Pyrazole compounds inhibiting janus kinase and uses thereof

Abstract

Provided herein are pyrazole compounds.In particular, provided herein are compounds that affect the function of kinases in cells and are useful as therapeutic agents or together with therapeutic agents.Provided herein are compounds that are useful in treating various diseases and conditions, including cardiovascular disease, JAK-related disease, disease characterized by abnormal growth, such as cancer, and inflammatory disease, or eye disease, such as glaucoma.Also provided herein are compositions that include pyrazole compounds.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 253,026, filed October 6, 2021, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background The present disclosure relates to pyrazole compounds that affect the function of phosphotransferases, such as protein kinases, and are useful as or in conjunction with therapeutic agents.

[0003] Protein kinases play a role in biological pathways including adaptive immunity, adhesion and migration, angiogenesis, apoptosis, bone development, bone growth, bone remodeling, cancer, cell cycle, cell proliferation, differentiation, immunity, metabolism, and transcription. Kinases can be classified into serine / threonine kinases and tyrosine kinases according to their targets. Tyrosine kinases include receptor and non-receptor tyrosine kinases. Janus kinases (JAKs) are non-receptor tyrosine kinases and include four members JAK1, JAK2, JAK3, and TYK2.

[0004] The Janus kinase (JAK), signal transducer of activation (STAT) pathway is a signal transduction pathway used by cytokines, interferons, growth factors, and related molecules. The JAK / STAT pathway provides a mechanism by which extracellular factors control gene expression, thereby regulating cell growth and differentiation. Mutations and polymorphisms in components of the JAK / STAT pathway, as well as increased or decreased levels of cytokines that utilize JAK / STAT, are associated with various human diseases such as cancer and immune-related conditions. For example, mutations or polymorphisms in type 1 and type II cytokine receptors, JAK kinases, STAT proteins, and JAK / STAT regulatory proteins, such as phosphotyrosine phosphatases, SOCS proteins, and PIAS proteins, have been reported in various diseases. When dysregulated, JAK-mediated responses can positively or negatively affect cells, resulting in hyperactivation and malignant transformation, or immune and hematopoietic defects, respectively, suggesting the utility of using inhibitors of JAK kinases. The JAK / STAT signaling pathway is involved in various hyperproliferative and cancer-related processes, including cell cycle progression, apoptosis, angiogenesis, invasion, metastasis, and immune system evasion. In addition, the JAK / STAT signaling pathway is important in the development and differentiation of hematopoietic cells and in the regulation of both pro- and anti-inflammatory and immune responses.

[0005] In view of the role that the JAK / STAT pathway plays in disease states, there remains a need for ligands that inhibit or modulate the activity of JAKs. Summary of the Invention [Means for solving the problem]

[0006] overview Formula 1: [ka] or a pharma- ceutically acceptable salt thereof.

[0007] Formula 2: [ka] Also provided herein is a compound of the formula:

[0008] Formula 3: [ka] Also provided herein is a compound of the formula:

[0009] The following compounds: [ka] or a pharma- ceutically acceptable salt thereof are also provided herein.

[0010] Also provided herein are uses of the compounds and compositions provided herein, eg, for the treatment of disease. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 shows a first general scheme for the preparation of compounds provided herein.

[0012] [Diagram 2] FIG. 2 shows a second general scheme for the preparation of compounds provided herein.

[0013] [Diagram 3] FIG. 3 shows a second general scheme for the preparation of compounds provided herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description definition The terms "a" and "an" and "the" and similar referents used in the context of describing this disclosure (especially in the context of the claims below) should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is intended only to serve as a shorthand method of referring individually to each separate value within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if set forth individually herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. Any examples provided herein, or the use of exemplary language (e.g., "such as"), are intended only to further clarify the disclosure and do not limit the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosure.

[0015] The term "about" when referring to a measurable value such as an amount, duration, etc., refers to a variation of ±20%, where such variation is appropriate for carrying out the disclosed methods. In some embodiments, about refers to a variation of ±10%, ±5%, ±1%, or ±0.1% from the particular value.

[0016] The term "alkyl" refers to saturated aliphatic hydrocarbon radicals including straight-chain or branched-chain groups. "Alkyl" may be exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like.

[0017] The term "aryl" refers to an aromatic carbocyclic radical that can be monocyclic or polycyclic with fused or non-fused rings. In some embodiments, aryl is phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indanyl, or indenyl.

[0018] The term “C n~m " refers to a group containing a number of carbon atoms in the range designated by the integers "n" and "m."

[0019] The term "cycloalkyl" refers to a radical of a saturated carbocyclic ring system that is monocyclic or polycyclic having fused or non-fused rings. 3~8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, and cyclooctyl.

[0020] The term "haloalkyl" refers to a saturated aliphatic hydrocarbon radical that includes straight or branched chain groups having one or more halogens (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) in the hydrocarbon.

[0021] The term "halogen" or "halo" refers to a fluoro, chloro, bromo, or iodo moiety. In some embodiments, the halogen is fluoro, chloro, or bromo. In some embodiments, the halogen is fluoro or chloro.

[0022] The term "heteroalkyl" refers to saturated aliphatic hydrocarbon radicals including straight or branched chain groups having one or more heteroatoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) in the hydrocarbon.

[0023] The term "heteroaryl" refers to an aromatic carbocyclic radical having one or more heteroatoms (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) in the carbocyclic ring.

[0024] The term "heteroatom" or "hetero" refers, independently at each occurrence, to N, O, S, P, or Si. In some embodiments, each heteroatom is independently selected from N, O, or S.

[0025] The term "heterocycloalkyl" refers to a radical of a monocyclic or polycyclic saturated carbocyclic ring compound having one or more heteroatoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) in the carbocyclic ring.

[0026] The phrase "JAK-associated disease" refers to any disease, disorder, or condition that is directly or indirectly linked to expression or activity of JAK, including overexpression or abnormal activity levels, or that can be prevented, ameliorated, rendered undetectable by conventional means, neutralized, or avoided by modulating JAK activity.

[0027] Use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to refer to alternatives only or the alternatives are not mutually exclusive, however, the present disclosure supports a definition that refers to alternatives only and "and / or."

[0028] The phrase "pharmaceutically acceptable carrier" refers to a carrier that is generally compatible with the other components of the composition; is not harmful to the recipient; and is not biologically or otherwise undesirable and is useful in the preparation of a pharmaceutical composition. "Pharmaceutically acceptable carrier" includes both one carrier and more than one carrier. Some embodiments include carriers for topical, ophthalmic, parenteral, intravenous, intraperitoneal, intramuscular, sublingual, nasal, or oral administration. "Pharmaceutically acceptable carrier" also includes agents for the preparation of aqueous dispersions and sterile powders for injection or dispersion.

[0029] The phrase "pharmaceutically acceptable salt" refers to an ionizable therapeutic agent that combines with a counterion to form a neutral complex. Depending on the specific substituents found on the compounds provided herein, salts of the compounds are included that are prepared with relatively non-toxic acids or bases. The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Berge et al., 1977, "Pharmaceutically Acceptable Salts." J. Pharm. Sci., 66, pp. 1-19, each of which is incorporated herein by reference in its entirety.

[0030] Also included are "prophylactic" treatments, which may be directed to reducing the rate of progression of the disease or condition being treated, delaying the onset of the disease or condition, or reducing the severity of its onset. "Treatment" or "prophylaxis" does not necessarily indicate a complete eradication, cure, or prevention of the disease or condition, or its associated symptoms.

[0031] The term "therapeutically effective amount" refers to an amount of a compound or composition effective to affect, reduce or inhibit the activity of, or prevent the activation of, a kinase. The term also refers to an amount effective to produce a desired in vivo effect in a subject, preferably a human.

[0032] "Treatment" refers to any type of intervention in a subject or cell that is provided as a means of modifying the natural course of a disease or condition of an individual or cell. Treatment includes, but is not limited to, administration of one or more compounds provided herein or pharmaceutical compositions thereof, and can be performed either prophylactically or following the initiation of a pathological event or contact with a pathogenic agent. Treatment includes any desired effect on the symptoms or pathology of a disease or condition associated with inflammation, among those provided herein. compound

[0033] Provided herein are pyrazole compounds that are useful as or in conjunction with therapeutic agents. In some embodiments, the pyrazole compounds have the formula: [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, R 1 is N, CH, CF, CCl, or CBr; R 2 ,NH, [ka] and; R 3 is C 6~10 Aryl or C 2~10 is heteroaryl; R 4 , H, C 1~4 Alkyl, C 1~4 Haloalkyl, F, Cl, Br, I, O(C 1~4 Alkyl), C 1~4 Alkyl-OH, CH 2 NH 2 , C.H. 2 N(C 1~4 Alkyl)(C 1~4 alkyl), Boc, C(O)N(H)(C 1~4 alkyl), CH 2 N(H)Boc, C(O)O(C 1~4 Alkyl), C 2~8 Heterocycloalkyl, CH 2 -(C2~8 Heterocycloalkyl), (C 2~8 Heterocycloalkyl)-CH 3 , C.H. 2 -(C 2~8 Heterocycloalkyl)-CH 3 , C(O)OH, S(O 2 )(C 1~4 alkyl), C(O)NH 2 , C 1~6 Heteroalkyl, CH 2 O.C.(O)-(C 6~10 Aryl), (C 2~8 Heterocycloalkyl)-Boc, (C 1~6 Heteroalkyl)-(C 2~8 Heterocycloalkyl)-(C 1~4 alkyl), CH 2 O.C.(O)(C 1~6 Heteroalkyl), CH 2 OC(O)CH 2 CH 2 -(C 2~8 Heterocycloalkyl), C(O)N(C 1~4 Alkyl)(C 1~4 alkyl), CH 2 N(H)C(O)C(CH 3 )N(H)Boc, CH 2 N(H)C(O)-Pyrrolidinyl-Boc, CH 2 N(H)C(O)C(CH 3 )NH 2 , C.H. 2 N(H)C(O)-pyrrolidinyl, CH 2 N(H)Boc, CH 2 N(H)C(O)CH 2 N(CH 3 ) 2 , C.H. 2 N(H)C(O)C(N(H)Boc)CH 2 CH 2 CH 2 -Guanidinyl (Boc) 2 , C.H. 2 N(H)C(O)C(NH 2 )CH 2 CH 2 CH 2 -guanidinyl, (C 2~8Heterocycloalkyl)-N(C 1~4 Alkyl)(C 1~4 alkyl), or C 5~10 is spiroheterocycloalkyl; R 5 are H, F, Cl, Br, I, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 O-Alkyl, C 1~4 Alkyl-OH, =O, or C(O)O(C 1~4 alkyl); Or, R 4 and R 5 are combined, -ON=C(H)-, -C(H 2 )-N(H)-C(O)-, -C(O)-N(CH 3 )-C(O)-, -C(H 2 )-N(CH 3 )-C(H 2 )-, or =C(H)-C(H)=N-; R 6 is H and R 7 are H, F, Cl, Br, I, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 O-alkyl or C 3~6 Is cycloalkyl; Or, R 6 and R 7 Together, C 2~5 Alkylene or C 2~5 forming a heteroalkylene; R 8 is a bond, NH, O, CH 2 , N(Boc), N(CH 2 F), N(CHF 2 ), N(CF 3 ), N(CH 2 CH 2 F), N(CH 2 CHF 2 ), N(CH 2 CF 3 ), N(CH 2 CN), or N(CH 2 CH 2 CN); R 9 is N and Z is 0; Or, R 9 is C and Z is 1; R 10 , H, CH 2 F, CHF 2 , C.F. 3 , C.H. 2 Cl, CHCl 2 , CCl 3 , C.H. 2 Br, C.H. 2 I, F, Cl, Br, I, C 1~4 O-Alkyl, C 1~3 Alkylenes - OH, CN, CH 2 CN, CH 2 CH 2 CN, C(O)OH, OH, NH 2 , N(H)CH 3 , N(CH 3 ) 2 , C.H. 2 NH 2 , C.H. 2 N(H)CH 3 , C.H. 2 N(CH 3 ) 2 , or N(Boc)CH 3 and; J is 0, 1, or 2; X is 0, 1, or 2; M is 1 or 2; each hydrogen may be independently replaced with deuterium] are provided herein.

[0034] In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hydrogens are independently replaced with deuterium.

[0035] In some embodiments, J is 1 or 2. In some embodiments: J is 1 or 2; R 9 is C; Z is 1.

[0036] In some embodiments, X is 0. In some embodiments, X is 1 or 2. In some embodiments: X is 1; M is 1; R 8 NH, O, CH 2 , N(Boc), N(CH 2 F), N(CHF 2 ), N(CF 3 ), N(CH 2 CH 2 F), N(CH 2 CHF 2 ), N(CH 2 CF 3 ), N(CH 2 CN), or N(CH 2 CH 2 CN). In some embodiments: X is 1; M is 1; R 8 is a bond; R 9 is C; Z is 1.

[0037] In some embodiments, R 1 is N, CH, or CF. In some embodiments, R 1 is N. In some embodiments, R 1 is CH or CF.

[0038] In some embodiments, R 6 is H and R 7 are H, F, Cl, CH 3 , C.H. 2 CH 3 , O.C.H. 3 or cyclopropyl. In some embodiments, R 6 is H and R 7 is H, F, Cl, or CH 3 It is.

[0039] In some embodiments, [ka] is R defined as follows: 12 It is.

[0040] In some embodiments, [ka] teeth, [ka] It is.

[0041] In some embodiments, R 8 is a bond, NH, O, CH 2 , N(CH 2 F), or N(CH 2 CN). In some embodiments, R 8 is a bond. In some embodiments, R 8 NH, O, N(CH 2 F), or N(CH 2 CN).

[0042] In some embodiments, R 9 is C and Z is 1. In some embodiments, R 9 is N and Z is 0.

[0043] In some embodiments, R 10 , H, CH 2 F, CHF 2 , F, Cl, CH 2 OH, CN, CH 2 CN, C(O)OH, N(H)CH 3 , or C.H. 2 N(CH 3 ) 2 It is.

[0044] In some embodiments, [ka] is R defined as follows: 11 It is.

[0045] In some embodiments, [ka] teeth, [ka] It is.

[0046] In some embodiments, [ka] teeth, [ka] It is.

[0047] In some embodiments, R 4 , H, CH 3 , C.H. 2 NH 2 , C.H. 2 N(CH 3 ) 2 , Boc, C(O)N(H)CH 3 , C.H. 2 N(H)Boc, piperazinyl, C(O)OCH 3 , piperazinyl-CH 3 , C(O)OH, S(O 2 )CH 3 , C(O)NH 2 , morpholinyl, CH 2 OH, Cl, OCH 3 , C.H. 2 -morpholinyl, CH 2 OCH 3 , C.H. 2 -Piperazinyl-CH 3 , C.H. 2 CH 2 N(CH 3 ) 2 , C.H. 2 OC(O)-phenyl, CH 2 N(H)CH 3 , piperazinyl-Boc, CH 2 OCH 2 CH 2 OCH 3 , C.H. 2 OC(O)CH 2 CH 2 -Piperazinyl-CH 3 , C.H. 2 OC(O)CH2 CH 2 N(CH 3 ) 2 , C.H. 2 OC(O)CH 2 CH 2 -morpholinyl, C(O)N(CH 3 ) 2 , C.H. 2 N(H)C(O)C(CH 3 )N(H)Boc, CH 2 N(H)C(O)-Pyrrolidinyl-Boc, CH 2 N(H)C(O)C(CH 3 )NH 2 , C.H. 2 N(H)C(O)-pyrrolidinyl, CH 2 N(H)Boc, CH 2 N(H)C(O)CH 2 N(CH 3 ) 2 , C.H. 2 N(H)C(O)C(N(H)Boc)CH 2 CH 2 CH 2 -Guanidinyl (Boc) 2 , C.H. 2 N(H)C(O)C(NH 2 )CH 2 CH 2 CH 2 -Guanidinyl, CF 3 , O.C.H. 2 CH 2 N(CH 3 ) 2 , O.C.H. 2 CH 2 OCH 3 , azetidinyl-N(CH 3 ) 2 or 2-oxa-6-azaspiro[3.3]heptanyl.

[0048] In some embodiments, R 4 , H, CH 3 , C.H. 2 NH 2 , C.H. 2 N(CH 3 ) 2 , C(O)N(H)CH 3, piperazinyl, C(O)OCH 3 , piperazinyl-CH 3 , C(O)OH, S(O 2 )CH 3 , C(O)NH 2 , morpholinyl, CH 2 OH, Cl, OCH 3 , C.H. 2 -morpholinyl, CH 2 OCH 3 , C.H. 2 -Piperazinyl-CH 3 , C.H. 2 CH 2 N(CH 3 ) 2 , C.H. 2 OC(O)-phenyl, CH 2 N(H)CH 3 , C.H. 2 OCH 2 CH 2 OCH 3 , C.H. 2 OC(O)CH 2 CH 2 -Piperazinyl-CH 3 , C.H. 2 OC(O)CH 2 CH 2 N(CH 3 ) 2 , C.H. 2 OC(O)CH 2 CH 2 -morpholinyl, C(O)N(CH 3 ) 2 , C.H. 2 N(H)C(O)C(CH 3 )NH 2 , C.H. 2 N(H)C(O)-pyrrolidinyl, CH 2 N(H)Boc, CH 2 N(H)C(O)CH 2 N(CH 3 ) 2 , C.H. 2 N(H)C(O)C(NH 2 )CH 2 CH 2 CH 2 -Guanidinyl, CF 3 , O.C.H. 2 CH2 N(CH 3 ) 2 , O.C.H. 2 CH 2 OCH 3 , azetidinyl-N(CH 3 ) 2 or 2-oxa-6-azaspiro[3.3]heptanyl.

[0049] In some embodiments, R 4 is CH 3 , C.H. 2 NH 2 , C.H. 2 N(CH 3 ) 2 , C(O)N(H)CH 3 , piperazinyl, C(O)OCH 3 , piperazinyl-CH 3 , C(O)OH, S(O 2 )CH 3 , C(O)NH 2 , morpholinyl, CH 2 OH, Cl, OCH 3 , C.H. 2 -morpholinyl, CH 2 OCH 3 , C.H. 2 -Piperazinyl-CH 3 , C.H. 2 CH 2 N(CH 3 ) 2 , C.H. 2 OC(O)-phenyl, CH 2 N(H)CH 3 , C.H. 2 OCH 2 CH 2 OCH 3 , C.H. 2 OC(O)CH 2 CH 2 -Piperazinyl-CH 3 , C.H. 2 OC(O)CH 2 CH 2 N(CH 3 ) 2 , C.H. 2 OC(O)CH 2 CH 2 -morpholinyl, C(O)N(CH3 ) 2 , C.H. 2 N(H)C(O)C(CH 3 )NH 2 , C.H. 2 N(H)C(O)-pyrrolidinyl, CH 2 N(H)Boc, CH 2 N(H)C(O)CH 2 N(CH 3 ) 2 , C.H. 2 N(H)C(O)C(NH 2 )CH 2 CH 2 CH 2 -Guanidinyl, CF 3 , O.C.H. 2 CH 2 N(CH 3 ) 2 , O.C.H. 2 CH 2 OCH 3 , azetidinyl-N(CH 3 ) 2 or 2-oxa-6-azaspiro[3.3]heptanyl.

[0050] In some embodiments, 8 is a bond, NH, O, CH 2 , or N(CH 2 F); X is 1; and M is 1.

[0051] In some embodiments, R 3 is phenyl, isothiazolyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazolopyrimidinyl, triazolyl, or isoxazolyl. 3 is phenyl or isothiazolyl.

[0052] In some embodiments, R 5 are H, F, and CH 3 , =O, C(O)OCH 3 , or C.H. 2 In some embodiments, R 5 is H, F, or CH 3 In some embodiments, R5 =O, C(O)OCH 3 , or C.H. 2 In some embodiments, R 5 is H.

[0053] In some embodiments, [ka] is R defined as follows: 13 It is.

[0054] In some embodiments, [ka] teeth, [ka] [ka] It is.

[0055] In some embodiments, the compounds provided herein have the formula: [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, R 2 ,NH, [ka] and; R 11 teeth, [ka] [ka] and; R 12 teeth, [ka] and; R 13 teeth, [ka] [ka] [ka] [ka] [It is].

[0056] In some embodiments, R 2 ,NH, [ka] It is.

[0057] In some embodiments, R 2 is NH.

[0058] In some embodiments, the formula: [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, R 14 teeth, [ka] and; R 15 teeth, [ka] and; R 16 teeth, [ka] is provided herein.

[0059] In some embodiments, the formula: [ka] or a pharma- ceutically acceptable salt thereof. [In the formula, R 17 is H, Cl, or CH 3 and; R 18 teeth, [ka] [ka] is provided herein.

[0060] In some embodiments, the compounds provided herein have the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0061] In some embodiments, the compounds provided herein have the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0062] In some embodiments, R 100 is the corresponding moiety of the compounds or formulae provided herein. In some embodiments, R 100 is R 14 , [ka] It is.

[0063] In some embodiments, R 200 is the corresponding moiety of the compounds or formulae provided herein. In some embodiments, R 200 is R7 or R 17 It is.

[0064] In some embodiments, R 300 is the corresponding moiety of the compounds or formulae provided herein. In some embodiments, R 300 is R 16 , R 18 ,or [ka] It is. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

[0065] In some embodiments, the compounds described herein are selected from the compounds in Table 1, or a pharma- ceutically acceptable salt thereof.

[0066] The compounds provided herein may have one or more stereocenters, and each stereocenter may exist independently in either R or S configuration.In some embodiments, the compounds provided herein exist in optically active form or racemic form.It should be understood that the compounds provided herein encompass racemic, optically active, regioisomeric, and stereoisomeric forms, or combinations thereof, that have the therapeutically useful properties provided herein.

[0067] Preparation of optically active forms can be accomplished by any suitable method, including, but not limited to, resolution of racemates with recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases. In some embodiments, a mixture of one or more isomers can be utilized as the therapeutic compounds provided herein. In some embodiments, the compounds provided herein contain one or more chiral centers. The compounds provided herein can be prepared by any means, including stereoselective synthesis, enantioselective synthesis, or separation of a mixture of enantiomers or diastereomers. Resolution of the compounds and their isomers can be accomplished by any means, including, but not limited to, chemical processes, enzymatic processes, fractional crystallization, distillation, or chromatography.

[0068] In some embodiments, the compounds provided herein exist as tautomers. All tautomers may be included within the scope of the compounds presented herein.

[0069] In some embodiments, the compounds provided herein also include isotopically labeled compounds in which one or more atoms are replaced with an atom having the same atomic number but a different atomic mass or mass number than the atomic mass or mass number most frequently occurring in nature. Examples of isotopes suitable for inclusion in the compounds provided herein include: 2 H, 3 H, 11 C. 13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P and 35 In some embodiments, isotopically labeled compounds are useful for drug or substrate tissue distribution studies. In some embodiments, substitution with heavier isotopes such as deuterium confers greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or process in which an appropriate isotopically labeled reagent is substituted for a non-isotopically labeled reagent in another process.

[0070] In some embodiments, the compounds provided herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0071] The compounds provided herein, as well as other related compounds having different substituents, can be synthesized using the techniques and materials provided herein in, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989); March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001); and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999), all of which are incorporated herein by reference in their entireties for such disclosure. The general methods of preparation of the compounds provided herein are modified by using appropriate reagents and conditions for the introduction of the various moieties found in the formulas provided herein.

[0072] The compounds provided herein are synthesized using any suitable procedure starting from compounds available from commercial sources or prepared using the procedures provided herein.

[0073] In some embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxy groups, are protected to avoid unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protecting group is removed. In some embodiments, each protecting group can be removed by different means. Protecting groups that are cleaved under completely different reaction conditions meet the requirement of differential removal.

[0074] In some embodiments, the protecting groups are removed by acid, base, reducing conditions (e.g., hydrogenolysis), or oxidative conditions. For example, groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are acid labile and can be removed by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups, such as, but not limited to, methyl, ethyl, and acetyl, in the presence of acid labile groups, such as t-butyl carbamate, or amines blocked with carbamates, which are both acid and base stable, but can be removed by hydrolysis. method

[0075] The compounds disclosed herein and compositions comprising them have kinase inhibitory activity and are therefore useful for modulating the action of kinases and treating and / or preventing diseases or conditions affected by kinases. The compounds and compositions provided herein can be used to modulate the action of kinases in either cells in vitro or cells in an organism in vivo. In some embodiments, methods are provided herein that include applying a therapeutically effective inhibitory amount of a compound or composition provided herein to a medium, such as an assay medium, or contacting a cell, either a cell in vitro or a cell in an organism in vivo. In some embodiments, the kinase inhibited is a JAK kinase, such as JAK1, JAK2, JAK3, TYK2, or a combination thereof. In some embodiments, the compounds and compositions provided herein are useful as JAK inhibitors. Thus, in some embodiments, the compounds and compositions provided herein are useful for treating JAK-related diseases or disorders.

[0076] Examples of JAK-associated diseases include diseases involving the immune system, including, for example, organ transplant rejection (e.g., allograft rejection and graft-versus-host disease).Further examples of JAK-associated diseases include autoimmune disease, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, autoimmune thyroid disorder, chronic obstructive pulmonary disease (COPD), etc.In some embodiments, the autoimmune disease is arthritis.

[0077] Further examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, eczematous dermatitis, contact dermatitis, atopic dermatitis (atopic eczema) and rhinitis. Further examples of JAK-associated diseases include viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV 1, varicella-zoster virus (VZV) and human papillomavirus (HPV).

[0078] Further examples of JAK-related diseases or conditions include those characterized by solid tumors (e.g., prostate cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyoma, melanoma, etc.), blood cancers (e.g., lymphoma, leukemia, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or multiple myeloma), and skin cancers, such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Exemplary CTCLs include Sézary syndrome and mycosis fungoides. Other examples of JAK-related diseases or conditions include pulmonary arterial hypertension.

[0079] Other examples of JAK-associated diseases or conditions include inflammation-associated cancer. In some embodiments, the cancer is associated with inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the inflammatory bowel disease is Crohn's disease. In some embodiments, the inflammation-associated cancer is colitis-associated cancer. In some embodiments, the inflammation-associated cancer is colon cancer or colorectal cancer. In some embodiments, the cancer is gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), adenocarcinoma, small intestine cancer, or rectal cancer.

[0080] Thus, in one embodiment, provided herein is a method of treating a JAK-associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount or dose of a compound or composition provided herein.

[0081] In some embodiments, provided herein is a method of treating a JAK-associated disease in a subject in need thereof, comprising administering to the subject a compound provided in Table 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, provided herein is a method of treating a JAK-associated disease in a subject in need thereof, comprising administering to the subject a composition, such as a pharmaceutical composition, comprising a compound provided in Table 1, or a pharma- ceutically acceptable salt thereof.

[0082] In some embodiments, the JAK-related disease comprises diseases involving the immune system. In some embodiments, the JAK-related disease comprises organ transplant rejection, such as allograft rejection and graft-versus-host disease. In some embodiments, the JAK-related disease comprises autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, and autoimmune thyroid conditions. In some embodiments, the autoimmune disease is an autoimmune bullous skin condition, such as pemphigus vulgaris (PV) or bullous pemphigoid (BP).

[0083] In some embodiments, the JAK-associated disease comprises an allergic condition, hi some embodiments, the JAK-associated disease comprises asthma, food allergies, atopic dermatitis, and rhinitis.

[0084] In some embodiments, the JAK-associated disease comprises a viral disease. In some embodiments, the JAK-associated disease comprises Epstein-Barr virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster virus (VZV), Human Papillomavirus (HPV), and SARS-CoV-2 virus.

[0085] In some embodiments, the JAK-related disease comprises a skin condition. In some embodiments, the JAK-related disease comprises psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rash, skin irritation, skin sensitization, such as contact dermatitis or allergic contact dermatitis. Certain substances, including some pharmaceuticals, may cause skin sensitization when applied topically. In some embodiments, the simultaneous or sequential administration of at least one compound or composition provided herein with an agent that causes undesired sensitization can help treat such undesired sensitization or dermatitis. In some embodiments, the skin disorder is treated by topical administration of at least one compound or composition provided herein.

[0086] In some embodiments, the JAK-related disease comprises cancer. In some embodiments, the JAK-related disease comprises solid tumors, such as prostate cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, and melanoma. In some embodiments, the JAK-related disease comprises blood cancers, such as lymphomas, leukemias, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or multiple myeloma. In some embodiments, JAK-related diseases include myeloproliferative diseases or conditions, such as essential thrombocythemia, polycythemia vera, myelofibrosis, post-essential thrombocythemia, post-polycythemia vera, systemic mastocytosis, hypereosinophilic syndrome (HES), erythrocytosis, leukocytosis, thrombocytosis, polycythemia, chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome, myelofibrosis combined with myelofibrosis (MMM), and acute myeloid leukemia. In some embodiments, JAK-related diseases include skin cancer, such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Examples of cutaneous T-cell lymphoma include Sézary syndrome and mycosis fungoides.

[0087] In some embodiments, JAK-associated diseases include those characterized by expression of mutant JAK2. In some embodiments, JAK-associated diseases include those associated with a JAK having at least one mutation in the pseudokinase domain, e.g., JAK2V617F.

[0088] In some embodiments, JAK-related diseases include inflammation and inflammatory diseases. In some embodiments, JAK-related diseases include ocular inflammatory diseases, such as iritis, uveitis, scleritis, conjunctivitis, and related diseases. In some embodiments, JAK-related diseases include airway inflammatory diseases, such as upper airway diseases including nose and sinus, such as rhinitis or sinusitis, or lower airway diseases including bronchitis and chronic obstructive pulmonary disease. In some embodiments, JAK-related diseases include inflammatory myopathies, such as myocarditis, and other inflammatory diseases. Other inflammatory diseases treatable with the compounds or compositions provided herein include systemic inflammatory response syndrome (SIRS) or septic shock.

[0089] The compounds of the present disclosure are used in a method of inhibiting a kinase in a cell, tissue, or subject, such as a human, comprising contacting the cell with one or more of the compounds of the present disclosure in a therapeutically effective amount to inhibit the kinase. In one embodiment, the compound is administered in a pharma- ceutically acceptable composition, e.g., in or with a pharma- ceutically acceptable carrier.

[0090] In another embodiment, a compound of the present disclosure is used in a method for modulating the action of a kinase in a cell, comprising contacting a cell with a therapeutically effective amount of one or more compounds of the present disclosure to modulate the action of the kinase in the cell. In one embodiment, a compound of the present disclosure is administered in a pharma- ceutically acceptable composition, e.g., in or with a pharma- ceutically acceptable carrier.

[0091] The treatment or prevention of disease or condition that the compound of the present disclosure can be useful for includes any disease or condition related to kinase activity or affected by kinase.Examples of these types of disease or condition include neurodegenerative disease, such as Alzheimer's disease; eye disease, such as diabetic eye disease, wet age-related macular degeneration or dry age-related macular degeneration, inflammatory eye disease, retinal degeneration and glaucoma; cardiovascular disease; and cancer.Additional examples include bone disorder, obesity, liver disease, kidney disease, pancreatitis, stomach disorder, hypertension, fertility control, hair growth disorder, nasal congestion, neurogenic bladder disorder, gastrointestinal disorder, skin disorder and respiratory symptoms.

[0092] In some embodiments, the compound of the present disclosure is administered together with one or more additional therapeutic agents.Suitable classes of additional therapeutic agents include, but are not limited to, beta blockers, alpha agonists, carbonic anhydrase inhibitors, prostaglandin-like compounds, miotics or cholinergic agents, epinephrine compounds, or neuroprotective or anti-inflammatory compounds.

[0093] Beta-blockers. These compounds are believed to lower intraocular pressure (IOP) by reducing the production of aqueous humor. Examples include levobunolol (BETAGAN™), timolol (BETIMOL™, TIMOPTIC™), betaxolol (BETOPTIC™) and metipranolol (OPTIPRANOLOL™).

[0094] Alpha agonists. These compounds are believed to lower IOP by decreasing aqueous humor production and increasing drainage. Examples include apraclonidine (IOPIDINE™) and brimonidine (ALPHAGAN™).

[0095] Carbonic anhydrase inhibitors. These compounds are believed to lower IOP by also reducing aqueous humor production. Examples include dorzolamide (TRUSOPT™) and brinzolamide (AZOPT™).

[0096] Prostaglandin-like compounds. These compounds are believed to lower IOP by increasing the outflow of aqueous humor through the uveoscleral pathway. Examples include AR-102, latanoprost (XALATAN™), bimatoprost (LUMIGAN™), tafluprost (ZIOPTAN™), and travoprost (TRAVATAN™).

[0097] Miotics or cholinergic agents. These drugs are thought to work by causing the pupil to constrict, thereby opening the eye's drainage canals. Examples include pilocarpine (ISOPTO CARPINE™, PILOPINE™) and carbachol (ISOPTO CARBACHOL™).

[0098] Epinephrine Compounds. These compounds, such as dipivefrin (PROPINE™), are believed to work by both reducing aqueous humor outflow and increasing fluid drainage.

[0099] Neuroprotective or anti-inflammatory compounds. These compounds, such as aflibercept (EYLEA™), are treatments for retinal conditions such as macular degeneration, and are designed as anti-VEGF treatments or have similar types of anti-growth or anti-inflammatory activity.

[0100] Also provided herein are methods of treating an ophthalmic condition in a subject in need thereof, comprising administering to the subject a compound, composition, or pharmaceutical composition provided herein.

[0101] Also provided herein are methods of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound, composition, or pharmaceutical composition provided herein.

[0102] In one aspect, provided herein is a method of treating an ocular disorder in a subject in need thereof, comprising administering to the subject a compound provided herein, or a pharma- ceutically acceptable salt thereof.

[0103] In some embodiments, the eye disorder is glaucoma.

[0104] In some embodiments, provided herein is a method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound provided herein or a pharma- ceutically acceptable salt thereof.

[0105] In some embodiments, the compound is administered topically to the subject, for example to a mucosa of the subject, to the skin of the subject, or to the eye of the subject.

[0106] In some embodiments, provided herein is a method of treating an ocular disorder in a subject in need thereof, comprising administering to the subject a compound of one of the formulas provided herein or a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments, provided herein is a method of treating an ocular disorder in a subject in need thereof, comprising administering to the subject a compound provided in Table 1 or a pharma- ceutically acceptable salt thereof.

[0108] In some embodiments, provided herein is a method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound of one of the formulas provided herein or a pharma- ceutically acceptable salt thereof.

[0109] In some embodiments, provided herein is a method of reducing intraocular pressure in a subject in need thereof, comprising administering to the subject a compound provided in Table 1 or a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments of these methods, the method further comprises administering one or more additional therapeutic agents.In some embodiments, the one or more additional therapeutic agents are beta-blockers, alpha agonists, carbonic anhydrase inhibitors, prostaglandins or prostaglandin-like compounds, miotics or cholinergic agents, epinephrine compounds, or neuroprotective or anti-inflammatory compounds.In some embodiments, the one or more additional therapeutic agents are prostaglandins or prostaglandin-like compounds.In some embodiments, the prostaglandin-like compounds are AR-102, latanoprost, bimatoprost, tafluprost, or travoprost.

[0111] Also provided herein is a method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a compound, composition, or pharmaceutical composition provided herein.

[0112] In some embodiments, provided herein is a method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a compound of one of the formulas provided herein, or a pharma- ceutically acceptable salt thereof.

[0113] In some embodiments, provided herein is a method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a compound provided in Table 1 or a pharma- ceutically acceptable salt thereof.

[0114] In some embodiments, the autoimmune disease is multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, autoimmune thyroid disorder, or chronic obstructive pulmonary disease. Compositions and Administration

[0115] The additional therapeutic agent(s) can be administered simultaneously or sequentially with the compound of the present disclosure. Sequential administration includes administration before and after the compound of the present disclosure. In some embodiments, the additional therapeutic agent(s) can be administered in the same composition as the compound of the present disclosure. In other embodiments, there can be a time interval between administration of the additional therapeutic agent and the compound of the present disclosure.

[0116] In some embodiments, administration of an additional therapeutic agent with a compound of the present disclosure allows for lower doses of the other therapeutic agent to be administered for a longer period of time.

[0117] Also provided herein is a composition comprising a compound provided herein, or a pharma- ceutically acceptable salt thereof. In one embodiment, the composition provided herein is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier.

[0118] The pharmaceutical composition for use according to the present disclosure can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.Thus, the compounds and their physiologically acceptable salts and solvates can be formulated for example, solid dosage, drops, topical oily formulations, injection (including injection of drug-eluting devices into either the whole body or specific tissues of the eye), inhalation (through either the mouth or nose), administration by implant, or oral, buccal, parenteral or rectal administration.Techniques and formulations can generally be found in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, PA).

[0119] The route of administration of the compound of the present disclosure (component A) and the form of the composition will determine the type of carrier (component B) used. The composition can be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant or parenteral, or intraocular injection into one of the chambers of the eye, e.g., intravitreal injection, intracameral injection or injection into the aqueous humor), or local administration (e.g., ocular liposomal delivery system, or topical application to the skin using iontophoresis).

[0120] Carriers for systemic administration typically include at least one of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, h) antioxidants, j) preservatives, k) glidants, m) solvents, n) suspending agents, o) wetting agents, p) surfactants, combinations thereof, etc. All carriers are optionally present in systemic compositions.

[0121] Component a) is a diluent. Suitable diluents for solid dosage forms include sugars such as glucose, lactose, dextrose and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerin; mannitol; and sorbitol. The amount of component a) in the systemic or topical composition is typically about 50% to about 90%.

[0122] Component b) is a lubricant.Suitable lubricants for solid dosage forms are exemplified by solid lubricants, including silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants, such as polyethylene glycol and vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and Theobroma oil.The amount of component b) in the systemic or topical composition is typically about 5 to about 10%.

[0123] Component c) is a binder. Suitable binders for solid dosage forms include polyvinylpyrrolidone; magnesium aluminum silicate; starches, such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose and sodium carboxymethylcellulose. The amount of component c) in systemic compositions is typically about 5 to about 50%, and in ophthalmic solid dosage forms, it is up to 99%.

[0124] Component d) is a disintegrant. Suitable disintegrants for solid dosage forms include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays and ion exchange resins. The amount of component d) in the systemic or topical composition is typically about 0.1 to about 10%.

[0125] Ingredient e) for solid dosage forms is a colorant, such as an FD&C dye. If used, the amount of ingredient e) in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0126] Ingredient f) for solid dosage forms is a flavoring such as menthol, peppermint, and fruit flavors. The amount of ingredient f) in a systemic or topical composition, if used, is typically about 0.1 to about 1.0%.

[0127] Ingredient g) for solid dosage forms are sweeteners such as aspartame and saccharin. The amount of ingredient g) in a systemic or topical composition is typically from about 0.001 to about 1%.

[0128] Ingredient h) is an antioxidant such as butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT") and vitamin E. The amount of ingredient h) in a systemic or topical composition is typically from about 0.1 to about 5%.

[0129] Ingredient j) is a preservative such as benzalkonium chloride, methylparaben, and sodium benzoate. The amount of ingredient j) in a systemic or topical composition is typically about 0.01 to about 5%.

[0130] Ingredient k) for solid dosage forms is a glidant such as silicon dioxide. The amount of ingredient k) in a systemic or topical composition is typically about 1 to about 5%.

[0131] Ingredient m) is a solvent, such as water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohols such as ethanol, and phosphate buffer solutions. The amount of ingredient m) in a systemic or topical composition is typically from about 0 to about 100%.

[0132] Ingredient n) is a suspending agent. Suitable suspending agents include AVICEL® RC-591 (FMC Corporation, Philadelphia, PA) and sodium alginate. The amount of ingredient n) in a systemic or topical composition is typically about 1 to about 8%.

[0133] Ingredient o) is a surfactant, such as lecithin, polysorbate 80 and sodium lauryl sulfate, and TWEEN® from Atlas Powder Company, Wilmington, Delaware. Suitable surfactants include those disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of ingredient o) in the systemic or topical composition is typically about 0.1% to about 5%.

[0134] The amounts of components A and B in a systemic composition will vary depending on the systemic composition being prepared, the particular derivative selected for component A, and the type of component B ingredient, but generally, a systemic composition will contain 0.01%-50% component A and 50-99.99% component B.

[0135] A composition for parenteral administration typically comprises A) 0.1-10% of a compound of the present disclosure and B) 90-99.9% of a carrier, including a) a diluent and m) a solvent. In one embodiment, component a) comprises propylene glycol, and m) comprises ethanol or ethyl oleate.

[0136] Compositions for oral administration may have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and therapeutically effective amount of component A), usually at least about 5%, more specifically about 25% to about 50%. Oral administration compositions further contain about 50% to about 95% of component B), more specifically about 50% to about 75%.

[0137] Tablets can be compressed, can be molded tablets, can be enteric coated, can be sugar coated, can be film coated, or can be multiple compressed. Tablets typically include component A and component B, which is a carrier that includes a component selected from the group consisting of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, k) glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are FD&C dyes, which can be added for appearance. Chewable tablets preferably contain g) sweeteners, such as aspartame and saccharin, or f) flavors, such as menthol, peppermint, fruit flavors, or combinations thereof.

[0138] Capsules (including implants, time release and sustained release formulations) typically comprise component A and a carrier comprising one or more a) diluents as disclosed above in a capsule comprising gelatin. Granules typically comprise component A, and preferably further comprise k) glidants, such as silicon dioxide, which improve flow properties. Implants can be of biodegradable or non-biodegradable type. Implants can be prepared using any known biocompatible formulation.

[0139] The selection of ingredients in the carrier for oral compositions depends on secondary considerations such as taste, cost, and shelf stability, which are not critical for the purposes of this disclosure. Those skilled in the art will know how to select appropriate ingredients without undue experimentation.

[0140] The solid compositions can also be coated by conventional methods, typically with a pH or time dependent coating, so that Component A is released into the gastrointestinal tract in the vicinity of the desired application or at various points and times that extend the desired effect. The coating typically comprises one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Rohm & Haas GMBH, Darmstadt, Germany), waxes and shellac.

[0141] Compositions for oral administration can also have liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, etc. Orally administered liquid compositions typically include component A and component B, i.e., carriers that include components selected from the group consisting of a) diluents, e) colorants, f) flavorants, g) sweeteners, j) preservatives, m) solvents, n) suspending agents, and o) surfactants. Oral liquid compositions preferably include one or more components selected from the group consisting of e) colorants, f) flavorants, and g) sweeteners.

[0142] Other compositions useful for obtaining systemic delivery of target compound include injection, sublingual, buccal and nasal dosage forms.Such compositions typically comprise soluble filler material, such as a) diluent, including sucrose, sorbitol and mannitol; and c) binder, such as one or more of acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.Such compositions may further comprise b) lubricant, e) colorant, f) flavor, g) sweetener, h) antioxidant and k) glidant.

[0143] In one embodiment of the present disclosure, the compound of the present disclosure is administered topically.The topical composition that can be applied topically to the eye can be in any form known in the art, including, but not limited to, a solid, a gellable liquid drop, a spray, an ointment, or a sustained or non-sustained release unit that is placed in the conjunctival cul-du-sac or another suitable location of the eye.

[0144] The topical composition that can be applied topically to the skin can be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on-rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. The topical composition comprises component A, which is the compound described above, and component B, which is a carrier. The carrier of the topical composition preferably aids in the penetration of the compound into the eye. Component B may further comprise one or more optional components.

[0145] The therapeutically effective amount of a compound according to the present disclosure will vary depending on factors such as the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of the concomitant therapy, the route of administration, the particular pharma- ceutically acceptable carrier being utilized, and within the knowledge and expertise of the attending physician. For example, a therapeutically effective amount of a compound of the present disclosure for systemic administration is about 0.01 to about 1000 μg / kg body weight per day, preferably about 0.1 to about 100 μg / kg body weight, and most preferably about 1 to about 50 μg / kg body weight. Transdermal dosages are designed to obtain similar serum or plasma levels based on techniques known to those skilled in the art of pharmacokinetics and transdermal formulations. Plasma levels for systemic administration are expected to be in the range of 0.01 to 100 ng / mL, more preferably 0.05 to 50 ng / mL, and most preferably 0.1 to 10 ng / mL. While these dosage amounts are based on daily dosing rates, the compounds of the present disclosure may also be administered at other intervals, such as twice a day, twice a week, once a week, or once a month. Those skilled in the art will be able to calculate appropriate therapeutically effective amounts for other dosing intervals.

[0146] The compounds of the present disclosure are useful in the method of reducing or alleviating intraocular pressure.The compounds of the present disclosure can be administered to the subject in need of treatment in a therapeutically effective amount to reduce intraocular pressure.Therefore, these compounds are useful for treating glaucoma.The preferred route of administration for treating glaucoma is topical.

[0147] The exact amount of each component of the topical composition depends on a variety of factors. The amount of component A added to the topical composition is determined by the IC 50 It depends on the concentration of the drug and is typically expressed in nanomolar (nM) units. For example, the IC 50 When the IC of the drug is 1 nM, the amount of component A is about 0.001 to about 0.3%. 50 When the IC of the drug is 10 nM, the amount of component A) is about 0.01 to about 1%. 50 When the IC is 100 nM, the amount of component A is about 0.1 to about 10%. If the amount of component A is outside the range specified above (i.e., low), the efficacy of the treatment may be reduced. Those skilled in the art will appreciate that the IC 50 Understand how to calculate and understand the remainder of the composition, up to 100%, is component B.

[0148] The amount of carrier utilized together with component A is sufficient to provide a practical amount of the composition for administration per unit dose of pharmaceutical. Techniques and compositions for making dosage forms useful in the methods of the present disclosure are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0149] Component B may comprise a single component or a combination of two or more components. In topical compositions, component B comprises a topical carrier. Suitable topical carriers include one or more components selected from the group consisting of phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol, symmetric alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oil, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide, and water, and even more specifically, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol, and symmetric alcohol.

[0150] The topical composition carrier may further comprise one or more ingredients selected from the group consisting of q) emollients, r) propellants, s) solvents, t) humectants, u) thickeners, v) powders, w) fragrances, x) pigments, and y) preservatives.

[0151] Component q) is an emollient. The amount of component q) in a skin topical composition is typically about 5 to about 95%. Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, sebacic acid, and the like. Examples of emollients include di-n-butyl, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum oil, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof.Specific emollients for the skin include stearyl alcohol and polydimethylsiloxane.

[0152] Component r) is a propellant. The amount of component r) in the topical composition is typically about 0 to about 95%. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.

[0153] Ingredient s) is a solvent. The amount of ingredient s) in the topical composition is typically about 0 to about 95%. Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohol.

[0154] Ingredient t) is a humectant. The amount of ingredient t) in the topical composition is typically 0-95%. Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin.

[0155] Component u) is a thickening agent. The amount of component u) in a topical composition is typically from about 0 to about 95%.

[0156] Component v) is a powder. The amount of component v) in the topical composition is typically 0-95%. Suitable powders include beta-cyclodextrin, hydroxypropylcyclodextrin, chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. For application to the eye, specific powders include beta-cyclodextrin, hydroxypropylcyclodextrin, and sodium polyacrylate. For gel dosing of eye preparations, sodium polyacrylate may be used.

[0157] Component w) is a fragrance. The amount of component w) in a topical composition is typically about 0 to about 0.5%, particularly about 0.001 to about 0.1%. For application to the eye, fragrances are typically not used.

[0158] Component x) is a pigment. Suitable pigments for skin application include inorganic pigments, organic lake pigments, pearlescent pigments and their mixtures. Inorganic pigments useful in the present disclosure include those selected from the group consisting of rutile or anatase titanium dioxide, which is coded by color index with reference CI 77,891; black, yellow, red and brown iron oxides, which are coded by reference CI 77,499, 77,492 and 77,491; manganese violet (CI 77,742); ultramarine blue (CI 77,007); chromium oxide (CI 77,288); chromium hydrate (CI 77,289); and ferric blue (CI 77,510), and mixtures thereof.

[0159] Organic pigments and lakes useful in this disclosure include D&C Red No. 19 (CI 45,170), D&C Red No. 9 (CI 15,585), D&C Red No. 21 (CI 45,380), D&C Orange No. 4 (CI 15,510), D&C Orange No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&C Red No.13(CI 15,630), D&C Red No.7(CI 15,850), D&C Red No.6(CI 15,850), D&C Yellow No.5(CI 19,140), D&C Red No.36(CI 12,085), D&C Orange No.10(CI 45,425), D&C Yellow No.6(CI 15,985), D&C Red No. 30 (CI 73,360), D&C Red No. 3 (CI 45,430), dyes or lakes based on cochineal carmine (CI 75,570), and mixtures thereof.

[0160] Pearlescent pigments useful in the present disclosure include those selected from the group consisting of white pearlescent pigments, such as mica coated with titanium oxide, bismuth oxychloride, colored pearlescent pigments, such as titanium mica with iron oxide, titanium mica with ferric blue, titanium mica with chromium oxide, and other organic pigments of the types mentioned above, and those based on bismuth oxychloride, and mixtures thereof. The amount of pigment in topical compositions is typically about 0 to about 10%. For ocular applications, pigments are typically not used.

[0161] In particularly preferred embodiments of the present disclosure, a topical pharmaceutical composition for administration to the eye is prepared, typically comprising components A and B (carriers), e.g., purified water, and one or more ingredients selected from the group consisting of y) sugars or sugar alcohols, e.g., dextrans, particularly mannitol and dextran 70, z) cellulose or derivatives thereof, aa) salts, bb) disodium EDTA (disodium edetate), and cc) pH adjusting additives.

[0162] Examples of z) cellulose derivatives suitable for use in topical pharmaceutical compositions for administration to the eye include sodium carboxymethylcellulose, ethylcellulose, methylcellulose and hydroxypropyl-methylcellulose, in particular hydroxypropyl-methylcellulose.

[0163] Examples of aa) salts suitable for use in topical pharmaceutical compositions for administration to the eye include mono-, di- and trisodium phosphate, sodium chloride, potassium chloride, and combinations thereof.

[0164] cc) Examples of pH adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of a topical pharmaceutical composition for administration to the eye to within the range of 4.5 to 7.5 pH units. kit

[0165] Component A may be included in a kit that includes a compound described herein, a systemic or topical composition as described above, or both; and information, instructions, or both, that the use of the kit provides treatment for cosmetic and medical conditions in mammals (especially humans). The information and instructions may be in the form of words, drawings, or both, and the like. Additionally or alternatively, the kit may include a medicament, composition, or both, preferably with the benefit of treating or preventing cosmetic or medical conditions in mammals (e.g. humans); and information, instructions, or both, about the method of application of the medicament or composition.

[0166] In some embodiments, provided herein is a packaged dosage form comprising a container holding a therapeutically effective amount of a compound provided herein or a salt thereof, or a composition provided herein, and instructions for using the dosage form according to one or more of the methods provided herein.

[0167] The dosage forms and related materials can be completed as commercial products by the usual steps performed in the art, such as appropriate sterilization and packaging steps. For example, the materials can be treated with UV / vis irradiation (200-500 nm), for example using photoinitiators with different absorption wavelengths (e.g., Irgacure 184, 2959), preferably water-soluble inhibitors (e.g., Irgacure 2959). Such irradiation is usually performed for irradiation times of 1-60 minutes, although longer irradiation times can also be applied depending on the specific method. The materials according to the present disclosure can be terminally sterilized and wrapped to preserve sterility until use, and packaged in suitable containers (such as boxes) (e.g., with the addition of a specific product information leaflet).

[0168] According to further embodiments, the dosage form can also be provided in the form of a kit in combination with other components necessary for administration of the material to a patient. The disclosed kits, such as for use in the treatments described herein, can further include, for example, administration materials.

[0169] The kits can be designed in a variety of configurations based on the particular defect they are designed to treat.

[0170] The compounds or compositions herein can be prepared and placed in a container for storage at ambient or elevated temperatures. When the compounds or compositions provided herein are stored in, for example, a polyolefin plastic container compared to a polyvinyl chloride plastic container, discoloration of the compounds or compositions can be reduced. Without wishing to be bound by theory, the container can reduce exposure of the contents of the container to electromagnetic radiation, whether visible light (e.g., having a wavelength of about 380-780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190-320 nm (UV B light) or about 320-380 nm (UV A light)). Some containers also include the ability to reduce adhesion or adsorption of active ingredients to the surface of the container, effectively diluting the concentration of the active compound in the contained solution. Some containers also include the ability to reduce exposure of the contents of the container to infrared light, or a second component having such ability. Some containers further include the ability to reduce exposure of the contents of the container to heat or humidity. The containers that can be used include those made of polyolefins, such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, polyester, or any combination thereof. In some embodiments, the container is made of a polymer that includes polyethylene, polypropylene, or a combination thereof. In some embodiments, the container is a glass container. The container can be further placed in a second container, such as a paper container, a cardboard container, a paperboard container, a metal film container, or a foil container, or a combination thereof, to further reduce the exposure of the contents of the container to UV, visible light, or infrared light. Products that benefit from reduced discoloration, decomposition, or both during storage include the compounds described herein, whether in neutral form, as a salt, or in compositions thereof. The compounds or compositions provided herein may need to be stored for up to three months or longer, and in some cases for up to one year or longer. The container can be in any form suitable for containing the contents, such as a bag, a bottle, or a box.

[0171] The present disclosure is further illustrated by the following illustrative examples, which are considered non-limiting. EXAMPLES

[0172] Example 1 Preparation of E3. Scheme 1. [ka] Preparation of 3-(4-(2,5-dichloropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E2): To a dry vial was added 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (E1, 1 eq.), 2,4,5-trichloropyrimidine (1.2 eq.), tetrakis(triphenylphosphine)palladium(0) (5 mol%), and 2 mL of aqueous sodium carbonate. The solution was diluted with 1,4-dioxane and then heated to 100° C. for 6 h. The solution was cooled to room temperature and then buffered to pH=7. The reaction mixture was extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, then filtered and evaporated. Column chromatography (hexane:ethyl acetate) afforded 3-(4-(2,5-dichloropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E2, 48%) which was carried forward without any further purification.

[0173] Preparation of 3-(4-(5-chloro-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E3). To a dry microwave vial was added 3-(4-(2,5-dichloropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E2) (1 eq), 3-methyl-1,2-thiazol-5-amine (1.2 eq), palladium(II) acetate (5 mol%), BINAP (15 mol%), potassium carbonate (4 eq), 1,4-dioxane, and tert-butyl alcohol. The microwave vial was stoppered under a blanket of nitrogen. The reaction mixture was irradiated at 150° C. for 1 h. The reaction mixture was filtered through a syringe filter and then buffered to pH=7. The aqueous layer was first extracted with 3:1 DCM:IPA, then ethyl acetate (3x). The combined organics were dried over magnesium sulfate, then filtered and evaporated. Column chromatography (hexanes:ethyl acetate, then dichloromethane:methanol) gave 3-(4-(5-chloro-2-((3-methylisothiazol-5-yl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E3, 35%). Example 2 Preparation of E7. Scheme 2. [ka]

[0174] Preparation of 3-(4-(5-methyl-2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E5). 4-Chloro-5-methyl-2-(methylthio)pyrimidine (E4) dissolved in dioxane and water was added with 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile, Na 2 CO 3 and Pd(PPh 3 ) 4was added and the solution was heated to 98-100° C. for 4-5 h. The mixture was cooled, poured into EtOAc and water, extracted with EtOAc, dried (Na 2 SO 4 ), filtered and evaporated. Column chromatography (hexane-ethyl acetate) gave 3-(4-(5-methyl-2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E5, 72%).

[0175] Preparation of 3-(4-(5-methyl-2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E6). 2 Cl 2 To 3-(4-(5-methyl-2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E5) in 10 mL of 10 ... 2 Cl 2 (or EtOAc) and NaHCO 3 (saturated), extracted and dried (Na 2 SO 4 ), filtered and evaporated. 2 Cl 2 —MeOH) gave pure 3-(4-(5-methyl-2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E6, 49%).

[0176] Preparation of 3-(4-(5-methyl-2-((2-morpholinoethyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E7). To 3-(4-(5-methyl-2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E6) in DMSO was added 2-morpholinoethan-1-amine (10 equiv.) and the mixture was heated to 100 °C for 4-12 h. The solution was cooled to room temperature and purified by CH 2 Cl 2 and NaHCO 3(saturated), and poured into CH 2 Cl 2 Extracted with and dried (Na 2 SO 4 ), filtered and evaporated. 2 Cl 2 —MeOH) to give pure 3-(4-(5-methyl-2-((2-morpholinoethyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E7, 76%). Example 3 Preparation of E10. Scheme 3. [ka]

[0177] Preparation of tert-butyl 3-(4-((4-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (E9). To 3-(4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E8) in 1,4-dioxane was added tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate and pTsOH, and the mixture was heated to 100° C. in a pressure tube for 12 h. The solution was cooled to room temperature and diluted with EtOAc and NaHCO. 3 (saturated), extracted with EtOAc and dried (Na 2 SO 4 ), filtered and evaporated. 2 Cl 2 -MeOH and or hexane-ethyl acetate) to give tert-butyl 3-(4-((4-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2yl)amino)phenyl)azetidine-1-carboxylate (E9, 30%).

[0178] Preparation of 3-(4-(2-((4-(azetidin-3-yl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile hydrochloride (E10). CH 2 Cl 2 To tert-butyl 3-(4-((4-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (E9) in HCl-ether (1N) was added and the solution was stirred at 30° C. for 12 h. The solvent was evaporated and purified by column chromatography (CH 2 Cl 2 -MeOH and CH 2 Cl 2 —EtOH) to give 3-(4-(2-((4-(azetidin-3-yl)phenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile hydrochloride (E10).

[0179] Using procedures similar to those set forth above for Schemes 1, 2, and 3, but substituting the appropriate starting materials, additional compounds provided herein were prepared. Example 4 Preparation of E12. Scheme 4. [ka]

[0180] Preparation of 5-chloro-2-((4-(2-hydroxyethyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E11). To a dry microwave vial was added 3-(4-(2,5-dichloropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E2) (1 eq), 2-(4-aminophenyl)ethan-1-ol (1.2 eq), palladium(II) acetate (5 mol%), BINAP (15 mol%), potassium carbonate (4 eq), 1,4-dioxane, and tert-butyl alcohol. The microwave vial was stoppered under a blanket of nitrogen. The reaction mixture was irradiated at 150° C. for 1 h. The reaction mixture was filtered through a syringe filter and then buffered to pH=7. The aqueous layer was extracted first with 3:1 DCM:IPA and then with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, then filtered and evaporated. Column chromatography (dichloromethane:methanol) afforded 5-chloro-2-((4-(2-hydroxyethyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E11, 30%).

[0181] Preparation of 5-chloro-4-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenethyl dihydrogen phosphate (E).

[0182] To a dry vial was added 5-chloro-2-((4-(2-hydroxyethyl)phenyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (E2) (1 eq), phosphoric acid (0.95 eq), pyridine (4.8 eq), and acetonitrile. DIPEA (1.9 eq) was added and the reaction mixture was stirred for 5 min. Acetic anhydride (1.9 eq) was added and the reaction was brought to 90° C. overnight. Cooled to room temperature and evaporated onto celite. Column chromatography (dichloromethane:methanol) gave 4-((5-chloro-4-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)phenethyl dihydrogen phosphate (E11, 30%). Example 5 Preparation of E16. Scheme 5. [ka]

[0183] Preparation of (1-chlorocyclopropyl)methanol (E14): To a dry round bottom flask was added 1-chlorocyclopropane-1-carboxylic acid (E13) (1 eq) in anhydrous THF. The solution was cooled to 0° C. in an ice / water bath. A solution of 1M lithium aluminum hydride (3.2 eq) in THF was added dropwise. The solution was stirred at room temperature for 1 h. The solution was cooled to 0° C. in an ice / water bath. A solution of ethyl acetate / water (1:1) was added slowly due to the evolution of hydrogen gas. The resulting slurry was filtered through a plug of celite and rinsed thoroughly with ethyl acetate and water. The organic layer was separated. The aqueous layer was extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, then filtered and evaporated. Upon evaporation, (1-chlorocyclopropyl)methanol (E14) was carried forward without any further purification.

[0184] Preparation of (1-chlorocyclopropyl)methyl methanesulfonate (E15) To a dry round bottom flask was added (1-chlorocyclopropyl)methanol (E14) (1 eq.) followed by anhydrous DCM and triethylamine (2 eq.). The solution was cooled to 0° C. in an ice / water bath. Mesyl chloride (1.1 eq.) was added dropwise. The solution was stirred at 0° C. for 2 h. The solution was quenched with saturated sodium bicarbonate and diluted with diethyl ether. The reaction mixture was stirred at room temperature for 30 min. The layers were separated and the aqueous layer was further extracted with diethyl ether. The combined organics were dried over magnesium sulfate then filtered and evaporated. Upon evaporation, (1-chlorocyclopropyl)methyl methanesulfonate (E15, 74%) was carried forward without any further purification.

[0185] Preparation of 1-((1-chlorocyclopropyl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (E16) To a dry round bottom flask was added 4-(4,4,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 eq) and anhydrous DMF. The solution was cooled to 0° C. in an ice / water bath. Sodium hydride (1.2 eq) was added all at once. The solution was stirred at 0° C. for 30 minutes. (1-chlorocyclopropyl)methyl methanesulfonate (E15) was then added via cannula to the DMF. Following the addition, the reaction mixture was heated to 120° C. overnight. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with saturated sodium chloride and then extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate then filtered and evaporated. Column chromatography (hexanes:ethyl acetate) afforded 1-((1-chlorocyclopropyl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (E16, 72%) which was carried forward without any further purification. Example 6 Preparation of E18. Scheme 6. [ka]

[0186] Preparation of 2,5-dichloro-4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)pyrimidine (E17). To a dry vial was added 1-((1-chlorocyclopropyl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (E16) (1 eq), 2,4,5-trichloropyrimidine (1.2 eq), tetrakis(triphenylphosphine)palladium(0) (5 mol%), and 2 mL of aqueous sodium carbonate. The solution was diluted with 1,4-dioxane and then heated to 100° C. for 6 h. The solution was cooled to room temperature and then buffered to pH=7. The reaction mixture was extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, then filtered and evaporated. Column chromatography (hexanes:ethyl acetate) afforded 2,5-dichloro-4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)pyrimidine (E17, 48%) which was carried forward without any further purification.

[0187] Preparation of 5-chloro-4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (E18) To a dry microwave vial was added 2,5-dichloro-4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)pyrimidine (E17) (1 eq), 4-methyl-1-(4-aminophenyl)piperazine (1.2 eq), palladium(II) acetate (5 mol%), BINAP (15 mol%), potassium carbonate (4 eq), 1,4-dioxane, and tert-butyl alcohol. The microwave vial was stoppered under a blanket of nitrogen. The reaction mixture was irradiated at 150° C. for 1 h. The reaction mixture was filtered through a syringe filter and then buffered to pH=7. The aqueous layer was extracted first with 3:1 DCM:IPA, then with ethyl acetate (3x). The combined organics were dried over magnesium sulfate, then filtered and evaporated. Column chromatography (hexanes:ethyl acetate, then dichloromethane:methanol) gave 5-chloro-4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine (E18, 35%). Example 7 Preparation of E22. Scheme 7. [ka]

[0188] Preparation of 2-chloro-4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidine (E19). To a dry vial was added 1-((1-chlorocyclopropyl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (E16) (1 eq), 5-methyl-2,4-trichloropyrimidine (1.2 eq), tetrakis(triphenylphosphine)palladium(0) (5 mol%), and 2 mL of aqueous sodium carbonate. The solution was diluted with 1,4-dioxane and then heated to 100° C. for 6 h. The solution was cooled to room temperature and then buffered to pH=7. The reaction mixture was extracted with ethyl acetate (3×). The combined organics were dried over magnesium sulfate, then filtered and evaporated. Column chromatography (hexanes:ethyl acetate) afforded 2-chloro-4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidine (EX, 48%) which was carried forward without any further purification.

[0189] Preparation of (4-((4-1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)-1,2-phenylenedimethanol (E20) To a dry microwave vial was added 2-chloro-4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidine (E19) (1 eq), (4-amino-1,2-phenylene)dimethanol (1.2 eq), palladium(II) acetate (5 mol%), BINAP (15 mol%), potassium carbonate (4 eq), 1,4-dioxane, and tert-butyl alcohol. The microwave vial was stoppered under a blanket of nitrogen. The reaction mixture was irradiated at 150° C. for 1 h. The reaction mixture was filtered through a syringe filter and then buffered to pH=7. The aqueous layer was extracted first with 3:1 DCM:IPA, then with ethyl acetate (3x). The combined organics were dried over magnesium sulfate, then filtered and evaporated. Column chromatography (hexanes:ethyl acetate, then dichloromethane:methanol) gave (4-((4-1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)-1,2-phenylenedimethanol (E20, 42%).

[0190] Preparation of (4-((4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)-1,2-phenylene)bis(methylene)dimethanesulfonate (E21) To a dry round bottom flask was added (4-((4-1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)-1,2-phenylenedimethanol (EX) (1 eq.) followed by anhydrous DCM and triethylamine (2 eq.). The solution was cooled to 0° C. in an ice / water bath. Mesyl chloride (1.1 eq.) was added dropwise. The solution was stirred at 0° C. for 2 hours. The solution was quenched with saturated sodium bicarbonate and diluted with DCM. The reaction mixture was stirred at room temperature for 30 minutes. The layers were separated and the aqueous layer was further extracted with DCM. The combined organics were dried over magnesium sulfate, then filtered and evaporated. Upon evaporation, (4-((4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)-1,2-phenylene)bis(methylene)dimethanesulfonate (E21, 75%) was carried forward without any further purification.

[0191] Preparation of N-4-(1-((1-chlorocyclopropyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)-2-methylisoindoline-5-amine (E22) To a dry round bottom flask was added (4-((4-(1-((1-chlorocyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)-1,2-phenylene)bis(methylene)dimethanesulfonate (E21) (1 eq) in methanol followed by methylamine solution (2M in methanol) (5 mL) at 0° C. in an ice / water bath. Allow to come to room temperature overnight. The reaction mixture was evaporated onto silica and purified by column chromatography (hexane:ethyl acetate, then dichloromethane:methanol) to give N-4-(1-((1-chlorocyclopropyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)-2-methylisoindoline-5-amine (E21). N-4-(1-((1-chlorocyclopropyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)-2-methylisoindoline-5-amine (E21) was suspended in 4N HCl in dioxane followed by sonication for 5 minutes. After evaporation and drying under high vacuum, N-4-(1-((1-chlorocyclopropyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)-2-methylisoindoline-5-amine hydrochloride (E21) was obtained in 25% yield. Example 8 Preparation of E25 and E26. Scheme 8. [ka]

[0192] Preparation of 4-(1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-amine (E24). 1-((1-(fluoromethyl)cyclopropyl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (E23) in dioxane (3.7 mL) and water (1.2 mL) was treated with sodium carbonate (3 eq.), 4-chloro-5-methylpyrimidin-2-amine (1 eq.) and Pd(Cl). 3 ) 4 (0.1 equiv.) was added and the solution was stirred at 95-98 °C for 6 h. The mixture was cooled and poured into EtOAc and water. The aqueous solution was extracted with EtOAc and the organics were dried (Na 2 SO 4 ), filtered and evaporated to give crude E24. 2 Cl 2 —MeOH) gave pure 4-(1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-amine (E24, 93%).

[0193] Preparation of 1-(4-chlorophenyl)-3-(4-(1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)urea (E25). CH 2 Cl 2 To 4-(1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-amine (E24) in water was added DMAP (0.05 equiv.) and 4-chlorophenyl isocyanate (1.5 equiv.) and the solution was stirred at room temperature for 12 h. The mixture was diluted with EtOAc and NaHCO 3 (saturated), extracted further with EtOAc and dried (Na 2 SO 4 ), filtered and evaporated. 2 Cl 2—MeOH) to give 1-(4-chlorophenyl)-3-(4-(1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)urea (E25, 27%).

[0194] Preparation of 4-chlorophenyl(4-(1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)carbamate (E26). To 4-(1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-amine (E24) in pyridine at 0° C. was added 4-chlorophenyl chloroformate (1.1 eq) and the solution was allowed to warm slowly to room temperature (3 h). The reaction was then diluted with EtOAc and NaHCO 3 (saturated), extracted further with EtOAc and dried (Na 2 SO 4 ), filtered and evaporated. 2 Cl 2 —MeOH) to give pure 4-chlorophenyl (4-(1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)carbamate (E26, 46%). Example 9 JAK assay.

[0195] All compounds were initially prepared as 10 mM stocks in anhydrous dimethyl sulfoxide (DMSO). A 20 μL aliquot of the 10 mM solution was transferred to each well in column 1 of a 96-well polypropylene microtiter plate (Corning #3363) and diluted with DMSO to give a final compound concentration of 4 mM. Test compounds were then serially diluted 1:5 in DMSO for an 11-point concentration response and further diluted in assay buffer to give a final range of all compound concentrations from 100 μM to 10 pM in 2.5% DMSO. Assays were performed in 20 mM HEPES (pH 7.5), 10 mM MgCl 2 6H 2The assays were performed in white 96-well, flat-bottom, half-area, non-binding assay plates (Corning #3642) in assay buffer consisting of 0, 100 μM sodium orthovanadate, 0.05% CHAPS, and 0.1% bovine serum albumin. A 10 μL aliquot of compound from each well of the intermediate dilution plate and 20 μL of 2× JAK substrate / enzyme solution containing receptor substrate (800 nM Abl peptide), JAK enzyme (10 nM JAK1, JAK2, JAK3, or TYK2), and 1,4-dithiothreitol (DTT, 2 μM) were added to all wells. The reaction was initiated by adding 10 μL of 4× undiluted ATP (2 μM). The reaction was mixed thoroughly by hand, covered, and incubated at room temperature for 75 minutes. Protein kinase activity was quantified using Promega's KINASE-GLO™ Luminescent Kinase Assay Kit according to the manufacturer's instructions. The ATP concentrations remaining in the test wells after the enzymatic reaction was terminated were compared to control wells (CTRL) containing an equivalent amount of DMSO without inhibitor. The ATP concentrations in both the test wells and the CTRL wells were normalized to the background (BKG) ATP concentration in wells containing a concentration of inhibitor that completely inhibited the protein kinase under investigation (i.e., a concentration that prevented any consumption of ATP over the course of incubation). Percent of control (POC) values ​​were determined for each concentration of compound tested according to the equation: POC = ((Test well value - BKG) / (CTRL - BKG)) x 100

[0196] I C 50 Values ​​were calculated using the following four-parameter logistic curve-fitting algorithm: f(x)=(A+((BA) / (1+((x / C)^D))))

[0197] I C 50 The value of K is calculated using the Cheng-Prusoff equation: i Converted to value: K i =IC 50 / (1+([ATP] / Km ATP])) Example 10 Reference Example - Pharmacological Activity for Glaucoma Assay.

[0198] Pharmacological activity against glaucoma can also be demonstrated using assays designed to test the ability of the target compound to reduce intraocular pressure.Examples of such assays are described in the following reference: C. Liljebris, G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, "Derivatives of 17-phenyl-18,19,20-trinorprostaglandin F2α Isopropyl Ester: Potential Anti-glaucoma Agents," Journal of Medicinal Chemistry 1995, 38 (2): 289-304, which is incorporated herein by reference.

[0199] Although the present disclosure has been described in detail and with reference to specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the disclosure.

[0200] The preceding disclosures are exemplary embodiments. Those skilled in the art should understand that the devices, techniques and methods disclosed herein reveal representative embodiments that work well in the practice of the present disclosure. However, those skilled in the art should understand in light of the present disclosure that many changes can be made in the specific embodiments disclosed without departing from the spirit and scope of the present disclosure and still yield the same or similar results.

[0201] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and the like used in the specification and claims should be understood to be modified in all instances by the term "about". Thus, unless otherwise indicated, the numerical parameters set forth in the following specification and the accompanying claims are approximations that may vary depending on the desired properties sought to be obtained by the present disclosure. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0202] Grouping of alternative elements or embodiments of the disclosure provided herein should not be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is expected that one or more members of a group may be included in or deleted from a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group modified to meet the description of all Markush groups used in the appended claims.

[0203] Preferred embodiments of the present disclosure are described herein, including the best mode for carrying out the disclosure known to the inventors. Of course, variations on the preferred embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect those skilled in the art to make appropriate use of such variations, and the inventors intend for the present disclosure to be carried out otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[0204] Specific embodiments disclosed herein may be further limited in the claims using the language "consisting of" or "consisting essentially of." When used in the claims, whether as filed or added as an amendment, the transition term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transition term "consisting essentially of" limits the claim to those materials or steps specified and that do not materially affect the basic and novel characteristics. The embodiments of the present disclosure so claimed are essentially or explicitly described and enabled herein.

[0205] Moreover, it should be understood that the embodiments of the present disclosure provided herein are illustrative of the principles of the present disclosure. Other modifications that can be utilized are within the scope of the present disclosure. Thus, by way of example, but not of limitation, alternative configurations of the present disclosure can be utilized in accordance with the teachings herein. Thus, the present disclosure is not limited to that precisely as shown and described.

Claims

1. formula: 【Chemistry 48】 or a pharmaceutically acceptable salt thereof [In the formula, R １ is N, CH, CF, CCl, or CBr; R ２ ,NH, 【Chemistry 49】 and R ３ is C ６～１０ Aryl or C ２～１０ is heteroaryl; R ４ is H, C １～４ Alkyl, C １～４ Haloalkyl, F, Cl, Br, I, O(C １～４ alkyl), C １～４ Alkyl-OH, CH ２ NH ２ , C.H. ２ N (C １～４ alkyl) (C １～４ alkyl), Boc, C(O)N(H)(C １～４ alkyl), CH ２ N(H)Boc, C(O)O(C １～４ alkyl), C ２～８ Heterocycloalkyl, CH ２ -(C ２～８ heterocycloalkyl), (C ２～８ Heterocycloalkyl)-CH ３ , C.H. ２ -(C ２～８ Heterocycloalkyl)-CH ３ , C(O)OH, S(O ２ ) (C １～４ alkyl), C(O)NH ２ , C １～６ Heteroalkyl, CH ２ OC(O)-(C ６～１０ aryl), (C ２～８ heterocycloalkyl)-Boc, (C １～６ heteroalkyl)-(C ２～８ heterocycloalkyl)-(C １～４ alkyl), CH ２ OC(O)(C １～６ heteroalkyl), CH ２ OC(O)CH ２ CH ２ -(C ２～８ heterocycloalkyl), C(O)N(C １～４ alkyl) (C １～４ alkyl), CH ２ N(H)C(O)C(CH ３ )N(H)Boc,CH ２ N(H)C(O)-pyrrolidinyl-Boc, CH ２ N(H)C(O)C(CH ３ ) NH ２ , C.H. ２ N(H)C(O)-pyrrolidinyl, CH ２ N(H) Boc, CH ２ N(H)C(O)CH ２ N (CH ３ ) ２ , C.H. ２ N(H)C(O)C(N(H)Boc)CH ２ CH ２ CH ２ -guanidinyl (Boc) ２ , C.H. ２ N(H)C(O)C(NH ２ ) CH ２ CH ２ CH ２ -guanidinyl, (C ２～８ heterocycloalkyl)-N(C １～４ alkyl) (C １～４ alkyl), or C ５～１０ is spiroheterocycloalkyl; R ５ are H, F, Cl, Br, I, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ O-alkyl, C １～４ Alkyl-OH, ═O, or C(O)O(C １～４ alkyl); Or, R ４ and R ５ together form -O-N=C(H)-, -C(H ２ )-N(H)-C(O)-, -C(O)-N(CH ３ )-C(O)-,-C(H ２ )-N(CH ３ )-C(H ２ )-, or =C(H)-C(H)=N-; R ６ is H and R ７ are H, F, Cl, Br, I, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ O-alkyl, or C ３～６ is cycloalkyl; Or, R ６ and R ７ Together, C ２～５ Alkylene or C ２～５ forming a heteroalkylene; R ８ is a bond, NH, O, CH ２ , N(Boc), N(CH ２ F), N(CHF ２ ), N(CF ３ ), N(CH ２ CH ２ F), N(CH ２ CHF ２ ), N(CH ２ CF ３ ), N(CH ２ CN), or N(CH ２ CH ２ CN); R ９ is N and Z is 0; Or, R ９ is C and Z is 1; R １０ is H, CH ２ F, CHF ２ , C.F. ３ , C.H. ２ Cl, CHCl ２ , CCl ３ , C.H. ２ Br, CH ２ I, F, Cl, Br, I, C １～４ O-alkyl, C １～３ Alkylene -OH, CN, CH ２ C.N., C.H. ２ CH ２ CN, C(O)OH, OH, NH ２ , N(H)CH ３ , N(CH ３ ) ２ , C.H. ２ NH ２ , C.H. ２ N(H)CH ３ , C.H. ２ N (CH ３ ) ２ , or N(Boc)CH ３ and J is 0, 1, or 2; X is 0, 1, or 2; M is 1 or 2; Each hydrogen may be independently replaced with a deuterium.

2. R １ is N, CH, or CF.

3. R ６ is H and R ７ H, F, Cl, CH ３ , C.H. ２ CH ３ , OCH ３ or cyclopropyl.

4. R ８ is a bond, NH, O, CH ２ , N(CH ２ F), or N(CH ２ CN).

5. R ９ 2. The compound of claim 1, wherein: is C and Z is 1.

6. R １０ But H, CH ２ F, CHF ２ , F, Cl, CH ２ OH, CN, CH ２ CN, C(O)OH, N(H)CH ３ , or C.H. ２ N (CH ３ ) ２ 2. The compound of claim 1, wherein:

7. R ４ But H, CH ３ , C.H. ２ NH ２ , C.H. ２ N (CH ３ ) ２ , Boc, C(O)N(H)CH ３ , C.H. ２ N(H)Boc, piperazinyl, C(O)OCH ３ , piperazinyl-CH ３ , C(O)OH, S(O ２ ) CH ３ , C(O)NH ２ , morpholinyl, CH ２ OH, Cl, OCH ３ , C.H. ２ -morpholinyl, CH ２ OCH ３ , C.H. ２ -piperazinyl-CH ３ , C.H. ２ CH ２ N (CH ３ ) ２ , C.H. ２ OC(O)-phenyl, CH ２ N(H)CH ３ , piperazinyl-Boc, CH ２ OCH ２ CH ２ OCH ３ , C.H. ２ OC(O)CH ２ CH ２ -piperazinyl-CH ３ , C.H. ２ OC(O)CH ２ CH ２ N (CH ３ ) ２ , C.H. ２ OC(O)CH ２ CH ２ -morpholinyl, C(O)N(CH ３ ) ２ , C.H. ２ N(H)C(O)C(CH ３ )N(H)Boc,CH ２ N(H)C(O)-pyrrolidinyl-Boc, CH ２ N(H)C(O)C(CH ３ ) NH ２ , C.H. ２ N(H)C(O)-pyrrolidinyl, CH ２ N(H) Boc, CH ２ N(H)C(O)CH ２ N (CH ３ ) ２ , C.H. ２ N(H)C(O)C(N(H)Boc)CH ２ CH ２ CH ２ -guanidinyl (Boc) ２ , C.H. ２ N(H)C(O)C(NH ２ ) CH ２ CH ２ CH ２ -guanidinyl, CF ３ , OCH ２ CH ２ N (CH ３ ) ２ , OCH ２ CH ２ OCH ３ , azetidinyl-N(CH ３ ) ２ or 2-oxa-6-azaspiro[3.3]heptanyl.

8. R ４ But H, CH ３ , C.H. ２ NH ２ , C.H. ２ N (CH ３ ) ２ ,C(O)N(H)CH ３ , piperazinyl, C(O)OCH ３ , piperazinyl-CH ３ , C(O)OH, S(O ２ ) CH ３ , C(O)NH ２ , morpholinyl, CH ２ OH, Cl, OCH ３ , C.H. ２ -morpholinyl, CH ２ OCH ３ , C.H. ２ -piperazinyl-CH ３ , C.H. ２ CH ２ N (CH ３ ) ２ , C.H. ２ OC(O)-phenyl, CH ２ N(H)CH ３ , C.H. ２ OCH ２ CH ２ OCH ３ , C.H. ２ OC(O)CH ２ CH ２ -piperazinyl-CH ３ , C.H. ２ OC(O)CH ２ CH ２ N (CH ３ ) ２ , C.H. ２ OC(O)CH ２ CH ２ -morpholinyl, C(O)N(CH ３ ) ２ , C.H. ２ N(H)C(O)C(CH ３ ) NH ２ , C.H. ２ N(H)C(O)-pyrrolidinyl, CH ２ N(H) Boc, CH ２ N(H)C(O)CH ２ N (CH ３ ) ２ , C.H. ２ N(H)C(O)C(NH ２ ) CH ２ CH ２ CH ２ -guanidinyl, CF ３ , OCH ２ CH ２ N (CH ３ ) ２ , OCH ２ CH ２ OCH ３ , azetidinyl-N(CH ３ ) ２ or 2-oxa-6-azaspiro[3.3]heptanyl.

9. R ８ is a bond, NH, O, CH ２ , or N(CH ２ F); X is 1; M is 1, The compound of claim 1.

10. R ３ 2. The compound of claim 1, wherein is phenyl, isothiazolyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrazolopyrimidinyl, triazolyl, or isoxazolyl.

11. R ５ But H, F, CH ３ ,=O,C(O)OCH ３ , or C.H. ２ 2. The compound of claim 1, wherein:

12. The compound has the formula: 【Chemistry 50】 2. The compound of claim 1, wherein the compound is: [In the formula, R ２ ,NH, 【Chemistry 51】 and R １１ teeth, 【Chemistry 52】 and R １２ teeth, 【Chemistry 53】 and R １３ teeth, 【Chemical 54】 【Chemistry 55】 【Chemical Formula 56】 【Chemical 57】 is.

13. R ２ The compound of claim 12, wherein is NH.

14. The compound is 【Chemistry 58】 【Chemical 59】 【Chemistry 60】 【Hua 61】 【Hua 62】 【Chemistry 63】 【Hua 64】 【Chemistry 65】 【Hua 66】 【Chemical Formula 67】 【Chemistry 68】 【Chemical 69】 【Chemistry 70】 【Chemical Formula 71】 【Chemical Formula 72】 【Chemical 73】 【Chemical 74】 【Chemistry 75】 【Chemical 76】 2. The compound of claim 1, wherein:

15. formula: 【Chemical 77】 or a pharmaceutically acceptable salt thereof [In the formula, R １４ teeth, 【Chemical 78】 and R １５ teeth, 【Chemical Formula 79】 【Chemistry 80】 and R １６ teeth, 【Chemistry 81】 is.

16. The compound is 【Chemistry 82】 【Chemistry 83】 【Chemistry 84】 16. The compound of claim 15, wherein:

17. 【Chemical 85】 【Chemistry 86】 or a pharmaceutically acceptable salt thereof.

18. formula: 【Hua 87】 or a pharmaceutically acceptable salt thereof [In the formula, R １７ is H, Cl, or CH ３ and R １８ teeth, 【Hua 88】 【Chemistry 89】 is.

19. The compound is 【Chemistry 90】 【Chemistry 91】 【Chemistry 92】 【Chemistry 93】 19. The compound of claim 18, wherein:

20. 【Catalog 94】 or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, 【Chemistry 95】 【Chemistry 96】 【Chemistry 97】 【Chemistry 98】 【Hua99】 2. The compound of claim 1, wherein:

22. 22. A composition comprising a compound according to any one of claims 1 to 21.

23. 23. The composition of claim 22, wherein the composition is a pharmaceutical composition and further comprises a pharmaceutically acceptable carrier.

24. 24. The composition of claim 23 for treating a disease in a subject in need thereof.

25. 25. The composition of claim 24, wherein the disease is associated with modulation of kinase activity.

26. 22. The compound of claim 1, wherein the compound is contained in a container.

27. The composition of claim 22, wherein the composition is contained in a container.

28. The composition of claim 23, wherein the composition is contained in a container.

29. 24. The composition of claim 23 for use in a method, wherein the method comprises contacting a Janus kinase with the compound or composition, and optionally the Janus kinase is within a subject.

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