independently halogen, —O—(C1-C6 alkyl), or —N(C1-C6 alkyl)2.

[0143] In some embodiments, R 10 is one or more R 1S is C1-C6 alkyl optionally substituted with

[0144] In some embodiments, R 10 is C1-C6 alkyl optionally substituted with one or more halogens (eg, F, Cl, Br, or I).

[0145] In some embodiments, R 10 is C1-C6 alkyl optionally substituted with one or more F.

[0146] In some embodiments, R 10is one or more R 1S is methyl optionally substituted with

[0147] In some embodiments, R 10 is methyl optionally substituted with one or more halogens (eg, F, Cl, Br, or I).

[0148] In some embodiments, R 10 is CF3.

[0149] In some embodiments, R 10 is C3-C8 cycloalkyl, C6-C 10 aryl, 3-8 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C3-C8 cycloalkyl, C6-C 10 An aryl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heteroaryl may be one or more R 1S is optionally replaced by

[0150] In some embodiments, R 10 is one or more R 1S is a C3-C8 cycloalkyl optionally substituted with

[0151] In some embodiments, R 10 is one or more R 1S C6-C optionally substituted with 10 It is aryl.

[0152] In some embodiments, R 10 is one or more R 1S is a 3- to 8-membered heterocycloalkyl optionally substituted with

[0153] In some embodiments, R 10 is one or more R 1S is a 5-10 membered heteroaryl optionally substituted with

[0154] In some embodiments, at least one R 1S is a halogen (e.g., F, Cl, Br, or I).

[0155] In some embodiments, at least one R 1S is F.

[0156] In some embodiments, at least one R 1S is —O—(C1-C6 alkyl).

[0157] In some embodiments, at least one R 1S is —N(C1-C6 alkyl)2.

[0158] In some embodiments, the compound of formula (VII) is compound number 7.

[0159] In some embodiments, the compound of Formula (VIII) is Compound No. 8.

[0160] In some embodiments, the compound of formula (IX) is compound number 9.

[0161] In some embodiments, the compound of Formula (X) is Compound No. 10.

[0162] In some embodiments, the compound of Formula (XII) is Compound No. 12.

[0163] In some embodiments, the compound of Formula (XIII) is Compound No. 13.

[0164] In some embodiments, the compound of Formula (XIV) is Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)).

[0165] In some embodiments, the compound is selected from Compound Nos. 1-14.

[0166] In some embodiments, the compound is selected from Compound Nos. 6, 10, 14, and salts thereof.

[0167] In some embodiments, the compound is selected from compound numbers 6, 10, and 14.

[0168] In some embodiments, the compound is selected from Compound Nos. 7-14.

[0169] In some embodiments, the compound is selected from Compound Nos. 9-10 and 12-13.

[0170] In embodiments, the present disclosure provides compounds prepared by the methods described herein.

[0171] In some embodiments, the present disclosure provides a compound prepared by the methods disclosed herein, wherein the compound is selected from Compound Nos. 1-14.

[0172] In some embodiments, the present disclosure provides a compound prepared by the methods disclosed herein, wherein the compound is selected from Compound Nos. 6, 10, 14, and salts thereof.

[0173] In some embodiments, the present disclosure provides a compound prepared by the methods disclosed herein, wherein the compound is selected from Compound Nos. 6, 10, and 14.

[0174] In some embodiments, the present disclosure provides a compound prepared by the methods disclosed herein, wherein the compound is selected from Compound Nos. 7-10.

[0175] In some embodiments, the present disclosure provides a compound prepared by the methods disclosed herein, wherein the compound is selected from Compound Nos. 12-14.

[0176] In some embodiments, the present disclosure provides Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)), or a salt thereof, prepared by the methods disclosed herein.

[0177] In some embodiments, the present disclosure provides Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)), prepared by the methods disclosed herein.

[0178] 1. Structure In some embodiments, the present disclosure provides a compound of formula (XXV): The present invention provides a compound of formula TIFF0007767301000085.tif35128, or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the present disclosure provides a compound of formula (XV): TIFF0007767301000086.tif25128, or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; Ar 2 is a C6-C10 aryl or 5-6 membered heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0180] In some embodiments, the compound of formula (XV) is TIFF0007767301000087.tif25128.

[0181] In some embodiments, the compound of formula (XV) has the formula: It has a structure represented by TIFF0007767301000088.tif24128.

[0182] In some embodiments, the compound of formula (XV) has the formula: TIFF0007767301000089.tif39128, In the formula, R 30a , R 30b , R 30c , R 30d, and R 30e are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, with the proviso that R 30a , R 30b , R 30c , R 30d , and R 30e are hydrogen.

[0183] In some embodiments, the compound of formula (XV) is TIFF0007767301000090.tif39132.

[0184] In some embodiments, the compound of formula (XV) has a structure represented by the following formula: TIFF0007767301000091.tif39128

[0185] In some embodiments, the compound of formula (XV) is Selected from TIFF0007767301000092.tif85128TIFF0007767301000093.tif183128TIFF0007767301000094.tif192131TIFF0007767301000095.tif183136TIFF0007767301000096.tif179132TIFF0007767301000097.tif188135TIFF0007767301000098.tif195133TIFF0007767301000099.tif194133TIFF0007767301000100.tif137128

[0186] In some embodiments, the compound of formula (XV) is: TIFF0007767301000101.tif34128

[0187] In some embodiments, the compound of formula (XV) is Selected from TIFF0007767301000102.tif222128TIFF0007767301000103.tif191134TIFF0007767301000104.tif188133TIFF0007767301000105.tif180136TIFF0007767301000106.tif186132TIFF0007767301000107.tif190133TIFF0007767301000108.tif197133TIFF0007767301000109.tif188128

[0188] In some embodiments, the compound of formula (XV) is: TIFF0007767301000110.tif34128

[0189] In some embodiments, the compound of formula (XV) is Selected from TIFF0007767301000111.tif175128TIFF0007767301000112.tif190132TIFF0007767301000113.tif190134TIFF0007767301000114.tif179136TIFF0007767301000115.tif187132TIFF0007767301000116.tif188133TIFF0007767301000117.tif199133TIFF0007767301000118.tif189129TIFF0007767301000119.tif42128

[0190] In some embodiments, the compound of formula (XV) is: TIFF0007767301000120.tif34128

[0191] In some embodiments, the disclosed pyrazolo[1,5-α]pyrimidine compounds are enantiomerically pure. Thus, in various embodiments, the disclosed pyrazolo[1,5-α]pyrimidine compounds have an enantiomeric purity of at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or greater than 99%.

[0192] In some embodiments, the disclosed pyrazolo[1,5-α]pyrimidine compounds can be provided in enantiomeric excess (ee). Thus, in various embodiments, the enantiomeric excess of the desired enantiomer of the disclosed pyrazolo[1,5-α]pyrimidine compounds is at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In further embodiments, the "S" forms of the disclosed pyrazolo[1,5-α]pyrimidine compounds are substantially free of the "R" forms. In yet further embodiments, the "R" forms of the disclosed pyrazolo[1,5-α]pyrimidine compounds are substantially free of the "S" forms.

[0193] In some embodiments, the "S" forms of the disclosed pyrazolo[1,5-α]pyrimidine compounds are present in an amount greater than about 50%, greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 98%, or greater than about 99% relative to the "R" forms.

[0194] In some embodiments, the "R" forms of the disclosed pyrazolo[1,5-α]pyrimidine compounds are present in an amount greater than about 50%, greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 98%, or greater than about 99% relative to the "S" forms.

[0195] a.R 10 base In some embodiments, R 10is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C4 alkyl) OR 20 , -(C1-C4 alkyl)SR 20 , -(C1-C4 alkyl)C(O)R 20 , -(C1-C4 alkyl)S(O)R 20 , -(C1-C4 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 In some embodiments, R 10 represents hydrogen, -F, -Cl, -CN, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2Cl, -CH2CH2CHCl2, -CH2CH2CCl3, -CH(CH3)CH2F, -CH(CH3)CHF2, -CH(CH3)CF3, -CH(CH3)CH2Cl, -CH(CH3)CHCl2, -CH(CH3)CCl3, -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, -CH(CH3)CH2CN, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -CH2OR 20 , -CH2CH2OR 20 , -CH2CH2CH2OR 20 , -CH(CH3)CH2OR 20 , -CH2SR 20 , -CH2CH2SR 20 , -CH2CH2CH2SR 20 , -CH(CH3)CH2SR 20 , -CH2C(O)R 20 , -CH2CH2C(O)R 20 , -CH2CH2CH2C(O)R 20 , -CH(CH3)CH2C(O)R 20 , -CH2C(S)R 20 , -CH2CH2C(S)R 20 , -CH2CH2CH2C(S)R 20 , -CH(CH3)CH2C(S)R 20 , -CH2SO2R 20 , -CH2CH2SO2R 20 , -CH2CH2CH2SO2R 20, -CH(CH3)CH2SO2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -CH2NR 22a R 22b , -CH2CH2NR 22a R 22b , -CH2CH2CH2NR 22a R 22b , -CH(CH3)CH2NR 22a R 22b , -CH2P(O)R 22a R 22b , -CH2CH2P(O)R 22a R 22b , -CH2CH2CH2P(O)R 22a R 22b , -CH(CH3)CH2P(O)R 22a R 22b , and Cy 1 In some embodiments, R 10 represents hydrogen, -F, -Cl, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CN, -CH2CH2CN, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -CH2OR 20 , -CH2CH2OR 20 , -CH2SR 20 , -CH2CH2SR 20 , -CH2C(O)R 20 , -CH2CH2C(O)R 20 , -CH2C(S)R 20 , -CH2CH2C(S)R 20 , -CH2SO2R 20 , -CH2CH2SO2R 20 , -NR 21 C(O)R20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -CH2NR 22a R 22b , -CH2CH2NR 22a R 22b , -CH2P(O)R 22a R 22b , -CH2CH2P(O)R 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CN, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -CH2OR 20 , -CH2SR 20 , -CH2C(O)R 20 , -CH2C(S)R 20 , -CH2SO2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -CH2NR 22a R 22b , -CH2P(O)R 22a R 22b , and Cy 1 is selected from.

[0196] In some embodiments, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, C1-C4 alkyl, C1-C4 haloalkyl, and Cy 1In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2Cl, -CH2CH2CHCl2, -CH2CH2CCl3, -CH(CH3)CH2F, -CH(CH3)CHF2, -CH(CH3)CF3, -CH(CH3)CH2Cl, -CH(CH3)CHCl2, -CH(CH3)CCl3, and Cy 1 In some embodiments, R 10 represents hydrogen, -F, -Cl, -CN, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, and Cy 1 is selected from.

[0197] In some embodiments, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 cyanoalkyl, and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, C1-C4 alkyl, C1-C4 cyanoalkyl, and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, ethyl, n-propyl, isopropyl, -CHCN, -CHCHCN, -CHCHCHCN, -CH(CH)CHCN, and Cy 1 In some embodiments, R 10is hydrogen, -F, -Cl, -CN, methyl, ethyl, -CHCN, -CHCHCN, and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, -CHCN, and Cy 1 is selected from.

[0198] In some embodiments, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, -OR 20 , -C(O)R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)C(O)R 20 , -NR 21 C(O)R 20 , -NR 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, C1-C4 alkyl, -OR 20 , -C(O)R 20 , -(C1-C4 alkyl) OR 20 , -(C1-C4 alkyl)C(O)R 20 , -NR 21 C(O)R 20 , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, ethyl, n-propyl, isopropyl, -OR 20 , -C(O)R 20 , -CH2OR 20 , -CH2CH2OR 20 , -CH2CH2CH2OR 20 , -CH(CH3)CH2OR 20 , -CH2C(O)R 20 , -CH2CH2C(O)R 20 , -CH2CH2CH2C(O)R 20 , -CH(CH3)CH2C(O)R 20 , -NR 21 C(O)R 20 , and Cy 1In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, ethyl, -OR 20 , -C(O)R 20 , -CH2OR 20 , -CH2CH2OR 20 , -CH2C(O)R 20 , -CH2CH2C(O)R 20 , -NR 21 C(O)R 20 , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, -OR 20 , -C(O)R 20 , -CH2OR 20 , -CH2C(O)R 20 , -NR 21 C(O)R 20 , and Cy 1 is selected from.

[0199] In some embodiments, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 S(O)2R 20 , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, -S(O)R 20 , -S(O)2R 20 , -(C1-C4 alkyl)SR 20 , -(C1-C4 alkyl)S(O)R 20 , -(C1-C4 alkyl)S(O)2R 20 , -NR 21 S(O)2R 20 , and Cy 1 In some embodiments, R 10is hydrogen, -F, -Cl, -CN, methyl, ethyl, n-propyl, isopropyl, -S(O)R 20 , -S(O)2R 20 , -CH2SR 20 , -CH2CH2SR 20 , -CH2CH2CH2SR 20 , -CH(CH3)CH2SR 20 , -CH2C(S)R 20 , -CH2CH2C(S)R 20 , -CH2CH2CH2C(S)R 20 , -CH(CH3)CH2C(S)R 20 , -CH2SO2R 20 , -CH2CH2SO2R 20 , -CH2CH2CH2SO2R 20 , -CH(CH3)CH2SO2R 20 , -NR 21 S(O)2R 20 , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, ethyl, -S(O)R 20 , -S(O)2R 20 , -CH2SR 20 , -CH2CH2SR 20 , -CH2C(S)R 20 , -CH2CH2C(S)R 20 , -CH2SO2R 20 , -CH2CH2SO2R 20 , -NR 21 S(O)2R 20 , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, -S(O)R 20 , -S(O)2R 20 , -CH2SR 20 , -CH2C(S)R 20 , -CH2SO2R 20 , -NR 21 S(O)2R 20 , and Cy 1 is selected from.

[0200] In some embodiments, R 10 is hydrogen, halogen, -CN, -NR 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, -NR 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, ethyl, n-propyl, isopropyl, -NR 22a R 22b , -CH2NR 22a R 22b , -CH2CH2NR 22a R 22b , -CH2CH2CH2NR 22a R 22b , -CH(CH3)CH2NR 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, ethyl, -NR 22a R 22b , -CH2NR 22a R 22b , -CH2CH2NR 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, -NR 22a R 22b , -CH2NR 22a R 22b , and Cy 1 is selected from.

[0201] In some embodiments, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, -P(O)R 22a R 22b, -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, C1-C4 alkyl, -P(O)R 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, ethyl, n-propyl, isopropyl, -P(O)R 22a R 22b , -CH2P(O)R 22a R 22b , -CH2CH2P(O)R 22a R 22b , -CH2CH2CH2P(O)R 22a R 22b , -CH(CH3)CH2P(O)R 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, ethyl, -P(O)R 22a R 22b , -CH2P(O)R 22a R 22b , -CH2CH2P(O)R 22a R 22b , and Cy 1 In some embodiments, R 10 is hydrogen, -F, -Cl, -CN, methyl, -P(O)R 22a R 22b , -CH2P(O)R 22a R 22b , and Cy 1 is selected from.

[0202] In some embodiments, R 10 is selected from hydrogen and C1-C6 alkyl. In some embodiments, R 10 is selected from hydrogen and C1-C4 alkyl. In some embodiments, R10 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. 10 is selected from hydrogen, methyl, and ethyl. In some embodiments, R 10 is selected from hydrogen and ethyl. In some embodiments, R 10 is selected from hydrogen and methyl.

[0203] In some embodiments, R 10 is selected from hydrogen and halogen, and in some embodiments, R 10 is selected from hydrogen, —F, —Cl, and —Br. In some embodiments, R 10 is selected from hydrogen, —F, and —Cl. In some embodiments, R 10 is selected from hydrogen and —Cl. In some embodiments, R 10 is selected from hydrogen and —F.

[0204] In some embodiments, R 10 is hydrogen and Cy 1 is selected from.

[0205] In some embodiments, R 10 is selected from hydrogen and C1-C6 haloalkyl. 10 is selected from hydrogen and C1-C4 haloalkyl. 10 is selected from hydrogen, —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —CHCHF, —CHCHF, —CHCF, —CHCHCl, —CHCHCl, —CHCCl, —CHCHCHF, —CHCHCHF, —CHCHCF, —CHCHCHCl, —CHCHCl, —CHCCl, —CHCHCHF, —CHCHCHF, —CHCHCF, —CHCHCHCHCl, —CHCHCHCl, —CHCHCCl, —CH(CH)CHF, —CH(CH)CHF, —CH(CH)CF, —CH(CH)CHCl, —CH(CH)CHCl, and —CH(CH)CCl. 10is selected from hydrogen, —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —CHCHF, —CHCHF, —CHCF, —CHCHCl, —CHCHCl, and —CHCCl. 10 is selected from hydrogen, —CHF, —CHF, —CF, —CHCl, —CHCl, and —CCl.

[0206] In some embodiments, R 10 is C1-C6 haloalkyl. In a further embodiment, R 10 is C1-C4 haloalkyl. In a further embodiment, R 10 is selected from —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —CHCHF, —CHCHF, —CHCF, —CHCHCl, —CHCHCl, —CHCCl, —CHCHCHF, —CHCHCHF, —CHCHCF, —CHCHCHCl, —CHCHCl, —CHCCl, —CHCHCHF, —CHCHCHF, —CHCHCF, —CHCHCHCHCl, —CHCHCHCl, —CHCHCCl, —CH(CH)CHF, —CH(CH)CHF, —CH(CH)CF, —CH(CH)CHCl, —CH(CH)CHCl, and —CH(CH)CCl. 10 is selected from —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —CHCHF, —CHCHF, —CHCF, —CHCHCl, —CHCHCl, and —CHCCl. 10 is selected from —CHF, —CHF, —CF, —CHCl, —CHCl, and —CCl.

[0207] In a further embodiment, R 10 is -CF3.

[0208] b. R 20 Group, R 21 Group, R 22a groups, and R 22b base In some embodiments, R20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl. 20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, -CHF, -CHF, -CF, -CHCl, -CHCl, -CCl, -CHCHF, -CHCHF, -CHCF, -CHCHCl, -CHCHCl, -CHCCl, -CHCHCHF, -CHCHCHF, -CHCHCF, -CHCHCHCl, -CHCHCl, -CHCCl, -CHCHCHF, -CHCHCHF, -CHCHCF, -CHCHCHCHCl, -CHCHCHCl, -CHCHCCl, -CH(CH)CHF, -CH(CH)CHF, -CH(CH)CHF, -CH(CH)CF, -CH(CH)CHCl, -CH(CH)CHCl, and -CH(CH)CCl. 20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen, methyl, ethyl, —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —CHCHF, —CHCHF, —CHCF, —CHCHCl, —CHCHCl, and —CHCCl. In some embodiments, R 20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen, methyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , and —CCl 3 .

[0209] In some embodiments, R 20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen and C1-C4 alkyl. In some embodiments, R 20 , R21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In some embodiments, R 20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen, methyl, and ethyl. In some embodiments, R 20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen and ethyl. In some embodiments, R 20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen and methyl.

[0210] In some embodiments, R 20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen and C1-C4 haloalkyl. In some embodiments, R 20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen, —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —CHCHF, —CHCHF, —CHCF, —CHCHCl, —CHCHCl, —CHCCl, —CHCHCHF, —CHCHCHF, —CHCHCF, —CHCHCHCl, —CHCHCl, —CHCCl, —CHCHCHF, —CHCHCHF, —CHCHCF, —CHCHCHCHCl, —CHCHCHCl, —CHCHCCl, —CH(CH)CHF, —CH(CH)CHF, —CH(CH)CF, —CH(CH)CHCl, —CH(CH)CHCl, and —CH(CH)CCl. 20 , R 21 , R 22a , and R 22bEach, if present, is independently selected from hydrogen, —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —CHCHF, —CHCHF, —CHCF, —CHCHCl, —CHCHCl, and —CHCCl. In some embodiments, R 20 , R 21 , R 22a , and R 22b Each, if present, is independently selected from hydrogen, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , and —CCl 3 .

[0211] In some embodiments, R 20 , R 21 , R 22a , and R 22b Each, if present, is hydrogen.

[0212] c.R 30a Group, R 30b Group, R 30c Group, R 30d groups, and R 30e base In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, with the proviso that R 30a , R 30b , R 30c , R 30d , and R 30e In some embodiments, at least two of R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy. 30a , R 30b , R30c , R 30d , and R 30e respectively represent hydrogen, -F, -Cl, methyl, ethyl, n-propyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2CH2Cl, -CH2CHCl2, -CH2CCl3, -CH2CH2CH2F, -CH2CH2CHF2, -CH2CH2CF3, -CH2CH2CH2Cl, -CH2CH2CHCl2, -CH2CH2CCl3, -CH(CH3)CH2F, -CH(CH3)CHF2, -CH(CH3)CF3, -CH(CH3)CH2Cl, -CH(CH3)CHCl2, -CH(CH3)CCl3, -OCH3, -OCH2CH3, -OCH 2CH2CH3, -OCH(CH3)CH3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHCl2, -OCCl3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, -OCH2CH2CH2Cl, -OCH2CH2CHCl2, -OCH2CH2CCl3, -OCH2CH2CH2F, -OCH2CH2CHF2, -OCH2CH2CF3, -OCH2CH2CH2Cl, -OCH2CH2CHCl2, -OCH2CH2CCl3, -OCH(CH3)CH2F, -OCH(CH3)CHF2, -OCH(CH3)CF3, -OCH(CH3)CH2Cl, -OCH(CH3)CHCl2, and -OCH(CH3)CCl3. 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, -F, -Cl, methyl, ethyl, -CHF, -CHF, -CF, -CHCl, -CHCl, -CCl, -CHCHF, -CHCHF, -CHCF, -CHCHCl, -CHCHCl, -CHCCl, -OCH, -OCHCH, -OCHF, -OCHF, -OCF, -OCHCl, -OCHCl, -OCCl, -OCHCHF, -OCHCHF, -OCHCF, -OCHCHCl, -OCHCHCl, and -OCHCCl.30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, —F, —Cl, methyl, —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —OCH, —OCHF, —OCHF, —OCF, —OCHCl, —OCHCl, and —OCCl.

[0213] In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl, with the proviso that R 30a , R 30b , R 30c , R 30d , and R 30e In some embodiments, at least two of R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4 haloalkyl. 30a , R 30b , R 30c , R 30d , and R 30eare each independently selected from hydrogen, -F, -Cl, methyl, ethyl, n-propyl, isopropyl, -CHF, -CHF, -CF, -CHCl, -CHCl, -CCl, -CHCHF, -CHCHF, -CHCF, -CHCHCl, -CHCHCl, -CHCCl, -CHCHCHF, -CHCHCHF, -CHCHCF, -CHCHCHCl, -CHCHCl, -CHCCl, -CHCHCHF, -CHCHCHF, -CHCHCF, -CHCHCHCHCl, -CHCHCHCl, -CHCHCCl, -CH(CH)CHF, -CH(CH)CHF, -CH(CH)CF, -CH(CH)CHCl, -CH(CH)CHCl, and -CH(CH)CCl. 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, —F, —Cl, methyl, ethyl, —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —CHCHF, —CHCHF, —CHCF, —CHCHCl, —CHCHCl, and —CHCCl. 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, —F, —Cl, methyl, —CHF, —CHF, —CF, —CHCl, —CHCl, and —CCl.

[0214] In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, C1-C6 alkoxy, and C1-C6 haloalkoxy, with the proviso that R 30a , R 30b , R 30c , R 30d , and R 30e In some embodiments, at least two of R 30a , R 30b , R 30c, R 30d , and R 30e are each independently selected from hydrogen, C1-C4 alkoxy, and C1-C4 haloalkoxy. 30a , R 30b , R 30c , R 30d , and R 30e are hydrogen, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)CH3, -OCH2F, -OCHF2, -OCF3, -OCH2Cl, -OCHC, respectively. l2, -OCCl3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCH2CH2Cl, -OCH2CHCl2, -OCH2CCl3, -OCH2CH2CH2 F, -OCH2CH2CHF2, -OCH2CH2CF3, -OCH2CH2CH2Cl, -OCH2CH2CHCl2, -OCH2CH2CCl3, -OCH(CH3)CH2F, independently selected from -OCH(CH3)CHF2, -OCH(CH3)CF3, -OCH(CH3)CH2Cl, -OCH(CH3)CHCl2, and -OCH(CH3)CCl3. In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, —OCH, —OCHCH, —OCHF, —OCHF, —OCF, —OCHCl, —OCHCl, —OCCl, —OCHCHF, —OCHCHF, —OCHCF, —OCHCHCl, —OCHCHCl, and —OCHCCl. 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 Cl, —OCHCl 2 , and —OCCl 3 .

[0215] In some embodiments, R 30a , R 30b , R 30c , R 30d , and R30e are each independently selected from hydrogen and C1-C6 alkyl, with the proviso that R 30a , R 30b , R 30c , R 30d , and R 30e In some embodiments, at least two of R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen and C1-C4 alkyl. In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e Each is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, methyl, and ethyl. In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e Each is independently selected from hydrogen and ethyl. In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen and methyl.

[0216] In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen and C1-C6 haloalkyl, with the proviso that R 30a , R 30b , R 30c , R 30d , and R 30eIn some embodiments, at least two of R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen and C1-C4 haloalkyl. 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —CHCHF, —CHCHF, —CHCF, —CHCHCl, —CHCHCl, —CHCCl, —CHCHCHF, —CHCHF, —CHCHCF, —CHCHCl, —CHCHCl, —CHCCl, —CHCHCHF, —CHCHCHF, —CHCHCF, —CHCHCHCl, —CHCHCHCl, —CHCHCCl, —CH(CH)CHF, —CH(CH)CHF, —CH(CH)CF, —CH(CH)CHCl, —CH(CH)CHCl, and —CH(CH)CCl. 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, —CHF, —CHF, —CF, —CHCl, —CHCl, —CCl, —CHCHF, —CHCHF, —CHCF, —CHCHCl, —CHCHCl, and —CHCCl. 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, —CHF, —CHF, —CF, —CHCl, —CHCl, and —CCl.

[0217] In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30eare each independently selected from hydrogen and halogen. 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, —F, —Cl, and —Br. In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, —F, and —Cl. 30a , R 30b , R 30c , R 30d , and R 30e Each is independently selected from hydrogen and —Cl. In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen and —F.

[0218] In some embodiments, R 30a , R 30b , R 30c , R 30d , and R 30e are hydrogen atoms.

[0219] d. Cy 1 base In some embodiments, Cy 1 When present, Cy is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl.1 When present, Cy is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, Cy is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, Cy is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is monosubstituted with a group selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is unsubstituted.

[0220] In some embodiments, Cy 1When present, Cy is selected from C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, Cy is selected from C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, Cy is selected from C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1When present, Cy is selected from C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, and is monosubstituted with a group selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, is selected from C3-C8 cycloalkyl and 3- to 8-membered heterocycloalkyl, and is unsubstituted.

[0221] In some embodiments, Cy 1 When present, Cy is C3-C8 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. Examples of C3-C8 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and spiro[2.4]heptane. In some embodiments, Cy is 1 When present, Cy is C3-C8 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1When present, Cy is C3-C8 cycloalkyl substituted with zero or one group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In some embodiments, Cy 1 When present, Cy is C3-C8 cycloalkyl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In some embodiments, Cy 1 When present, is unsubstituted C3-C8 cycloalkyl.

[0222] In some embodiments, Cy 1 When present, Cy is a 3- to 8-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. Examples of 3- to 8-membered heterocycloalkyl include, but are not limited to, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, thiane, 1,3-dithiane, 1,4-dithiane, thiomorpholine, dioxane, morpholine, and hexahydro-1H-furo[3,4-c]pyrrole. In some embodiments, Cy is a 3- to 8-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. Examples of 3- to 8-membered heterocycloalkyl include, but are not limited to, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, thiane, 1,3-dithiane, 1,4-dithiane, thiomorpholine, dioxane, morpholine, 1When present, Cy is a 3-8 membered heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, Cy is a 3-8 membered heterocycloalkyl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In some embodiments, Cy 1 When present, Cy is a 3-8 membered heterocycloalkyl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In some embodiments, Cy 1 When present, is unsubstituted 3-8 membered heterocycloalkyl.

[0223] In some embodiments, Cy 1When present, Cy is selected from C6-C10 aryl and 5-10 membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, Cy is selected from C6-C10 aryl and 5-10 membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, Cy is selected from C6-C10 aryl and 5-10 membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1When present, Cy is selected from C6-C10 aryl and 5-10 membered heteroaryl, and is monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, is selected from C6-C10 aryl and 5-10 membered heteroaryl, and is unsubstituted.

[0224] In some embodiments, Cy 1 When present, Cy is C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. Examples of C6-C10 aryl include, but are not limited to, phenyl and naphthyl. In some embodiments, Cy is 1 When present, Cy is C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1When present, Cy is C6-C10 aryl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, Cy is a C6-C10 aryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1 When present, is unsubstituted C6-C10 aryl.

[0225] In some embodiments, Cy 1When present, is a 5-10 membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. Examples of 5-10 membered heteroaryls include furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, and pyrazoloyl. Examples include, but are not limited to, pyridinyl, pyrazolopyrimidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl. 1 When present, Cy is a 5-10 membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. 1When present, Cy is a 5-10 membered heteroaryl substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In some embodiments, Cy 1 When present, Cy is a 5-10 membered heteroaryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In some embodiments, Cy 1 When present, is unsubstituted 5-10 membered heteroaryl.

[0226] e. Ar 2 base In some embodiments, Ar 2 is a C6-C10 aryl or 5-6 membered heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is a C6-C10 aryl or 5-6 membered heteroaryl and is substituted with 0, 1, or 2 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is a C6-C10 aryl or 5-6 membered heteroaryl and is substituted with 0 or 1 group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.2 is a C6-C10 aryl or 5-6 membered heteroaryl and is monosubstituted with a group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is a C6-C10 aryl or 5- or 6-membered heteroaryl, and is unsubstituted.

[0227] In some embodiments, Ar 2 is a C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. Examples of C6-C10 aryl include, but are not limited to, phenyl and naphthyl. In some embodiments, Ar 2 is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is a C6-C10 aryl monosubstituted with a group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is an unsubstituted C6-C10 aryl.

[0228] In some embodiments, Ar 2 is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is phenyl substituted with 0 or 1 group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is phenyl monosubstituted with a group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is unsubstituted phenyl.

[0229] In some embodiments, Ar 2 is a 5- to 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. Examples of 5- to 6-membered heteroaryl include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, and pyrazinyl. In some embodiments, Ar 2 is a 5-6 membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In some embodiments, Ar 2 is a 5-6 membered heteroaryl substituted with 0 or 1 group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. In some embodiments, Ar 2is a 5-6 membered heteroaryl monosubstituted with a group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is an unsubstituted 5-6 membered heteroaryl.

[0230] In some embodiments, Ar 2 is pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is pyridinyl substituted with 0 or 1 group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is pyridinyl monosubstituted with a group selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. 2 is unsubstituted pyridinyl.

[0231] 2. Examples of pyrazolo[1,5-α]pyrimidine compounds In some embodiments, the compound has the structure: TIFF0007767301000121.tif34128, or a pharmaceutically acceptable salt thereof.

[0232] C. Compound of Formula (XVI) In various embodiments, compounds of formula (XVI) useful in the disclosed methods are disclosed. It is understood that the disclosed compounds can be provided by the disclosed methods.

[0233] In various embodiments, the disclosed compounds of formula (XVI) are useful as intermediates in the synthesis of pyrazolo[1,5-α]pyrimidine compounds useful as TRK inhibitors.

[0234] 1. Structure In some embodiments, the present disclosure provides a compound of formula (XVI): TIFF0007767301000122.tif25128[where, X 1 is a leaving group and R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1is, if present, selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl, or a salt thereof.

[0235] In some embodiments, the compound of formula (XVI) is Selected from TIFF0007767301000123.tif26128TIFF0007767301000124.tif187128TIFF0007767301000125.tif199120TIFF0007767301000126.tif187128TIFF0007767301000127.tif191128TIFF0007767301000128.tif204118TIFF0007767301000129.tif71128

[0236] In some embodiments, the compound of formula (XVI) has the structure: TIFF0007767301000130.tif25128

[0237] In some embodiments, X 1 is a leaving group. Examples of leaving groups include, but are not limited to, halides, alkyl halides (e.g., trifluoromethyl), and sulfonate esters (e.g., triflate, mesylate, tosylate, brosylate). In further embodiments, X 1 is a halide. In still further embodiments, X 1 is fluoride, chloride, or bromide. 1is fluoride or chloride. 1 is chloride or bromide. In still further embodiments, X 1 is bromide or iodide. In still further embodiments, X 1 is chloride.

[0238] 2. Examples of compounds of formula (XVI) In some embodiments, the compound has the following structure: TIFF0007767301000131.tif25128 or a pharmaceutically acceptable salt thereof.

[0239] D. Amides of formula (XVIII) In various embodiments, disclosed are amides of formula (XVIII) useful in the disclosed methods. It is understood that the disclosed compounds can be provided by the disclosed methods.

[0240] In various embodiments, the disclosed amides of formula (XVIII) are useful as intermediates in the synthesis of pyrazolo[1,5-α]pyrimidine compounds useful as TRK inhibitors.

[0241] 1. Structure In some embodiments, the present disclosure provides a compound of formula (XVIII): TIFF0007767301000132.tif26128[where, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 is, if present, selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl, or a salt thereof.

[0242] In some embodiments, the compound of formula (XVIII) is Selected from TIFF0007767301000133.tif221115TIFF0007767301000134.tif199120TIFF0007767301000135.tif188128TIFF0007767301000136.tif191128TIFF0007767301000137.tif204118TIFF0007767301000138.tif71128

[0243] In some embodiments, the compound of Formula (XVIII) has the structure: I have TIFF0007767301000139.tif25128.

[0244] 2. Examples of amides of formula (XVIII) In some embodiments, the compound has the following structure: TIFF0007767301000140.tif25128, or a pharmaceutically acceptable salt thereof.

[0245] E. Additional Compounds Various embodiments relate to compounds useful in the disclosed methods. It is understood that the disclosed compounds can be provided by the disclosed methods.

[0246] In various embodiments, the disclosed compounds are useful as intermediates in the synthesis of pyrazolo[1,5-α]pyrimidine compounds that are useful as TRK inhibitors.

[0247] Thus, in some embodiments, the present disclosure provides a compound having the structure: The present invention provides a compound having the formula TIFF0007767301000141.tif25128, or a salt thereof.

[0248] In some embodiments, the present disclosure provides a compound having the structure: The present invention provides a compound having the formula TIFF0007767301000142.tif29128, or a salt thereof.

[0249] In some embodiments, the present disclosure provides a compound of formula (XVII): TIFF0007767301000143.tif15128[where, Ar 2 is a C6-C10 aryl or 5-6 membered heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. or a pharmaceutically acceptable salt thereof.

[0250] In a further embodiment, the compound of formula (XVII) is TIFF0007767301000144.tif24128, In the formula, R 30a , R 30b , R 30c , R 30d , and R 30e are each independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy, with the proviso that R 30a , R 30b , R 30c , R 30d , and R 30e are hydrogen.

[0251] In a further embodiment, the compound of formula (XVII) has the formula: It has a structure represented by TIFF0007767301000145.tif23128.

[0252] In a further embodiment, the compound of formula (XVII) has the structure: I have TIFF0007767301000146.tif23128.

[0253] In a further embodiment, the compound of formula (XVII) is It has a structure selected from TIFF0007767301000147.tif23128.

[0254] In a further embodiment, the compound of formula (XVII) has the structure: I have TIFF0007767301000148.tif23128.

[0255] In some embodiments, the present disclosure provides a compound of formula (XIX): TIFF0007767301000149.tif25128[where, R 10is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. or a pharmaceutically acceptable salt thereof.

[0256] In some embodiments, the compound of Formula (XIX) has the structure: I have TIFF0007767301000150.tif25128.

[0257] In some embodiments, the present disclosure provides a compound of formula (XX): The present invention provides a compound having a structure represented by TIFF0007767301000151.tif18128, or a salt thereof.

[0258] In some embodiments, the present disclosure provides a compound of formula (XXI): TIFF0007767301000152.tif30128[where, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; R 31a and R 31b are each independently C1-C4 alkyl. or a pharmaceutically acceptable salt thereof.

[0259] In some embodiments, the compound of formula (XXI) has the formula: It has a structure represented by TIFF0007767301000153.tif29128.

[0260] In some embodiments, the compound of Formula (XXI) has the structure: I have TIFF0007767301000154.tif29128.

[0261] In some embodiments, R 31a and R 31b are each independently C1-C4 alkyl. In some embodiments, R 31a and R 31b Each is independently selected from methyl, ethyl, n-propyl, and isopropyl. In some embodiments, R 31a and R 31b are each independently selected from methyl and ethyl. In some embodiments, R 31a and R 31b Each R is ethyl. 31a and R 31b are each methyl.

[0262] In some embodiments, the present disclosure provides a compound of formula (XXII): TIFF0007767301000155.tif19128[where, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. or a pharmaceutically acceptable salt thereof.

[0263] In some embodiments, the compound of Formula (XXII) has the structure: I have TIFF0007767301000156.tif18128.

[0264] In some embodiments, the present disclosure provides a compound of formula (XXIII): TIFF0007767301000157.tif16128[where, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the compound of formula (XXIII) has the formula: It has a structure represented by TIFF0007767301000158.tif15128.

[0266] In some embodiments, the present disclosure provides a compound of formula (XXIV): providing a compound having a structure represented by TIFF0007767301000159.tif6128; In the formula, X 2 is a halogen. Examples of halogen include, but are not limited to, -F, -Br, and -Cl. Thus, in some embodiments, X 2 is -F. In some embodiments, X 2 is -Br. In some embodiments, X 2 is -Cl.

[0267] In some embodiments, the compound of Formula (XXIV) has the structure: I have TIFF0007767301000160.tif4128.

[0268] F. Compound Preparation Method In some embodiments, the present disclosure provides a compound of formula (XXV):

[0013] The present invention provides a method for making a compound having a structure represented by the formula: TIFF0007767301000161.tif35128, or a pharmaceutically acceptable salt thereof, the method comprising: Formula (XXVI): TIFF0007767301000162.tif26128 and a compound having the structure represented by the formula: TIFF0007767301000163.tif25128, whereby TIFF0007767301000164.tif26128 is X 1 In the formula, X 1 is a leaving group.

[0269] In some embodiments, the present disclosure provides a compound having the structure: TIFF0007767301000165.tif35128, or a pharmaceutically acceptable salt thereof, the method comprising: (a) Structure: TIFF0007767301000166.tif18128 to form a nitrile having the structure: TIFF0007767301000167.tif15128 and a heteroaryl having formula (XXIV): TIFF0007767301000168.tif6128, (b) Structure: TIFF0007767301000169.tif29128 by reacting a nitrile with formamidine acetal; (c) Structure: TIFF0007767301000170.tif25128 by cyclizing acrylonitrile with hydrazine; (d) Structure: TIFF0007767301000171.tif25128 to form an amide having the structure: TIFF0007767301000172.tif17128 by reacting uracil with (e) Formula (XXVI): preparing a compound having a structure represented by the formula: TIFF0007767301000173.tif26128 by reacting an amide with a halogenating agent; and (f) reacting a compound of formula (XXV) with a compound of formula (XXVI) having the structure: TIFF0007767301000174.tif23128, In the formula, X 1 is a leaving group and X 2 is a halogen.

[0270] In some embodiments, the present disclosure provides a compound of formula (XV): TIFF0007767301000175.tif25128, or a pharmaceutically acceptable salt thereof, the method comprising: TIFF0007767301000176.tif25128 and a compound of formula (XVII): TIFF0007767301000177.tif14128, thereby forming R 1 is X 1 In the formula, X 1 is a leaving group and R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; Ar 2 is a C6-C10 aryl or 5-6 membered heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0271] In some embodiments, the present disclosure provides a compound of formula (XV): TIFF0007767301000178.tif25128, or a pharmaceutically acceptable salt thereof, the method comprising: (a) Formula (XXII): TIFF0007767301000179.tif19128, by reacting a nitrile having a structure represented by formula (XXIII): TIFF0007767301000180.tif16128 and a heteroaryl having a structure represented by formula (XXIV): with a haloacetonitrile having the structure represented by TIFF0007767301000181.tif6128; (b) Formula (XXI): preparing an acrylonitrile having a structure represented by TIFF0007767301000182.tif30128 by reacting a nitrile of formula (XXII) with formamidine acetal; (c) Formula (XIX): preparing an amine having a structure represented by TIFF0007767301000183.tif25128 by cyclizing an acrylonitrile of formula (XXI); (d) Formula (XVIII): TIFF0007767301000184.tif26128, by reacting an amine of formula (XIX) with an amide of formula (XX): TIFF0007767301000185.tif18128, (e) Formula (XVI): preparing a compound having a structure represented by TIFF0007767301000186.tif25128 by reacting an amide of formula (XVIII) with an activating agent; and (f) reacting a compound of formula (XV) with a compound of formula (XVI) and a compound of formula (XVII): TIFF0007767301000187.tif15128, In the formula, X 1 is a leaving group and X 2 is a halogen and R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20, -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; Ar 2 is a C6-C10 aryl or 5- to 6-membered heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; R 31a and R 31bare each independently C1 to C4 alkyl.

[0272] In some embodiments, the present disclosure provides a compound of formula (XVI): TIFF0007767301000188.tif25128, or a pharmaceutically acceptable salt thereof, the method comprising producing a compound having a structure represented by formula (XVIII): TIFF0007767301000189.tif26128 with an activating agent, wherein X 1 is a leaving group and R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl.

[0273] In some embodiments, the present disclosure provides a compound of formula (XVIII): TIFF0007767301000190.tif26128, or a pharmaceutically acceptable salt thereof, the method comprising producing a compound having a structure represented by formula (XIX): TIFF0007767301000191.tif25128 and an amine having a structure represented by formula (XX): with a uracil having a structure represented by the formula: TIFF0007767301000192.tif18128; In the formula, R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl.

[0274] In some embodiments, the disclosure provides compounds prepared by the disclosed methods.

[0275] In some embodiments, the coupling reaction is carried out in the presence of a base. Exemplary bases include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), methylamine, ethylamine, N,N-diisopropylethylamine (Hunig's base), pyridine, and 2-tert-butyl-1,1,3,3-tetramethylguanidine (Barton's base). In further embodiments, the base is an amine base. In still further embodiments, the amine base is a trialkylamine or pyridine (substituted or unsubstituted). In still further embodiments, the amine base is a pyridine base. In still further embodiments, the amine base is a trialkylamine base. In still further embodiments, the trialkylamine base is N,N-diisopropylethylamine.

[0276] In some embodiments, the coupling reaction is carried out at elevated temperatures, hi further embodiments, the temperature is within the range of about 70°C to about 110°C, about 70°C to about 100°C, about 70°C to about 90°C, about 70°C to about 80°C, about 80°C to about 110°C, about 90°C to about 110°C, about 110°C to about 110°C, about 80°C to about 100°C, or about 85°C to about 95°C.

[0277] In some embodiments, the compound of Formula (XVI) has the structure: I have TIFF0007767301000193.tif25128.

[0278] In some embodiments, the compound of Formula (XVII) has the structure: I have TIFF0007767301000194.tif20128.

[0279] In some embodiments, the method further comprises preparing a compound of formula (XVI), which comprises preparing a compound of formula (XVIII): The method includes reacting an amide having a structure represented by TIFF0007767301000195.tif26128 with an activating agent. Examples of activating agents include, but are not limited to, halogenating agents (e.g., phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, boron tribromide, phosphorus pentabromide) and triflate-forming agents (e.g., triflic acid, trifluoroacetic anhydride). Thus, in a further embodiment, the activating agent is a halogenating agent. In yet a further embodiment, the halogenating agent is phosphorus oxychloride, thionyl chloride, or phosphorus pentachloride. In yet a further embodiment, the halogenating agent is phosphorus oxychloride.

[0280] In some embodiments, the reaction is carried out at elevated temperatures, hi further embodiments, the temperature is within the range of about 80°C to about 120°C, about 80°C to about 110°C, about 80°C to about 100°C, about 80°C to about 90°C, about 90°C to about 120°C, about 100°C to about 120°C, about 110°C to about 120°C, about 90°C to about 110°C, or about 95°C to about 105°C.

[0281] In some embodiments, the method further comprises preparing an amide of formula (XVIII), which is an amide of formula (XIX): TIFF0007767301000196.tif25128 and an amine having a structure represented by formula (XX): This involves reacting uracil having the structure represented by TIFF0007767301000197.tif18128.

[0282] In some embodiments, the method further comprises preparing an amine of formula (XIX), which is an amine of formula (XXI): cyclizing acrylonitrile having a structure represented by TIFF0007767301000198.tif30128, In the formula, R 31a and R 31b are each independently C1 to C4 alkyl.

[0283] In some embodiments, cyclization is by reaction with hydrazine.

[0284] In some embodiments, the method further comprises preparing an acrylonitrile of formula (XXI), which is an acrylonitrile of formula (XXII): The method includes reacting a nitrile having a structure represented by TIFF0007767301000199.tif19128 with formamidine acetal. Examples of formamidine acetals include, but are not limited to, N,N-dimethylformamide diethyl acetal and N,N-dimethylformamide dimethyl acetal. Thus, in some embodiments, the formamidine acetal is N,N-dimethylformamide diethyl acetal.

[0285] In some embodiments, the method further comprises preparing a nitrile of formula (XXII), which is a nitrile of formula (XXIII): TIFF0007767301000200.tif16128 and a heteroaryl having a structure represented by formula (XXIV): TIFF0007767301000201.tif6128, In the formula, X 2 is a halogen.

[0286] In some embodiments, the products of the disclosed methods are enantiomerically pure. Thus, in various embodiments, the products of the disclosed methods have an enantiomeric purity of at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or greater than 99%.

[0287] In some embodiments, the products of the disclosed methods can be provided in enantiomeric excess (ee). Thus, in various embodiments, the enantiomeric excess of the desired enantiomer of the product of the disclosed methods is greater than 50%, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In further embodiments, the "S" forms of the products of the disclosed methods are substantially free of the "R" forms. In yet further embodiments, the "R" forms of the products of the disclosed methods are substantially free of the "S" forms.

[0288] In some embodiments, the "S" form of the product of the disclosed methods is present in an amount greater than 50%, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99% of the "R" form.

[0289] In some embodiments, the "R" form of the product of the disclosed methods is present in an amount greater than 50%, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99% of the "S" form.

[0290] Preparation of a Compound of Formula (X) (e.g., Compound No. 10). In some embodiments, the present disclosure provides a method for preparing a compound of Formula (X), comprising one or more of steps (i-1) through (i-3): (i-1) contacting a compound of Formula (VII) with an acetonitrile addition agent, thereby forming a compound of Formula (VIII); (i-2) contacting a compound of Formula (VIII) with N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof, thereby forming a compound of Formula (IX); or (i-3) contacting a compound of Formula (IX) with hydrazine, thereby forming a compound of Formula (X) or a salt thereof.

[0291] In some embodiments, the present disclosure provides use of a compound of Formula (VII) in the preparation of a compound of Formula (X) or a salt thereof, comprising one or more of steps (i-1) to (i-3).

[0292] In some embodiments, the method or use comprises two or more of steps (i-1) to (i-3).

[0293] In some embodiments, the method or use comprises steps (i-1) to (i-3).

[0294] Step (i-1): In some embodiments, step (i-1) comprises contacting compound number 7 with an acetonitrile addition agent, thereby forming compound number 8.

[0295] In some embodiments, the acetonitrile addition agent is 2-chloroacetonitrile, 2-bromoacetonitrile, or 2-iodoacetonitrile. In some embodiments, the acetonitrile addition agent is 2-bromoacetonitrile.

[0296] In some embodiments, in step (i-1), the contacting is carried out in the presence of a base. In some embodiments, the base is an inorganic base (e.g., potassium carbonate).

[0297] In some embodiments, the contacting in step (i-1) is carried out in the presence of a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is an aprotic solvent (e.g., N,N-dimethylformamide).

[0298] In some embodiments, step (i-1) includes one or more of steps (i-1-1) through (i-1-3): (i-1-1) providing a first mixture of Compound No. 7 and a solvent (e.g., N,N-dimethylformamide); (i-1-2) adding a base (e.g., potassium carbonate) and an acetonitrile addition agent (e.g., 2-bromoacetonitrile) to the first mixture, thereby forming a second mixture; or (i-1-3) heating the second mixture.

[0299] In some embodiments, in step (i-1-2), the addition is performed at room temperature. In some embodiments, in step (i-1-2), the addition is performed at about 20±10°C, about 20±5°C, about 20±2°C, or about 20±1°C (e.g., about 20°C).

[0300] In some embodiments, step (i-1-3) includes heating the second mixture to about 70±20°C, about 70±15°C, about 70±10°C, about 70±5°C, about 70±2°C, about 70±1°C (e.g., about 70°C).

[0301] In some embodiments, step (i-1-3) includes heating the second mixture for about 5±2 hours, about 5±1 hours, about 5±0.5 hours, about 5±0.2 hours, about 5±0.1 hours (e.g., about 5 hours).

[0302] In some embodiments, step (i-1) further comprises one or more of the following steps: i-1-4) cooling the second mixture (e.g., to room temperature); (i-1-5) adding the second mixture to water (e.g., ice water) to form a third mixture; (i-1-6) extracting the third mixture one or more times with an organic solvent (e.g., ethyl acetate) and combining one or more organic phases from the extractions to form a fourth mixture; and optionally washing the fourth mixture one or more times with a brine solution; or (i-1-7) drying and filtering the fourth mixture; (i-1-8) removing at least a portion of the solvent from the fourth mixture to thereby isolate compound no. 8.

[0303] Step (i-2): In some embodiments, step (i-2) comprises contacting compound number 8 with N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof, thereby forming compound number 9.

[0304] In some embodiments, step (i-2) includes one or both of steps (i-2-1) and (i-2-2): (i-2-1) providing a first mixture of Compound No. 8 and N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof, or (i-2-2) heating the first mixture.

[0305] In some embodiments, step (i-2-2) includes heating the first mixture to about 115±20°C, about 115±15°C, about 115±10°C, about 115±5°C, about 115±2°C, about 115±1°C (e.g., about 115°C).

[0306] In some embodiments, step (i-2-2) includes heating the first mixture for about 16±10 hours, about 16±5 hours, about 16±2 hours, about 16±1 hour, about 16±0.5 hours, about 16±0.2 hours, about 16±0.1 hours (e.g., about 16 hours).

[0307] In some embodiments, step (i-2) further comprises one or more of the following steps: (i-2-3) cooling the first mixture (e.g., to room temperature); (i-2-4) adding the first mixture to water (e.g., ice water) to form a second mixture; (i-2-5) extracting the second mixture one or more times with an organic solvent (e.g., ethyl acetate) and combining one or more organic phases from the extractions to form a third mixture; and optionally washing the third mixture one or more times with a brine solution; or (i-2-6) drying and filtering the third mixture; (i-2-7) removing at least a portion of the solvent from the third mixture to isolate Compound No. 9.

[0308] Step (i-3): In some embodiments, step (i-3) comprises contacting compound number 9 with hydrazine, thereby forming compound number 10, or a salt thereof.

[0309] In some embodiments, the hydrazine is in the form of hydrazine hydrate. In some embodiments, the hydrazine is in the form of hydrazine monohydrate.

[0310] In some embodiments, in step (i-3), the contacting is performed in the presence of a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is a protic solvent. In some embodiments, the solvent is an alcohol (e.g., ethanol).

[0311] In some embodiments, step (i-3) includes one or more of steps (i-3-1) through (i-3-5): (i-3-1) providing a first mixture of Compound No. 9 and a solvent (e.g., ethanol); (i-3-2) adding hydrazine (e.g., hydrazine monohydrate) to the first mixture, thereby forming a second mixture; (i-3-3) cooling the second mixture; (i-3-4) adding an acid (e.g., hydrochloric acid) to the second mixture, thereby forming a third mixture; or (i-3-5) heating the third mixture.

[0312] In some embodiments, step (i-3-3) includes cooling the second mixture to about −20±20° C., about −20±15° C., about −20±10° C., about −20±5° C., about −20±2° C., about −20±1° C. (e.g., about −20° C.).

[0313] In some embodiments, in step (i-3-4), the addition is carried out at about -20±20°C, about -20±15°C, about -20±10°C, about -20±5°C, about -20±2°C, or about -20±1°C (e.g., about -20°C).

[0314] In some embodiments, step (i-3-5) includes heating the third mixture to about 90±20°C, about 90±15°C, about 90±10°C, about 90±5°C, about 90±2°C, about 90±1°C (e.g., about 90°C).

[0315] In some embodiments, step (i-3-5) includes heating the second mixture for about 16±10 hours, about 16±5 hours, about 16±2 hours, about 16±1 hour, about 16±0.5 hours, about 16±0.2 hours, about 16±0.1 hours (e.g., about 16 hours).

[0316] In some embodiments, step (i-3) further includes one or more of the following steps: (i-3-6) removing at least a portion of the solvent (e.g., ethanol) from the third mixture, thereby forming a concentrated third mixture; (i-3-7) adding water (e.g., ice water) and a base (e.g., potassium carbonate) to the concentrated third mixture, thereby forming a fourth mixture; (i-3-8) filtering the fourth mixture, thereby isolating Compound No. 10 or a salt thereof.

[0317] Preparation of a compound of formula (XIV) (e.g., Compound No. 14). In some embodiments, the present disclosure provides a method for preparing a compound of formula (XIV) or a salt thereof, the method comprising one or more of the following steps (f-1) to (f-3): (f-1) contacting a compound of formula (X) or a salt thereof with compound No. 11 or a synthetic equivalent thereof, thereby forming a compound of formula (XII); (f-2) contacting a compound of formula (XII) with a chlorinating agent, thereby forming a compound of formula (XIII); or (f-3) contacting a compound of formula (XIII) with compound No. 6 (e.g., Compound No. 6R or 6S (e.g., Compound No. 6R)) or a salt thereof, thereby forming a compound of formula (XIV) or a salt thereof.

[0318] In some embodiments, the present disclosure provides use of a compound of formula (X) or a salt thereof in the preparation of a compound of formula (XIV) or a salt thereof, comprising one or more of steps (f-1) to (f-3).

[0319] In some embodiments, the method or use comprises two or more of steps (f-1) to (f-3).

[0320] In some embodiments, the method or use comprises steps (f-1) to (f-3).

[0321] In some embodiments, the compound of formula (X) or salt thereof is prepared by the methods disclosed herein.

[0322] In some embodiments, the method or use further comprises one or more of steps (i-1) to (i-3).

[0323] In some embodiments, the method or use further comprises two or more of steps (i-1) to (i-3).

[0324] In some embodiments, the method or use further comprises steps (i-1) to (i-3).

[0325] In some embodiments, Compound No. 6 (e.g., Compound No. 6R or 6S (e.g., Compound No. 6R)) is prepared by the methods described in PCT Application Publication No. WO / 2008 / 052734, which is incorporated by reference in its entirety.

[0326] In some embodiments, compound No. 6 (e.g., compound No. 6R or 6S (e.g., compound No. 6R)) is prepared by a method comprising one or more of steps (s-1) through (s-4): (s-1) contacting compound No. 1 with compound No. 2 (e.g., compound No. 2R or 2S (e.g., compound No. 2R)), thereby forming compound No. 3 (e.g., compound No. 3R or 3S (e.g., compound No. 3R)); (s-2) contacting compound No. 4, or a synthetic equivalent thereof, with magnesium, or a synthetic equivalent thereof, thereby forming compound No. 4a or (s-3) contacting compound No. 3 (e.g., compound No. 3R or 3S (e.g., compound No. 3R)) with compound No. 4a or a synthetic equivalent thereof, thereby forming compound No. 5 (e.g., compound No. 5R or 5S (e.g., compound No. 5R)); (s-4) contacting compound No. 5 (e.g., compound No. 5R or 5S (e.g., compound No. 5R)) with an acid (e.g., HCl) and a reducing agent (e.g., NaBH4), thereby forming compound No. 6 (e.g., compound No. 6R or 6S (e.g., compound No. 6R)) or a salt thereof.

[0327] In some embodiments, the method or use further comprises one or more of steps (s-1) to (s-4).

[0328] In some embodiments, the method or use further comprises two or more of steps (s-1) to (s-4).

[0329] In some embodiments, the method or use further comprises three or more of steps (s-1) to (s-4).

[0330] In some embodiments, the method or use further comprises steps (s-1) to (s-4).

[0331] Step (f-1): In some embodiments, step (f-1) comprises contacting compound number 10, or a salt thereof, with compound number 11, or a synthetic equivalent thereof, thereby forming compound number 12.

[0332] In some embodiments, step (f-1) comprises contacting compound No. 10, or a salt thereof, with a synthetic equivalent of compound No. 11, thereby forming compound No. 12.

[0333] In some embodiments, in step (f-1), the contacting is carried out in the presence of a base. In some embodiments, the base is an organic base (e.g., sodium methoxide (MeONa)).

[0334] In some embodiments, in step (f-1), the contacting is carried out in the presence of a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is a protic solvent. In some embodiments, the solvent is an alcohol (e.g., ethanol).

[0335] In some embodiments, step (f-1) includes one or more of steps (f-1-1) through (f-1-4): (f-1-1) providing a first mixture of Compound No. 10 or a salt thereof in a solvent (e.g., ethanol); (f-1-2) adding a base (e.g., MeONa) to the first mixture, thereby forming a second mixture; (f-1-3) adding Compound No. 11 or a synthetic equivalent thereof to the second mixture, thereby forming a third mixture; or (f-1-4) heating the third mixture.

[0336] In some embodiments, step (f-1-2) includes adding a solution of a base (eg, MeONa in methanol (eg, 25% MeONa in methanol)) to the first mixture.

[0337] In some embodiments, in step (f-1-2), the addition is performed at room temperature. In some embodiments, in step (f-1-2), the addition is performed at about 20±10°C, about 20±5°C, about 20±2°C, or about 20±1°C (e.g., about 20°C).

[0338] In some embodiments, in step (f-1-2), the addition is carried out for about 15±10 minutes, about 15±5 minutes, about 15±2 minutes, about 15±1 minutes (eg, about 15 minutes).

[0339] In some embodiments, in step (f-1-3), the addition is performed at room temperature. In some embodiments, in step (f-1-3), the addition is performed at about 20±10°C, about 20±5°C, about 20±2°C, or about 20±1°C (e.g., about 20°C).

[0340] In some embodiments, step (f-1-4) includes heating the third mixture to about 90±20°C, about 90±15°C, about 90±10°C, about 90±5°C, about 90±2°C, about 90±1°C (e.g., about 90°C).

[0341] In some embodiments, step (f-1-4) includes heating the third mixture for about 16±10 hours, about 16±5 hours, about 16±2 hours, about 16±1 hour, about 16±0.5 hours, about 16±0.2 hours, about 16±0.1 hours (e.g., about 16 hours).

[0342] In some embodiments, step (f-1) further includes one or more of the following steps: (f-1-5) removing at least a portion of the solvent from the third mixture, thereby forming a concentrated third mixture; (f-1-6) adding water (e.g., ice water) to the concentrated third mixture, thereby forming a diluted third mixture; (f-1-7) adding an acid (e.g., acetic acid) to the diluted third mixture, thereby forming a fourth mixture (e.g., one having a pH value of about 5); or (f-1-8) filtering the fourth mixture, thereby isolating compound number 12.

[0343] Step (f-2): In some embodiments, step (f-2) comprises contacting compound no. 12 with a chlorinating agent, thereby forming compound no. 13.

[0344] In some embodiments, the chlorinating agent is phosphoryl chloride (POCl 3 , also known as phosphorus oxychloride), phosphorus pentachloride (PCl 5 ), or thionyl chloride (SOCl 2 ).

[0345] In some embodiments, the chlorinating agent is phosphoryl chloride.

[0346] In some embodiments, in step (f-2), the contacting is carried out in the presence of a catalyst. In some embodiments, the catalyst is N,N-dimethylformamide.

[0347] In some embodiments, in step (f-2), the contacting is carried out in the presence of a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is an aprotic solvent (e.g., 1,2-dichloroethane, toluene, acetonitrile, or any combination thereof). In some embodiments, the solvent is 1,2-dichloroethane.

[0348] In some embodiments, step (f-2) includes one or more of steps (f-2-1) to (f-2-3): (f-2-1) providing a first mixture of Compound No. 12 in a solvent (e.g., 1,2-dichloroethane, toluene, acetonitrile, or any combination thereof); (f-2-2) adding a chlorinating agent (e.g., phosphoryl chloride) and a catalyst (e.g., N,N-dimethylformamide) to the first mixture, thereby forming a second mixture; or (f-2-3) heating the second mixture.

[0349] In some embodiments, in step (f-2-2), the addition is performed at room temperature. In some embodiments, in step (f-2-2), the addition is performed at about 20±10°C, about 20±5°C, about 20±2°C, or about 20±1°C (e.g., about 20°C).

[0350] In some embodiments, step (f-2-3) includes heating the second mixture to about 100±20°C, about 100±15°C, about 100±10°C, about 100±5°C, about 100±2°C, or about 100±1°C (e.g., about 100°C).

[0351] In some embodiments, step (f-2-3) comprises heating the second mixture for about 16±10 hours, about 16±5 hours, about 16±2 hours, about 16±1 hour, about 16±0.5 hours, about 16±0.2 hours, about 16±0.1 hours (e.g., about 16 hours).

[0352] In some embodiments, step (f-2) further comprises one or more of the following steps: (f-2-4) removing at least a portion of the solvent from the second mixture, thereby forming a concentrated second mixture; (f-2-5) adding a solvent (e.g., methyl tert-butyl ether) to the concentrated mixture, thereby forming a diluted second mixture; (f-2-6) adding the diluted second mixture to an aqueous solution (e.g., saturated sodium bicarbonate solution), thereby forming a third mixture having an organic phase and an aqueous phase; (f-2-7) isolating the organic phase from the third mixture and optionally washing the organic phase one or more times with brine solution; (f-2-8) drying and filtering the organic phase; or (f-2-9) removing at least a portion of the solvent from the organic phase, thereby isolating Compound No. 13.

[0353] Step (f-3): In some embodiments, step (f-3) includes contacting compound No. 13 with compound No. 6 (e.g., compound No. 6R or 6S (e.g., compound No. 6R)) or a salt thereof, thereby forming compound No. 14 (e.g., compound No. 14R or 14S (e.g., compound No. 14R)) or a salt thereof.

[0354] In some embodiments, in step (f-3), the contacting is carried out in the presence of a base. In some embodiments, the base is an organic base (e.g., N,N-diisopropylethylamine).

[0355] In some embodiments, the contacting in step (f-3) is carried out in the presence of a solvent. In some embodiments, the solvent is an organic solvent. In some embodiments, the solvent is an aprotic solvent (e.g., N,N-dimethylformamide).

[0356] In some embodiments, step (f-3) includes one or more of steps (f-3-1) to (f-3-3): (f-3-1) providing a first mixture of Compound No. 13 in a solvent (e.g., N,N-dimethylformamide); (f-3-2) adding Compound No. 6 (e.g., Compound No. 6R or 6S (e.g., Compound No. 6R)) or a salt thereof and a base (e.g., N,N-diisopropylethylamine) to the first mixture, thereby forming a second mixture; or (f-3-3) heating the second mixture.

[0357] In some embodiments, in step (f-3-2), the addition is performed at room temperature. In some embodiments, in step (f-3-2), the addition is performed at about 20±10°C, about 20±5°C, about 20±2°C, or about 20±1°C (e.g., about 20°C).

[0358] In some embodiments, step (f-3-3) includes heating the second mixture to about 90±20°C, about 90±15°C, about 90±10°C, about 90±5°C, about 90±2°C, about 90±1°C (e.g., about 90°C).

[0359] In some embodiments, step (f-3-3) includes heating the second mixture for about 4±2 hours, about 4±1 hours, about 4±0.5 hours, about 4±0.2 hours, about 4±0.1 hours (e.g., about 4 hours).

[0360] In some embodiments, step (f-3) further comprises one or more of the following steps: (f-3-4) adding the second mixture to water (e.g., ice water), thereby forming a third mixture; (f-3-5) extracting the third mixture one or more times with an organic solvent (e.g., ethyl acetate) and combining one or more organic phases from the extractions, thereby forming a fourth mixture; and optionally washing the fourth mixture one or more times with brine solution; (f-3-6) drying and filtering the fourth mixture; (f-3-7) removing at least a portion of the solvent from the fourth mixture, thereby forming a concentrated fourth mixture; (f-3-8) adding ethanol to the fourth mixture, thereby forming a fifth mixture; and (f-3-9) filtering the fifth mixture, thereby isolating Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)) or a salt thereof.

[0361] The compounds of the present invention can be prepared by using the reactions shown in the following schemes, in addition to other standard manipulations known in the literature, illustrated in the experimental section, or apparent to one skilled in the art. For clarity, examples with a single substituent are shown where multiple substituents are permitted under the definitions disclosed herein.

[0362] The reactions used to produce the compounds of the present invention, as described and exemplified below, are prepared by using the reactions shown in the following reaction schemes. In certain embodiments, the disclosed compounds can be prepared by Routes I-VI, as described and exemplified below. The following examples are provided so that the invention may be more fully understood and are illustrative only and should not be construed as limiting.

[0363] 1. Route I In one aspect, the disclosed compounds can be prepared as shown below.

[0364] Scheme 1A TIFF0007767301000202.tif30128 The compound is represented in the general form, where R 4a and R 4b are hydrogen, and Q is -CR 10 and other substituents are as described in the description of compounds elsewhere herein. More specific examples are described below.

[0365] Scheme 1B In one embodiment, compounds of type 1.3 and similar compounds can be prepared according to Reaction Scheme 1B above. Thus, compounds of type 1.3 can be prepared by the alkylation reaction of a suitable pyrazole, such as 1.2 as shown above, with a suitable halide, such as 1.1 as shown above. Suitable pyrazoles and suitable halides are commercially available or prepared by methods known to those skilled in the art. The alkylation is carried out in the presence of a suitable base, such as potassium carbonate, in a suitable solvent, such as dimethylformamide (DMF), at a suitable temperature, such as 70° C. As will be appreciated by those skilled in the art, the above reaction provides an example of a generalized approach in which structurally similar compounds (e.g., compounds similar to compounds of types 1.4 and 1.5) can be substituted for the specific reactants above to provide compounds similar to formula 1.6.

[0366] 2. Route II In one aspect, the disclosed compounds can be prepared as shown below.

[0367] Scheme 2A The compound is represented in the general form: where R and R′ are each independently C1-C8 alkyl; R 4a and R 4b are hydrogen, and Q is -CR 10and other substituents are as described in the description of compounds elsewhere herein. More specific examples are described below.

[0368] Scheme 2B In one embodiment, compounds of type 2.3 and similar compounds can be prepared according to Reaction Scheme 2B above. Thus, compounds of type 2.3 can be prepared by activating an appropriate cyano compound, such as 2.1, as shown above. Activation is carried out in the presence of an appropriate formamidine acetal, such as 2.5, as shown above, at a suitable temperature, such as 115° C., for a suitable length of time, such as 12 hours. Suitable formamidine acetals are commercially available or prepared by methods known to those skilled in the art. As will be appreciated by those skilled in the art, the above reaction provides an example of a generalized approach in which structurally similar compounds (e.g., compounds similar to compounds of types 2.4 and 2.5) can be substituted for the specific reactants above to provide compounds similar to formula 2.6.

[0369] 3. Route III In one aspect, the disclosed compounds can be prepared as shown below.

[0370] Scheme 3A TIFF0007767301000206.tif39128 The compound is represented in the general form, where R 4a and R 4b are hydrogen, and Q is -CR 10 and other substituents are as described in the description of compounds elsewhere herein. More specific examples are described below.

[0371] Scheme 3B In one embodiment, compounds of type 3.2 and similar compounds can be prepared according to Reaction Scheme 3B above. Thus, compounds of type 3.2 can be prepared by cyclizing an appropriate cyanoamine, such as 3.1, as shown above. The cyclization is carried out in the presence of a suitable cyclization agent, such as hydrazine monohydrate, in a suitable solvent, such as ethanol (EtOH), at a suitable temperature, such as 90° C., for a suitable length of time, such as 16 hours. Those skilled in the art will recognize that the above reaction provides an example of a generalized approach in which structurally similar compounds (e.g., compounds similar to compounds of type 3.3) can be substituted for the specific reactants above to provide compounds similar to formula 3.4.

[0372] 4. Route IV In one aspect, the disclosed compounds can be prepared as shown below.

[0373] Scheme 4A TIFF0007767301000208.tif41136 The compound is represented in the general form, where R 2 , R 3 , R 4a , and R 4b are hydrogen, and Q is -CR 10 and other substituents are as described in the description of compounds elsewhere herein. More specific examples are described below.

[0374] Scheme 4B In one embodiment, compounds of type 4.3 and similar compounds can be prepared according to Reaction Scheme 4B above. Thus, compounds of type 4.3 can be prepared by reacting an appropriate aminopyrazole, such as 4.1 as shown above, with an appropriate uracil derivative, such as 4.2 as shown above. As would be readily apparent to one skilled in the art, alternative 1,3-dicarbonyl agents, including but not limited to dialkyl malonates, alkyl oxopropanoates, alkyl propiolates, 2-cyanoacetohydrazides, and substituted alkyloxymethacrylates, may be used in place of the uracil derivative. The reaction is carried out in the presence of a suitable base, such as sodium methoxide, in a suitable solvent, such as ethanol (EtOH), at a suitable temperature, such as 90°C. Those skilled in the art will appreciate that the above reaction provides an example of a generalized approach in which structurally similar compounds (e.g., compounds similar to compounds of type 4.4 and 4.5) can be substituted for the specific reactants above to provide compounds similar to formula 4.6.

[0375] 5. Route V In one aspect, the disclosed compounds can be prepared as shown below.

[0376] Scheme 5A TIFF0007767301000210.tif43128 The compound is represented in the general form, where R 2 , R 3 , R 4a , and R 4b are hydrogen, and Q is -CR 10 and other substituents are as described in the description of compounds elsewhere herein. More specific examples are described below.

[0377] Scheme 5B In one embodiment, compounds of type 5.2 and similar compounds can be prepared according to Reaction Scheme 5B above. Thus, compounds of type 5.2 can be prepared by activating an appropriate amide, such as 5.3, as shown above. The reaction is carried out in the presence of a suitable activating agent, such as phosphoryl chloride, in a suitable solvent, such as 1,2-dichloroethane (1,2-DCE), at a suitable temperature, such as 100° C. Those skilled in the art will recognize that the above reaction provides an example of a generalized approach in which structurally similar compounds (e.g., compounds similar to compounds of type 5.3) can be substituted for the specific reactants above to provide compounds similar to formula 5.4.

[0378] 6. Route VI In one aspect, the disclosed compounds can be prepared as shown below.

[0379] Scheme 6A TIFF0007767301000212.tif42128 The compound is represented in the general form, where R 1 teeth TIFF0007767301000213.tif14128, R 2 , R 3 , R 4a , and R 4b are hydrogen, and Q is -CR 10 and other substituents are as described in the description of compounds elsewhere herein. More specific examples are described below.

[0380] Scheme 6B In one embodiment, compounds of type 6.3 and similar compounds can be prepared according to Reaction Scheme 6B above. Thus, compounds of type 6.3 can be prepared by the coupling reaction of an appropriate activated pyrazolo[1,5-α]pyrimidine, such as 6.4 as shown above, with an appropriate alcohol or an appropriate amine, such as 6.5. Suitable alcohols and amines are commercially available or prepared by methods known to those skilled in the art. The coupling reaction is carried out in the presence of a suitable base, such as N,N-diisopropylethylamine (DIPEA), in a suitable solvent, such as dimethylformamide (DMF), at a suitable temperature, such as 90° C. Those skilled in the art will appreciate that the above reactions provide examples of generalized approaches in which structurally similar compounds (e.g., compounds similar to compounds of type 6.1 and 6.2) can be substituted for the specific reactants above to provide substituted pyrazolo[1,5-α]pyrimidine compounds similar to formula 6.3.

[0381] It is contemplated that each of the disclosed methods may further include additional steps, operations, and / or components. It is also contemplated that any one or more steps, operations, and / or components may optionally be omitted from the present invention. It is understood that the disclosed methods can be used to produce the disclosed compounds. It is also understood that the products of the disclosed methods can be used in the disclosed methods of use.

[0382] G. Combination In some embodiments, the present disclosure provides a combination comprising a compound of formula (VII) and an acetonitrile addition agent (e.g., 2-bromoacetonitrile).

[0383] In some embodiments, the present disclosure provides a combination comprising a compound of formula (VII) and an acetonitrile addition agent (e.g., 2-bromoacetonitrile) for preparing a compound of formula (X) or a salt thereof.

[0384] In some embodiments, the combination includes Compound No. 7 and an acetonitrile additive (e.g., 2-bromoacetonitrile).

[0385] In some embodiments, the present disclosure provides a combination comprising Compound No. 7 and an acetonitrile addition agent (e.g., 2-bromoacetonitrile) for preparing Compound No. 10, or a salt thereof.

[0386] In some embodiments, the present disclosure provides a combination comprising a compound of formula (VIII) and N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof.

[0387] In some embodiments, the present disclosure provides a combination comprising a compound of formula (VIII) and N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof for preparing a compound of formula (X) or a salt thereof.

[0388] In some embodiments, the combination comprises Compound No. 8 and N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof.

[0389] In some embodiments, the present disclosure provides a combination comprising Compound No. 8 and N,N-dimethylformamide diethyl acetal or a synthetic equivalent thereof for preparing Compound No. 10 or a salt thereof.

[0390] In some embodiments, the present disclosure provides a combination comprising a compound of formula (IX) and hydrazine (e.g., hydrazine monohydrate).

[0391] In some embodiments, the present disclosure provides a combination comprising a compound of formula (IX) and hydrazine (e.g., hydrazine monohydrate) for preparing a compound of formula (X) or a salt thereof.

[0392] In some embodiments, the combination includes Compound No. 9 and hydrazine (e.g., hydrazine monohydrate).

[0393] In some embodiments, the present disclosure provides a combination comprising Compound No. 9 and hydrazine (e.g., hydrazine monohydrate) for preparing Compound No. 10, or a salt thereof.

[0394] In some embodiments, the present disclosure provides a combination comprising a compound of formula (X) or a salt thereof and Compound No. 11 or a synthetic equivalent thereof.

[0395] In some embodiments, the present disclosure provides a combination comprising a compound of formula (X) or a salt thereof and compound number 11 or a synthetic equivalent thereof for preparing a compound of formula (XIV) or a salt thereof.

[0396] In some embodiments, the combination comprises Compound No. 10, or a salt thereof, and Compound No. 11.

[0397] In some embodiments, the present disclosure provides a combination comprising Compound No. 10, or a salt thereof, and Compound No. 11 for preparing Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)), or a salt thereof.

[0398] In some embodiments, the present disclosure provides a combination comprising a compound of formula (XII) and a chlorinating agent (eg, phosphoryl chloride).

[0399] In some embodiments, the present disclosure provides a combination comprising a compound of formula (XII) and a chlorinating agent (e.g., phosphoryl chloride) for preparing a compound of formula (XIV) or a salt thereof.

[0400] In some embodiments, the combination comprises Compound No. 12 and a chlorinating agent (e.g., phosphoryl chloride).

[0401] In some embodiments, the present disclosure provides a combination comprising Compound No. 12 and a chlorinating agent (e.g., phosphoryl chloride) for preparing Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)), or a salt thereof.

[0402] In some embodiments, the disclosure provides a combination comprising a compound of Formula (XIII) and Compound No. 6 (e.g., Compound No. 6R or 6S (e.g., Compound No. 6R)), or a salt thereof.

[0403] In some embodiments, the present disclosure provides a combination comprising a compound of Formula (XIII) and Compound No. 6 (e.g., Compound No. 6R or 6S (e.g., Compound No. 6R)) or a salt thereof for preparing a compound of Formula (XIV) or a salt thereof.

[0404] In some embodiments, the combination includes Compound No. 13 and Compound No. 6 (e.g., Compound No. 6R or 6S (e.g., Compound No. 6R)), or a salt thereof.

[0405] In some embodiments, the present disclosure provides a combination comprising Compound No. 13 and Compound No. 6 (e.g., Compound No. 6R or 6S (e.g., Compound No. 6R)), or a salt thereof, for preparing Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)), or a salt thereof.

[0406] In some embodiments, the present disclosure provides an effective amount of a compound of formula (XVI): TIFF0007767301000215.tif26128 and an effective amount of a compound having a structure represented by formula (XVII): a composition comprising the compound of TIFF0007767301000216.tif14128; In the formula, X 1 is a leaving group and R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20, -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; Ar 2 is a C6-C10 aryl or 5-6 membered heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0407] In some embodiments, the present disclosure provides an effective amount of a compound of formula (XVIII): and an activator, wherein R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20 , -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl, or a salt thereof.

[0408] H. Pharmaceutical Compositions In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients.

[0409] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound prepared by the methods described herein (e.g., Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R))) and one or more pharmaceutically acceptable carriers or excipients.

[0410] In some embodiments, the present disclosure provides an effective amount of a compound of formula (XXV): Pharmaceutical compositions are provided comprising a compound of formula (XXV) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the compound has an enantiomeric purity of at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or greater than 99%. In some embodiments, the compound of formula (XXV) can be provided with an enantiomeric excess (ee). Thus, in various embodiments, the enantiomeric excess of the desired enantiomer of the disclosed pyrazolo[1,5-α]pyrimidine compound is at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In further embodiments, the "S" forms of the disclosed pyrazolo[1,5-α]pyrimidine compounds are substantially free of the "R" forms. In yet further embodiments, the "R" forms of the disclosed pyrazolo[1,5-α]pyrimidine compounds are substantially free of the "S" forms.

[0411] In some embodiments, the "S" form of the compound of Formula (XXV) is present in the composition in an amount of greater than about 50%, greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 98%, or greater than about 99% relative to the "R" form.

[0412] In some embodiments, the "R" form of the compound of Formula (XXV) is present in the composition in an amount of greater than about 50%, greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 98%, or greater than about 99% relative to the "S" form.

[0413] In some embodiments, the present disclosure provides an effective amount of a compound of formula (XV): TIFF0007767301000219.tif25128, or a pharmaceutically acceptable salt thereof [wherein R 10 is hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, -OR 20, -C(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -(C1-C6 alkyl)OR 20 , -(C1-C6 alkyl)SR 20 , -(C1-C6 alkyl)C(O)R 20 , -(C1-C6 alkyl)S(O)R 20 , -(C1-C6 alkyl)S(O)2R 20 , -NR 21 C(O)R 20 , -NR 21 S(O)2R 20 , -NR 22a R 22b , -P(O)R 22a R 22b , -(C1-C6 alkyl)NR 22a R 22b , -(C1-C6 alkyl)P(O)R 22a R 22b , and Cy 1 where R 20 , R 21 , R 22a , and R 22b each, if present, is independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; Cy 1 when present, is selected from C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; Ar 2is a C-C aryl or 5-6 membered heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, and C-C haloalkoxy; and a pharmaceutically acceptable carrier, wherein the compound has an enantiomeric purity of at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or greater than 99%. In some embodiments, the compound of Formula (XV) can be provided in enantiomeric excess (ee). Thus, in various embodiments, the enantiomeric excess of the desired enantiomer of the disclosed pyrazolo[1,5-α]pyrimidine compounds is at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In further embodiments, the "S" forms of the disclosed pyrazolo[1,5-α]pyrimidine compounds are substantially free of the "R" forms. In yet further embodiments, the "R" forms of the disclosed pyrazolo[1,5-α]pyrimidine compounds are substantially free of the "S" forms.

[0414] In some embodiments, the "S" form of the compound of Formula (XV) is present in the composition in an amount greater than about 50%, greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 98%, or greater than about 99% relative to the "R" form.

[0415] In some embodiments, the "R" form of the compound of Formula (XV) is present in the composition in an amount greater than about 50%, greater than about 60%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 98%, or greater than about 99% relative to the "S" form.

[0416] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, and any product resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0417] The compounds of the present disclosure may be formulated for oral administration in the form of tablets, capsules (each including sustained or extended release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, and the like. The compounds of the present disclosure may also be formulated for intravenous administration (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those skilled in the pharmaceutical arts.

[0418] The formulations of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0419] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0420] Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[0421] Any suitable preservative can be used. Examples of preservatives include quaternary ammonium salts, such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, butyl p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0422] The aqueous vehicle may contain a tonicity agent to adjust tonicity (osmotic pressure), which may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0423] The aqueous vehicle may contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycols (such as polyethylene glycol 300 and polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers), such as polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycols (e.g., the Carbopols, such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0424] To adjust the formulation to an acceptable pH (typically, a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically an inorganic acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to an acceptable target pH range. Therefore, it may not be necessary to use both an acid and a base. Depending on the formulation, the addition of either an acid or a base may be sufficient to bring the mixture into the desired pH range.

[0425] The aqueous vehicle may contain a buffering agent to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or salts thereof including disodium tetraborate), citrate buffers (such as citric acid or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0426] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0427] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier. These can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be combined with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is applied to the oral cavity, swished, expectorated, or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavoring.

[0428] According to a further embodiment of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, together with a pharmaceutically acceptable diluent or carrier.

[0429] Compositions of the disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), inhaled administration (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as a suppository for rectal administration).

[0430] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients that are well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents, and / or preservatives.

[0431] The size of a therapeutic or prophylactic dose of a compound of formula (VII)-(X) and (XII)-(XIV) or compound Nos. 1-14 will, of course, vary according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0432] I. How to use In some embodiments, the present disclosure provides a method of inhibiting tyrosine receptor kinase (TRK) in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound (e.g., Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R))) prepared by a method disclosed herein.

[0433] In some embodiments, the present disclosure provides a compound (e.g., Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)) prepared by the methods disclosed herein for inhibiting tyrosine receptor kinase (TRK) in a subject.

[0434] In some embodiments, the disclosure provides the use of a compound (e.g., Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)) prepared by the methods disclosed herein in the manufacture of a medicament for inhibiting tyrosine receptor kinase (TRK) in a subject.

[0435] In some embodiments, the disclosure provides a method of preventing or treating a disease or disorder in a subject, the method comprising administering to the subject a pharmaceutically effective amount of a compound (e.g., Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R))) prepared by a method disclosed herein.

[0436] In some embodiments, the present disclosure provides a compound (e.g., Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)) prepared by the methods disclosed herein for preventing or treating a disease or disorder in a subject.

[0437] In some embodiments, the disclosure provides the use of a compound (e.g., Compound No. 14 (e.g., Compound No. 14R or 14S (e.g., Compound No. 14R)) prepared by the methods disclosed herein in the manufacture of a medicament for preventing or treating a disease or disorder in a subject.

[0438] In some embodiments, the subject is a mammal.

[0439] In some embodiments, the subject in need thereof is a human.

[0440] In some embodiments, the disease is associated with elevated tyrosine receptor kinase (TRK) expression or activity.

[0441] In some embodiments, administration of the formulation results in inhibition of tyrosine receptor kinase (TRK).

[0442] In some embodiments, administration of the formulation results in a reduction in the activity of a tyrosine receptor kinase (TRK).

[0443] In some embodiments, the TRK is TRKA, TRKB, or TRKC.

[0444] In some embodiments, the TRK is TRKA.

[0445] In some embodiments, the TRK is TRKB.

[0446] In some embodiments, the TRK is TRKC.

[0447] In some embodiments, the disease or disorder is selected from inflammatory diseases, infectious diseases, autoimmune disorders, stroke, ischemia, cardiac dysfunction, neurological disorders, dermatological disorders, fibrotic disorders, proliferative disorders, hyperproliferative disorders, non-cancerous hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, malignant diseases, vascular restenosis, psoriasis, atopic dermatitis, pruritus, eczema, Gorlin syndrome, Netherton syndrome, basal cell carcinoma, dermatomyositis, cylindroma, atherosclerosis, rheumatoid arthritis, osteoarthritis, heart failure, chronic pain, and neuropathic pain.

[0448] In some embodiments, the disease or disorder is selected from an inflammatory disease, an autoimmune disease, and a cancer.

[0449] In some embodiments, the disease or disorder is cancer.

[0450] In some embodiments, the disease or disorder is adrenocortical carcinoma, AIDS-related lymphoma, AIDS-related malignancies, anal cancer, cerebellar astrocytoma, extrahepatic bile duct cancer, bladder cancer, osteosarcoma / malignant fibrous histiocytoma, brain stem glioma, ependymoma, glioma of the visual pathway and hypothalamus, breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal carcinoid tumor, carcinoma, adrenal cortex, pancreatic islet cell carcinoma, primary central nervous system lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell sarcoma of the tendon sheath, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma. / family tumors, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer including intraocular melanoma and retinoblastoma, gallbladder cancer, gastrointestinal carcinoid tumors, ovarian germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, Hodgkin's disease, hypopharyngeal cancer, gliomas of the hypothalamus and visual pathway, intraocular melanoma, Kaposi's sarcoma, laryngeal cancer, acute lymphoblastic leukemia, acute myeloid leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, non-Hodgkin's lymphoma, Waldenstrom's hypergammaglobulinemia, malignant mesothelioma, malignant thymoma, medulloblastoma, melanoma, intraocular melanoma, Merkel cell carcinoma, primary Metastatic squamous cell carcinoma of the neck of unknown origin, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, chronic myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative disorders, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cavity cancer, oral cavity and lip cancer, oropharyngeal cancer, osteosarcoma / malignant fibrous histiocytoma of bone, ovarian cancer, ovarian low malignant potential tumor, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, transitional cell carcinoma (e.g., renal pelvis and ureter), retinoblastoma, rhabdomyosarcoma, salivary gland cancer, bone malignancies The cancer is selected from: fibrous histiocytoma, soft tissue sarcoma, Sezary syndrome, skin cancer, small intestine cancer, gastric cancer (gastric carcinoma), supratentorial primitive neuroectodermal tumor and pineal tumor, cutaneous T-cell lymphoma, testicular cancer, malignant thymoma, thyroid cancer, mammary analogue secretory carcinoma (MASC), lung adenocarcinoma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, childhood glioma, sarcoma, glioblastoma, spitzoid neoplasm, astrocytoma, squamous cell carcinoma of the head and neck, low-grade glioma, high-grade glioma, congenital mesodermal nephroma, adenoid cystic carcinoma, cylindroma, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0451] In some embodiments, the cancer is selected from glioma, thyroid cancer, breast cancer, small cell lung cancer, non-small cell carcinoma, gastric cancer, colon cancer, gastrointestinal stromal cancer, pancreatic cancer, bile duct cancer, CNS cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cancer, anaplastic large cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma.

[0452] The foregoing description illustrates and describes the present disclosure. Moreover, while the present disclosure has shown and described only preferred embodiments, it should be understood that the present disclosure can be used in various other combinations, modifications, and environments, as described above, and that changes or modifications are possible within the scope of the inventive concepts expressed herein and commensurate with the above teachings and / or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain the best mode known to the applicant and to enable one skilled in the art to utilize the disclosure in such or other embodiments and to make various modifications as required for a particular application or use. Therefore, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended that the appended claims be construed to include alternative embodiments.

[0453] All publications and patent documents cited herein are incorporated by reference in their entirety as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute an admission as to the contents or date thereof. While the present invention has been described above by written description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are intended to be illustrative, not limiting, of the scope of the claims which follow. [Example]

[0454] J. Working Example Representative examples of the disclosed compounds and disclosed methods are shown in the following non-limiting schemes and examples.

[0455] 1. Chemical methods a. General experimental procedures Generally, starting materials used were obtained from commercial sources or prepared in other examples unless otherwise noted.

[0456] UPLC-MS analysis conditions. The UPLC-MS analysis conditions used to analyze compound No. 14R are shown in Table 2 below. See also Figures 1A-D.

[0457] [Table 2]

[0458] The following abbreviations have the indicated meanings: aq aqueous solution CDCl3 chloroform-d d double line DCE Dichloroethane DCM dichloromethane DEA Diethylamine DIPEA N,N-Diisopropylethylamine DMF N,N-dimethylformamide DMF-DEA N,N-dimethylformamide diethyl acetal DMSO dimethyl sulfoxide DMSO-d6 hexadeuterated dimethyl sulfoxide ESI electrospray ionization EtOAc ethyl acetate EtOH ethanol g grams(s) h hour(s) 1 H NMR Proton Nuclear Magnetic Resonance Spectroscopy HPLC High Performance Liquid Chromatography Hz Hertz i-PrOH isopropanol LC-MS Liquid Chromatography-Mass Spectrometry m multiplet MeOH Methanol MeONa Sodium methoxide mg milligram MHz Megahertz min Minute(s) mL milliliter(s) mmol millimoles(s) MS mass spectrometry N Normal Nm nanometer(s) NMR nuclear magnetic resonance ppm parts per million psi pounds per square inch q quartet RT room temperature s single line t triple line TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran UPLC Ultra High Performance Liquid Chromatography vol Volume(s)

[0459] b. Synthesis of (R)-2-(2,5-difluorophenyl)pyrrolidine (Compound No. 6R) Synthesis of Compound No. 3R. To a solution of 2,5-difluorobenzaldehyde (Compound No. 1, 50.0 g, 352 mmol) in tetrahydrofuran (500 mL) was added (R)-2-methylpropane-2-sulfinamide (Compound No. 2R, 51.0 g, 422 mmol). Titanium ethoxide (160 mL, 704 mmol) was added dropwise at room temperature, heated to 60° C., and stirred for 1 hour. Upon completion, the reaction mixture was cooled to room temperature, poured into brine solution, diluted with ethyl acetate, and filtered through a Celite bed. The Celite bed was washed with ethyl acetate, and the organic layer was separated from the filtrate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude mass was purified by column chromatography using silica gel (60-120 mesh) with 50% ethyl acetate in hexane as eluent. The desired fractions were concentrated under reduced pressure to give (R,E)-N-(2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (compound no. 3R) as a light green liquid. Yield: 80 g, 93%; MS (ESI) m / z 246.07 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.76-7.73 (t, J=8.08 Hz, 1H), 7.54-7.47 (m, 2H), 1.19 (s, 9H); Chiral HPLC (Column: CHIRALPAK IC (4.6X250mm), 5 μm; Mobile phase: CO2 / i-PrOH (90:10, isocratic); Flow rate: 2.0 mL / min; Column temperature: 35°C; Automatic back pressure regulator: 1500 psi): Retention time: 5.14 min, Peak area: 0.3%; Retention time: 6.24, Peak area: 99.7%.

[0460] Synthesis of Compound No. 4a. Anhydrous tetrahydrofuran (234 mL, 8.0 vol) was added to a 2 L flask containing magnesium turnings (29.3 g, 204 mmol). A solution of 2-(2-bromoethyl)-1,3-dioxolane (Compound No. 4, 110.8 g, 612 mmol) in THF (664 mL, 6.0 vol) was prepared in a separate flask, and 50 mL of the solution was added to the flask containing the magnesium turnings. Iodine (1.3 g) was added to the flask containing the magnesium turnings and stirred at 45°C until the color of the iodine disappeared (the internal temperature needed to be kept below 45°C). The remaining 614 mL of the tetrahydrofuran solution of 2-(2-bromoethyl)-1,3-dioxolane (Compound No. 4) was added dropwise to the mixture at room temperature at a rate that did not allow the internal temperature of the reaction to rise above 30°C. After completion, the reaction was allowed to stir at room temperature for an additional 45 minutes to give (2-(1,3-dioxolan-2-yl)ethyl)magnesium bromide (compound number 4a). This solution was used directly for further steps.

[0461] Synthesis of Compound No. 5R. The above (2-(1,3-dioxolan-2-yl)ethyl)magnesium bromide (Compound No. 4a) solution was added to a −60° C. solution of (R,E)—N-(2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (Compound No. 3R, 50.0 g, 204 mmol) in tetrahydrofuran (250 mL, 5.0 vol). The reaction mixture was allowed to stir at 0° C. for 2 hours. Upon completion, the mixture was poured into ice-cold ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The resulting crude material was triturated with n-pentane and stirred for 30 minutes, and the solid was filtered and dried under high vacuum to give (R)-N-((R)-1-(2,5-difluorophenyl)-3-(1,3-dioxolan-2-yl)propyl)-2-methylpropane-2-sulfinamide (compound no. 5R) as a white solid. Yield: 60.0 g, 85%; MS (ESI) m / z 348.14 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.36 (s, 1H), 7.23-7.17 (m, 1H), 7.15-7.10 (m, 1H), 5.78 (d, J=9.56 Hz, 1H), 4.78-4.76 (t, J=3.96 Hz, 1H), 4.46 (d, J=4.96 Hz, 1H), 3.84-3.82 (t, J=4.44 Hz, 2H), 3.74-3.71 (t, J=6.12 Hz, 2H), 1.87-1.78 (m, 1H), 1.72-1.65 (m, 2H), 1.52-1.47 (m, 1H), 1.10 (s, 9H); HPLC (Column: CHIRALPAK IC (4.6X250mm), 5 μm; Mobile phase: CO2 / i-PrOH (80:20, isocratic); Flow rate: 3.0 mL / min; Column temperature: 35°C; Automatic backpressure regulator: 1500 psi): Retention time: 3.16 min, Peak area: 99.8%; Retention time: 3.69, Peak area: 0.2%.

[0462] Synthesis of Compound No. 6R. (R)-N-((R)-1-(2,5-difluorophenyl)-3-(1,3-dioxolan-2-yl)propyl)-2-methylpropane-2-sulfinamide (Compound No. 5R, 50.0 g, 144 mmol) in 5N aqueous hydrochloric acid (800 mL, 16 vol) was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C., and a solution of sodium borohydride (27.2 g, 720 mmol) in water (272 mL) was added dropwise at 0° C. and stirred for 1 hour. Upon completion, the reaction mixture was poured into ice water, basified with solid potassium carbonate (to pH=8), and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give (R)-2-(2,5-difluorophenyl)pyrrolidine (Compound No. 6R) as a brown liquid. Yield: 26.0 g, 82%;MS (ESI) m / z 183.97 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ 7.35-7.30 (m, 1H), 7.18-7.10 (m, 1H), 7.08-7.02 (m, 1H), 4.29-4.26 (m, 1H), 2.99-2.85 (m, 3H), 2.19-2.14 (m, 1H), 1.75-1.68 (m, 2H), 1.45-1.37 (m, 1H); HPLC (column: CHIRALPAK IG (4.6X250mm), 5 μm; mobile phase: 0.2% TEA in CO2 / MeOH (80:20, isocratic); flow rate: 2.0 mL / min; column temperature: 35 °C; automatic back pressure regulator: 1500 psi): Retention time: 1.72 min, Peak area: 99.5%; Retention time: 2.04 min, Peak area: 0.5%.

[0463] c. Synthesis of 4-(trifluoromethyl)-1'H-[1,4'-bipyrazole]-5'-amine (Compound No. 10) Synthesis of Compound No. 8. To a solution of 4-(trifluoromethyl)-1H-pyrazole (Compound No. 7, 10.0 g, 73.5 mmol) in N,N-dimethylformamide (70 mL) was added potassium carbonate (30.4 g, 220 mmol) and bromoacetonitrile (7.1 mL, 102 mmol) at room temperature. The reaction mixture was heated to 70° C. and stirred for 5 hours. After completion, the reaction mass was cooled to room temperature, poured into ice water, and extracted with methyl tert-butyl ether. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetonitrile (Compound No. 8) as a light brown liquid. Yield: 12.5 g, 96%;MS (ESI) m / z 174.12 [M-1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.06 (s, 1H), 5.56 (s, 2H).

[0464] Synthesis of Compound No. 9. A solution of 2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acetonitrile (Compound No. 8, 12.5 g, 71.42 mmol) in N,N-dimethylformamide diethyl acetal (21.1 mL, 142.8 mmol) was heated to 115° C. and stirred for 16 hours. After completion, the reaction mass was cooled to room temperature, poured into ice water, and extracted with methyl tert-butyl ether. The organic portion was washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-(dimethylamino)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acrylonitrile (Compound No. 9) (E / Z-mixture) as a light brown liquid. Yield: 14.0 g, 85%; MS (ESI) m / z 231.10 [M+1] + .

[0465] Synthesis of Compound No. 10. To a solution of 3-(dimethylamino)-2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)acrylonitrile (Compound No. 9, 12.0 g, 52.1 mmol) in ethanol (120 mL, 10 Vol) (E / Z-mixture), hydrazine monohydrate (65%, 12.6 mL, 26.0 mmol) was added and cooled to −20° C. Concentrated hydrochloric acid (27 mL, to pH=1) was added dropwise to the solution at −20° C. The reaction mixture was heated to 90° C. for 16 hours. After completion, the reaction mass was concentrated to remove ethanol. The resulting crude product was diluted with ice water and basified with potassium carbonate. The solid compound was filtered, washed with diethyl ether, and dried under high vacuum to give 4-(trifluoromethyl)-1′H-[1,4′-bipyrazole]-5′-amine (Compound No. 10) as an off-white solid. Yield: 8.7 g, 76 %;MS (ESI) m / z 218.20 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 11.90 (br s, 1H), 8.63 (s, 1H), 8.05 (s, 1H), 7.81 (s, 1H), 5.04 (s, 2H).

[0466] d. Synthesis of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazolo[1,5-α]pyrimidine (Compound No. 14R) TIFF0007767301000223.tif74128 Synthesis of Compound No. 12. To a solution of 4-(trifluoromethyl)-1'H-[1,4'-bipyrazole]-5'-amine (Compound No. 10, 9.4 g, 43.3 mmol) in ethanol (94 mL), sodium methoxide solution (25% in methanol, 46.7 mL, 216 mmol) was added at room temperature and stirred for 15 minutes, followed by the addition of 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Compound No. 11, 9.0 g, 64.9 mmol) at room temperature. The reaction mixture was heated to 90°C for 16 hours. After completion, the reaction mass was concentrated. The obtained crude was diluted with ice water and acidified with acetic acid (to pH=5), and the solid compound was filtered, washed with n-pentane, and dried under high vacuum to give 3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (compound number 12) as a yellow solid. Yield: 9.0 g, 77%; MS (ESI) m / z 270.09 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.72 (s, 1H), 8.61 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 6.15 (s, 1H).

[0467] Synthesis of Compound No. 13. To a solution of 3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (Compound No. 12, 8.5 g, 31.5 mmol) in 1,2-dichloroethene (130 mL, 15 Vol) was added phosphorus oxychloride (14.7 mL, 157.9 mmol) and a catalytic amount of N,N-dimethylformamide (0.25 ml, 3 mmol) at room temperature. The reaction mixture was heated to 100° C. for 16 hours. After completion, the reaction mass was concentrated. The resulting crude product was dissolved in methyl tert-butyl ether and poured into saturated sodium bicarbonate (pH=8). The organic portion was washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-chloro-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine (compound number 13) as a yellow solid. Yield: 7.8 g, 86%; MS (ESI) m / z 288.15 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.30 (d, J=7.28 Hz, 1H), 8.84 (s, 1H), 8.73 (s, 1H), 8.25 (s, 1H), 7.32 (d, J=7.28 Hz, 1H).

[0468] Synthesis of Compound No. 14R. To a solution of 5-chloro-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine (Compound No. 13, 7.8 g, 27 mmol) in N,N-dimethylformamide (54 mL, 7.0 vol) was added (R)-2-(2,5-difluorophenyl)pyrrolidine (Compound No. 6R, 5.47 g, 29.8 mmol) and N,N-diisopropylethylamine (25 mL, 135 mmol) at room temperature. The reaction mixture was heated to 90° C. for 4 hours. Upon completion, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude material was triturated with ethanol and the solid was filtered to give (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a]pyrimidine (compound no. 14R) as an off-white solid. Yield: 7.5 g, 63%; MS (ESI) m / z 435.03 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J=7.68 Hz, 1H), 8.25-8.04 (m, 3H), 7.33-6.95 (m, 3H), 6.66 (d, J=7.72 Hz, 1H), 5.46-5.35 (m, 1H), 4.06-4.00 (m, 1H), 3.77- 3.63 (m, 1H), 2.45-2.40 (m, 1H), 2.07-2.03 (m, 2H), 1.86-1.82 (m, 1H). 1H NMR (400 MHz, DMSO-d6 @ HT) δ 8.64 (d, J=7.76 Hz, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.18-7.12 (m, 1H), 7.06-7.01 (m, 1H), 6.98-6.94 (m, 1H), 6.52 (s, 1H), 5.45 (d, J=5.40 Hz, 1H), 4.04-3.98 (m, 1H), 3.77-3.71 (m, 1H), 2.55-2.45 (m, 1H), 2.12-2.05 (m, 2H), 1.94-1.89 (m, 1H); HPLC (Column: CHIRALPAK IG (4.6x250mm), 5 μm; Mobile phase: 0.2% TEA in CO₂ / MeOH (80:20, isocratic); Flow rate: 2.0 mL / min; Column temperature: 35 °C; Automatic backpressure regulator: 1500 psi): Retention time: 3.15 min, Peak area: 0.6%; Retention time: 3.56, Peak area: 99.4%; HPLC (Column: BRIDGESHIELD RP18 (4.6x50mm), 5 μm; Mobile phase: [A: 5mM aqueous ammonium acetate; B: acetonitrile], A% 0-10%, 10 min; Flow rate: 1.0 mL / min; Column temperature: Ambient): Retention time: 3.15 min, Peak area: 0.6%; Retention time: 3.56, Peak area: 99.4%; UPLC-MS (column: Acquity HSS-T3 (2.1 x 100 mm), 1.8 μm; mobile phase: [A: 0.1% TFA in water, B: acetonitrile], B% 10-90%, 8 min; flow rate: 0.3 mL / min; column temperature: 30 °C; UV max 214.0 nm): retention time: 7.16 min, peak area: 99.5%, MS (ESI) m / z 435.37; melting point: 182-184 °C.

[0469] 2. Biological Test Methods The TrkA kinase domain was provided by SignalChem. The Ulight PolyGT peptide substrate and europium-labeled W1024 anti-phosphotyrosine antibody were provided by Perkin Elmer. The assay buffer contained 50 mM HEPES, 10 mM MgCl2, 1 mM EGTA, 2 mM DTT, 0.1 mg / mL BSA, and 0.005% w / v Tween 20, pH 7.5. The enzyme dilution buffer was made by supplementing the assay buffer with 25% w / v glycerol. The antibody dilution buffer contained 20 mM Tris, 137 mM NaCl, and 0.05% w / v Tween 20, pH 8.0. Buffers were prepared at room temperature. The enzyme solution was made on ice, while other solutions were made at room temperature, and all subsequent assay steps were performed at room temperature. TrkA stock solution (0.1 mg / mL) was diluted 156-fold in enzyme dilution buffer and then 100-fold in assay buffer. 5 μL / well of enzyme solution was added to the assay plate (Greiner black 384-well non-binding plate), and buffer without enzyme was added to negative control wells. Test compounds were serially diluted in DMSO to a 300-fold final assay concentration. 1 μL of each test compound dilution was mixed with 99 μL of assay buffer containing ATP (30 μM), and 5 μL of each test compound-ATP solution was added to wells containing enzyme. Positive control wells contained enzyme and substrate but no test compound. After a 15-minute preincubation of the enzyme with test compound, 5 μL of substrate diluted in assay buffer was added to all wells. The final assay concentrations were 33 pM TrkA, 100 nM peptide substrate, and 10 μM ATP. After a 5-minute reaction, 5 μL of 80 mM EDTA was added, followed 5 minutes later by 5 μL of 2 nM antibody solution. The ratio of fluorescence at 665 nm and 615 nM for each well was determined using a Tecan Infinite Pro F200 plate reader. Percent inhibition was calculated for each test compound well (% inhibition = 100 - 100 * (test value - negative control) / (positive control - negative control)). Percent inhibition values ​​were fitted to a four-parameter logistic regression to determine the IC for each test compound. 50 value was determined.

[0470] A list of pyrazolo[1,5-α]pyrimidine compounds that were evaluated for their ability to inhibit TRK is shown below in Table 3. As will be readily apparent to those skilled in the art, these compounds can be prepared by the disclosed methods or by alternative methods known in the art. All examples have an IC of less than 5 nM. 50 inhibits TrK kinase.

[0471] [Table 3] TIFF0007767301000225.tif197107TIFF0007767301000226.tif219107TIFF0007767301000227.tif214107 TIFF0007767301000228.tif194107TIFF0007767301000229.tif208107TIFF0007767301000230.tif205107 TIFF0007767301000231.tif213107TIFF0007767301000232.tif226107TIFF0007767301000233.tif221107 TIFF0007767301000234.tif207107TIFF0007767301000235.tif226107TIFF0007767301000236.tif159128

[0472] [Table 3A] TIFF0007767301000238.tif190128TIFF0007767301000239.tif21484TIFF0007767301000240.tif23284TIFF0007767301000241.tif85128

[0473] K. Equivalents It should be understood that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments, therefore, are to be considered in all respects as illustrative and not limiting of the invention described herein. The scope of the invention is, therefore, indicated by the appended claims, rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. Formula (XXV): or a pharmaceutically acceptable salt thereof, said method comprising: Formula (XXVI): and a compound having a structure represented by the formula: whereby is X １ In the formula, X １ is a halogen, The method.

2. The method of claim 1 , wherein the coupling reaction is carried out in the presence of a base.

3. 3. The method of claim 2, wherein the base is an amine base.

4. 4. The method of claim 3, wherein the amine base is a trialkylamine or pyridine.

5. 10. The method of claim 1, wherein the coupling reaction is carried out at an elevated temperature, the temperature being in the range of 70°C to 110°C.

6. Formula (XXV): or a salt thereof, said method comprising: (a) Formula (XIX): and an amine having a structure represented by formula (XX): by reacting uracil having a structure represented by formula (XVIII): preparing an amide having a structure represented by (b) reacting the amide with a halogenating agent to form a compound of formula (XXVI): preparing a compound having a structure represented by (c) combining a compound of formula (XXVI) with the structure: by coupling a compound having is replaced by X 1 . wherein X 1 is a halogen.

Images