Compounds and methods for treating cytokine release syndrome - Patents.com

Abstract

Disclosed herein are embodiments of methods for treating or preventing cytokine release syndrome (CRS). In certain embodiments, the methods include administering a compound, or a salt, solvate, prodrug, or pharmaceutical composition thereof, to a subject suffering from or at risk of developing CRS. The compound can be a kinase inhibitor, such as a JAK inhibitor and / or an IRAK inhibitor, and / or the compound can have a structure represented by Formula I, III, IV, or VII. The methods can also include administering the compound to a subject who has undergone, is currently undergoing, and / or will undergo cell therapy. TIFF2022543843000173.tif75129

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 62 / 884,457, filed on August 8, 2019, under 35 U.S.C. § 119(e), the entire disclosure of which is incorporated herein by reference.

[0002] This application relates to compounds, and salts, solvates and / or prodrugs thereof, pharmaceutical compositions containing them, and methods of using the compounds, and salts, solvates, prodrugs and / or compositions thereof for treating cytokine release syndrome.

Background Art

[0003] Background Cytokine release syndrome (CRS) is a life - threatening disease that can result from a variety of factors including administration of antibodies used in immunotherapies such as cancer immunotherapy, non - protein - based anti - cancer agents such as oxaliplatin and lenalidomide, and severe viral infections such as influenza. Immunotherapy can involve high levels of immune activation beyond naturally occurring levels of immune activation, and CRS is a resulting non - antigen - specific toxicity. Immunotherapy - based treatments are becoming more powerful, and CRS is being diagnosed more frequently. CRS has also been observed in the context of haploidentical donor - derived stem cell transplantation and graft - versus - host disease. Shimabukuro - Vornhagen et al., Journal for ImmunoTherapy of Cancer 6:56 (2018) (Non - Patent Document 1). CRS is associated with elevated blood levels of several cytokines including interleukin (IL) - 6 and interferon γ. Lee et al., Blood 124(2):188 - 195 (10 July 2014; Epub 29 May 2014) (Non - Patent Document 2).

[0004] CRS is typically observed clinically when a significant number of lymphocytes and / or myeloid cells are activated and release inflammatory cytokines. Cytokine release can be induced by chemotherapy or biological therapy and / or associated with treatment with therapeutic antibodies, such as immunotherapy for cancer treatment. Exemplary immunotherapies that can cause CRS include, but are not limited to, therapy in which cells express recombinant receptors, such as chimeric antigen receptors (CARs) and / or other transgenic receptors, such as T cell receptors (TCRs). CRS induced by CAR T therapy generally occurs within a few days of T cell infusion at the peak of CAR T cell proliferation. Giavridis et al., Nat Med. 24(6):731-738 (June 2018; Epub 28 May 2018) (Non-Patent Document 3). Examples of CAR T therapies that can induce CRS include axicabtagenecilloreucel (sold as YESCARTA®) and tisagenlecleucel (sold as KYMRIAH®).

[0005] Highly elevated interleukin 6 (IL-6) levels have been observed in patients with CRS and even in mouse models of the disease, indicating that IL-6 may play a role in the pathophysiology of CRS. Shimabukuro-Vornhagen, J Immunother Cancer 6(1),56(2018). IL-6 can signal by two different modes. Classical IL-6 signaling involves the binding of IL-6 to the membrane-bound IL-6 receptor. However, the IL-6 receptor does not have an intracellular signaling domain. Instead, after soluble IL-6 binds to the membrane-bound IL-6 receptor, the IL-6 / IL-6 receptor complex binds to membrane-bound gp130, which initiates signaling through its intracellular domain. In trans-signaling, IL-6 binds to a soluble form of the IL-6 receptor, which is typically cleaved from the cell surface by metalloproteinases. The resulting soluble IL-6 / IL-6 receptor complex binds to gp130 and is therefore capable of inducing signaling even in cell types that do not express membrane-bound IL-6 receptors.

[0006] IL-6 contributes to many of the major symptoms of CRS. Through trans-signaling, IL-6 leads to the hallmark symptoms of severe CRS, namely vascular leakage and the coagulation cascade that induces complement activation and disseminated intravascular coagulation (DIC). In addition, IL-6 likely contributes to the cardiomyopathy often observed in patients with CRS by promoting myocardial dysfunction. In mouse models, CRS develops within 2-3 days of CAR T cell infusion and can be fatal. Giavridis et al., Nat Med. 24(6):731-738(2018) (Non-Patent Document 3). CRS symptoms can begin within minutes or hours of initiation of antibody treatment and can include fever that can reach or exceed 40°C, nausea, fatigue, headache, tachycardia, hypotension, rash, shortness of breath, and / or muscle pain. However, in some cases, additional, potentially more serious complications may occur, including cardiac dysfunction, adult respiratory distress syndrome, neurotoxicity, renal and / or hepatic failure, and / or disseminated intravascular coagulation.

[0007] The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v.5.0, pub. November 27, 2017) (Non-Patent Document 4) includes a scoring system for CRS. Grade 1: Fever with or without systemic symptoms. Grade 2: Hypotension in response to fluids; hypoxia in response to <40% O2. Grade 3: Hypotension controlled by one vasopressor; hypoxia requiring ≥40% O2. Grade 4: Life-threatening consequences; urgent intervention is indicated. Grade 5: Death.

[0008] Other diseases associated with elevated cytokines, including CRS, have also been identified, for example syndromes associated with viral infections such as COVID-19. One such syndrome is acute respiratory syndrome or "ARDS," in which fluid accumulates in the alveoli, limiting the amount of oxygen that can be absorbed. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Shimabukuro-Vornhagen et al., Journal for ImmunoTherapy of Cancer 6:56(2018) [Non-Patent Document 2] Lee et al.,Blood 124(2):188-195(10 July 2014;Epub 29 May 2014) [Non-Patent Document 3] Giavridis et al., Nat Med.24(6):731-738(June 2018;Epub 28 May 2018) [Non-Patent Document 4] The National Cancer Institute Common Terminology Criteria for Adverse Events(CTCAE v.5.0,pub.November 27,2017) Summary of the Invention

[0010] Disclosed herein are embodiments of methods for treating or preventing damage caused by elevated levels of inflammatory cytokines, such as CRS. In some embodiments, the methods include administering an effective amount of a compound to a subject suffering from or at risk of developing CRS. The compound can be a kinase modulator and / or inhibitor, such as a Janus kinase (JAK) and / or an interleukin receptor associated kinase (IRAK) modulator and / or inhibitor. The compound can be a pyrimidinediamine compound and / or have a structure represented by Formula I or III, or a salt, solvate, N-oxide and / or prodrug thereof. Alternatively, the compound can be a pyrazole compound and / or have a structure represented by Formula IV or VII, or a salt, solvate, N-oxide and / or prodrug thereof. TIFF0007682155000001.tif86148

[0011] With respect to formula I, X and Y are each independently O, S, S(O), SO 2 or NR 1 and each R 1 are independently expressed as H, C 1~6 Alkyl, C(O)-C 1~6 Alkyl, CO 2 -C 1~6 Alkyl or R 50 and each R 50 is C(R 9 ) 2 -OR 10 or C(R 9 ) 2 -SR 10 and each R 9 are independently expressed as H, C 1~6 Alkyl, C 6~10 Aryl or C 7~16 arylalkyl; or alternatively, two R 9 along with the carbon to which they are attached, C 3~8 R forms a cycloalkyl group or a 3- to 8-membered heteroalicyclic group; 10 is R a Or-P(O)(OR11 ) 2 and each R 11 independently for each occurrence, R a or a monovalent cationic group; or two R 11 form, together with the atoms to which they are attached, a 4- to 8-membered cyclic phosphate group, or two R 11 together represent a divalent cationic group; ring A is C 6~10 aryl or 5- to 10-membered heteroaryl; each R 2 are independently determined for each occurrence by H, R e , R b , the same or different R a and / or R b R replaced by one or more of e , the same or different R a and / or R b -OR replaced by one or more of e , the same or different R a and / or R b -SR substituted with one or more of e , the same or different R a and / or R b -C(O)R substituted with one or more of e , -N(R a )R e (where R e are the same or different R a and / or R b substituted with one or more of the same or different R a and / or R b -S(O) substituted with one or more of 2 R e , -B(OR a ) 2 , -B(N(R c ) 2 ) 2 , -(C(R a ) 2 ) m -R b , -O-(C(R a ) 2 ) m -R b , -S-(C(R a ) 2 )m -R b ,-O-(C(R b )) 2 )-R m -R a ,-N(R a )(C(R a )) 2 ))-R m -R b ,-O-(CH 2 ))-CH((CH m ))R 2 ))R m R b -R b ,-C(O)N(R a )(C(R a )) 2 ))-R m -R b ,-O-(C(R a )) 2 ))-C(O)N(R m )(C(R a )) a ))-R 2 -R m ,-N((C(R b ))R a )) 2 ))-R m R b -R 2 ,-S-(C(R a )) 2 ))-C(O)N(R m )(C(R a )) a ))-R 2 -R m ,-N(R b )(C(O)-N(R a )(C(R a )) a ))-R 2 ))-R m -R b ,-N(R a )(C(O)(C(R a )) 2 ))-C(R m (R a )(R b ))-R 2 Or-N(R a )(C(R a )) 2 ))-C(O)-N(R m )(C(R a)-(C(R a ) 2 ) m -R b p is 0, 1, 2, 3, or 4; each m is 1, 2, or 3; each n is 0, 1, 2, or 3; or two R 2 The groups, together with the atom or atoms to which they are attached, may in combination contain one or more heteroatoms and one or more R a and / or R b forming a 4-10 membered partially or completely saturated monocyclic or bicyclic ring, optionally substituted by 1 and Z 2 are independently CH, CR 2 or N;R 3 , H, C 1~6 Alkyl or R 50 ;R 4 , H, C 1~6 Alkyl or R 50 ;R 5 , halo, -CN, C 1~6 Alkyl, alkynyl, hydroxy, C 1~6 Alkoxy, nitro, -N(R a ) 2 , -C(O)N(R a ) 2 , -CO 2 R a Or -C(O)R a Furthermore, each R a are independently H, deuterium, and C 1~6 Alkyl, C 3~8 Cycloalkyl, C 4~11 Cycloalkylalkyl, C 6~10 Aryl, C 7~16 arylalkyl, 2- to 6-membered heteroalkyl, 3- to 10-membered heteroalicyclic, 4- to 11-membered heteroalicyclic alkyl, 5- to 15-membered heteroaryl, or 6- to 16-membered heteroarylalkyl; each R b are independently, =O, -OR in each occurrence. a , -O-(C(R a ) 2 ) m -OR a , HaroC1~3 アルキルオキシ、=S、-SR a 、=NR a 、=NOR a 、-N(R c ) 2 、ハロ、-CF 3 、-CN、-NC、-OCN、-SCN、-NO、-NO 2 、=N 2 、-N 3 、-S(O)R a 、-S(O) 2 R a 、-SO 3 R a 、-S(O)N(R c ) 2 、-OS(O)R a 、-OS(O) 2 R a 、-SO 3 R a 、-OS(O) 2 N(R c ) 2 、-C(O)R a 、-CO 2 R a 、-C(O)N(R c ) 2 、-C(NR a )-N(R c ) 2 、-C(NOH)-R a 、-C(NOH)-N(R c ) 2 、-OC(O)R a 、-OC(O)OR a 、-OC(O)N(R c ) 2 、-OC(NH)-N(R c ) 2 、-OC(NR a )-N(R c ) 2 、-[N(R a )C(O)] n R a 、-[N(R a )C(O)] n OR a 、-[N(R a )C(O)] n N(R c ) 2Or -[N(R a )C(NR a )] n -N(R c ) 2 and each R c independently for each occurrence, R a or alternatively, two R c may, together with the nitrogen atom to which they are attached, contain one or more of the same or different additional heteroatoms and may be the same or different R a and / or R d R 1 to R 2 form a 3- to 10-membered heteroalicyclic or 5- to 10-membered heteroaryl ring system, each of which may be substituted with one or more of the following groups: d =O, -OR a , HaroC 1~3 Alkyloxy, C 1~6 Alkyl, =S, -SR a , =NR a , =NOR a , -N(R a ) 2 , Halo, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R a , -S(O 2 )R a , -SO 3 R a , -S(O)N(R a ) 2 , -S(O) 2 N(R a ) 2 , -OS(O)R a , -OS(O) 2 R a , -OSO 3 R a , -OS(O) 2 N(R a ) 2 , -C(O)R a , -CO 2 R a , -C(O)N(R a ) 2 , -C(NR a )N(R a )2 , -C(NOH)R a , -C(NOH)N(R a ) 2 , -OCO 2 R a , -OC(O)N(R a ) 2 , -OC(NR a )N(R a ) 2 , -[N(R a )C(O)] n R a , -(C(R a ) 2 ) n -OR a , -N(R a )-S(O) 2 R a , -C(O)-C 1~6 Haloalkyl, -S(O) 2 C 1~6 Haloalkyl, -OC(O)R a , -O(C(R a ) 2 ) m -OR a , -S(C(R a ) 2 ) m -OR a , -N(R a ) C 1~6 Haloalkyl, -P(O)(OR a ) 2 , -N(R a )-(C(R a ) 2 ) m -OR a , -[N(R a )C(O)] n OR a , -[N(R a )C(O)] n N(R a ) 2 , -[N(R a )C(NR a )] n N(R a ) 2 Or -N(R a )C(O)C 1~6 haloalkyl; or two R dmay, in combination with the atom or atoms to which they are attached, contain one or more heteroatoms and one or more R a each R e independently for each occurrence, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 4~11 Cycloalkylalkyl, C 6~10 Aryl, C 7~16 It is an arylalkyl, a 2- to 6-membered heteroalkyl, a 3- to 10-membered heteroalicyclic, a 4- to 11-membered heteroalicyclic alkyl, a 5- to 15-membered heteroaryl, or a 6- to 16-membered heteroarylalkyl.

[0012] In some embodiments, the compound has formula IA or IA3 For formula IA, R may have the structure represented by the formula: TIFF0007682155000002.tif25128, or a salt, solvate, N-oxide, or prodrug thereof. 2a , R 2b , R 2c and R 2d Each of, independently at each occurrence, R 2 In certain embodiments, R 5 is halo or C 1~6 Alkyl, e.g., F or CH 3 and / or Z 1 is CH, C-halo or CC 1~6 is alkyl, and Z 2 is CH. Also, with respect to formula IA3, R b OH, C 1~6 Alkyl, -CO 2 C 1~6 Alkyl, -C(O)C 1~6 Alkyl or -S(O) 2 C 1~6 It is an alkyl.

[0013] In other embodiments, the compound has formula IB or formula II With respect to formula IB, Q has the structure represented by the formula: 1 and Q 2 are each independently N or CH, with the proviso that Q 1 and Q 2 At least one of X and Y is N. In some embodiments, X and Y are each independently O or NR 1 and each R 1 are independently expressed as H, C 1~6 Alkyl or R 50 p is 0, 1, 2 or 3; and / or R 5 , halo, -CN, C 1~6 Alkyl, nitro, -N(R a ) 2 , -C(O)N(R a ) 2 , -CO 2 R a Or -C(O)R a Also, with respect to formula II, ring B, together with the two phenyl ring atoms to which it is attached, is N(R c ), forming a 5-, 6- or 7-membered ring optionally containing 1, 2 or 3 heteroatoms independently selected from O and S; a is C 1~6 alkyl; each R b are independently, =O, -OR in each occurrence. a , HaroC 1~3 Alkyloxy, -SR a , -N(R c ) 2 , Halo, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -N(R a )-S(O) 2 R aOr -C(R a ) 2 -N(R c ) 2 In certain embodiments, Z 1 is CH, C-halo, or CC 1~6 It is an alkyl.

[0014] In another embodiment, the compound has formula III The pyrimidinediamine compound represented by formula III is represented by TIFF0007682155000004.tif31128, or a salt, solvate, N-oxide or prodrug thereof. B is alkyl, alkoxy, amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, or alkynyl; R B is hydrogen, alkyl, alkenyl, alkynyl, or cycloalkyl; Ring A B is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclic, where Ring A B is not indolyl or benzimidazolyl; r is 0, 1, 2, or 3; each R B2 is independently alkyl, alkoxy, amino, aryl, aryloxy (i.e., aryl-O-), cyano, cycloalkyl, cycloalkoxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclyloxy, aminoacyl, carboxyl, carboxyl ester, carbonate ester, sulfonyl, oxo, nitro, or halo, preferably alkoxy; Z B1 , Z B2 , and Z B3 are each independently carbon or nitrogen, B1 If is nitrogen, Z B2 and Z B3 is carbon and Z B2 If is nitrogen, Z B1 and Z B3 is carbon and Z B3 If is nitrogen, Z B1 and Z B2 is carbon and Z B1 , Z B2 , or ZB3 If is nitrogen, SO 2 R B4 R B5 is not attached to a nitrogen; s is 0, 1, 2, or 3; each R B3 are independently hydrogen, alkyl, alkoxy, or cycloalkyl, halo, or heterocyclic; R B4 and R B5 Each of is independently hydrogen, alkyl, acyl, or M + where M + is K + , Na + , Li + or + N(R 6 ) 4 where R is a metal counterion selected from B6 is hydrogen or alkyl, and SO 2 NR B4 R B5 Nitrogen is N - or R B4 or R B5 Ca 2+ , Mg 2 + and Ba 2+ is a divalent counterion selected from SO 2 NR B4 R B5 Nitrogen is N - In certain embodiments, the compound is Selected from TIFF0007682155000005.tif18136.

[0015] In another embodiment, the compound is a pyrazole compound and may have formula IV or a salt, prodrug, solvate and / or N-oxide thereof. With respect to formula IV, Het-1 is a 5-membered heteroaryl, such as thiazolyl or furanyl; y is 1 to 2; R C2 is H, aliphatic, heteroaliphatic, heteroalicyclic, aryl, amido, heterocyclyl, or araliphatic, H can be alkyl, haloalkyl, or cycloalkyl, e.g., H or alkyl; each RC3 are independently H or aliphatic; R C4 , R C5 , R C6 and R C7 are each independently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl, carboxyl ester, acyl, amido, amino, sulfonyl, sulfonamido, sulfanyl, or sulfinyl; R C8 and R C9 are each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, halogen, haloalkyl, carboxyl ester, cyano, or amino, e.g., H, halogen, haloalkyl, or alkyl; R C10 is H, aliphatic, alkoxy, heteroaliphatic, carboxyl ester, araliphatic, NO 2 , CN, OH, haloalkyl, acyl, alkyl phosphate or alkyl phosphonate, for example, H, alkyl, alkyl phosphate or alkyl phosphonate. C4 , R C6 , and R C7 Each of R is independently H, halo, alkyl, or haloalkyl, and may be H or F. Also, in certain embodiments, R C5 is H, halo, aliphatic, alkoxy, heterocyclyl, or -O-heterocyclyl; R C5 H, F, CF 3 , methoxy, -O-CH 2 C(CH 3 ) 2 It can be -OH, morpholin-4-yl, 1-methylpiperidin-4-yl, or -O-(oxetan-3-yl).

[0016] In some embodiments, the compound has the structure represented by formula V or VI. TIFF0007682155000007.tif40128 or a salt, prodrug, solvate and / or N-oxide thereof, With respect to Formulas V and VI, RC11 , R C12 and R C14 Each of is independently H or aliphatic.

[0017] In another embodiment, the compound is a pyrazole compound of formula VII, or a salt, prodrug, solvate and / or N-oxide thereof. TIFF0007682155000008.tif52128 or its salt, solvate or N-oxide. With respect to formula VII, R is H, aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkyl phosphoramidate, or alkyl phosphate. In some embodiments, R is not H, or alternatively, R is H, and the compound is a salt. In other embodiments, R is alkyl, acyl, carboxyl ester, amide, non-aromatic heterocyclyl, alkyl phosphoramidate, or alkyl phosphate. Those skilled in the art will understand that a compound (wherein R is not H) can act as a prodrug of a compound (wherein R is H), for example, when administered to a subject.

[0018] In any of the methods, the subject may not exhibit signs or symptoms of CRS and / or may be at risk for developing CRS, in such embodiments, administering the compound substantially prevents the onset of CRS or prevents the onset of Grade 2 or higher CRS.

[0019] In other embodiments, the subject may exhibit at least one sign or symptom of CRS, and may exhibit at least one sign or symptom of grade 1 CRS. Alternatively, the subject may exhibit at least one sign or symptom of grade 2 or higher CRS, such as grade 3 or higher CRS. The compound may be administered within 24 hours of onset of the sign or symptom, and / or administering the compound may improve the sign or symptom of CRS compared to the severity of the sign or symptom prior to administration of the compound, such as reducing the grade of CRS from 4 to 3, 2 or 1, or from 3 to 2 or 1, or from 2 to 1. Alternatively, the symptom of CRS is substantially reduced below grade 1 level, such that the subject no longer experiences symptoms associated with CRS. In some embodiments, the sign or symptom is fever, and may be a fever of 40° C. or higher.

[0020] High levels of inflammatory cytokines have also been reported during COVID-19 infection. These cytokines include interferons, interleukins, chemokines, colony-stimulating factors, and tumor necrosis factors, and contribute to the symptoms of coronavirus infection. One consequence of the cytokine storm associated with COVID-19 infection is acute organ damage, which is the case for lung damage, which can progress to a more severe form called acute respiratory distress syndrome. Thus, the compounds of the present invention can be administered to patients infected with COVID-19 to prevent, ameliorate, or treat inflammation associated with the disease, and for the treatment of the same.

[0021] The method may include administering to a subject who has previously received a first treatment in which harmful inflammatory cytokine production, such as CRS, is a known, possible, or potential side effect. Administration of the first treatment may begin more than 0 to 10 days prior to administration of the compound. Alternatively, the compound may be administered to a subject who is about to receive or is currently receiving a first treatment in which CRS is a known, possible, and / or potential side effect. In any embodiment, the first treatment may include cell therapy, including but not limited to chimeric antigen receptor (CAR) expression therapy and / or transgenic receptor therapy. It is also known that acellular antibodies, including but not limited to CAMPATH 1-H, blinatumomab, and / or rituximab, can cause this syndrome, especially those that activate T cells.

[0022] In some embodiments, the method may further include administering a second therapeutic agent, such as a steroid, an antiviral agent, an anti-inflammatory agent, an immunosuppressant, or a combination thereof. The steroid may be a corticosteroid, such as dexamethasone or prednisone, or a combination thereof. In any embodiment, the compound may be administered substantially simultaneously with the second therapeutic agent, or the compound and the second therapeutic agent may be administered sequentially in any order.

[0023] [The present invention 1001] A method for treating and / or preventing cytokine release syndrome (CRS), the method comprising administering to a subject suffering from CRS or at risk of developing CRS an effective amount of a compound having activity as a kinase inhibitor. [The present invention 1002] The method of the present invention 1001, wherein the compound is a JAK inhibitor, an IRAK inhibitor, or a combination thereof. [The present invention 1003] The compound is a pyrimidine diamine compound represented by formula I TIFF0007682155000009.tif26128 (wherein, X and Y are each independently O, S, S(O), SO 2 or NR 1 ; each R 1 is independently, at each occurrence, H, C 1~6alkyl, C(O)-C 1~6 alkyl, CO 2 -C 1~6 alkyl or R 50 ; each R 50 is C(R 9 ) 2 -O-R 10 or C(R 9 ) 2 -S-R 10 ; each R 9 is independently, at each occurrence, H, C 1~6 alkyl, C 6~10 aryl or C 7~16 arylalkyl; or alternatively, two R 9 together with the carbon to which they are attached form a C 3~8 cycloalkyl group or a 3- to 8-membered heterocyclic alicyclic ring; R 10 is R a or -P(O)(OR 11 ) 2 ; each R 11 is independently, at each occurrence, R a or a monovalent cationic group; or two R 11 together with the atom to which they are attached form a 4- to 8-membered cyclic phosphate group, or two R 11 together represent a divalent cationic group; ring A is C 6~10 aryl or a 5- to 10-membered heteroaryl; each R 2 is independently, at each occurrence, H, R e 、R b , R a and / or R b substituted R e identical or different, -OR a substituted with one or more of R b and / or Re identical or different, -SR a substituted with one or more of R b and / or R e identical or different, -C(O)R a , -N(R b wherein R e is substituted with one or more of R a )R e and / or R e identical or different, -S(O) a substituted with one or more of R b and / or R a identical or different, -B(OR b , -B(N(R 2 R e , -(C(R a ) 2 , -O-(C(R c ) 2 ) 2 , -S-(C(R a ) 2 ) m -R b , -O-(C(R a ) 2 ) m -R b , -N(R a ) 2 ) m -R b )-(C(R b ) 2 ) m -R a , -O-(CH a -CH((CH a) 2 ) m -R b , -C(O)N(R 2 ) m )-(C(R 2 ) m R b )R b , -O-(C(R a -C(O)N(R a ) 2 ) m -R b )-(C(R a ) 2 ) m , -N((C(R a , -S-(C(R a ) 2 ) m -R b -C(O)N(R a ) 2 ) m R b ) 2 )-(C(R a ) 2 ) m , -N(R a )-C(O)-N(R a ) 2 ) m -R b )-(C(R a , -N(R a )-C(O)-(C(R a )2 ) m -R b -C(R a or -N(R a ) 2 ) m )-(C(R a )(R b ) 2 -C(O)-N(R a )-(C(R a ) 2 ) m ; a each R a ) 2 ) m -R b ​ ​ a are independently H, deuterium, and C 1~6 Alkyl, C 3~8 Cycloalkyl, C 4~11 Cycloalkylalkyl, C 6~10 Aryl, C 7~16 arylalkyl, 2- to 6-membered heteroalkyl, 3- to 10-membered heteroalicyclic, 4- to 11-membered heteroalicyclic alkyl, 5- to 15-membered heteroaryl, or 6- to 16-membered heteroarylalkyl; Each R b are independently, =O, -OR in each occurrence. a , -O-(C(R a ) 2 ) m -OR a , HaroC 1~3 Alkyloxy, =S, -SR a , =NR a , =NOR a , -N(R c ) 2 , Halo, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 、=N 2 、-N 3 , -S(O)R a , -S(O) 2 R a , -SO 3 R a , -S(O)N(R c ) 2 , -OS(O)R a , -OS(O) 2 R a , -OSO 3 R a , -OS(O) 2 N(R c ) 2 , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -C(NR a )-N(R c ) 2 , -C(NOH)-R a , -C(NOH)-N(R c ) 2 , -OC(O)R a , -OC(O)OR a , -OC(O)N(R c ) 2 , -OC(NH)-N(R c ) 2 , -OC(NR a )-N(R c )2 , -[N(R a )C(O)] n R a , -[N(R a )C(O)] n OR a , -[N(R a )C(O)] n N(R c ) 2 Or -[N(R a )C(NR a )] n -N(R c ) 2 and; Each R c independently for each occurrence, R a or alternatively, two R c may, together with the nitrogen atom to which they are attached, contain one or more of the same or different additional heteroatoms and may be the same or different R a and / or R d forming a 3- to 10-membered heteroalicyclic or 5- to 10-membered heteroaryl, optionally substituted with one or more groups; Each R d =O, -OR a , HaroC 1~3 Alkyloxy, C 1~6 Alkyl, =S, -SR a , =NR a , =NOR a , -N(R a ) 2 , Halo, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 、=N 2 、-N 3 , -S(O)R a , -S(O 2 )R a , -SO 3 R a , -S(O)N(R a ) 2 , -S(O) 2 N(R a ) 2 , -OS(O)R a , -OS(O) 2 R a , -OSO 3 R a , -OS(O) 2 N(R a ) 2 , -C(O)R a , -CO 2 R a , -C(O)N(R a ) 2 , -C(NR a )N(R a ) 2 , -C(NOH)R a , -C(NOH)N(R a ) 2 , -OCO 2 R a , -OC(O)N(R a ) 2 , -OC(NR a )N(R a ) 2 , -[N(R a )C(O)] n R a , -(C(R a ) 2 )n -OR a , -N(R a )-S(O) 2 R a , -C(O)-C 1~6 Haloalkyl, -S(O) 2 C 1~6 Haloalkyl, -OC(O)R a , -O(C(R a ) 2 ) m -OR a , -S(C(R a ) 2 ) m -OR a , -N(R a )C 1~6 Haloalkyl, -P(O)(OR a ) 2 , -N(R a )-(C(R a ) 2 ) m -OR a , -[N(R a )C(O)] n OR a , -[N(R a )C(O)] n N(R a ) 2 , -[N(R a )C(NR a )] n N(R a ) 2 Or -N(R a)C(O)C 1~6 haloalkyl; or two R d may, in combination with the atom or atoms to which they are attached, contain one or more heteroatoms and one or more R a forming a 3-10 membered partially or fully saturated monocyclic or bicyclic ring, optionally substituted with Each R e independently for each occurrence, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 4~11 Cycloalkylalkyl, C 6~10 Aryl, C 7~16 arylalkyl, 2- to 6-membered heteroalkyl, 3- to 10-membered heteroalicyclic, 4- to 11-membered heteroalicyclic alkyl, 5- to 15-membered heteroaryl, or 6- to 16-membered heteroarylalkyl; p is 0, 1, 2, 3 or 4; each m is 1, 2, or 3; each n is 0, 1, 2, or 3; or 2 R 2 The groups, together with the atom or atoms to which they are attached, may in combination contain one or more heteroatoms and one or more R a and / or R b forming a 4-10 membered partially or fully saturated monocyclic or bicyclic ring, optionally substituted with Z 1 and Z 2 are independently CH, CR 2 or N; R 3 , H, C 1~6 Alkyl or R 50 and; R 4 , H, C 1~6 Alkyl or R 50 and; R 5 , halo, -CN, C 1~6 Alkyl, alkynyl, hydroxy, C 1~6 Alkoxy, nitro, -N(R a ) 2 , -C(O)N(R a ) 2 , -CO 2 Ra Or -C(O)R a is) or a salt, solvate, or N-oxide thereof The method of the present invention 1001 or 1002, [The present invention 1004] The compound is represented by the formula: Formula IA: TIFF0007682155000010.tif25128 or a salt, solvate, or N-oxide thereof (In the formula, R 2a 、R 2b 、R 2c and R 2d Each of, independently at each occurrence, R 2 as previously defined for Formula IA3: TIFF0007682155000011.tif23128 or a salt, solvate, N-oxide or prodrug thereof (In the formula, R b OH, C 1~6 Alkyl, -CO 2 C 1~6 Alkyl, -C(O)C 1~6 Alkyl or -S(O) 2 C 1~6 is alkyl); Formula IB: TIFF0007682155000012.tif24128 or a salt, solvate, N-oxide or prodrug thereof (In the formula, Q 1 and Q 2 are each independently N or CH, with the proviso that Q 1 and Q 2 at least one of is N; or Formula II: TIFF0007682155000013.tif27128 or a salt, solvate, N-oxide or prodrug thereof (In the formula, Ring B, together with the two phenyl ring atoms to which it is attached, is N(R c ), forming a 5-, 6- or 7-membered ring optionally containing 1, 2 or 3 heteroatoms independently selected from O and S; Each R a is C 1~6 is alkyl; Each R b are independently, =O, -OR in each occurrence. a , HaroC 1~3 Alkyloxy, -SR a , -N(R c ) 2 , Halo, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -N(R a )-S(O) 2 R a Or -C(R a ) 2 -N(R c ) 2 is) The method of the present invention 1003, comprising: [The present invention 1005] The compound is N2-(3,4,5-trimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine, or a pharma- ceutically acceptable salt thereof; 5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine, or a pharma- ceutically acceptable salt thereof; 5-Methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine bis-sodium salt; N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,4-pyrimidinediamine, or a pharma- ceutically acceptable salt thereof; N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,4-pyrimidinediamine bis-sodium salt; 5-(2-(3-methoxy-4,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one, or a pharma- ceutically acceptable salt thereof; (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl dihydrogen phosphate; 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one, or a pharma- ceutically acceptable salt thereof; or (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate sodium salt The method according to any one of claims 1001 to 1004 of the present invention. [The present invention 1006] The compound is a pyrimidinediamine compound represented by formula III TIFF0007682155000014.tif31128 (In the formula, X B is alkyl, alkoxy, amino, carboxyl, carboxylester, cyano, halo, nitro, alkenyl, or alkynyl; R B is hydrogen, alkyl, alkenyl, alkynyl, or cycloalkyl; Ring A B is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclic, where Ring A is not indolyl or benzimidazolyl; r is 0, 1, 2 or 3; Each R B2 is independently alkyl, alkoxy, amino, aryl, aryloxy (i.e., aryl-O-), cyano, cycloalkyl, cycloalkoxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclyloxy, aminoacyl, carboxyl, carboxyl ester, carbonate ester, sulfonyl, oxo, nitro, or halo, preferably alkoxy; Z B1 、Z B2 , and Z B3 are each independently carbon or nitrogen, B1 If is nitrogen, Z B2 and Z B3 is carbon and Z B2 If is nitrogen, Z B1 and Z B3 is carbon and Z B3 If is nitrogen, Z B1 and Z B2 is carbon and Z B1 、Z B2 , or Z B3 If is nitrogen, SO 2 R B4 R B5 is not bonded to said nitrogen; s is 0, 1, 2 or 3; Each RB3 is independently hydrogen, alkyl, alkoxy, or cycloalkyl, halo, or heterocyclic; R B4 and R B5 Each of is independently hydrogen, alkyl, acyl, or M + where M + is K + , Na + , Li + or + N(R 6 ) 4 where R is a metal counterion selected from B6 is hydrogen or alkyl, and SO 2 NR B4 R B5 Nitrogen is N - and; or R B4 or R B5 Ca 2+ , Mg 2 + and Ba 2+ is a divalent counterion selected from SO 2 NR B4 R B5 Nitrogen is N - is) or a salt, solvate, N-oxide or prodrug thereof The method of the present invention 1001 or 1002, [The present invention 1007] The compound is TIFF0007682155000015.tif18136 The method of the present invention 1006. [The present invention 1008] The compound is a pyrazole compound represented by formula IV TIFF0007682155000016.tif40128 (In the formula, Het-1 is a 5-membered heteroaryl; y is 1 to 2; R C2 is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl, amide, heterocyclyl or araliphatic; Each R C3 is independently H or aliphatic; R C4 、R C5 、R C6 and R C7 are each independently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl or sulfinyl; R C8 and R C9 are each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, halogen, haloalkyl, carboxyl ester, cyano or amino; R C10 is H, aliphatic, alkoxy, heteroaliphatic, carboxyl ester, araliphatic, NO 2 , CN, OH, haloalkyl, acyl, alkyl phosphate or alkyl phosphonate) or a salt, solvate and / or N-oxide thereof of the method of the present invention 1001 or the present invention 1002. [The present invention 1009] Het-1 is thiazolyl or furanyl; R C10 is H, alkyl, alkyl phosphate or alkyl phosphonate; R C4 、R C6 , and R C7 each are independently H, halo, alkyl or haloalkyl; or these combinations of the method of the present invention 1008. [The present invention 1010] R C4 、R C6 , and R C7 each are independently H or F; R C5 is H, F, CF 3 , methoxy, -O-CH 2 C(CH 3 ) 2OH, morpholin-4-yl, 1-methylpiperidin-4-yl, or -O-(oxetan-3-yl); or these combinations of the method of the present invention 1008 or the present invention 1009. [The present invention 1011] The compound is a pyrazole compound represented by formula V or formula VI TIFF0007682155000017.tif41128 (wherein, R C11 and R C12 each are independently H or aliphatic; R C14 is H or aliphatic) or a salt, solvate and / or N-oxide thereof of any of the methods of the present invention 1008 to 1010. [The present invention 1012] The pyrazole compound is TIFF0007682155000018.tif82141 or a pharmaceutically acceptable salt thereof of any of the methods of the present invention 1008 to 1011. [The present invention 1013] The compound is selected from List 1 or List 2 of the method of the present invention 1001 or the present invention 1002. [The present invention 1014] The method of any of claims 1001 to 1013, wherein administering the compound ameliorates a sign or symptom of CRS compared to the severity of the sign or symptom prior to administration of the compound. [The present invention 1015] The method of claim 1014, wherein the sign or symptom is fever. [The present invention 1016] The administering step comprises: administering to a subject who has previously received a first treatment for which CRS is a known, possible, or potential side effect; or Administered to a subject who is about to receive or is currently receiving a first treatment for which CRS is a known, possible, or potential side effect. Any of the methods of 1001 to 1015 of the present invention. [The present invention 1017] The method of claim 1016, wherein said first treatment comprises cell therapy. [The present invention 1018] The method of claim 1017, wherein the cell therapy comprises chimeric antigen receptor (CAR) expression therapy, transgenic receptor therapy, or a combination thereof. [The present invention 1019] The method of any of claims 1001 to 1018, wherein the step of administering said compound further comprises administering a second therapeutic agent. [The present invention 1020] The method of any one of claims 1 to 19, wherein said second therapeutic agent is a steroid, an anti-inflammatory agent, an immunosuppressant, or a combination thereof. [The present invention 1021] The steroid may be alclometasone, algestone, beclomethasone, betamethasone, budesonide, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, fludrocortisone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin, fluocortolone, fluorometh ... bromine, fluperolone, fluprednidene, fluprednisolone, flurandrenolide, fluticasone, formocortal, halcinonide, halobetasol, halometasone, halopredone, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone, paramethasone, prednicarbate, prednisolone, prednisone, prednibal, prednylidene, rimexolone, tixocortol, triamcinolone, or any combination thereof; the anti-inflammatory agent is an aminosalicylate, a cyclooxygenase inhibitor, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof; or The method of the present invention 1020, wherein the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inhibitor of inosine monophosphate dehydrogenase (IMPDH), an agent designed to preserve the recipient's humoral immune response intact while suppressing cellular immunity, or a combination thereof. [The present invention 1022] The method of claim 1020, wherein said second therapeutic agent is dexamethasone or prednisone, or a combination thereof. The above and other objects, features and advantages of the present invention will become more apparent from the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Detailed Description I. Definition The following explanations of terms and methods are provided to more fully describe the present disclosure and to guide those skilled in the art in the practice of the present disclosure. The singular forms "a", "an" and "the" mean one or more, unless the context clearly dictates otherwise. The word "or" refers to a single element or a combination of two or more elements of the presented alternative elements, unless the context clearly dictates otherwise. As used herein, "comprises" means "includes." Thus, "comprises A or B" means "includes A, B or A and B" and does not exclude additional elements. All references cited herein, including patents and patent applications, are hereby incorporated by reference.

[0025] Unless otherwise specified, all numbers expressing amounts of ingredients, molecular weights, percentages, temperatures, times, etc. used in the specification or claims should be understood to be modified by the word "about". Thus, unless otherwise specified, either implicitly or explicitly, the numerical parameters recited are approximations that may depend on the desired properties sought and / or detection limits under standard testing conditions / methods. When directly and explicitly distinguishing an embodiment from the prior art presented, the numbers of that embodiment are not approximations unless the word "about" is recited.

[0026] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The materials, methods, and examples are for illustrative purposes only and are not intended to be limiting.

[0027] When chemical structures are depicted or described, unless expressly stated otherwise, all carbons are considered to include hydrogens such that each carbon has a valence of 4. For example, in the structure on the left in the schematic diagram below, the presence of 9 hydrogen atoms is implied. In the structure on the right, 9 hydrogen atoms are depicted. TIFF0007682155000019.tif21128

[0028] Identify specific atoms in the structure as hydrogen or containing hydrogen atoms with a string, e.g. -CH 2 CH 2 Those skilled in the art will appreciate that the notation described above is common in the chemical arts as a concise and simple way to represent organic structures.

[0029] The group R is not "fixed" to the ring system, for example the group shown below: When depicted as TIFF0007682155000020.tif13128, unless otherwise specified, the substituent R may be located on any atom of the fused bicyclic ring system so long as a stable structure is formed according to standard valence constraints understood by those of skill in the art. In the example shown, the R group may be located on an atom on either the 5- or 6-membered ring of the indolyl ring system, including heteroatoms by replacing hydrogens as explicitly stated, but the symbol TIFF0007682155000021.tif4128, excluding atoms bridging the carbon atoms.

[0030] When more than one such "free" group is depicted, for example in the formula: Where there are two groups, i.e., R and a bond, such as in TIFF0007682155000022.tif17128, which indicate a bond to a parent structure; unless otherwise specified, each "unfixed" group may be located on any atom on the ring system, which also contemplates that each of the depicted, implied, or explicitly defined hydrogens on the ring system may be replaced to form a chemically stable compound by configuration, etc.

[0031] Examples of R groups present on ring systems containing saturated carbons include those of the formula: When written as TIFF0007682155000023.tif11128, in this example, y can be greater than 1, assuming that each R replaces a hydrogen on the ring that is then depicted, implied, or explicitly defined; in that case, unless otherwise specified, two Rs can be located on the same carbon. A simple example is when R is a methyl group. In the illustrated structure, it can also exist as a geminal dimethyl on the illustrated ring carbon (an "annular" carbon). In another example, two Rs on the same carbon can form within a ring that includes that carbon, thus forming a spiro ring ("spirocyclic" group) structure. For example, the two Rs shown below are: A piperidine ring may be formed together with the cyclohexane ring in a spiro ring arrangement such as TIFF0007682155000024.tif11128.

[0032] One of ordinary skill in the art will understand that definitions may be combined to further describe a particular compound, for example, hydroxyaliphatic refers to an aliphatic group substituted with a hydroxy (-OH) group, haloalkylaryl refers to an aryl group substituted with an alkyl group, where the alkyl group is also substituted with a halogen, and where aryl is the base name for the substituent, so that the point of attachment to the parent structure is through the aryl moiety.

[0033] As used herein, the term "substituted" refers to any modifier that follows it in a term, such as "substituted arylC1~8 The term "alkyl" means "C 1~8 "Alkyl" moiety, "aryl" moiety or aryl C 1~8 Substitution can occur at both positions on the alkyl group. Also, by way of example, alkyl includes substituted cycloalkyl groups.

[0034] When "substituted" is used to modify a particular group or moiety, it means that at least one hydrogen atom, and possibly two or more hydrogen atoms, of that particular group or moiety are independently replaced with the same or different substituents as defined below. In certain embodiments, a group, moiety, or substituent may be substituted or unsubstituted unless specifically defined as either "unsubstituted" or "substituted". Thus, any of the groups defined herein may be substituted or unsubstituted. In certain embodiments, it is contemplated that a substituent may or may not be specifically defined as substituted, but may still be substituted. For example, an "alkyl" or "pyrazolyl" moiety may be substituted or unsubstituted, but an "unsubstituted alkyl" or an "unsubstituted pyrazolyl" is not substituted.

[0035] A "substituent" or "substituent group" that replaces one or more hydrogen atoms on a saturated carbon atom of a particular group or moiety is represented by the formula -R, unless otherwise specified. 60 , halo, =O, -OR 70 , -SR 70 , -N(R 80 ) 2 , haloalkyl, perhaloalkyl, -CN, -NO 2 , =N 2 , -N 3 , -SO 2 R 70 , -SO 3 - M + , -SO 3 R 70 , -OSO 2 R 70 , -OSO 3 - M+ 、 -OSO 3 R 70 、 -P(O)(O - ) 2 (M + ) 2 、 -P(O)(O - ) 2 M 2+ 、 -P(O)(OR 70 )O - M + 、 -P(O)(OR 70 ) 2 、 -C(O)R 70 、 -C(S)R 70 、 -C(NR 70 )R 70 、 -CO 2 - M + 、 -CO 2 R 70 、 -C(S)OR 70 、 -C(O)N(R 80 ) 2 、 -C(NR 70 )(R 80 ) 2 、 -OC(O)R 70 、 -OC(S)R 70 、 -OCO 2 - M + 、 -OCO 2 R 70 、 -OC(S)OR 70 、 -NR 70 C(O)R 70 、 -NR 70 C(S)R 70 、 -NR 70 CO 2 - M + 、 -NR 70 CO 2 R 70 、 -NR 70 C(S)OR 70 、 -NR 70 C(O)N(R 80 ) 2 、 -NR 70 C(NR 70 )R 70 Or -NR 70 C(NR 70 )N(R 80) 2 and R 60 is C 1~10 Aliphatic, heteroaliphatic or alicyclic, typically C 1~6 Aliphatic, more typically C 1~6 is alkyl, R 60 may be substituted; each R 70 is independently at each occurrence hydrogen or R 60 and each R 80 independently for each occurrence, R 70 or alternatively, two R 80 The groups, together with the nitrogen atom to which they are attached, form a 3- to 7-membered aliphatic heterocycle which may contain 1 to 4 identical or different additional heteroatoms selected from O, N and S, of which N is R 70 Substituents such as H or C 1 ~C 3 Each M may have an alkyl substituent. + is a counterion with a net positive charge. + may independently represent, at each occurrence, an alkali metal ion, e.g., K + , Na + Or Li + ammonium ion, e.g. + N(R 70 ) 4 a protonated amino acid ion, such as a lysine ion or an arginine ion; or an alkaline earth metal ion, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 Or [Ba 2+ ] 0.5 (The subscript "0.5" means, for example, that one of the counterions to such divalent alkaline earth metal ions is an ionized form of a compound of the invention and the other may be a typical counterion such as chloride, or that a two-ionized compound may serve as the counterion to such divalent alkaline earth ions, or alternatively, that a doubly ionized compound may serve as the counterion to such divalent alkaline earth ions.) As a specific example, -N(R 80 )2 is -NH 2 , -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, N-morpholinyl, etc. Any two hydrogen atoms on a single carbon can be replaced by, for example, =O, =NR 70 , =N-OR 70 , =N 2 or =S.

[0036] The substituent that replaces the hydrogen atom on the unsaturated carbon atom of the group containing an unsaturated carbon is, unless otherwise specified, -R 60 , halo, -O - M + , -OR 70 , -SR 70 , -S - M + , -N(R 80 ) 2 , perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO 2 , -N 3 , -SO 2 R 70 , -SO 3 - M + , -SO 3 R 70 , -OSO 2 R 70 , -OSO 3 - M + , -OSO 3 R 70 , -PO 3 -2 (M + ) 2 , -PO 3 -2 M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 ) 2 , -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO 2 - M+ , -CO 2 R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR 70 )N(R 80 ) 2 , -OC(O)R 70 , -OC(S)R 70 , -OCO 2 - M + , -OCO 2 R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 , -NR 70 CO 2 - M + , -NR 70 CO 2 R 70 , -NR 70 C(S)OR 70 , -NR 70 C(O)N(R 80 ) 2 , -NR 70 C(NR 70 )R 70 and -NR 70 C(NR 70 )N(R 80 ) 2 and R 60 , R 70 , R 80 and M + is as defined above. In the case of an alkene or alkyne, the substituent is -O - M + , -OR 70 , -SR 70 Or -S - M + isn't it.

[0037] The substituent replacing the hydrogen atom on the nitrogen atom of such a nitrogen-containing group is, unless otherwise specified, -R 60 , -O - M + , -OR70 、-SR 70 、-S - M + 、-N(R 80 ) 2 、パーハロアルキル、-CN、-NO、-NO 2 、-S(O) 2 R 70 、-SO 3 - M + 、-SO 3 R 70 、-OS(O) 2 R 70 、-OSO 3 - M + 、-OSO 3 R 70 、-PO 3 2- (M + ) 2 、-PO 3 2- M 2+ 、-P(O)(OR 70 )O - M + 、-P(O)(OR 70 )(OR 70 )、-C(O)R 70 、-C(S)R 70 、-C(NR 70 )R 70 、-CO 2 R 70 、-C(S)OR 70 、-C(O)NR 80 R 80 、-C(NR 70 )NR 80 R 80 、-OC(O)R 70 、-OC(S)R 70 、-OCO 2 R 70 、-OC(S)OR 70 、-NR 70 C(O)R 70 、-NR 70 C(S)R 70 、-NR 70 CO 2 R 70 、-NR 70 C(S)OR 70 、-NR70 C(O)N(R 80 ) 2 , -NR 70 C(NR 70 )R 70 or -NR 70 C(NR 70 )N(R 80 ) 2 and R 60 , R 70 , R 80 and M + is synonymous with the above.

[0038] In one embodiment, a substituted group has 1 substituent, 2 substituents, 3 substituents or 4 substituents.

[0039] Also, in embodiments where a group or moiety is substituted with substituted substituents, the nesting of such substituted substituents is limited to three, thereby preventing the formation of polymers. Thus, in a group or moiety that includes a first group that is a substituent on a second group (which is itself a substituent on a third group attached to the parent structure), the first (outermost) group can only be substituted with unsubstituted substituents. For example, in a group that includes -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can itself only be substituted with unsubstituted substituents.

[0040] The term "acute respiratory distress syndrome" or "ARDS" refers to a syndrome characterized by severe shortness of breath, difficulty and abnormally rapid breathing, hypotension, confusion, and extreme fatigue. The syndrome can be diagnosed on the basis of a PaO2 / FiO2 ratio of less than 300 mmHg, despite a PEEP of more than 5 cm of HO (Fan et al. JAMA. 319:698-71).

[0041] ARDS occurs when fluid accumulates in the alveoli. The fluid prevents the lungs from filling with enough air, limiting the amount of oxygen that reaches the bloodstream, thereby depriving organs of the oxygen they need to function. ARDS symptoms can vary in intensity depending on its cause and severity. The severe shortness of breath that characterizes ARDS usually develops within hours to days after COVID-19 infection. Many people who develop ARDS do not survive, and the risk of death increases with age and the severity of the disease. Some patients who survive ARDS recover fully, while others have long-term damage to their lungs.

[0042] "Acyl" refers to the group -C(O)R, where R is H, aliphatic, heteroaliphatic, heterocyclic, or aromatic. Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C 1 ~C 6 Alkyl, -C(O)C 1 ~C 6 haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl or -C(O)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et or -C(O)cyclopropyl.

[0043] "Aliphatic" refers to a group or moiety that is substantially hydrocarbon-based. An aliphatic group or moiety can be in its acyclic form, including alkyl, alkenyl, or alkynyl groups, its cyclic form (such as alicyclic groups or moieties, including cycloalkyl, cycloalkenyl, or cycloalkynyl), and further includes linear and branched configurations, and all stereo and positional isomers. Unless expressly stated otherwise, an aliphatic group contains from 1 to 25 carbon atoms (C 1~25 For example, in the case of a saturated acyclic aliphatic group or moiety, 1 to 15 (C 1~15 ), 1~10 pieces (C 1~10 ), 1~6 pieces (C 1~6 ), or 1 to 4 carbon atoms (C 1~4 ), 2 to 25 carbon atoms (C 2~25For example, in the case of an unsaturated acyclic aliphatic group or moiety, 2 to 15 (C 2~15 ), 2~10 pieces (C 2~10 ), 2~6 pieces (C 2~6 ), or 2 to 4 carbon atoms (C 2~4 ), or in the case of an alicyclic group or moiety, 3 to 15 (C 3~15 ), 3~10 pieces (C 3~10 ), 3~6 pieces (C 3~6 ), or 3 to 4 (C 3~4 ) carbon atoms. An aliphatic group may be substituted or unsubstituted, unless expressly designated as "unsubstituted aliphatic" or "substituted aliphatic." An aliphatic group may be substituted with one or more substituents (up to two substituents for each methylene carbon in the aliphatic chain, or up to one substituent for each carbon of a -C=C- double bond in the aliphatic chain, or up to one substituent for the carbon of a terminal methine group).

[0044] "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group. In certain instances, R is 1~6 Alkyl group or C 3~6 An exemplary alkoxy group is methoxy (-OCH 3 ) and ethoxy (-OCH 2 CH 3 In the substituted alkoxy, R is a substituted alkyl or a substituted cycloalkyl, examples of which include -OCF 2 H or -OCF 3 and the like haloalkoxy groups.

[0045] "Alkyl" is a group consisting of 1 to 25 (C 1~25 ) or more carbon atoms, more typically 1 to 10 (C 1~10 ) carbon atoms, e.g., 1 to 8 (C 1~8 ) carbon atoms, 1 to 6 (C 1~6 ) carbon atom or 1 to 4 (C 1~4(CH ) carbon atoms. The alkyl portion can be substituted or unsubstituted. This term refers to, for example, straight chain and branched hydrocarbyl groups, such as methyl (CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n-Butyl (-CH 2 CH 2 CH 2 CH 3 ), isobutyl (-CH 2 CH 2 (CH 3 ) 2 ), sec-Butyl (-CH(CH 3 )(CH 2 CH 3 ), t-Butyl (-C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ) and neopentyl (-CH 2 C(CH 3 ) 3 As used herein, "lower alkyl" includes (C 1 ~C 8 ) alkyl.

[0046] "Amino" is -NH 2 , -NHR or -NRR groups, where each R is independently selected from aliphatic, heteroaliphatic, aromatic (including both aryl and heteroaryl), or heterocycloaliphatic, or two R groups taken together with the nitrogen to which they are attached form a heterocycle. An example of such a heterocycle is one in which two R groups taken together with the nitrogen to which they are attached form: TIFF0007682155000025.tif9128 groups (in the formula, R g is R 70 , -C(O)R 70, -C(O)OR 60 or -C(O)N(R 80 ) 2 -O- or -N(R g ) may be interrupted by one or two additional heteroatom groups such as -(CH 2 ) 2~5 Examples include those that form a ring.

[0047] "Amido" or "carboxamide" refers to an -N(R) acyl group or an -C(O) amino group, where R is hydrogen, heteroaliphatic, aromatic or aliphatic, such as alkyl, especially C 1~6 It is an alkyl.

[0048] "Aromatic" refers to a conjugated cyclic group or moiety, unless otherwise specified, having 5-15 ring atoms, either a single ring (e.g., phenyl, pyridinyl, or pyrazolyl) or multiple fused rings in which at least one ring is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl), i.e., at least one ring, optionally multiple fused rings, has a contiguous delocalized π-electron system. The number of out-of-plane π-electrons usually follows Hückel's rule (4n+2). The point of attachment to the parent structure is usually through an aromatic portion of the fused ring system. Examples are shown below. However, in certain instances, context, or explicit disclosure, the point of attachment may be suggested to be via a non-aromatic portion of the fused ring system. TIFF0007682155000027.tif14128 An aromatic group or moiety may contain only carbon atoms in the ring, such as, for example, an aryl group or moiety, or it may contain one or more ring carbon atoms and one or more ring heteroatoms (e.g., S, O, N, P, or Si) having an unshared electron pair, such as, for example, a heteroaryl group or moiety. Unless otherwise specified, an aromatic group may be substituted or unsubstituted.

[0049] "Aryl" refers to an aromatic carbocyclic group having 6 to 15 carbon atoms, unless otherwise specified, having a single ring (e.g., phenyl) or having multiple fused rings in which at least one ring is aromatic, multiple fused rings in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinone, benzodioxole, etc.), provided that the point of attachment is through the aromatic portion of the ring system. If any portion of the aromatic ring contains a heteroatom, the group is a heteroaryl and not an aryl. Aryl groups can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, aryl groups can be substituted or unsubstituted.

[0050] "Araliphatic" refers to an aryl group that is attached to its parent through an aliphatic moiety. Araliphatic groups include aralkyl or arylalkyl groups, such as benzyl and phenylethyl.

[0051] "Carboxyl" or "carboxylic acid" is -CO 2 Point to H, "Carboxylate" is -C(O)O - Or its salt.

[0052] "Carboxyl ester" or "carboxylate ester" refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, alicyclic, heterocyclic, and aromatic (including both aryl and heteroaryl).

[0053] A "combination" refers to two or more components administered such that the effective period of at least one component overlaps with the effective period of at least one other component. The combination, or its components, may be a composition. In some embodiments, the effective periods of all administered components overlap with each other. In an exemplary embodiment of a combination comprising three components, the effective period of the first component administered may overlap with the effective period of the second and third components, but the effective periods of the second and third components may independently overlap or not overlap with each other. In another exemplary embodiment of a combination comprising three components, the effective period of the first component administered overlaps with the effective period of the second component, but does not overlap with the effective period of the third component; the effective period of the second component overlaps with the effective period of the first and third components. The combination may be a composition comprising the components, a composition comprising one or more components and another separate component (or components), or a composition comprising the remaining components, or the combination may be two or more individual components. In some embodiments, the two or more components can include the same component administered at two or more different times, two or more different components administered substantially simultaneously or sequentially in any order, or a combination thereof.

[0054] The term "COVID-19" refers to the coronavirus COVID-19 (previously known as 2019-nCoV) first identified in Wuhan, China. The term "COVID-19-associated ARDS" refers to ARDS caused by COVID-19 infection. Patients with COVID-19-associated ARDS may have been diagnosed with COVID-19 infection, may have been in contact with another person with COVID-19 infection, or may be suspected of having COVID-19 infection based on their symptoms.

[0055] "Cyano" refers to the radical -CN.

[0056] "Alicyclic" refers to a cyclic aliphatic group having a single ring (e.g., cyclohexyl) or multiple rings, such as fused, bridged, or spiro ring systems, at least one of which is aliphatic. Usually, the point of attachment to the parent structure is through the aliphatic portion of the multiple ring system. Alicyclic encompasses saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. An alicyclic group can contain 3 to 25 carbon atoms; e.g., 3 to 15, 3 to 10, or 3 to 6 carbon atoms. Unless otherwise specified, an alicyclic group can be substituted or unsubstituted. Exemplary alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl. As used herein, lower cycloalkyl refers to any of the C 3~8 Refers to cycloalkyl.

[0057] "Halo", "halide" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0058] "Haloalkyl" refers to an alkyl moiety, as defined herein, that is substituted with one or more halogens. Exemplary haloalkyl moieties include -CH 2 F, -CHF 2 and -CF 3 Examples include:

[0059] "Heteroaliphatic" refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., an aliphatic compound or group containing at least two carbon atoms, in which at least one or more carbon atoms are replaced with an atom having at least one unshared pair of electrons, typically nitrogen, oxygen, phosphorus, silicon or sulfur. For example, a heteroalkyl moiety is a heteroaliphatic moiety, and the base aliphatic moiety is an alkyl as defined herein. A heteroaliphatic compound or group can be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic, for example a heteroalicyclic group.

[0060] "Heteroaryl" refers to an aromatic group or moiety having 5-15 ring atoms, unless otherwise specified, and having at least one carbon atom and at least one heteroatom, such as N, S, O, P, Si. A heteroaryl group or moiety can contain a single ring (e.g., pyridinyl, pyrimidinyl, or pyrazolyl) or multiple condensed rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). A heteroaryl group or moiety can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, a heteroaryl group or moiety can be substituted or unsubstituted.

[0061] "Heterocyclyl", "heterocyclo" and "heterocycle" refer to both aromatic and non-aromatic ring systems, and more specifically to stable 3- to 15-membered ring moieties containing at least one carbon atom, typically multiple carbon atoms, and at least one, e.g., 1-5, heteroatoms. The heteroatom may be a nitrogen, phosphorus, oxygen, silicon or sulfur atom. A heterocyclyl moiety may be a monocyclic moiety or may contain multiple rings, such as a bicyclic or tricyclic ring system, e.g., where at least one ring contains a heteroatom. Polycyclic moieties of this type may include spiro ring systems, in addition to fused or bridged ring systems; any of the nitrogen, phosphorus, carbon, silicon or sulfur atoms of the heterocyclyl moiety may be oxidized or may be in various oxidation states. For convenience, nitrogens, particularly (but not limited to) those defined as nitrogens in aromatic rings, are meant to include their corresponding N-oxide forms, even though specific examples do not explicitly define such. Thus, for example, in the case of a compound having a pyridinyl ring, the corresponding pyridinyl-N-oxide is included as another compound of the invention, unless expressly excluded or excluded by context. In addition, the nitrogen atom in the ring may be quaternized. Heterocycles include heteroaryl moieties (wherein the heterocyclyl moiety is aromatic), which are partially or fully saturated heterocyclyl rings, and heteroalicyclic moieties, such as heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl.Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, and quinoxalinyl. , quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl , pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieryl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphosphoranyl and oxadiazolyl.

[0062] "Hydroxyl" refers to the -OH group.

[0063] "Nitro" is -NO 2 Refers to the base.

[0064] "Oxo" refers to the group =O (double bonded oxygen).

[0065] "Phosphate" is -OP(O)(OR')2 In the present specification, the term refers to the group, where each -OR' is independently -OH; -O-aliphatic, e.g., -O-alkyl or -O-cycloalkyl; -O-aromatic (including both -O-aryl and -O-heteroaryl); -O-aralkyl; or -OR' is -O - M + And M + is a counter ion having a single positive charge. + is an alkali ion, e.g., K + , Na + , Li + ammonium ion, e.g. + N(R”) 4 (wherein each R″ is independently H, aliphatic, heterocyclyl, or aryl); or an alkaline earth metal ion, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 Or [Ba 2+ ] 0.5 Phosphonooxyalkyl can be an -alkyl-phosphate group, e.g., -CH 2 OP(O)(OH) 2 or a salt thereof (e.g., -CH 2 OP(O)(O - Na + ) 2 ), and (((dialkoxyphosphoryl)oxy)alkyl) refers to the dialkyl ester of a phosphonooxyalkyl group (e.g., -CH 2 OP(O)(O-tert-butyl) 2 etc.).

[0066] "Phosphonate" refers to -P(O)(OR') 2 In the present specification, the term refers to the group, where each -OR' is independently -OH; -O-aliphatic, e.g., -O-alkyl or -O-cycloalkyl; -O-aromatic, (including both -O-aryl and -O-heteroaryl); or -O-aralkyl; or -OR' is -O - M + And M + is a counter ion having a single positive charge. +is a positively charged counter ion, for example an alkali metal ion, e.g., K + , Na + , Li + ammonium ion, e.g. + N(R”) 4 where each R″ is independently H, aliphatic, heterocyclyl, or aryl; or an alkaline earth metal ion, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 Or [Ba 2+ ] 0.5 A phosphonoalkyl can be an -alkyl-phosphonate group, such as -CH 2 P(O)(OH) 2 or -CH 2 P(O)(O - Na + ) 2 etc., ((dialkoxyphosphoryl)alkyl) refers to the dialkyl ester of a phosphonoalkyl group, e.g., -CH 2 P(O)(O-tert-butyl) 2 etc.

[0067] "Phosphoramidate" refers to a -OP(O)(OR')(N(R') 2 ) group, where each R' is independently H, aliphatic, e.g., alkyl, aryl, or aralkyl, or -OR' is -O - M + And M + is a counterion with one positive charge. + is an alkali ion, e.g., K + , Na + , Li + ammonium ions, e.g. + N(R”) 4 (wherein each R″ is independently H, aliphatic, e.g., alkyl, hydroxyalkyl, or combinations thereof, heterocyclyl, or aryl); or an alkaline earth metal ion, e.g., [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+] 0.5 The alkyl phosphoramidate can be an -alkyl phosphoramidate group, e.g., -CH 2 OP(O)(OR')(N(R' 2 )) or -CH 2 (CH 3 )OP(O)(OR')(N(R' 2 )), e.g., -CH 2 OP(O)(O-phenyl)[NHC(CH 3 )CO 2 isopropyl], or -CH 2 OP(O)(OH)(N(H)alkyl), or a salt thereof, such as -CH 2 OP(O)(O - Na + )(N(H)alkyl).

[0068] "Patient" or "subject" refers to mammals and other animals, particularly humans. Thus, the disclosed methods are applicable to both human therapy and veterinary applications.

[0069] "Pharmaceutically acceptable excipient" refers to a substance other than the active ingredient contained in a formulation containing the active ingredient. As used herein, an excipient may be incorporated within or physically mixed with the particles of the pharmaceutical composition. An excipient may be used, for example, to dilute the active agent and / or to modify the properties of the pharmaceutical composition. The excipient may include, but is not limited to, an anti-adherent, a binder, a coating, an enteric coating, a disintegrant, a flavoring agent, a sweetener, a coloring agent, a lubricant, a glidant, a sorbent, a preservative, an adjuvant, a carrier, or a solvent. The excipient may be starch and modified starch, cellulose and cellulose derivatives, sugars and their derivatives, such as disaccharides, polysaccharides, and sugar alcohols, proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids, or preservatives. Exemplary additives include, but are not limited to, magnesium stearate, stearic acid, vegetable stearic acid, sucrose, lactose, starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as Vitamin E TPGS or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or wool fat.

[0070] An "adjuvant" is an excipient that modifies the effect of another agent, typically an active ingredient. Adjuvants are often agents that have a pharmacological and / or immunological effect. Adjuvants can modify the effect of an active ingredient by increasing the immune response. Adjuvants can also act as stabilizers for the formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, surfactants, cytokines, paraffin oil, and combinations of adjuvants, such as complete or incomplete Freund's adjuvant.

[0071] The term "pharmaceutically acceptable carrier" refers to an additive that is a carrier or a solvent, such as a suspending aid, a dissolving aid, or an aerosolizing aid. Pharmaceutically acceptable carriers are conventional. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, &Wilkins, Philadelphia, PA, 21 st Edition (2005) describes compositions and formulations suitable for the pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0072] Generally, the nature of the carrier will depend on the particular mode of administration to be used. For example, parenteral formulations usually contain medicamentously and physiologically acceptable fluids, such as injectable fluids, such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol, or solvents. In some cases, the pharmaceutically acceptable carriers can be sterilized so that they are suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, and the like, such as sodium acetate or sorbitan monolaurate.

[0073] "Pharmaceutically acceptable salts", as known to those skilled in the art, refer to pharmaceutically acceptable salts of compounds derived from various organic and inorganic counterions. For the purpose of illustration only, they include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc. When the molecule contains a basic functional group, it also includes salts of organic or inorganic acids, such as hydrochloride, bromate, tartrate, mesylate, acetate, maleate, oxalate, etc. "Pharmaceutically acceptable acid addition salts" are part of "pharmaceutically acceptable salts", which are formed by the corresponding acid and maintain the biological effectiveness of the free base. In particular, the disclosed compounds, although not limited thereto, in addition to inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., also include formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, salicylic acid, xinafoic acid, lactic acid, palmitic acid, alkylsulfonic acids (such as methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (such as benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc., and form salts with various pharmaceutically acceptable acids. Pharmaceutically acceptable salts also include salts formed when the acidic proton present in the parent compound is replaced by a metal ion (such as an alkali metal ion, alkaline earth metal ion or aluminum ion) or coordinates with an organic base (such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, ammonia, etc.).

[0074] "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" and are derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine (see, e.g., SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference).

[0075] An "effective amount", such as a therapeutically effective amount, refers to an amount of a compound sufficient to achieve a desired result, for example, to treat a specified disorder or disease, or to reduce or eradicate one or more of its symptoms and / or prevent the occurrence of a disease or disorder. The amount of a compound that constitutes an "effective amount" may vary depending on the compound, the state of the disease and its severity, the age of the patient to be treated, and the like. An effective amount can be determined by one of ordinary skill in the art. An appropriate "effective" amount in any individual case can be determined using any suitable technique, such as a dose escalation study.

[0076] "Prodrug" refers to a compound that is converted in vivo to a biologically active compound, particularly the parent compound, which may occur, for example, by intestinal hydrolysis or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of compounds in which the activated form bears a carboxylic acid moiety. Examples of pharma- ceutically acceptable esters suitable for use with the disclosed compounds include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (e.g., C 1~6 Other prodrug moieties include phosphate esters, e.g., -CH 2 -OP(O)(OR') 2 or a salt thereof (wherein R' is H or C 1~6Further acceptable esters include cycloalkyl esters and arylalkyl esters, such as, but not limited to, benzyl. Examples of pharma- ceutically acceptable amides of the disclosed compounds include, but are not limited to, primary amides and secondary and tertiary alkyl amides (e.g., having from about 1 to about 6 carbon atoms). Amides and esters of the disclosed compounds can be prepared according to conventional methods. A thorough discussion of prodrugs is given in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems”, Vol 14 of the ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0077] "Protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed as needed during the course of a synthesis. Examples of protecting groups are described in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rdEd., 1999, John Wiley & Sons, NY, and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups), and allyl ethers.

[0078] "Spray-dried dispersion" refers to a single-phase dispersion of one or more compounds in a polymer matrix. Typically, the one or more compounds are amorphous.

[0079] "Solvate" refers to a complex formed when a solvent molecule combines with a molecule or ion of a solute. The solvent may be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, ethyl acetate, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. The compounds described herein may exist in unsolvated as well as solvated forms when combined with pharma- ceutically acceptable or unacceptable solvents, such as water, ethanol, etc. Solvated and unsolvated forms of the compounds of the present disclosure are encompassed within the scope of the embodiments disclosed herein.

[0080] "Subject" refers to human and non-human subjects.

[0081] "Sulfanyl" refers to the groups or -SH, -S-aliphatic, -S-heteroaliphatic, -S-cyclic, -S-heterocyclyl (including -S-aryl and -S-heteroaryl).

[0082] "Sulfinyl" refers to the group or moiety -S(O)H, -S(O)aliphatic, -S(O)heteroaliphatic, -S(O)cyclic, -S(O)heterocyclyl (including -S(O)aryl and -S(O)heteroaryl).

[0083] "Sulfonyl" refers to the group: -SO 2 H, -SO 2 Aliphatic, -SO 2 Heteroaliphatic, -SO 2 Cyclic, -SO 2 Heterocyclyl (-SO 2 Aryl and -SO 2 (including heteroaryl).

[0084] "Sulfonamide" refers to the group or moiety -SO 2 Amino or -N(R c ) sulfonyl, where R c is H, aliphatic, heteroaliphatic, cyclic, and heterocyclic (including aryl and heteroaryl).

[0085] As used herein, "treat" or "treatment" refers to the treatment of CRS in a patient or subject, particularly a human suffering from CRS, including, by way of example and not limitation: (i) inhibiting CRS, e.g., stopping or slowing its progression; (ii) alleviating CRS, e.g., causing regression of CRS or its symptoms; or (iii) stabilizing CRS by preventing it from increasing in grade and / or severity; Examples include:

[0086] For example, in the case of COVID-19-associated cytokine increases resulting in ARDS, successful treatment may include reduced shortness of breath, reduced difficulty or pressure to breathe, higher blood pressure, reduced confusion, and / or reduced fatigue. Treatment may be administered prophylactically, i.e., prior to the onset of ARDS. Prophylactic treatment prevents ARDS and may be administered to patients who have or are suspected of having a COVID-19 infection but do not have severe symptoms of ARDS. For example, prophylactic treatment may be administered to patients who have a cough without other symptoms of ARDS.

[0087] "Prevention" as used herein relates to reducing cytokine levels or their inflammatory effects in order to prevent CRS from occurring in a patient or subject, particularly if such a patient or subject is at risk of developing CRS but has not yet been diagnosed as having it.

[0088] As used herein, the terms "disease" and "condition" may be used interchangeably, but may differ in that a particular disorder or condition may not have a known causative agent (and thus has yet to be determined its etiology) and is therefore merely an undesirable condition or syndrome not yet recognized as a disease, although a more or less specific set of symptoms has been identified by clinicians.

[0089] The definitions given above and the general formulae set forth below are not intended to encompass impermissible substitution patterns (e.g., methyl substituted with five fluoro groups) that would be readily recognized by one of ordinary skill in the art.

[0090] Any of the groups set forth herein may be optionally substituted with at least one, and optionally more than one, substituent as described herein, i.e., a substituted group has at least one, and optionally more than one, replaceable hydrogen atom(s) with one or more substituents as defined herein, unless the context indicates otherwise or the specific structural formula excludes substitution.

[0091] Those skilled in the art will understand that compounds may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may contain one or more asymmetric centers and / or double bonds, and may therefore exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. Thus, the compounds and compositions may be provided as individual pure enantiomers or diastereomers, or as stereoisomeric mixtures, including racemic mixtures. In certain embodiments, the compounds disclosed herein are synthesized or purified to be in substantially enantiopure form, e.g., in substantially enantiopure form, e.g., with 85% enantiomeric excess (ee), 90% enantiomeric excess, 95% enantiomeric excess, 97% enantiomeric excess, 98% enantiomeric excess, 99% enantiomeric excess, or greater than 99% enantiomeric excess. One of skill in the art will understand that compounds containing one or more asymmetric centers, one or both enantiomers or diastereomers are contemplated, unless a specific enantiomer or diastereomer is shown or described.

[0092] As another example, certain disclosed compounds can exist in several tautomeric forms, such as enol forms, keto forms, and mixtures thereof. Although the various compound names, formulas, and compound drawings in this specification and claims may represent only one of the possible tautomeric, conformational, optical, or geometric isomers, those skilled in the art will understand that the disclosed compounds also encompass any tautomeric, conformational, optical, and / or geometric isomers of the compounds described herein, as well as mixtures of these various different isomers. For example, when rotation around an amide bond or between two directly bonded rings of a pyrazolyl or pyridinyl ring is restricted, atropisomers are also possible and are specifically included in the compounds of the present invention as well.

[0093] In any embodiment, any hydrogen present in the compound or in a particular group or portion of the compound may be replaced with deuterium or tritium. Thus, when alkyl is referred to, deuterated alkyl is also included, where one to the maximum number of hydrogens present may be replaced with deuterium. For example, ethyl is C 2 H 5 or C with 1 to 5 hydrogens replaced by deuterium 2 H 5 , for example C 2 D x H 5-x It could be.

[0094] II. Compounds Disclosed herein are compounds, prodrugs, corresponding salts and / or solvate forms, and methods of using these compounds, prodrugs, and salt / solvate forms to treat and / or prevent CRS. The compounds can be compounds that modulate the Janus kinase (JAK) and / or interleukin receptor associated kinase (IRAK) pathways, and / or kinase inhibitors, including but not limited to JAK inhibitors, e.g., JAK1, JAK2, JAK3 and / or JAK4 inhibitors; and / or IRAK inhibitors, e.g., IRAK1, IRAK2, IRAK3 and / or IRAK4 inhibitors. The compounds can be pyrimidinediamine compounds, e.g., compounds represented by formula I or formula III, or pyrazole compounds, e.g., compounds represented by formula IV.

[0095] A. Pyrimidinediamine Compounds Represented by Formula I In some embodiments, the compound is a pyrimidinediamine compound represented by formula I TIFF0007682155000028.tif26128 or a salt, solvate, prodrug and / or N-oxide thereof. With reference to Formula I: X and Y are each independently O, S, S(O), SO 2 or NR 1 and; Each R 1 are independently expressed as H, C 1~6Alkyl, C(O)-C 1~6 Alkyl, CO 2 -C 1~6 Alkyl or R 50 and; Each R 50 is C(R 9 ) 2 -OR 10 or C(R 9 ) 2 -SR 10 and; Each R 9 are independently expressed as H, C 1~6 Alkyl, C 6~10 Aryl or C 7~16 arylalkyl; or alternatively, two R 9 along with the carbon to which they are attached, C 3~8 R forms a cycloalkyl group or a 3- to 8-membered heteroalicyclic group; 10 is R a Or-P(O)(OR 11 ) 2 and each R 11 independently for each occurrence, R a or a monovalent cationic group; or two R 11 form, together with the atoms to which they are attached, a 4- to 8-membered cyclic phosphate group, or two R 11 taken together represent a divalent cationic group; Ring A is C 6~10 aryl or 5-10 membered heteroaryl; Each R 2 are independently determined for each occurrence by H, R e , R b , the same or different R a and / or R b R replaced by one or more of e , the same or different R a and / or R b -OR replaced by one or more of e , the same or different R a and / or R b -SR substituted with one or more of e , the same or different R a and / or R b-C(O)R substituted with one or more of e , -N(R a )R e (where R e are the same or different R a and / or R b substituted with one or more of the same or different R a and / or R b -S(O) substituted with one or more of 2 R e , -B(OR a ) 2 , -B(N(R c ) 2 ) 2 , -(C(R a ) 2 ) m -R b , -O-(C(R a ) 2 ) m -R b , -S-(C(R a ) 2 ) m -R b , -O-(C(R b ) 2 ) m -R a , -N(R a )-(C(R a ) 2 ) m -R b , -O-(CH 2 ) m -CH((CH 2 ) m R b )R b , -C(O)N(R a )-(C(R a ) 2 ) m -R b , -O-(C(R a ) 2 ) m -C(O)N(R a )-(C(R a ) 2 ) m -R b , -N((C(R a ) 2 ) mR b ) 2 , -S-(C(R a ) 2 ) m -C(O)N(R a )-(C(R a ) 2 ) m -R b , -N(R a )-C(O)-N(R a )-(C(R a ) 2 ) m -R b , -N(R a )-C(O)-(C(R a ) 2 ) m -C(R a )(R b ) 2 Or -N(R a )-(C(R a ) 2 ) m -C(O)-N(R a )-(C(R a ) 2 ) m -R b and; Each R a are independently H, deuterium, and C 1~6 Alkyl, C 3~8 Cycloalkyl, C 4~11 Cycloalkylalkyl, C 6~10 Aryl, C 7~16 arylalkyl, 2- to 6-membered heteroalkyl, 3- to 10-membered heteroalicyclic, 4- to 11-membered heteroalicyclic alkyl, 5- to 15-membered heteroaryl, or 6- to 16-membered heteroarylalkyl; Each R b are independently, =O, -OR in each occurrence. a , -O-(C(R a ) 2 ) m -OR a , HaroC 1~3 Alkyloxy, =S, -SR a , =NR a , =NOR a , -N(R c ) 2, halo, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R a , -S(O) 2 R a , -SO 3 R a , -S(O)N(R c ) 2 , -OS(O)R a , -OS(O) 2 R a , -OSO 3 R a , -OS(O) 2 N(R c ) 2 , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -C(NR a )-N(R c ) 2 , -C(NOH)-R a , -C(NOH)-N(R c ) 2 , -OC(O)R a , -OC(O)OR a , -OC(O)N(R c ) 2 , -OC(NH)-N(R c ) 2 , -OC(NR a )-N(R c ) 2 , -[N(R a )C(O)] n R a , -[N(R a )C(O)] n OR a , -[N(R a )C(O)] n N(R c ) 2 or -[N(R a )C(NR a )] n , -N(R c ) 2 ; each Rc independently for each occurrence, R a or alternatively, two R c may, together with the nitrogen atom to which they are attached, contain one or more of the same or different additional heteroatoms and may be the same or different R a and / or R d forming a 3- to 10-membered heteroalicyclic or 5- to 10-membered heteroaryl, optionally substituted with one or more groups; Each R d =O, -OR a , HaroC 1~3 Alkyloxy, C 1~6 Alkyl, =S, -SR a , =NR a , =NOR a , -N(R a ) 2 , Halo, -CF 3 , -CN, -NC, -OCN, -SCN, -NO, -NO 2 , =N 2 , -N 3 , -S(O)R a , -S(O 2 )R a , -SO 3 R a , -S(O)N(R a ) 2 , -S(O) 2 N(R a ) 2 , -OS(O)R a , -OS(O) 2 R a , -OSO 3 R a , -OS(O) 2 N(R a ) 2 , -C(O)R a , -CO 2 R a , -C(O)N(R a ) 2 , -C(NR a )N(R a ) 2 , -C(NOH)R a , -C(NOH)N(R a ) 2 , -OCO2 R a , -OC(O)N(R a ) 2 , -OC(NR a )N(R a ) 2 , -[N(R a )C(O)] n R a , -(C(R a ) 2 ) n -OR a , -N(R a )-S(O) 2 R a , -C(O)-C 1~6 Haloalkyl, -S(O) 2 C 1~6 Haloalkyl, -OC(O)R a , -O(C(R a ) 2 ) m -OR a , -S(C(R a ) 2 ) m -OR a , -N(R a ) C 1~6 Haloalkyl, -P(O)(OR a ) 2 , -N(R a )-(C(R a ) 2 ) m -OR a , -[N(R a )C(O)] n OR a , -[N(R a )C(O)] n N(R a ) 2 , -[N(R a )C(NR a )] n N(R a ) 2 Or -N(R a )C(O)C 1~6 haloalkyl; or two R d may, in combination with the atom or atoms to which they are attached, contain one or more heteroatoms and one or more R aforming a 3-10 membered partially or fully saturated monocyclic or bicyclic ring, optionally substituted with Each R e independently for each occurrence, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 4~11 Cycloalkylalkyl, C 6~10 Aryl, C 7~16 arylalkyl, 2-6 membered heteroalkyl, 3-10 membered heteroalicyclic, 4-11 membered heteroalicyclic alkyl, 5-15 membered heteroaryl, or 6-16 membered heteroarylalkyl; p is 0, 1, 2, 3 or 4; each m is 1, 2, or 3; each n is 0, 1, 2, or 3; or 2 R 2 The groups, together with the atom or atoms to which they are attached, may in combination contain one or more heteroatoms and one or more R a and / or R b forming a 4-10 membered partially or fully saturated monocyclic or bicyclic ring, optionally substituted with Z 1 and Z 2 are independently CH, CR 2 or N; R 3 , H, C 1~6 Alkyl or R 50 and; R 4 , H, C 1~6 Alkyl or R 50 and; R 5 , halo, -CN, C 1~6 Alkyl, alkynyl, hydroxy, C 1~6 Alkoxy, nitro, -N(R a ) 2 , -C(O)N(R a ) 2 , -CO 2 R a Or -C(O)R a It is.

[0096] The compound of formula I can be represented by formula IA: For formula IA, the variables are as defined for formula I, and R 2a , R 2b , R 2c and R 2d Each of, independently at each occurrence, R 2 In some embodiments, X and Y are each independently O or NR 1 and each R 1 , H, C 1~6 Alkyl or R 50 ;R 5 , halo, -CN, C 1~6 Alkyl, nitro, -N(R a ) 2 , -C(O)N(R a ) 2 , -CO 2 R a Or -C(O)R a In certain embodiments, one of X and Y is O and the other is NR 1 It is.

[0097] In some embodiments of formula IA, the compound has formula IA1 or IA2. Also in some embodiments of formula IA, IA1 or IA2, R 2d is H;R 5 is halo or C 1~6 Alkyl; Z 1 is CH, C-halo or CC 1~6 Alkyl; Z 2 is CH.

[0098] Another embodiment is a compound of formula IA1 or IA2, where R 5 is F or CH 3 In a more particular embodiment, R 2a , R 2b and R 2c Each of the following may be independently determined at each occurrence: C 1~6Alkyl, -OR a , -OCF 3 , -SR a , -N(R c ) 2 , Halo, -OCF 2 H, -OCH 2 F, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -(C(R a ) 2 ) m -R b , -N(R a )-S(O) 2 R a Or -[N(R a )C(O)] n R a In another more particular embodiment, R 2a , R 2b and R 2c are each independently 1~6 Alkyl, -OR a , -OCF 3 , Halo, -CF 3 or -CN. In one embodiment, R 2a CH 3 ;R 2b is halo;R 2c CH 3 In another embodiment, R 2a CH 3 ;R 2b CH 3 ;R 2c is halo. In another embodiment, R 2a CH 3 ;R 2b CH 3 ;R 2c CH 3 In a more particular embodiment, R 2a CH 3;R 2b CH 3 and R 2c CH 3 and R 5 CH 3 It is.

[0099] Another embodiment is a compound of formula IA1, where R 5 CH 3 and R 2a , R 2b and R 2c Each of the following may be independently determined at each occurrence: C 1~6 Alkyl, haloC 1~6 Alkyl, -OR a , -OCF 3 , -SR a , -N(R c ) 2 , Halo, -OCF 2 H, -OCH 2 F, -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -(C(R a ) 2 ) m -R b , -N(R a )-S(O) 2 R a又は -[N(R a )C(O)] n R a In another more particular embodiment, R 2a , R 2b and R 2c are each independently 1~6 Alkyl, -OR a , -OCF 3 , Halo, -CF 3 or -CN. In one embodiment, R 2a CH 3 ;R 2b is halo;R2c is CH 3 In another embodiment, R 2a is CH 3 ; R 2b is CH 3 ; R 2c is halo. In another embodiment, R 2a , R 2b and R 2c each, at each occurrence independently, is C 1~6 alkyl or halo C 1~6 alkyl. In another embodiment, R 2a , R 2b and R 2c each, at each occurrence independently, is C 1~6 alkyl. In a more specific embodiment, R 2a is CH 3 ; R 2b is CH 3 , and R 2c is CH 3 .

[0100] Another embodiment is a compound of structural formula IA1 or IA2, where R 2b is H; R 5 is F or CH 3 . In a more specific embodiment, R 2a and R 2c each, at each occurrence independently, is H, C 1~6 alkyl, -OR a , -OCF 3 , -SR a , -N(R c ), 2 halo, -OCF 2 H, -OCH 2 F, -CF 3 , -CN, -S(O) 2 N(R c ), 2 -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ), 2 , -N(Ra )-S(O) 2 R a , -C(R a ) 2 -N(R c ) 2 Or -[N(R a )C(O)] n R a ;R 2a and R 2c is not H. In another embodiment, one of R 2a and R 2c Each of the following may be independently selected at each occurrence: H, C 1~6 Alkyl, -OR a , -OCF 3 , Halo, -CF 3 , -C(R a ) 2 -N(R c ) 2 or -CN. In another embodiment, R 2a -CF 3 or -CH 3 ;R 2c is halo or -CH 3 In another embodiment, R 2a -H, -CH 3 , -CF 3 , -OR a Or -OCF 3 ;R 2c is -C(R a ) 2 -N(R c ) 2 It is.

[0101] Another embodiment is a compound of formula IA1 or IA2, where R 2c is H;R 5 is F or CH 3 In one particular embodiment, R 2a and R 2b Each of these is H, C 1~6 Alkyl, -OR a , -OCF 2 H, -OCH 2 F, -OCF 3 , -SR a , -N(Rc ) 2 、 halo, -CF 3 、 -CN, -S(O) 2 N(R c ) 2 、 -S(O) 2 R a 、 -C(O)R a 、 -CO 2 R a 、 -C(O)N(R c ) 2 、 -N(R a )-S(O) 2 R a 、 -C(R a ) 2 -N(R c ) 2又は -[N(R a )C(O)] n R a ; R 2a and R 2b one of which is not H. In another embodiment, R 2a and R 2b each is H, C 1~6 alkyl, -OR a 、 -OCF 3 、 halo, -N(R c ) 2 、 -CF 3 、 -C(R a ) 2 -N(R c ) 2 or -CN. In another embodiment, R 2b is -CF 3 or -CH 3 ; R 2a is halo or -CH 3 . In another embodiment, R 2a is H, -CH 3 、 -CF 3 、 -OR a or -OCF 3 ; R 2b is -N(R c ) 2 or -C(R a ) 2 -N(R c ) 2 . In yet another embodiment, R2a is -N(R c ) 2 Or -C(R a ) 2 -N(R c ) 2 ;R 2b -H, -CH 3 , -CF 3 , -OR a Or -OCF 3 It is.

[0102] Yet another embodiment is a compound of formula IA1 or IA2, where R 2c and R 2d is H and R 5 is F or CH 3 ;R 2a and R 2b are, together with the carbons to which they are attached, fused to a phenyl ring, which may contain one or more heteroatoms and one or more R a and / or R b To further aid in describing such fused ring systems, examples of fused rings, ignoring the unit of unsaturation between the two phenyl ring atoms solely for the sake of brevity in nomenclature, are cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine, piperidine, dioxane, oxathiazinane, piperazine, cycloheptane, cycloheptene, azepane, tetrahydroazepine, diazepane, cyclooctane, cyclooctene, azocane, hexahydroazocine, diazocane or hexahydrodiazocine. That is, for example, R 2a and R 2b is described as "cyclohexane", the compound represented by formula IA1 is It would be TIFF0007682155000031.tif24128.

[0103] In one embodiment, the fused ring is a 5-membered ring, and in a more particular embodiment, the 5-membered ring isa and / or R b In a particular embodiment, the five-membered ring is pyrrolidine, and in an even more particular embodiment, the compound has the formula IA3: TIFF0007682155000032.tif21128, where R b OH, C 1~6 Alkyl, -CO 2 C 1~6 Alkyl, -C(O)C 1~6 Alkyl or -S(O) 2 C 1~6 In another embodiment, R 2a and R 2b may, together with the carbons to which they are attached, contain one or more heteroatoms and one or more R a and / or R b In one embodiment, when the ring is 6-membered, the ring is optionally substituted with one or more R a and / or R b In another embodiment, when the ring is seven-membered, the ring is optionally substituted with one or more R a and / or R b In yet another embodiment, the ring is cycloheptane, cycloheptene, azepane, tetrahydroazepine or diazepane, optionally substituted with one or more R a and / or R b R is cyclooctane, cyclooctene, azocane, hexahydroazocine, diazocane, or hexahydrodiazocine, optionally substituted with R 2a and R 2bFor each of the above embodiments, there are more specific embodiments in which R is present 0, 1, 2 or 3, together with the carbons to which they are attached, to form a 5-, 6-, 7- or 8-membered partially or fully saturated monocyclic ring; a and R b , and R a Each of the C 1~6 alkyl; each R b are independently, =O, -OR in each occurrence. a , HaroC 1~3 Alkyloxy, -SR a , -N(R c ) 2 , Halo, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -N(R a )-S(O) 2 R a Or -C(R a ) 2 -N(R c ) 2 For example, in one embodiment, at least one R b i.e., =O; and optionally substituted C 1~6 R is alkyl a There is.

[0104] Alternatively, the compound may be represented by formula IB: Q: Regarding TIFF0007682155000033.tif24128 IB 1 and Q 2 are each independently N or CH, with the proviso that Q 1 and Q 2 In some embodiments, at least one of X and Y is N. In some embodiments, X and Y are each independently O or NR 1 and each R 1 are independently expressed as H, C1~6 Alkyl or R 50 p is 0, 1, 2 or 3; R 5 , halo, -CN, C 1~6 Alkyl, nitro, -N(R a ) 2 , -C(O)N(R a ) 2 , -CO 2 R a Or -C(O)R a It is.

[0105] In some embodiments of formula IB, the compound is represented by formula IB1, IB2, or IB3. TIFF0007682155000034.tif52128 For formulas IB1, IB2 and IB3, R 2a , R 2b , R 2c and R 2d Each of, when present, independently in each occurrence, R 2 As defined for

[0106] One embodiment is a compound of formula IB1 or IB2, where X and Y are each independently NR 1 In a more particular embodiment, X and Y are each independently NH or NC 1~6 In yet more particular embodiments, X and Y are each independently NH or NCH 3 In one embodiment, where X and Y are more specifically defined as described, R 5 is halo or C 1~6 Alkyl; Z 1 is CH, C-halo or CC 1~6 Alkyl; Z 2 is CH. In another embodiment, R 2a and R 2d is H;R 5 is F or CH 3 In another embodiment, R 2b and R 2c Each of the following may be independently selected at each occurrence: H, C 1~6Alkyl, -OR a , -OCH 2 F, -OCF 3 , -SR a , -N(R c ) 2 , Halo, -OCF 2 H, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -N(R a )-S(O) 2 R a , -C(R a ) 2 -N(R c ) 2又は -[N(R a )C(O)] n R a ;R 2b and R 2c is not H. In another such embodiment, one of R 2b and R 2c Each of the following may be independently selected at each occurrence: H, C 1~6 Alkyl, -N(R c ) 2 , Halo, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -C(R a ) 2 -N(R c ) 2又は -N(R a )-S(O) 2 R a In another embodiment, R 2b H, halo, -CF3 , -CN or -CH 3 ;R 2c is -N(R c ) 2 , -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)N(R c ) 2 Or -C(R a ) 2 -N(R c ) 2 It is.

[0107] Another embodiment is a compound of formula IB1 or IB2, where X is O and Y is NR 1 In one embodiment, R 5 is halo or C 1~6 Alkyl; Z 1 is CH, C-halo or CC 1~6 Alkyl; Z 2 is CH. In another embodiment, R 2a and R 2d is H;R 5 is F or CH 3 In a more particular embodiment, R 2b and R 2c Each of the following may be independently selected at each occurrence: H, C 1~6 Alkyl, -OR a , -OCF 3 , -SR a , -N(R c ) 2 , Halo, -OCF 2 H, -OCH 2 F, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -N(R a )-S(O)2 R a 、 -C(R a ) 2 -N(R c ) 2 or -[N(R a )C(O)] n R a wherein; R 2b and R 2c are such that one of them is not H. In another embodiment, each of R 2b and R 2c is independently, at each occurrence, H, C 1~6 alkyl, -N(R c ) 2 , halo, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -C(R a ) 2 -N(R c ) 2又は -N(R a )-S(O) 2 R a In a more specific embodiment, R 2b is H, halo, -CF 3 , -CN or -CH 3 ; R 2c is -N(R c ) 2 , -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)N(R c ) 2 or -C(R a ) 2 -N(R c ) 2 In another embodiment, R 2b is H, halo, -CF 3 , -CN or -CH 3 ; R2c is -N(R c ) 2 Or -C(R a ) 2 -N(R c ) 2 It is.

[0108] Another embodiment is a compound of formula IB1 or IB2, where X is O; Y is NR 1 ;Z 1 is CH, C-halo or CC 1~6 Alkyl; Z 2 is CH;R 2a and R 2d is H;R 5 is F or CH 3 and R 2b and R 2c may, together with the carbons to which they are attached, contain one or more heteroatoms and one or more R a and / or R b In one embodiment, the ring forms a 4-10 membered partially or fully saturated monocyclic or bicyclic ring, optionally substituted with one or more R a and / or R b In one embodiment, the 5-, 6-, 7- or 8-membered partially or fully saturated monocyclic ring is optionally substituted with one or more R a and / or R b R is cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine, piperidine, dioxane, oxathiazinane, piperazine, cycloheptane, cycloheptene, azepane, tetrahydroazepine, diazepane, cyclooctane, cyclooctene, azocane, hexahydroazocine, diazocane, or hexahydrodiazocine, optionally substituted with R 2b and R 2cand R are, taken together with the carbons to which they are attached, form a 5-, 6-, 7-, or 8-membered partially or fully saturated monocyclic ring. For each of the above embodiments, there are more specific embodiments in which there are 0, 1, 2, or 3 a and R b , and R a Each of the C 1~6 alkyl; each R b are independently, =O, -OR in each occurrence. a , HaroC 1~3 Alkyloxy, -SR a , -N(R c ) 2 , Halo, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -N(R a )-S(O) 2 R a Or -C(R a ) 2 -N(R c ) 2 For example, in one embodiment, at least one R b i.e. =O; and optionally, C 1~6 R is alkyl a In this embodiment, compounds such as IV-45, IV-46 and IV-47 are included.

[0109] One embodiment is a compound of formula IB3, where X is O and Y is NR 1 In one embodiment, R 5 is halo or C 1~6 Alkyl; Z 1 is CH, C-halo or CC 1~6 Alkyl; Z 2 is CH. In another embodiment, R 2a is H;R5 is F or CH 3 In a more specific embodiment, R 2b and R 2c each, at each occurrence independently, is H, C 1~6 alkyl, -OR a , -OCF 3 , -SR a , -N(R c ) 2 , halo, -OCF 2 H, -OCH 2 F, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -N(R a )-S(O) 2 R a , -C(R a ) 2 -N(R c ) 2 or -[N(R a )C(O)] n R a ; one of R 2b and R 2c is not H. In another embodiment, each of R 2b and R 2c is, at each occurrence independently, H, C 1~6 alkyl, -N(R c ) 2 , halo, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -C(R a ) 2 -N(R c )2又は -N(R a )-S(O) 2 R a In a more particular embodiment, R 2b H, halo, -CF 3 , -CN or -CH 3 ;R 2c is -N(R c ) 2 , -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)N(R c ) 2 Or -C(R a ) 2 -N(R c ) 2 In another embodiment, R 2b H, halo, -CF 3 , -CN or -CH 3 ;R 2c is -N(R c ) 2 Or -C(R a ) 2 -N(R c ) 2 It is.

[0110] Another embodiment is a compound of formula IB3, where X is O; Y is NR 1 ;Z 1 is CH, C-halo or CC 1~6 Alkyl; Z 2 is CH;R 2c and R 2d is H;R 5 is F or CH 3 and R 2b and R 2c may, together with the carbons to which they are attached, contain one or more heteroatoms and one or more R a and / or R b In one embodiment, the ring forms a 4-10 membered partially or fully saturated monocyclic or bicyclic ring, optionally substituted with one or more R a and / or Rb In one embodiment, the 5-, 6-, 7- or 8-membered partially or fully saturated monocyclic ring is optionally substituted with one or more R a and / or R b R is cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine, piperidine, dioxane, oxathiazinane, piperazine, cycloheptane, cycloheptene, azepane, tetrahydroazepine, diazepane, cyclooctane, cyclooctene, azocane, hexahydroazocine, diazocane, or hexahydrodiazocine, optionally substituted with R 2b and R 2c and R are, taken together with the carbons to which they are attached, form a 5-, 6-, 7-, or 8-membered partially or fully saturated monocyclic ring. For each of the above embodiments, there are more specific embodiments in which there are 0, 1, 2, or 3 a and R b , and R a Each of the C 1~6 alkyl; each R b are independently, =O, -OR in each occurrence. a , HaroC 1~3 Alkyloxy, -SR a , -N(R c ) 2 , Halo, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -N(R a )-S(O) 2 R a Or -C(R a ) 2 -N(R c ) 2 It is.

[0111] Another embodiment of the compound of structural formula I is a compound of formula II: TIFF0007682155000035.tif26128, wherein the variables are defined as in formula I, and further: 2 are combined to form ring B; ring B, together with the two phenyl ring atoms to which it is attached, is N(R c ), forming a 5-, 6- or 7-membered ring optionally containing 1, 2 or 3 heteroatoms independently selected from O and S; a is C 1~6 alkyl; each R b are independently, =O, -OR in each occurrence. a , HaroC 1~3 Alkyloxy, -SR a , -N(R c ) 2 , Halo, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -N(R a )-S(O) 2 R a Or -C(R a ) 2 -N(R c ) 2 In a more particular embodiment, Z 1 is CH, C-halo or CC 1~6To further aid in describing ring B, examples of ring B, ignoring the units of unsaturation between the two phenyl ring atoms solely for the sake of brevity in nomenclature, are cyclopentane, pyrrolidine, imidazolidine, 1,3-dioxolane, oxazolidine, tetrahydrofuran, cyclohexane, morpholine, piperidine, dioxane, oxathiazinane, piperazine, cycloheptane, cycloheptene, azepane, tetrahydroazepine, diazepane, cyclooctane, cyclooctene, azocane, hexahydroazocine, diazocane, or hexahydrodiazocine. That is, for example, if ring B is described as "cyclohexane", the compound has the formula would be represented as TIFF0007682155000036.tif19128.

[0112] Another embodiment is a compound of formula IA1, where R 2d is H;R 5 is halo or C 1~6 Alkyl; Z 1 is CH, C-halo or CC 1~6 Alkyl; Z 2 is CH;R 2a , R 2b and R 2c Each of the following may be independently determined at each occurrence: C 1~6 Alkyl, -OR a , -OCF 3 , -SR a , -N(R c ) 2 , Halo, -OCF 2 H, -OCH 2 F, -CF 3 , -CN, -S(O) 2 N(R c ) 2 , -S(O) 2 R a , -C(O)R a , -CO 2 R a , -C(O)N(R c ) 2 , -(C(R a ) 2 ) m -Rb , -N(R a )-S(O) 2 R a又は -[N(R a )C(O)] n R a where R 2a , R 2b and R 2c One of them is -N(R c ) 2 , -C(O)N(R c ) 2 Or -(C(R a ) 2 ) m -R b In a more particular embodiment, R 5 is F or CH 3 In another embodiment, R 2a , R 2b and R 2c One of them is -N(R c ) 2 In another embodiment, R 2a , R 2b and R 2c One of them is -(C(R a ) 2 ) m -R b In a more particular embodiment, R 5 is F or CH 3 In a more particular embodiment, -N(R c ) 2 R 2a , R 2b and R 2c One of the R a and / or R b optionally substituted with one or more groups; TIFF0007682155000037.tif51147. In a more particular embodiment, -(C(R a ) 2 ) m -R b R 2a , R 2b and R 2c One of the groups is, more specifically, -C(R a ) 2-N(R c ) 2 In still more particular embodiments, -C(R a ) 2 -N(R c ) 2 R 2a , R 2b and R 2c One of the R a and / or R b optionally substituted with one or more groups; The file is TIFF0007682155000038.tif69146.

[0113] In one embodiment, at least one R 2 The group is a water-solubilizing group, i.e., a group having sufficient hydrophilic properties to improve or increase the water solubility of a compound in which it is included, as compared to a similar compound that does not contain that group. Hydrophilic properties can be achieved, for example, by including a functional group that ionizes under the conditions of use to form a charged moiety (e.g., carboxylic acid, sulfonic acid and salts, phosphoric acid and salts, amines, etc.); a group that contains a permanent charge (e.g., a quaternary ammonium group); and / or a heteroatom or heteroatom group. For example, -O-(C(R a ) 2 ) m -R b , -S-(C(R a ) 2 ) m -R b , -O-(C(R b ) 2 ) m -R a , -N(R a )-(C(R a ) 2 ) m -R b , -O-(CH 2 ) m -CH((CH 2 ) m R b )R b , -C(O)N(R a )-(C(R a ) 2 ) m -Rb and -N((C(R a ) 2 ) m R b ) 2 A more specific example is -OC 1~6 Alkylene-R b , -SC 1~6 Alkylene-R b , -OC 1~6 Alkylene-R a (where R a is heterocyclyl), -N(R a )-C 1~6 Alkylene-R b , -OC 1~6 Alkylene-CH((CH 2 ) 1~2 R b )R b , -C(O)N(R a )-C 1~6 Alkylene-R b and -N((C(R a ) 2 ) 1~3 R b ) 2 An even more specific example is -OC 1~4 Alkylene-R b , -SC 1~4 Alkylene-R b , -OC 1~4 Alkylene-R a (where R a is heterocyclyl), -N(H)-C 1~4 Alkylene-R b , -OC 1~4 Alkylene-CH((CH 2 ) 1~2 R b )R b , -C(O)N(H)-C 1~4 Alkylene-R b and -N((CH 2 ) 1~3 R b ) 2In another particular example, according to the formula shown above for the water-solubilizing group, the water-solubilizing group is an amino acid linked from the molecule by a bond to the nitrogen of the amino acid. In a more particular example, the water-solubilizing group is attached to the parent ring, e.g., ring A, and / or to the Z ring. 1 or Z 2 In the formula (I), an α-amino acid or a derivative thereof is bonded via the nitrogen of the α-amino acid, such as -N(H)C(R a ) 2 -R b where R b -CO 2 R a or -C(O)N(R c ) 2 In another particular embodiment, the water solubilizing group is morpholino, piperidinyl, NC 1~6 Alkyl piperidinyl, piperazinyl, NC 1~6 Alkylpiperazinyl, Pyrrolidinyl, NC 1~6 Alkylpyrrolidinyl, diazepinyl, NC 1~6 Alkylazepinyl, homopiperazinyl, NC 1~6 alkylhomopiperazinyl, imidazoyl, etc. In another example, the water-solubilizing group is one of the above rings linked to the parent molecule via an alkylene, alkylidene, alkylidyne linker. In a more specific embodiment, the water-solubilizing group is C 1~6 One of the above rings linked to the parent molecule via an alkylene, where one or two of the alkylene carbons are independently replaced with one of O, S, or NH, provided that any two of the above heteroatoms are not adjacent in the linker. Other water-solubilizing groups are well known and include hydrophilic groups such as alkyls, or heteroalicyclic groups substituted with one or more of amines, alcohols, carboxylic acids, phosphorous acids, sulfoxides, carbohydrates, sugar alcohols, amino acids, thiols, polyols, ethers, thioethers, and quaternary amine salts.

[0114] For each of the above embodiments of compounds of structural formulas I, IA, IA1, IA2, IA3, IB, IB1, IB2, IB3, and II, there is another embodiment, wherein R1 is H or R 50 ;R 50 is -CH 2 OP(O)(OR 11 ) 2 and each R 11 independently for each occurrence, R a or a monovalent cationic group; or two R 11 form, together with the atoms to which they are attached, a 4- to 8-membered cyclic phosphate group, or two R 11 together represent a divalent cationic group. And for each of these embodiments, there are more specific embodiments, where each R 11 is independently at each occurrence H, t-butyl, or a pharma- ceutically acceptable cation, e.g., HOCH 2 CH 2 N(CH 3 ) 3 + , Na + , Li + Or K + It is.

[0115] As described, 2,4-pyrimidinediamine compounds and prodrugs, as well as salts thereof, may also be in the form of hydrates, solvates, and N-oxides, as is well known in the art. One embodiment is a pharmaceutically acceptable salt form of the compound of formula I. The pharmaceutically acceptable salts of the present disclosure may be formed by conventional means, for example, by reacting the free base form of the product with one or more equivalents of a suitable acid in a solvent or medium in which the salt is insoluble or in a solvent such as water that is removed under reduced pressure, by lyophilization, or by exchanging the anion of an existing salt with another anion in a suitable ion exchange resin. The present disclosure contemplates within its scope the solvates of 2,4-pyrimidinediamine compounds as well as their salts and hydrates, such as hydrated formate salts.

[0116] Exemplary compounds of Formula I include, but are not limited to, those listed in List 1 below.

[0117] List 1: Exemplary compounds of formula I I-1 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(3-formylphenyl)-5-methylpyrimidine-2,4-diamine; I-2 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(3-aminocarbonylphenyl)-5-methylpyrimidine-2,4-diamine; I-3 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(4-aminocarbonylphenyl)-5-methylpyrimidine-2,4-diamine; I-4 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(4-formylphenyl)-5-methylpyrimidine-2,4-diamine; I-5 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(3-methyl-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)-5-methylpyrimidine-2,4-diamine; I-6 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(3-fluoro-4-(1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonan-3-yl)phenyl)-5-methylpyrimidine-2,4-diamine; I-7 N4-(3-n-propylbenzo[d]oxazol-2(3H)-one-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-9 N4-(3-isopropylbenzo[d]oxazol-2(3H)-one-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-16 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-17 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(4-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-20 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(3-methylsulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine; I-21 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(4-methylsulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine; I-22 N4-(benzimidazolin-2-one-5-yl)-N2-(3-methylsulfonyl)phenyl-5-methylpyrimidine-2,4-diamine; I-23 N4-(benzimidazolin-2-one-5-yl)-N2-(4-methylsulfonyl)phenyl-5-fluoropyrimidine-2,4-diamine; I-26 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(3-cyanophenyl)-5-methylpyrimidine-2,4-diamine; I-27 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(4-cyanophenyl)-5-methylpyrimidine-2,4-diamine; I-28 N4-(benzimidazolin-2-one-5-yl)-N2-(3-cyanophenyl)-5-methylpyrimidine-2,4-diamine; I-29 N4-(benzimidazolin-2-one-5-yl)-N2-(4-cyanophenyl)-5-methylpyrimidine-2,4-diamine; I-33 N4-(3-phosphorylmethylbenzo[d]oxazol-2(3H)-one-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-36 N4-(1,3-dimethylbenzimidazolin-2-one-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-41 N4-(1,3-Dimethylbenzimidazolin-2-one-5-yl)-N2-((3-methylsulfonyl)phenyl)-5-fluoropyrimidine-2,4-diamine; I-44 N4-(Benz[d]oxazol-2(3H)-one-5-yl)-N2-(3-cyanophenyl)-5-fluoropyrimidine-2,4-diamine; I-45 N4-(Benz[d]oxazol-2(3H)-one-5-yl)-N2-(4-cyanophenyl)-5-fluoropyrimidine-2,4-diamine; I-46 N4-(Benz[d]oxazol-2(3H)-one-5-yl)-N2-((3-morpholinyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-47 N4-(Benz[d]oxazol-2(3H)-one-5-yl)-N2-((3-morpholinyl)phenyl)-5-fluoropyrimidine-2,4-diamine; I-48 N4-(Benz[d]oxazol-2(3H)-one-6-yl)-N2-((3-morpholinyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-49 N4-(3-Methylbenz[d]oxazol-2(3H)-one-6-yl)-N2-((3-morpholinyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-59 N2-((3-Methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine; I-60 N2-(4-Methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-6-yl)-5-fluoropyrimidine-2,4-diamine; I-65 N2-((3-Methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine; I-66 N2-((4-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine; I-69 N2-((3-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine; I-70 N2-((4-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine; I-77 N2-((3-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine; I-78 N2-((4-methylsulfonyl)phenyl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine; I-100 N2-((3-methylsulfonyl)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine; I-101 N2-((4-methylsulfonyl)phenyl)-N4-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine; I-106 N4-(benzoxazolin-2-one-5-yl)-N2-(3-trifluoromethoxyphenyl)-5-methylpyrimidine-2,4-diamine trifluoroacetate; I-107 N4-(benzoxazolin-2-one-5-yl)-N2-(3-trifluoromethoxyphenyl)-5-fluoropyrimidine-2,4-diamine trifluoroacetate; I-108 N4-(benzoxazolin-2-one-5-yl)-N2-(4-trifluoromethoxyphenyl)- 5-methylpyrimidine-2,4-diamine trifluoroacetate; I-109 N4-(benzoxazolin-2-one-5-yl)-N2-(4-trifluoromethoxyphenyl)- 5-fluoropyrimidine-2,4-diamine trifluoroacetate; I-110 N4-(benzoxazolin-2-one-5-yl)-N2-[3-trifluoromethyl-4-(4-ethylpiperazin-1-yl)phenyl]-5-methylpyrimidine-2,4-diamine; I-111 N4-(benzoxazolin-2-one-5-yl)-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-5-methylpyrimidine-2,4-diamine; I-115 N4-(benzoxazolin-2-one-5-yl)-N2-(3,4,5-trimethoxyphenyl)-5-fluoropyrimidine-2,4-diamine; I-116 N2-(3-(difluoromethoxy)-4-methoxyphenyl)-N4-(benzo[d]oxazol-2(3H)-one-5-yl)-5-methylpyrimidine-2,4-diamine; I-117 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(4-trifluoromethylsulfonyl)phenyl-5-methylpyrimidine-2,4-diamine; I-118 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(3-trifluoromethylsulfonyl)phenyl-5-methylpyrimidine-2,4-diamine; I-119 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(3,4,5-trimethoxy)phenyl-5-methylpyrimidine-2,4-diamine; I-120 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-((4-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-3-methyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-121 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(4-(8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)phenyl)-5-methylpyrimidine-2,4-diamine; I-122 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-((4-(dihydro-1H-pyrido[1,2-a]pyrazine-2(6H,7H,8H,9H,9aH)-yl)-3-methyl)phenyl)-5-methylpyrimidine-2,4-diamine; I-123 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(4-(8-methyl-2,8-diazabicyclo[3.2.1]octan-2-yl)phenyl)-5-methylpyrimidine-2,4-diamine; I-124 N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-5-methyl-N2-[3-(morpholin-4-yl)-4-trifluoromethoxyphenyl]-2,4-pyrimidinediamine; I-125 N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-[3-trifluoromethyl-2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; I-126 4-[5-Methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzoic acid; I-127 N-(2-diethylamino-ethyl)-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-128 5-{2-[4-(3-diethylamino-pyrrolidine-1-carbonyl)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; I-129 5-[2-(4-acetyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-130 5-[2-(3-acetyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-131 2-Methyl-5-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzonitrile; I-132 N,N-Dimethyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-133 N-Methyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-134 N-Cyclopropyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide formate I-135 4-[5-Methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-N-phenyl-benzamide; I-136 4-[5-Methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-2-pyrrolidin-1-yl-benzamide; I-137 N-Ethyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-138 N-Cyclobutyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide formate; I-139 N-Isopropyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-140 N-Cyclopropyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzooxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide formate; I-141 2-Chloro-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-142 N-Cyclopropyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide trifluoroacetate; I-143 N-Cyclopropyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-144 N-Cyclobutyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-145 4-[5-methyl-4-(2-oxo-3-propionyl-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-146 Di-tert-butyl(5-(2-(4-carbamoylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate; I-147 (5-(2-(4-carbamoylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl dihydrogen phosphate; I-148 (5-(2-(4-carbamoylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate sodium; I-150 (5-(2-(4-(cyclobutylcarbamoyl)phenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl dihydrogen phosphate; I-151 (5-(2-(4-(cyclobutylcarbamoyl)phenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate sodium; I-152 Di-tert-butyl(5-(2-(4-(cyclobutylcarbamoyl)phenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate; I-153 5-[2-(4-chloro-3-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-154 5-[5-methyl-2-(4-methyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-155 5-[5-methyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-156 4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-2-(4-methyl-piperidin-1-yl)-benzamide; I-157 5-[2-(3-cyclopentanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-158 5-[5-Methyl-2-(3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-159 2-Methyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzoic acid methyl ester; I-160 5-[5-Methyl-2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-161 5-[5-methyl-2-(4-trifluoromethoxy-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-162 5-[2-(3-fluoro-5-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one trifluoroacetate; I-163 5-[2-(4-fluoro-3-trifluoromethoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-164 5-[5-methyl-2-(4-methyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one trifluoroacetate; I-165 5-{2-[4-(2-methoxy-ethoxy)-3-trifluoromethyl-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; I-166 5-[2-(4-isopropyl-3-methyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-167 5-[2-(3-chloro-4-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-168 5-[2-(4-ethoxy-3-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-169 5-[2-(3,5-bis-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-170 2-Methyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzoic acid; I-171 N-Ethyl-2-methyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-172 5-[2-(4-chloro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-173 5-[2-(3-chloro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-174 5-(5-methyl-2-phenylamino-pyrimidin-4-ylamino)-3H-benzoxazol-2-one; I-175 5-[2-(3-bromo-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-176 5-[2-(4-chloro-2,5-dimethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-177 N-{4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-2-trifluoromethyl-phenyl}-acetamide; I-178 5-[2-(3,4-dimethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-179 5-[2-(4-cyclohexylmethoxy-3-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-180 5-[2-(4-chloro-3-trifluoromethoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-181 5-[2-(4-chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-182 5-[2-(4-chloro-3-ethoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-183 5-[2-(4-fluoro-3-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-184 5-[2-(3,5-dichloro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-185 5-[2-(3-bromo-5-chloro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-186 5-[2-(3-chloro-5-fluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-187 3-Chloro-5-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzonitrile; I-188 5-[2-(4-bromo-3-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-189 5-[2-(3-bromo-5-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-190 N-Cyclobutyl-2-methyl-4-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-benzamide; I-191 5-{2-[3-chloro-4-(2-morpholin-4-yl-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; I-192 5-{5-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; I-193 5-[2-(2,4-difluoro-5-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-194 5-[2-(3-chloro-4-ethoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-195 5-[2-(4-cyclobutylmethoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-196 5-[2-(4-isobutoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-197 5-{5-methyl-2-[4-(3-methyl-butoxy)-phenylamino]-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; I-198 5-[2-(3-chloro-4-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one trifluoroacetate; I-199 5-[2-(3-fluoro-5-methyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-200 5-[2-(2,4-difluoro-3-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-201 5-(2-(4-(1-(azetidin-1-yl)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-202 5-(2-(4-(1-(cyclopropylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-203 5-(5-methyl-2-(4-(1-(pyrrolidin-1-yl)ethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-204 5-(5-methyl-2-(4-(1-morpholinoethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-205 5-(2-(4-(1-(3-(diethylamino)pyrrolidin-1-yl)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-206 5-(2-(4-(1-(benzylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-207 5-(2-(4-(1-(isopropylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-208 5-(5-methyl-2-(3-(1-(propylamino)ethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-209 5-(2-(3-(1-(isopropylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-210 5-(2-(3-(1-(isopropylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-211 5-(2-(3-(1-(azetidin-1-yl)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-212 5-(5-methyl-2-(3-(1-(pyrrolidin-1-yl)ethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-213 5-(2-(3-(1-(benzylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-214 5-(2-(3-(1-(3-(diethylamino)pyrrolidin-1-yl)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-215 5-(5-methyl-2-(3-(1-(piperidin-1-yl)ethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-216 5-(2-(3-(1-(diethylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-217 5-(5-methyl-2-(3-(1-morpholinoethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-218 N-Cyclobutyl-4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-2-(trifluoromethyl)benzamide; I-219 4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-N-phenyl-2-(trifluoromethyl)benzamide; I-220 N-cyclopropyl-2-methoxy-4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)benzamide; I-221 2-Methoxy-4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-N-phenylbenzamide; I-222 4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-2-(trifluoromethyl)benzoic acid; I-223 N-cyclopropyl-4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-2-(trifluoromethyl)benzamide; I-224 -(2-(3-isobutoxy-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-225 5-(2-(3-(cyclopropylmethoxy)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-226 5-(2-(3-cyclobutoxy-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-227 5-(2-(3-(cyclobutylmethoxy)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-228 5-(2-(3-deuterated methoxy-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-229 5-(2-(3-acetyl-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-230 5-(2-(3-chloro-4-fluoro-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-231 5-(2-(3-(1-(isopropylamino)ethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-232 5-(2-(3-methoxy-5-(1-(propylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-233 5-(2-(3-(1-(cyclopropylamino)ethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-234 5-(2-(3-methoxy-5-(1-(pyrrolidin-1-yl)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-235 5-(2-(3-(1-(azetidin-1-yl)ethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-236 5-(2-(3-methoxy-5-(1-(methylamino)ethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-237 5-(2-(3-(difluoromethyl)-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-238 5-(2-(3-(fluoromethyl)-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-239 5-(5-methyl-2-(4-methyl-3-(methylsulfonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-240 5-(2-(3-fluoro-5-morpholinophenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-241 5-(2-(3-fluoro-5-(4-methylpiperazin-1-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-242 5-(2-(4-fluoro-3-(methylsulfonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-244 7-Methyl-5-(5-methyl-2-(3-(methylsulfonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-245 5-(2-(4-fluoro-3-(methylsulfonyl)phenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one; I-246 5-(5-methyl-2-(3-(pyrrolidine-1-carbonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-247 5-(5-methyl-2-(4-(pyrrolidine-1-carbonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-249 7-Fluoro-5-(5-methyl-2-(3-(methylsulfonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-250 7-Fluoro-5-(2-(4-fluoro-3-(methylsulfonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-251 7-Fluoro-5-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-252 3-Methoxy-N,N-dimethyl-5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)benzamide; I-253 5-(2-(3-methoxy-5-(pyrrolidine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-254 5-(2-(3-methoxy-5-(morpholine-4-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-255 5-(2-(3-methoxy-5-(4-methylpiperazine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-256 5-(5-methyl-2-(3-(morpholine-4-carbonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-257 5-(5-methyl-2-(4-(morpholine-4-carbonyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-258 5-(2-(4-methoxy-3-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-259 5-(2-(3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-260 2-Methoxy-N,N-dimethyl-5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)benzamide; I-261 5-(2-(4-methoxy-3-(pyrrolidine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-262 5-(2-(4-methoxy-3-(morpholine-4-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-263 5-(2-(4-Methoxy-3-(4-methylpiperazine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-264 5-(2-(3-methyl-4-trideuteromethoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-265 5-(2-(3-chloro-4-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-266 5-(2-(3-methyl-5-trideuteromethoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-267 2-Methoxy-N,N-dimethyl-4-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)benzamide; I-268 5-(2-(3-methoxy-4-(pyrrolidine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-269 5-(2-(3-methoxy-4-(morpholine-4-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-270 5-(2-(3-methoxy-4-(4-methylpiperazine-1-carbonyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-271 5-(2-(3-(difluoromethyl)-4-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-272 5-(2-(4-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-273 5-(2-(3-(difluoromethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-274 5-(2-(3-(fluoromethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-275 N2-[4-(4,4-difluoropiperidinyl)-3-fluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-276 N2-[4-(4,4-difluoropiperidinyl)-3-trifluoromethyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-277 N2-[3-chloro-4-(4,4-difluoropiperidinyl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-278 N2-[3-chloro-4-(4-ethylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-279 N2-[4-(4,4-difluoropiperidinyl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-280 N2-(3,5-dimethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-281 N2-[3-fluoro-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-282 N2-[3,5-difluoro-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-283 N2-[4-chloro-3-(4-ethylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-284 N2-[4-chloro-3-(3,4,5-trimethylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-285 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[3-(4-propylpiperazino)-4-trifluoromethyl]phenyl-2,4-pyrimidinediamine; I-286 5-Methyl-N2-[3-(1,3-oxazol-5-yl)]phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-287 N2-(3-bromo)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-288 N2-(4-bromo)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-289 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[3-(pyridin-4-yl)]phenyl-2,4-pyrimidinediamine; I-290 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[3-(pyridin-3-yl)]phenyl-2,4-pyrimidinediamine; I-291 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[4-(pyridin-3-yl)]phenyl-2,4-pyrimidinediamine; I-292 N2-[4-methoxy-3-(2-methoxyethoxy)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-293 N2-[3-(cyclopropylaminocarbonylmethoxy)-4-methoxy]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-294 N2-(3-cyano-4-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-295 N2-[3-cyano-4-(1H-pyrrol-1-yl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-296 N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-297 N2-(4-methoxy-3-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-298 N2-{4-methoxy-3-[(pyridin-4-yl)methoxy]}phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-299 N2-{4-methoxy-3-[(pyridin-3-yl)methoxy]}phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-300 N2-{4-methoxy-3-[2-(dimethylamino)ethoxy]}phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-301 N2-[3,5-bis(trifluoromethyl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-302 N2-(3,5-dimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-303 N2-(4-cyano-3-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-304 N2-[3-(1-hydroxy-2,2,2-trifluoroethyl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-305 N2-(3-methoxycarbonylmethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-306 5-Methyl-N2-(3-methylaminocarbonylmethoxy)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-307 N2-(4-aminocarbonylmethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-308 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(4-phenylcarbonylamino)phenyl-2,4-pyrimidinediamine; I-309 N2-[4-(N-acetyl-N-methyl)amino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-310 N2-[3-cyano-4-(pyrrolidin-1-yl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-311 N2-(4-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-312 N2-(3-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-313 N2-(4-difluoromethoxy-3-ethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-314 N2-(3-chloro-4-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-315 N2-[3-(cyclopropylaminocarbonylmethoxy)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-316 N2-[3-aminocarbonyl-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-317 N2-[4-(isopropoxycarbonylmethoxy)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-318 N2-[4-(ethylaminocarbonylamino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-319 N2-[3-(aminocarbonylmethoxy)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-320 5-Methyl-N2-[3-(morpholinocarbonylmethoxy)]phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-321 5-Methyl-N2-[3-(4-methylpiperazin-1-yl)carbonyl]phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-322 5-Methyl-N2-[4-(4-methylpiperazin-1-yl)carbonyl]phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-323 5-Methyl-N2-[3-methylaminocarbonyl-4-(4-methylpiperazino)]phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-324 N2-[4-(1-aminocarbonyl-1-methyl)ethoxy]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-325 5-Methyl-N2-(2-methyl-3-methylaminocarbonylmethoxy)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-326 N2-(3-dimethylaminocarbonylmethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-327 N2-(3-cyano-4-morpholino)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-328 N2-(3-methoxy-2-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-329 N2-[3-chloro-4-(pyridin-4-yl)]phenyl 5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-330 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[4-(pyridin-4-yl)-3-trifluoromethyl]phenyl-2,4-pyrimidinediamine; I-331 N2-[3-hydroxymethyl-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-332 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(4-piperazino)phenyl-2,4-pyrimidinediamine; I-333 N2-[4-(4-ethylaminocarbonyl)piperazino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-334 N2-[4-(1-cyano-1-methyl)ethoxy]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-335 N2-[3-(1-aminocarbonyl-1-methyl)ethoxy]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-336 N2-(3-methoxy-4-methoxycarbonyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-337 N2-(3-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-338 5-Methyl-N2-(4-morpholino)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-339 N2-(3-cyano-4-thiomorpholino)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-340 N2-[3-methoxy-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-341 N2-[3-cyano-4-(4-methylpiperazino)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-342 N2-[3-(1-cyano-1-methyl)ethoxy]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-343 N2-[4-(4-acetyl)piperazino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-344 N2-[4-(4-ethoxycarbonyl)piperazino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-345 N2-[3-(4-acetyl)piperazino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-346 N2-[3-(4-ethoxycarbonyl)piperazino]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-347 N2-(4-Difluoromethoxy-3-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-348 N2-(3,5-Dichloro-4-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-349 N2-(4-Fluoro-3-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-350 N2-(3-Fluoro-4-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-351 N2-(3-Methoxy-4-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-352 N2-(3-Fluoro-5-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-353 N2-(3-Difluoromethoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-354 N2-(3-Methoxy-4-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-355 N2-(3,5-Di-tert-butyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-356 N4-{3-[bis(1,1-dimethylethoxy)]phosphinyloxymethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}-N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-2,4-pyrimidinediamine; I-357 N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,4-pyrimidinediamine; I-358 N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,4-pyrimidinediamine bis-sodium salt; I-359 N2-(3,5-difluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-360 N2-(3-fluoro-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-361 N2-(4-fluoro-3-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-362 N2-(4-fluoro-3-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-363 N2-(3-fluoro-4-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-364 N2-(3-chloro-4-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-365 N2-(3,4,5-trimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-366 N2-(3-chloro-4-trifluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-367 N2-(4-trifluoromethylthio)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-368 N2-(3-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-369 N2-(3,5-dimethyl-4-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-370 N2-(3-carboxamido-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-371 N2-(3,5-diisopropyl-4-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-372 N2-(3-isopropoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-373 N2-(3-cyano-4-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-374 N2-(3,5-dimethyl-4-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-375 N2-(4-fluoro-3-trifluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-376 N2-(3-fluoro-4-trifluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-377 N2-(4-chloro-3-trifluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-378 N2-(3-chloro-5-trifluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-379 5-Methyl-N2-(3-methyl-5-trifluoromethoxy)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-380 N2-(4-cyano-3-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-381 N2-(3,5-difluoro-4-methoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-382 5-Methyl-N2-(4-morpholinomethyl)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-383 N2-(4-chloro-3-cyano-5-ethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-384 N2-[3-(2-methoxy)ethoxy-5-trifluoromethyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-385 N2-(4-difluoromethoxy-3,5-dimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-386 N2-[3-(1-aminocarbonyl-1-methyl)ethoxy-4-fluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-387 N2-(4-difluoromethoxy-3-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-388 N2-(3,5-difluoro-4-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-389 N2-[4-(1-aminocarbonyl-1-methyl)ethoxy-3,5-dimethyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-390 N2-(3-difluoromethoxy-4-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-391 N2-[4-(1-aminocarbonyl-1-methyl)ethoxy-3-methyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-392 N2-[3-(1-aminocarbonyl-1-methyl)ethoxy-4-methyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-393 N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine besylate; I-394 N2-(4-chloro-3,5-dimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-395 N2-[4-(1-aminocarbonyl-1-methyl)ethoxy-3,5-difluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-396 N2-[3-(1-methoxy-2,2,2-trifluoroethyl)]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-397 N2-[3-(1-cyano-1-methyl)ethoxy-4-methyl]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-398 N2-(3,4-difluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-399 N2-(3-chloro-4-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-400 N2-(4-chloro-3-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-401 N2-(3-difluoromethoxy-5-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-402 N2-[3-(1-aminocarbonyl-1-methyl)ethoxy-5-fluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-403 5-(5-Methyl-2-m-tolylamino-pyrimidin-4-ylamino)-3H-benzoxazol-2-one; I-404 5-{2-[4-(3-dimethylamino-propoxy)-3-trifluoromethyl-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; I-405 N4-{3-[bis(1,1-dimethylethoxy)]phosphinyloxymethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}-N2-(3,4,5-trimethyl)phenyl-5-methyl-2,4-pyrimidinediamine; I-406 5-Methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine; I-407 5-Methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine bis-sodium salt; I-408 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(3,4,5-trifluoro)phenyl-2,4-pyrimidinediamine; I-409 N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine tosylate; I-410 N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine mesylate; I-411 N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine sulfate; I-412 N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine hydrochloride; I-413 N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine sodium salt; I-414 N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine choline salt; I-415 N2-(3,5-difluoro-4-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-416 N2-[3-(1-cyano-1-methyl)ethoxy-5-fluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-417 N2-[3-(1-cyano-1-methyl)ethoxy-4-fluoro]phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-418 N2-(4-chloro-3-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-419 5-(2-(4-isopropylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-420 5-(2-(4-tert-butylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-421 5-(2-(p-toluidino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-422 5-(2-(3-(isopropoxymethyl)-4-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-423 5-(2-(3-(1-hydroxyethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-424 5-[2-(3-chloro-4-hydroxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-425 5-[2-(4-hydroxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-426 5-{2-[4-(2-dimethylamino-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; I-427 5-(2-(3-methoxy-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one; I-428 5-(2-(3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one; I-429 5-(2-(4-methoxy-3-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one; I-430 7-Fluoro-5-(2-(3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-431 7-Fluoro-5-(2-(4-methoxy-3-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-432 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-433 5-(2-(4-(difluoromethoxy)-3-(fluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one formate; I-434 N2-(4-cyano-3-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-435 N2-(3-difluoromethoxy-4-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-436 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine sodium salt; I-437 N2-(3,5-dimethyl-4-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine sodium salt; I-438 5-(2-(3-(difluoromethyl)-4-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-439 5-(2-(3-(fluoromethyl)-4-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-440 5-(2-(3-(difluoromethyl)-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one formate; I-441 5-(2-(4-d 3 -Methoxy-3-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-442 5-(2-(4-(difluoromethoxy)-3-(difluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one formate; I-443 5-(5-methyl-2-(4-methyl-3-(pyridin-4-yl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-444 5-(5-methyl-2-(4-methyl-3-(pyridin-3-yl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-445 5-(2-(3-acetyl-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-446 5-(2-(3-(1-hydroxyethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-447 5-[2-(4-d 3 -Methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-448 5-[2-(3-chloro-4-d 3 -Methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-449 5-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; I-450 N4-{3-[bis(1,1-dimethylethoxy)]phosphinyloxymethyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}-N2-(3,5-dimethyl-4-fluoro)phenyl-5-methyl-2,4-pyrimidinediamine; I-451 N2-(3,5-dimethyl-4-fluoro)phenyl-5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,4-pyrimidinediamine bis-sodium salt; I-452 5-(2-(3,4-dimethoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-453 5-(2-(3,4-dimethoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one; I-454 5-(2-(3,4-dimethoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-fluorobenzo[d]oxazol-2(3H)-one; I-455 5-{2-[3-chloro-4-(2-diethylamino-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; I-456 5-[2-(2,4-difluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-457 5-(5-methyl-2-(3-(1-(methylamino)ethyl)-5-(trifluoromethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-458 5-(2-(3-chloro-4,5-dimethoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-459 5-(2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-460 5-(5-methyl-2-(3-(1-(methylamino)butyl)-5-(trifluoromethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-461 5-(2-(3-(1-(cyclopropylamino)ethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-462 5-(2-(3-(1-(ethylamino)ethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-463 5-(5-methyl-2-(3-(1-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethyl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-464 5-(2-(3-(1-(azetidin-1-yl)ethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-465 5-(2-(3-(1-(cyclobutylamino)ethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-466 5-[2-(2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-467 5-[2-(2,3-difluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-468 5-[2-(2-fluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-469 N-Cyclobutyl-3-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-5-trifluoromethyl-benzamide; I-470 5-[2-(4-fluoro-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-471 5-(2-(4-fluoro-3-(pyridin-4-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-472 5-(2-(4-fluoro-3-(pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-473 5-(2-(3-(1-(isopropylamino)ethyl)-5-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-474 5-(2-(3,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one; I-475 7-Methyl-5-(5-methyl-2-(3,4,5-trimethylphenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-476 5-(2-(4-fluoro-3,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one; I-477 5-[5-methyl-2-(2,3,4,5-tetrafluoro-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-478 N2-(3-cyano-5-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-479 5-Methyl-N2-(3-methyl-5-trifluoromethyl)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-480 5-[5-methyl-2-(2,3,5-trifluoro-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-481 5-[5-methyl-2-(2,4,5-trifluoro-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-482 5-(5-methyl-2-(3-methyl-4-(pyridin-4-yl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one formate; I-483 5-(5-methyl-2-(3-methyl-4-(pyridin-3-yl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one formate; I-484 5-(2-(3-fluoro-4-(pyridin-4-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-485 N2-(3,4-dimethoxy-5-trifluoromethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-486 5-(2-(4-methoxy-3-(pyridin-4-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one formate; I-487 5-(2-(4-methoxy-3-(pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one formate; I-488 5-(2-(3,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)-7-fluorobenzo[d]oxazol-2(3H)-one; I-489 7-Fluoro-5-(5-methyl-2-(3,4,5-trimethylphenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-490 7-Fluoro-5-(2-(4-fluoro-3,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-491 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one; I-492 7-Fluoro-5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-493 N2-(3,4-dimethyl-2-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-494 5-(2-(3-methoxy-4-(pyridin-4-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one formate; I-495 N2-(3-chloro-5-difluoromethoxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-496 5-[2-(3-chloro-4-methoxy-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-497 5-[2-(3-chloro-5-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-498 5-[2-(2-methoxy-5-trifluoromethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-499 5-(2-(o-toluidino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-500 5-(2-(2,3-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-501 5-(2-(2,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-502 5-(2-(2-ethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-503 5-(2-(3-ethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-504 5-(2-(4-ethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-505 5-(2-(3-fluoro-4-(pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate; I-506 5-(2-(3-methoxy-4-(pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one formate; I-507 5-(2-(2,4-difluoro-3-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)-7-methylbenzo[d]oxazol-2(3H)-one; I-508 5-(2-(2,4-difluoro-3-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)-7-fluorobenzo[d]oxazol-2(3H)-one; I-509 5-(2-(4-(6-chloropyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate; I-510 5-(2-(4-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate; I-511 5-(2-(4-(6-(3-(dimethylamino)propoxy)pyridin-3-yl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate; I-512 5-(5-methyl-2-(4-(6-morpholinopyridin-3-yl)phenylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate; I-513 5-(2-(2-fluoro-3-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-514 5-(2-(2-fluoro-4-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-515 5-(2-(2-fluoro-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-516 N2-(3-difluoromethoxy-5-methyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-517 5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine calcium salt; I-518 5-[5-methyl-2-(2-methyl-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-519 5-(2-(5-acetyl-2-fluorophenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-520 5-(2-(2-chlorophenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-521 5-(2-(2-chloro-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-522 N4-(7-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-5-methyl-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine; I-523 5-(2-(2-fluoro-5-(1-hydroxyethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-524 N4-{3-[bis(1,1-dimethylethoxy)]phosphinyloxymethyl-7-chloro-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl}-N2-(3,4,5-trimethyl)phenyl-5-methyl-2,4-pyrimidinediamine; I-525 N4-[7-chloro-3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-5-methyl-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine; I-526 5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine magnesium salt; I-527 5-[2-(4-iodo-3,5-dimethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; I-528 N4-[7-chloro-3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-5-methyl-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine bis-sodium salt; I-529 5-(2-(3,5-dimethoxy-4-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-530 5-(2-(2-fluoro-4,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-531 5-Methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine bis-choline salt; I-532 5-(2-(2-fluoro-4-methyl-3-(trifluoromethyl)phenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-533 5-(2-(2-fluoro-5-methoxyphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-534 5-(2-(2-fluoro-3,4,5-trimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-535 5-(2-(3-methoxy-4,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; I-536 (5-(2-(3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-7-methyl-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate sodium; I-537 N2-(3,4-dimethyl-5-fluoro)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; I-538 (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate sodium; II-1 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-dimethylaminopyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-2 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-((1S,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-pyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-3 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-4 N4-(3-n-propylbenzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-5 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-(4-tert-butyloxycarbonylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-6 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-(4-methylpiperidin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-7 N2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N4-(3-isopropylbenzo[d]oxazol-2(3H)-one-5-yl)-5-methylpyrimidine-2,4-diamine; II-8 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-(4-trifluoromethoxycarbonylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-9 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-(4-methoxycarbonylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-10 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-(piperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-11 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-(3-methyl-4-tert-butoxycarbonylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-12 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-(3-methylpiperazin-1-yl)pyridin-3-yl)-5-methylpyrimidine-2,4-diamine; II-13 N4-(benzoxazolin-2-one-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-14 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine; II-15 N4-(benzimidazolin-2-one-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-16 N4-(benzimidazolin-2-one-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine; II-17 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-((2-morpholinyl)pyridin-5-yl)-5-methylpyrimidine-2,4-diamine; II-18 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-((2-morpholinyl)pyridin-5-yl)-5-fluoropyrimidine-2,4-diamine; II-19 N4-(benzimidazolin-2-one-5-yl)-N2-((2-morpholinyl)pyridin-5-yl)-5-fluoropyrimidine-2,4-diamine; II-20 N4-(1,3-dimethylbenzimidazolin-2-one-5-yl)-N2-[2-(4-methylpiperazino)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-21 N4-(1,3-dimethylbenzimidazolin-2-one-5-yl)-N2-[2-(4-methylpiperazino)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine; II-22 N2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-methylpyrimidine-2,4-diamine; II-23 N2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-5-methylpyrimidine-2,4-diamine trifluoroacetate; II-24 N2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-N4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-5-fluoropyrimidine-2,4-diamine; II-25 6-(5-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-26 N4-(benzoxazolin-2-one-5-yl)-N2-[3-methyl-2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-27 N4-(benzimidazolin-2-one-5-yl)-N2-[3-methyl-2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-28 N4-(benzoxazolin-2-one-5-yl)-N2-[3-methyl-2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-29 N4-(benzoxazolin-2-one-5-yl)-N2-[3-methyl-2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine; II-30 N4-(benzoxazolin-2-one-5-yl)-N2-[3-methyl-2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine; II-31 N4-(benzoxazolin-2-one-5-yl)-N2-[2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-32 N4-(benzoxazolin-2-one-5-yl)-N2-[2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-33 N4-(benzoxazolin-2-one-5-yl)-N2-[2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine; II-34 N4-(benzoxazolin-2-one-5-yl)-N2-[2-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine; II-35 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-[2-(1-methylpiperidin-4-yl)aminopyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-36 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-[2-(1H-piperidin-4-yl)aminopyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-37 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-[2-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)aminopyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-38 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(4-(8-methyl-2,8-diazabicyclo[3.2.1]octan-2-yl)phenyl)-5-methylpyrimidine-2,4-diamine; II-39 N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-[3-trifluoromethyl-2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-40 N4-(benzoxazolin-2-one-5-yl)-N2-[3-fluoro-2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine; II-41 (S)-2-Methyl-4-{5-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester; II-42 5-[5-methyl-2-(pyridin-3-ylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; II-43 5-[2-(6-methanesulfonyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; II-44 5-{5-methyl-2-[6-((S)-3-methyl-piperazin-1-yl)-pyridin-3-ylamino]-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; II-45 5-{5-methyl-2-[6-(piperazine-1-carbonyl)-pyridin-3-ylamino]-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; II-46 5-{2-[6-(4-cyclopropylmethyl-piperazine-1-carbonyl)-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; II-47 5-{2-[6-(4-isobutyl-piperazine-1-carbonyl)-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; II-48 5-{3-fluoro-5-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-pyridin-2-yl}-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester; II-49 5-{3-fluoro-5-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-pyridin-2-yl}-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester; II-50 5-{2-[5-fluoro-6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; II-51 5-{2-[6-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-5-fluoro-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; II-52 5-{2-[6-(5-Cyclopropylmethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-5-fluoro-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; II-53 5-{2-[6-(5-Cyclopropanecarbonyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-5-fluoro-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; II-54 5-{2-[6-(5-Cyclopropylmethyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-5-fluoro-pyridin-3-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; II-55 (R)-5-(2-(6-(3,4-Dimethylpiperazin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-56 (R)-5-(2-(6-(4-(Cyclopropylmethyl)-3-methylpiperazin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-57 (R)-5-(5-Methyl-2-(6-(3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-58 (R)-Diethyl 2-methyl-4-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)piperazin-1-ylphosphonate; II-59 5-(2-(6-(4,4-Difluoropiperidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-60 5-(2-(6-(4,4-dimethylpiperidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-61 5-(2-(6-(3,8-diaza-bicyclo[3.2.1]octan-3-yl)-5-methylpyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-62 5-(5-methyl-2-(5-methyl-6-(8-acetyl)-3,8-diaza-bicyclo[3.2.1]octan-3-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-63 5-(5-methyl-2-(5-methyl-6-(8-(2,2,2-trifluoroacetyl)-3,8-diaza-bicyclo[3.2.1]octan-3-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-64 5-(5-methyl-2-(5-methyl-6-(8-methyl-3,8-diaza-bicyclo[3.2.1]octan-3-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-65 tert-Butyl 3-(3-methyl-5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate; II-66 5-(2-(6-(8-aza-bicyclo[3.2.1]octan-3-yl)-5-methylpyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-67 5-(2-(6-(8-(cyclopropylmethyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-methylpyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-68 Methyl 3-(3-methyl-5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate; II-69 5-(5-methyl-2-(5-methyl-6-(8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]octan-3-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-70 (R)-5-(2-(6-(4-isopropyl-3-methylpiperazin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-71 5-(5-methyl-2-(6-(pyrrolidin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-72 7-methyl-5-(5-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-73 7-methyl-5-(5-methyl-2-(6-morpholinopyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-74 5-(2-(6-(cyclopropylmethylamino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-75 7-fluoro-5-(5-methyl-2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-76 7-Fluoro-5-(5-methyl-2-(6-morpholinopyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-77 5-(2-(5-bromopyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-79 N-(5-(5-methyl-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)methanesulfonamide; II-80 5-(2-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-81 N-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)acetamide; II-82 5-(2-(6-(3-(diethylamino)pyrrolidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-83 2,2,2-trifluoro-N-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)acetamide; II-84 5-(5-methyl-2-(6-(3-morpholinopyrrolidin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-85 5-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-86 tert-Butyl 1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-ylcarbamate; II-87 (S)-tert-butyl methyl (1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)piperidin-3-yl)carbamate; II-88 (R)-5-(5-methyl-2-(6-(3-(methylamino)piperidin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-89 (R)-5-(2-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-90 (S)-5-(2-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-91 (R)-tert-butyl methyl (1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)piperidin-3-yl)carbamate; II-92 (R)-5-(5-methyl-2-(6-(3-(methylamino)piperidin-1-yl)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-94 5-(2-(6-(3-(cyclopropylmethylamino)pyrrolidin-1-yl)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-95 (S)-5-(2-(6-((1-benzylpiperidin-3-yl)(methyl)amino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-96 1-ethyl-3-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)urea; II-97 1-tert-butyl-3-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)urea; II-98 1-benzyl-3-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)urea; II-99 (S)-5-(2-(6-(1-benzylpiperidin-3-ylamino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-100 (S)-5-(2-(6-((1-benzylpiperidin-3-yl)(methyl)amino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-101 N-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)cyclopropanecarboxamide; II-102 N-(1-(5-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)pyridin-2-yl)pyrrolidin-3-yl)pivalamide; II-103 (S)-5-(5-methyl-2-(6-(methyl(piperidin-3-yl)amino)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-104 (S)-5-(5-methyl-2-(6-(piperidin-3-ylamino)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-105 (S)-5-(2-(6-(1-benzylpiperidin-3-ylamino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-106 (R)-5-(2-(6-((1-benzylpiperidin-3-yl)(methyl)amino)pyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-107 (R)-5-(5-methyl-2-(6-(piperidin-3-ylamino)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-108 (R)-5-(5-methyl-2-(6-(methyl(piperidin-3-yl)amino)pyridin-3-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-109 N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-5-methyl-N2-[2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-trifluoromethylpyridin-5-yl]-2,4-pyrimidinediamine; II-110 N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-[2-(4-ethylpiperazin-1-yl)-3-trifluoromethylpyridin-5-yl]-5-methyl-2,4-pyrimidinediamine; II-111 N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-[3-fluoro-2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methyl-2,4-pyrimidinediamine; II-112 N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-{2-[(8S)-1,4-diazabicyclo[4.3.0]nonan-1-yl]-3-fluoropyridin-5-yl}-5-methyl-2,4-pyrimidinediamine; II-113 N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-{2-[(8R)-1,4-diazabicyclo[4.3.0]nonan-1-yl]-3-fluoropyridin-5-yl}-5-methyl-2,4-pyrimidinediamine; II-114 N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-[2-(4-ethylpiperazin-1-yl)-3-fluoropyridin-5-yl]-5-methyl-2,4-pyrimidinediamine; II-115 N4-(benzo[d]oxazolin-2(3H)-one-5-yl)-N2-[3-cyano-2-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-5-yl]-5-methyl-2,4-pyrimidinediamine; II-116 N2-[3-chloro-2-(4-methylpiperazino)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-117 5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[2-(1,3,5-trimethyl-3,7-diazabicyclo[3.3.1]nonan-7-yl)pyridin-5-yl]-2,4-pyrimidinediamine; II-118 N2-[3-chloro-2-(3-ethyl-3,7-diazabicyclo[3.3.0]octan-7-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-119 N2-[2-(3-Ethyl-3,7-diazabicyclo[3.3.0]octan-7-yl)-3-(trifluoromethyl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-120 5-Methyl-N2-[2-(3-methyl-3,7-diazabicyclo[3.3.0]octan-7-yl)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-121 5-Methyl-N2-[2-(octahydroisoindol-1-yl)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-122 N2-[3-Chloro-2-(octahydroisoindol-1-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-123 N2-(2-Methoxypyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-124 N2-[2-(S-1,4-Diazabicyclo[4.3.0]nonan-4-yl)-3-(trifluoromethyl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-125 N2-[2-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-3-fluoropyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-126 N2-[2-(4R-Hydroxy-2-methylidene-pyrrolidin-1-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-127 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[2-(cis-3,4,5-trimethylpiperazino)pyridin-5-yl]-2,4-pyrimidinediamine; II-128 N2-[2-(1,4-diazabicyclo[4.4.0]decan-4-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-129 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-[2-(trans-2,4,5-trimethylpiperazino)pyridin-5-yl]-2,4-pyrimidinediamine; II-130 N2-[2-(trans-2,5-dimethylpiperazino)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)- 2,4-pyrimidinediamine; II-131 N2-[2-(cis-3,5-dimethylpiperazino)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-132 N2-[2-(R-1,4-diazabicyclo[4.3.0]nonan-4-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-133 5-methyl-N2-[2-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-134 5-Methyl-N2-[2-(3S-methylmorpholino)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-135 5-Methyl-N2-[2-(2R-methylmorpholino)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-136 N2-[2-(4-Isopropylpiperazino)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-137 N2-[2-(3-N,N-Dimethylamino-8-azabicyclo[3.2.1]octan-8-yl)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-138 5-Methyl-N2-[2-(2S-methylmorpholino)pyridin-5-yl]-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-139 5-Methyl-N2-{2-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyridin-5-yl}-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-140 N2-(2,3-Dimethoxypyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-141 N2-(2-Methoxy-3-methylpyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-142 N2-[2-(2-Hydroxy)ethoxypyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-143 N2-[4-methyl-2-(4-methylpiperazino)pyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-144 N2-(2-isopropoxypyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-145 N2-[2-(2-methoxy)ethoxypyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-146 N2-[2-(1-aminocarbonyl-1-methyl)ethoxypyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-147 N2-(2-methoxy-3-trifluoromethylpyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-148 N2-[2-(3-hydroxy)propoxypyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-149 N2-[2-(3-methoxy)propoxypyridin-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-150 5-(2-(6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-chloropyridin-3-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; II-151 5-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-pyridine-2-carboxylic acid cyclobutylamide; II-152 N2-(5-methoxypyridin-3-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; II-153 N2-(2,3-dimethylpyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; III-1 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(isoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-2 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(2-hydroxyisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-3 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(2-tert-butoxycarbonylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-4 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(2-methylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-5 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(2-ethylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-6 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(2-n-propylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-7 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(2-cyclopropylmethylylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-8 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(2-isobutylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-9 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(2-isopentylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-10 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(2-cyclopentylmethylisoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-11 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(2-(bicyclo[2.2.1]heptan-2-ylmethyl)isoindolin-5-yl)-5-methylpyrimidine-2,4-diamine; III-12 5-[2-(2-acetyl-2,3-dihydro-1H-isoindol-5-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; III-13 N-{2-[2-(2,2-dimethyl-propionyl)-2,3-dihydro-1H-isoindol-5-ylamino]-5-methyl-pyrimidin-4-yl}-N-[3-(2,2-dimethyl-propionyl)-2-oxo-2,3-dihydro-benzoxazol-5-yl]-2,2-dimethyl-propionamide; III-14 5-[2-(2-methanesulfonyl-2,3-dihydro-1H-isoindol-5-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-1 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-5-methylpyrimidine-2,4-diamine; IV-2 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one-3-yl)-5-methylpyrimidine-2,4-diamine; IV-3 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(6-(4-methylpiperazin-1-yl)pyridazin-3-yl)-5-methylpyrimidine-2,4-diamine; IV-4 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(1H-indazol-6-yl)-5-methylpyrimidine-2,4-diamine; IV-5 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(1,2-benzisoxazol-6-yl)-5-methylpyrimidine-2,4-diamine; IV-6 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(1H-indazol-5-yl)-5-methylpyrimidine-2,4-diamine; IV-7 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-[2-(piperazino)pyridin-4-yl]-5-methylpyrimidine-2,4-diamine; IV-8 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-[2-(4-methylpiperazino)pyridin-4-yl]-5-methylpyrimidine-2,4-diamine; IV-9 N4-(benzo[d]oxazol-2(3H)-one-5-yl)-N2-(3-methyl-1,2-benzisoxazol-5-yl)-5-methylpyrimidine-2,4-diamine; IV-10 (Z)-2-Methyl-9-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-3,6-dihydro-2H-benzo[c]azocin-1-one; IV-11 5-[2-(2,2-difluoro-benzo[1,3]dioxol-4-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-12 5-[2-(9-isopropylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-13 5-{2-[9-(3-diethylamino-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-5-methyl-pyrimidin-4-ylamino}-3H-benzoxazol-2-one; IV-14 2-Methyl-9-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-3,4,5,6-tetrahydro-2H-benzo[c]azocin-1-one; IV-15 6-[5-methyl-4-(2-oxo-2,3-dihydro-benzoxazol-5-ylamino)-pyrimidin-2-ylamino]-3,4-dihydro-2H-isoquinolin-1-one; IV-16 5-[2-(2,2-dioxo-1H-benzo[e][1,3,4]oxathiazin-7-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-17 5-[2-(2,2-dimethyl-benzo[1,3]dioxol-5-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-18 (Z)-5-(5-methyl-2-(1-oxo-2,3-dihydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-19 (Z)-5-(5-methyl-2-(2-methyl-1-oxo-2,3-dihydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-20 (Z)-5-(5-methyl-2-(2-methyl-1-oxo-2,3-dihydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-21 5-(5-methyl-2-(2-methyl-1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-22 5,5'-(5-Methylpyrimidine-2,4-diyl)bis(azanediyl)dibenzo[d]oxazol-2(3H)-one IV-23 5-(5-methyl-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-24 5-(5-methyl-2-(2-oxo-1,2,3,4-tetrahydroquinolin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-25 6-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-2H-benzo[b][1,4]oxazin-3(4H)-one; IV-26 5-(2-(3,3-dimethyl-2-oxoindolin-6-ylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-27 5-(5-methyl-2-(1-methyl-2-oxoindolin-5-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-28 5-(5-methyl-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-29 5-(5-methyl-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-30 5-(5-methyl-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-31 5-(5-methyl-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-32 7-(5-methyl-4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-ylamino)pyrimidin-2-ylamino)-2H-benzo[b][1,4]oxazin-3(4H)-one; IV-33 5-(5-methyl-2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-34 5-(5-methyl-2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-35 5-methyl-N2-(3,4-methylenedioxy)phenyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-36 N2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-37 N2-(3,4-ethylenedioxy)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-38 N2-(2,2-dimethyl-2H-1,3-benzodioxol-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-39 N2-[spiro(2,1'-cyclohexane)-1,3-benzodioxol-5-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-40 N2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-41 5-methyl-N2-(1-methylindazol-6-yl)-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-42 5-methyl-N2-(1-methylindazol-5-yl)-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-43 5-methyl-N2-(3-methylisoxazolo[5,4-b]pyridin-5-yl)-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-44 N2-[4-(2-methoxyethyl)-2H-1,4-benzoxazin-3(4H)-one-7-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-45 N2-[2,2-dimethyl-4-(2-methoxyethyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-on-7-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-46 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one-7-yl)-2,4-pyrimidinediamine; IV-47 5-Methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-N2-(2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one-6-yl)-2,4-pyrimidinediamine; IV-48 5-Methyl-N2-(3-methylindazol-6-yl)-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-49 5-methyl-N2-(3-methylindazol-5-yl)-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-50 N2-[2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one-7-yl]-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-51 5-(5-methyl-2-(6-methylpyridin-2-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-52 5-(5-methyl-2-(5-methylpyridin-2-ylamino)pyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-53 5-[2-(isoquinolin-6-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-54 5-[5-methyl-2-(naphthalen-2-ylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-55 5-[2-(4-methoxy-naphthalen-2-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-56 5-[2-(4-hydroxy-naphthalen-2-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-57 5-[2-(isoquinolin-7-ylamino)-5-methyl-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-58 N2-(4-methoxypyridin-2-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; IV-59 5-[5-methyl-2-(2,4,6-trifluoro-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-60 5-(2-(2,6-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-61 5-[5-methyl-2-(2,4,6-trimethyl-phenylamino)-pyrimidin-4-ylamino]-3H-benzoxazol-2-one; IV-62 5-(2-(2-fluoro-6-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one; IV-63 N2-(3-fluoropyridin-4-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine; or IV-64 N2-(3-fluoropyridin-4-yl)-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine trifluoroacetate.

[0118] In certain embodiments, the compound is N2-(3,4,5-trimethyl)phenyl-5-methyl-N4-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)-2,4-pyrimidinediamine, or a pharma- ceutically acceptable salt thereof; 5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine, or a pharma- ceutically acceptable salt thereof, preferably 5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-N2-(3,4,5-trimethyl)phenyl-2,4-pyrimidinediamine bis-sodium salt; N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,4-pyrimidinediamine, or a pharma- ceutically acceptable salt thereof, preferably N2-(3-methoxy-5-trifluoromethyl)phenyl-5-methyl-N4-[3-(phosphonooxy)methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl]-2,4-pyrimidinediamine bis-sodium salt; or 5-(2-(3-methoxy-4,5-dimethylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one, or a pharma- ceutically acceptable salt thereof; (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl dihydrogen phosphate; 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one, or a pharma- ceutically acceptable salt thereof; or (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate sodium salt It is.

[0119] Further information regarding compounds of formula I can be found in WO 2010 / 085684 (International Application No. PCT / US2010 / 021856), which is incorporated herein by reference in its entirety.

[0120] B. Pyrimidinediamine Compounds Represented by Formula III In some embodiments, the compound is a pyridinediamine compound represented by formula III TIFF0007682155000039.tif31128 or a salt, solvate, N-oxide or prodrug thereof. B is alkyl, alkoxy, amino, carboxyl, carboxylester, cyano, halo, nitro, alkenyl, or alkynyl, preferably halo, e.g., F; R B is hydrogen, alkyl, alkenyl, alkynyl, or cycloalkyl, preferably H; Ring A B is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclic, where Ring A B is not indolyl or benzimidazolyl, and in some embodiments, ring A B is aryl, for example phenyl; r is 0, 1, 2, or 3, and in certain embodiments, r is 1; Each R B2 is independently alkyl, alkoxy, amino, aryl, aryloxy (i.e., aryl-O-), cyano, cycloalkyl, cycloalkoxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclyloxy, aminoacyl, carboxyl, carboxyl ester, carbonate ester, sulfonyl, oxo, nitro or halo, preferably alkoxy, such as propynyloxy; Z B1 , Z B2 , and Z B3 are each independently carbon or nitrogen, B1 If is nitrogen, Z B2 and Z B3is carbon and Z B2 If is nitrogen, Z B1 and Z B3 is carbon and Z B3 If is nitrogen, Z B1 and Z B2 is carbon and Z B1 , Z B2 , or Z B3 If is nitrogen, SO 2 R B4 R B5 is not bonded to nitrogen, and preferably Z B1 , Z B2 , and Z B3 is carbon; s is 0, 1, 2 or 3, preferably 3; Each R B3 are independently hydrogen, alkyl, alkoxy, or cycloalkyl, halo, or heterocyclic, preferably H or C 1~6 alkyl, for example methyl; R B4 and R B5 Each of is independently hydrogen, alkyl, acyl, or M + where M + is K + , Na + , Li + or + N(R B6 ) 4 where R is a metal counterion selected from B6 is hydrogen or alkyl, and SO 2 NR B4 R B5 Nitrogen is N - or R B4 or R B5 Ca 2+ , Mg 2 + and Ba 2+ is a divalent counterion selected from SO 2 NR B4 R B5 Nitrogen is N - and in some embodiments, R B4 and R B5Each of is independently hydrogen, alkyl, or acyl, e.g., H or acyl, and in certain embodiments, one of or R B4 and R B5 is H and the other is H or acyl, e.g., propionyl.

[0121] In some embodiments: If r=0, then X B is not bromo; Ring A B When is cycloalkyl, X B is not bromo; r=2, R B2 When each of R is methoxy, halo, trihalomethyl, or trihalomethoxy, B4 and R B5 is not one hydrogen and one methyl; r=2, R B2 is fluoro and methyl, R B is not alkenyl; Ring A B is phenyl, r=1, and R B2 If is chloro, R B4 and R B5 is not one hydrogen and one methyl.

[0122] Exemplary compounds of formula III include, but are not limited to, TIFF0007682155000040.tif23140 or its pharma- ceutically acceptable salt, solvate, N-oxide or prodrug. Compound BI is also called N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine. Compound B-II is also called 5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine.

[0123] Those skilled in the art will appreciate that Compound B-II can be a prodrug of Compound BI, and that Compound B-II is not necessarily pharmacologically inactive until converted to Compound BI. The mechanism by which the propionyl progroup is metabolized is not critical and can be, for example, by hydrolysis under acidic conditions in the stomach and / or by enzymes present in the digestive tract and / or tissues or organs of the body, such as esterases, amidases, lipolases, phosphatases including ATPases and kinases, cytochrome P450 in the liver, and the like.

[0124] Further information regarding compounds of formula III, such as compounds BI and B-II, can be found in WO 2011 / 017178 (International Application No. PCT / US2010 / 043592) and WO 2006 / 133426 (International Application No. PCT / US2006 / 022590), both of which are incorporated by reference in their entireties.

[0125] C. Pyrazole Compounds In some embodiments, the compound is a pyrazole compound. The compound has formula IV TIFF0007682155000041.tif40128 or a salt, prodrug, solvate and / or N-oxide thereof. With respect to formula IV, Het-1 is a 5-membered heteroaryl, such as thiazolyl or furanyl; y is 1 to 2; R C2 is H, aliphatic, heteroaliphatic, heteroalicyclic, aryl, amido, heterocyclyl, or araliphatic, such as H alkyl, haloalkyl, or cycloalkyl, and in some embodiments, R C2 is alkyl, haloalkyl, or cycloalkyl; Each R C3 is independently H or aliphatic, e.g., H or alkyl; R C4 , R C5 , R C6 and RC7 each is independently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, -O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl, carboxyl ester, acyl, amido, amino, sulfonyl, sulfonamido, sulfanyl, or sulfinyl; R C8 and R C9 is each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, halogen, haloalkyl, carboxyl ester, cyano, or amino, e.g., H, halogen, haloalkyl, or alkyl; and in some embodiments, R C8 and R C9 Each of is independently H or aliphatic, for example, H, alkyl, or haloalkyl. R C10 is H, aliphatic, alkoxy, heteroaliphatic, carboxyl ester, araliphatic, NO 2 , CN, OH, haloalkyl, acyl, alkyl phosphate, or alkyl phosphonate, such as H, aliphatic, such as alkyl, carboxyl ester, acyl, alkyl phosphate, alkyl phosphonate, or aralkyl, and in some embodiments, R C10 is H, alkyl, alkyl phosphate or alkyl phosphonate.

[0126] In some embodiments, R C4 , R C6 , and R C7 each independently is H; halo, such as F; or aliphatic, such as alkyl or haloalkyl, preferably CF 3 and / or R C5 is H; halo, such as F; aliphatic, such as alkyl or haloalkyl, preferably CF 3 alkoxy, for example methoxy or -O-CH 2 C(CH 3 ) 2OH; heterocyclyl, such as morpholin-4-yl or 1-methylpiperidin-4-yl; or -O-heterocyclyl, such as -O-(oxetan-3-yl). C4 , R C5 , R C6 and R C7 Each of R is independently H or F. Also in certain embodiments, R C4 , R C5 , R C6 and R C7 At least one of is not H.

[0127] In some embodiments, the compound has formula V or VI TIFF0007682155000042.tif40128 or a salt, prodrug, solvate and / or N-oxide thereof. For Formula V and Formula VI, the variables are as previously defined for Formula IV, R C11 , R C12 and R C14 Each of is independently H or aliphatic, e.g., H or alkyl.

[0128] Exemplary compounds of formula IV include, but are not limited to, those listed in List 2 below.

[0129] List 2: Exemplary compounds of formula IV V-1: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide 2,2,2-trifluoroacetate; V-2: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide; V-3: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-4: tert-butyl 4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate; V-5: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-6: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide formic acid; V-9: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide; V-10: di-tert-butyl((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl)phosphate; V-11: tert-butyl((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl)hydrogen phosphate; V-12: (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate; V-13: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-14: sodium (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl phosphate; V-16: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-17: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide hydrochloride; V-18: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide; V-19: 1-(isobutyryloxy)ethyl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate; V-20: tert-butyl (S)-(1-(4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate; V-21: 1-methylcyclopropyl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate; V-22: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate; V-23: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-24: 5-(5-nitro-1H-pyrrol-3-yl)-N-(1-(propoxymethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-25: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-26: 5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-27: N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-28: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-29: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide; V-30: 5-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-31: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide; V-32: N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-33: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-34: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-35: (4-(5-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl phosphate bis-sodium salt; V-36: (4-(5-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate; V-37: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-38: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-39: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-ethyl-1H-pyrazol-4-yl)furan-2-carboxamide formate; V-40: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-ethyl-1H-pyrazol-4-yl)furan-2-carboxamide; V-41: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide formate; V-42: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-43: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)furan-2-carboxamide formate; V-44: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)furan-2-carboxamide; V-45: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide formate; V-46: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide; V-47: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-48: 5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate; V-49: 5-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)-N-(1-((3-methyloxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-52: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate; V-53: 5-(1-(2-(2-methoxyethoxy)ethyl)-1H-pyrazol-4-yl)-N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-54: (4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate; V-55: sodium (4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl phosphate; V-56: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide formate; V-57: N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide; V-58: 5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide formate; V-59: 5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-67: N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate; V-68: 5-(1-methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide; V-69: 5-(1-methyl-1H-pyrazol-4-yl)-N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}furan-2-carboxamide, formate; V-70: tert-butyl-3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate, formate; V-71: N-{1-(3-M ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate, cis isomer; V-72: N-{1-(3-M ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, cis isomer; V-73: N-{1-(3-benzyloxy)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, trans isomer; V-74: tert-butyl-3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate; V-75: N-(1-((1s,3s)-3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-76: N-(1-((1s,3s)-3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-77: N-{1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, free base; V-78: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, TFA salt; V-79: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-80: di-tert-butyl-[[4-{4-(5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl}methyl]phosphate; V-81: [4-{5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2yl}-1H-pyrazol-1-yl]methyl dihydrogen phosphate; V-82: sodium [4-{5-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl}-1H-pyrazol-1-yl]methyl phosphate; V-83: N-{1-(1-acetylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, free base; V-84: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-(tert-butyl)azetidine-1-carboxamide, free base; V-85: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-isopropylazetidine-1-carboxamide, free base; V-86: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-propylazetidine-1-carboxamide, free base.

[0130] V-87: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-cyclopropylazetidine-1-carboxamide, formate; V-88: 3-[4-{5-(1H-pyrazol-4-yl)furan-2-carboxamide}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]-N-cyclopropylazetidine-1-carboxamide; V-89: N-[1-{1-(cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate; V-90: N-[1-{1-(cyclopropanecarbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-91: N-[1-{1-pivaloylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate; V-92: N-[1-{1-pivaloylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-93: 5-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-(pyrrolidine-1-carbonyl)azetidin-3-yl}-1H-pyrazol-4-yl)furan-2-carboxamide, formate; V-94: 5-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-(pyrrolidine-1-carbonyl)azetidin-3-yl}-1H-pyrazol-4-yl)furan-2-carboxamide; V-95: N-[1-{1-isobutyrylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate; V-96: N-[1-{1-isobutyrylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-97: N-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl}-1H-pyrazol-4-yl}furan-2-carboxamide, TFA salt; V-98: N-(1H-pyrazol-4-yl)-N-{3-(pyridin-2-yl)-1-{1-(2,2,2-trifluoroethyl)azetidin-3-yl}-1H-pyrazol-4-yl}furan-2-carboxamide; V-99: N-[1-{1-butyrylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate; V-100: N-[1-{1-butyrylazetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-101: N-{1-(1-methylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate; V-102: N-{1-(1-methylazetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-103: N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide, formate; V-104: N-[1-{1-(2,2-difluorocyclopropane-1-carbonyl)azetidin-3-yl}-3-(pyridin-2-yl)-1H-pyrazol-4-yl]-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-105: N-(1-methyl-3-(5-morpholinopyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-106: N-(1-methyl-3-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-107: N-(3-(5-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-108: N-(1-methyl-3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-109: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-110: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-111: N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-112: N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-113: 5-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-114: N-(1-((1s,3s)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-115: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-116: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-117: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-122: 5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide 2,2,2-trifluoroacetate; V-123: 5-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-124: N-(1-((1s,4s)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-125: N-(1-((1s,4s)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-126: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-127: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-128: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide formate; V-129: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-130: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-131: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-132: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-133: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-134: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-135: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-136: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-137: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-138: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-139: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-140: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-141: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-142: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-143: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-144: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-145: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-146: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide formate; V-147: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)furan-2-carboxamide; V-148: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-149: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-150: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-151: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-152: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-153: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-154: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide formate; V-155: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; V-156: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; VI-1: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-2: 1-(isobutyryloxy)ethyl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; VI-3: tert-butyl (R)-(3-methyl-1-(4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-1-oxobutan-2-yl)carbamate; VI-4: 2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-5: 1-Methylcyclopropyl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; VI-6: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl 4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; VI-7: diethyl ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonate; VI-8: sodium ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonate; VI-9: ((4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphonic acid; VI-10: 2-(1H-Pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-11: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-12: N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-13: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-14: N-(1-((1,3-cis)-3-hydroxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-15: N-(1-((1s,3s)-3-(dimethylamino)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-16: (4-(4-((1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate bis-sodium salt; VI-17: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate; VI-18: N-(1-(2-Ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, formate salt; VI-19: N-(1-(2-Ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate salt; VI-20: N-(1-(2-Ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-21: N-(1-(2-Ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate salt; VI-22: N-(1-(2-Ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-23: 2-(3,5-Dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate salt; VI-24: 2-(3,5-Dimethyl-1H-pyrazol-4-yl)-N-(1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-25: N-(1-(2-Ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-26: N-(1-Methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-27: 2-(3-Methyl-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-28: N-(1-(2-Methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-29: N-(1-(2-Methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate; VI-30: N-(1-(2-Methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-31: N-(1-(2-Ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-32: 2-(1H-Pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-33: 2-(1H-Pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-34: N-(1-(Oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-35: (4-(4-((1-Methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate; VI-36: Sodium (4-(4-((1-Methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate; VI-37: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-38: potassium (4-(4-((1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate; VI-39: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-40: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-41: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide, formate; VI-42: 2-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-43: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-44: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-45: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-46: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-47: N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-48: N-(1-((3-(hydroxymethyl)oxetan-3-yl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-49: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, formate; VI-50: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-51: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(1-(3-methoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-52: N-(1-(2-fluoroethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-53: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-54: tert-butyl-3-[4-{2-(1H-pyrazol-4-yl)thiazole-2-carboxamido}-3-(pyridin-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate, free base; VI-55: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, TFA salt; VI-56: N-{1-(azetidin-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-57: N-{1-(3-M ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl}-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide, free base, cis isomer; VI-58: N-(3-(5-methoxypyridin-2-yl)-1-methyl-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-59: N-(1-isopropyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-60: N-(1-(2-morpholinoethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-61: N-(1-(2-(4-methylpiperazin-1-yl)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-65: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-66: 2-(1H-pyrazol-3-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-71: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-72: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-73: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-76: N-(1-((1s,3s)-3-isopropoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-77: potassium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate; VI-78: calcium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate; VI-79: N-(1-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-80: Ammonium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate; VI-81: 5-amino-5-carboxypentan-1-aminium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate; VI-82: 1-(4-amino-4-carboxybutyl)guanidinium(4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate; VI-83: ​​(4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate; VI-84: 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate; VI-85: triethylammonium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl hydrogen phosphate; VI-86: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-87: N-(1-(3-hydroxy-3-methylcyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-88: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-89: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-90: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-91: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-92: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-93: 2-(3,5-dimethyl-1H-pyrazol-4-yl)-N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-94: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-95: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-96: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-97: N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-98: 2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-(1-(difluoromethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-99: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)-2-(3-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-100: 2-(3-methyl-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-103: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-104: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-105: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-106: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-107: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-108: 2-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-117: N-(1-(2-(diethylamino)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-118: N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-119: N-(1-(2-(2-fluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-120: N-(1-benzyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-121: N-(1-cyclobutyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-122: N-(1-(2-(2,2-difluoroethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-123: N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-124: N-(1-(((1r,3r)-3-hydroxycyclobutyl)methyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-125: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-126: N-(1-(dimethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-127: N-(1-((1s,3s)-3-(ethoxy-d5)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-128: N-(1-(diethylcarbamoyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-129: N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-130: N-(1-((1s,3s)-3-(2-fluoroethoxy)cyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-131: N-(1-(morpholine-4-carbonyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-132: N-(1-(3-fluorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-133: N-(1-(3-fluorocyclobut-2-en-1-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-134: N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-135: N-(1-(3,3-difluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-140: N-(3-(3-fluoropyridin-2-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-141: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-142: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-143: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-144: N-(1-((1r,4r)-4-hydroxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-145: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-146: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-147: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-148: N-(1-((1S,3R)-3-ethoxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-149: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-150: N-(1-((1S,3R)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-151: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-152: N-(1-((1S,3S)-3-hydroxycyclopentyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-153: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-154: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-155: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-156: N-(1-((1S,3R)-3-ethoxy-2-fluorocyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-157: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-158: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-159: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(4-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-160: N-(1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-161: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-162: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-163: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate; VI-164: sodium (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate; VI-165: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-166: N-(3-(3-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-167: N-(3-(3-fluoropyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-168: N-(3-(3-fluoropyridin-2-yl)-1-((1r,3r)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-169: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-170: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide formate; VI-171: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-(2,2,2-trifluoroethoxy)cyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-172: N-(3-(6-fluoropyridin-2-yl)-1-((1s,3s)-3-hydroxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-173: (4-(4-((1-((1s,3s)-3-ethoxycyclobutyl)-3-(6-fluoropyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate; VI-174: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-175: N-(1-((1s,4s)-4-ethoxycyclohexyl)-3-(3-fluoropyridin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-176: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-177: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,4s)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; or VI-180: N-(3-(3,5-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide.

[0131] In certain embodiments, the compound is TIFF0007682155000043.tif85147 or a pharma- ceutically acceptable salt thereof.

[0132] Further information regarding pyrazole compounds, such as those represented by formula IV, can be found in US Pat. No. 9,982,000, which is incorporated herein by reference in its entirety.

[0133] D. Further Pyrazole Compounds Disclosed herein are pyrazole compounds, methods of making the compounds, and methods of using the compounds. In one embodiment, the disclosed compounds are tyrosine kinase inhibitors and / or may be useful for blocking one or more cytokine signaling pathways, such as the IL-17 signaling pathway. For certain embodiments, the pyrazole compounds are useful for treating diseases in which inhibition of the Interleukin-1 Receptor Associated Kinase (IRAK) pathway is therapeutically useful. In some embodiments, the compounds inhibit IRAK proteins, such as IRAK1, IRAK2, IRAK3, or IRAK4. In other embodiments, the compounds are useful for delivering IRAK inhibitor compounds and / or may be prodrugs of IRAK inhibitors. In certain embodiments, the pyrazole compounds are: It is a prodrug of TIFF0007682155000044.tif39128.

[0134] In some embodiments, the pyrazole compound has the general formula VII TIFF0007682155000045.tif52128 or its salt, solvate or N-oxide. With respect to formula VII, R is H, aliphatic, acyl, heterocyclyl, carboxyl ester, amide, alkyl phosphoramidate, or alkyl phosphate. In some embodiments, R is not H, or alternatively, R is H, and the compound is a salt. In other embodiments, R is alkyl, acyl, carboxyl ester, amide, non-aromatic heterocyclyl, alkyl phosphoramidate, or alkyl phosphate. Those skilled in the art will understand that a compound (wherein R is not H) can act as a prodrug of a compound (wherein R is H), for example, when administered to a subject.

[0135] In some embodiments, R is H, C 1~4 Alkyl phosphate, C 1~4 Alkyl phosphoramidate, C 1~6 Alkyl, C 1~6 Acyl, -C(O)OC1~6 Aliphatic, -C(O)N(R b ) 2 or 5- or 6-membered non-aromatic heterocyclyl, however in certain embodiments, R is not H or R is H and the compound is a salt.

[0136] Regarding the R part, C 1~6 The alkyl portion can be unsubstituted or it can be, for example, a 5- or 6-membered non-aromatic heterocyclyl, OH, -OC(O)-R a , -N(R b ) 2 , -OC(O)-R c , carboxyl, or combinations thereof; C 1~6 The acyl moiety can be unsubstituted or it can be -C(O)OC 1~4 Alkyl, -C(O)OC 1~4 Alkyl-N(R b ) 2 , N(R b ) 2 , -NHC(O)C 1~4 alkyl, or combinations thereof; The 5- or 6-membered heterocyclyl moiety may be a 5- or 6-membered oxygen-containing heterocyclyl and / or may be substituted with hydroxyl, hydroxymethyl, or combinations thereof; or -C(O)OC 1~6 Aliphatic is -OC(O)C 1~4 Alkyl or N(R b ) 2 -C(O)OC 1~6 It may be alkyl or -C(O)OC 1~6 Aliphatic is C 1~4 -C(O)OC optionally substituted with alkyl 3~6 It may be cycloalkyl.

[0137] In any embodiment, each R a are independently 5-membered non-aromatic heterocyclyl, -CH 2 N(R b ) 2substituted aryl, carboxyl substituted C 3~6 Cycloalkyl, C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl, or N(R b ) 2 , carboxyl, carboxyl ester, -OC 1~6 Acyl, -NHC(O)(NH 2 ) C 1~6 Alkyl or -(OCH 2 CH 2 ) 1~8 N(R b ) 2 C substituted with one or more, e.g., one, two or three, 1~6 is alkyl; Each R b are independently H, unsubstituted C 1~6 Alkyl, -N(R g ) 2 C replaced with 1~6 alkyl, carboxyl ester, or 5- or 6-membered non-aromatic heterocyclyl, or two R b may be, together with the nitrogen to which they are attached, one or two -O- or -N(R g ) may be interposed C 3~6 forming a non-aromatic heterocyclyl moiety, where R g is H or C 1~4 is alkyl; -OC(O)-R c is -OC(O)-R c The -OC(O)- portion of R is derived from an amino acid corresponding to the acid portion of the amino acid c is -N(R b ) 2or a nitrogen-containing non-aromatic heterocyclyl, such as a 5- or 6-membered unsaturated nitrogen-containing heterocyclyl, such as pyrrolidinyl. The amino acid can be any amino acid, such as a natural amino acid, selected from glycine, valine, alanine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine, glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine, or proline. Those skilled in the art will appreciate that amino acids contain one or more asymmetric centers, and all enantiomers, diastereomers, and / or mixtures thereof are contemplated. For example, the amino acid can be an L-amino acid, a D-amino acid, or a mixture thereof. In some embodiments, the amino acid is an L-amino acid. Also, in certain embodiments, -OC(O)-R c is -OC(O)CH(NH 2 )R d , TIFF0007682155000046.tif14128, or -OC(O)-(CH 2 ) 1~2 C(NH 2 )CO 2 H, where R d is an amino acid side chain, and / or H, -CH 3 , isopropyl, -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )Et, -CH 2 CH 2 SCH 3 , TIFF0007682155000047.tif20128,-CH 2 OH, -CH(OH)CH 3 , -CH 2 C(O)NH 2 , -CH 2 CH 2 C(O)NH 2 , -CH 2 SH, -CH 2 CH 2 CH 2 NHC(O)(NH)NH 2 , TIFF0007682155000048.tif11128,-CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CO 2 H or CH 2 CH 2 CO 2 It can be H.

[0138] In any embodiment, the compound may be a salt, such as a pharma- ceutically acceptable salt, as defined herein, and in some embodiments, the salt is a hydrochloride, citrate, hemicitrate, hemitartrate, tartrate, benzenesulfonate, mesylate, sodium, hemisuccinate, or succinate salt.

[0139] Some exemplary compounds of formula I include: TIFF0007682155000049.tif96138TIFF0007682155000050.tif196138TIFF0007682155000051.tif200138TIFF0007682155000052.tif195138 TIFF0007682155000053.tif216138TIFF0007682155000054.tif202138TIFF0007682155000055.tif224138TIFF0007682155000056.tif130138

[0140] Exemplary compounds of formula I include: VII-1: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-2: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate; VII-3: di-tert-butyl((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphate; VII-4: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate disodium salt; VII-5: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-6: 2-(1-(acetyl-L-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-7: 1-Methylcyclopropyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; VII-8: 1-(isobutyryloxy)ethyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; VII-9: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-10: 2-morpholinoethyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; VII-11: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hemitartrate; VII-12: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(morpholine-4-carbonyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-13: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-morpholinopropyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-14: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((3-(dimethylamino)propyl)carbamoyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-15: 3-morpholinopropyl 4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazole-1-carboxylate; VII-16: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate hydrochloride; VII-17: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-prolinate hydrochloride; VII-18: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate; VII-19: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl glycinate hydrochloride; VII-20: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate disodium salt; VII-21: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate hydrochloride; VII-22: 2-(1-acetyl-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-23: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-2-methylpropanoate hydrochloride; VII-24: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid; VII-25: methyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate; VII-26: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-morpholinoacetyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-27: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-hydroxy-3-morpholinopropyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-28: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-morpholinoacetate; VII-29: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate; VII-30: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate benzenesulfonate; VII-31: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-valinate mesylate; VII-32: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate; VII-33: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartate hydrochloride; VII-34: methyl N-(2-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-2-oxoethyl)-N-methylglycinate; VII-35: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate; VII-36: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate benzenesulfonate; VII-37: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-(morpholinomethyl)benzoate; VII-38: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartate hydrochloride; VII-39: (1R,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; VII-40: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (S)-2-amino-3,3-dimethylbutanoate mesylate; VII-41: (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid hydrochloride; VII-42: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4S)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((2S,3S,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-43: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-44: tert-butyl(1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl)hydrogen phosphate acetate sodium salt; VII-45: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl isopropyl carbonate; VII-46: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl di(((isopropoxycarbonyl)oxy)methyl)phosphate; VII-47: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartate; VII-48: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl L-aspartate benzenesulfonate; VII-49: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate tris salt; VII-50: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl glycinate benzenesulfonate; VII-51: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate benzenesulfonate; VII-52: 2-(4-methylpiperazin-1-yl)ethyl 4-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-oxobutanoate succinate; VII-53: (2R,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid; VII-54: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl acetate; VII-55: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartate benzenesulfonate; VII-56: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid tris salt; VII-57: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((S)-2-amino-3-methylbutanamido)butanoate hydrochloride; VII-58: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-59: 2-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)acetic acid; VII-60: ((((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(hydroxy)phosphoryl)oxy)methyl isopropyl carbonate; VII-61: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate hydrochloride; VII-62: isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate; VII-63: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate tris salt; VII-64: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hydrochloride; VII-65: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide benzenesulfonate; VII-66: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide tartrate; VII-67: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide sodium salt; VII-68: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hemicitrate; VII-69: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate ditris salt; VII-70: benzyl ((S)-1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate; VII-71: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl L-prolinate; VII-72: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl glycinate; VII-73: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl (R)-2-amino-3,3-dimethylbutanoate; VII-74: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-2-methylpropanoate; VII-75: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl L-aspartate; VII-76: (S)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid; VII-77: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((S)-2-amino-3-methylbutanamido)butanoate; VII-78: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 1-amino-3,6,9,12,15,18-hexaoxahenicosan-21-oate; VII-79: 2-(1-(acetyl-D-leucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-80: 2-(1-(acetylleucyl)-1H-pyrazol-4-yl)-N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-81: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl D-valinate; VII-82: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methylvalinate; VII-83: ​​(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl D-prolinate; VII-84: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl prolinate; VII-85: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 2-amino-3,3-dimethylbutanoate; VII-86: (1S,2S)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; VII-87: (1R,2S)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; VII-88: (1S,2R)-2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; VII-89: 2-(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)carbonyl)cyclohexane-1-carboxylic acid; VII-90: (R)-2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid; VII-91: 2-amino-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid; VII-92: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methyl D-aspartate; VII-93: 4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)1-methylaspartate; VII-94: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methyl D-aspartate; VII-95: 1-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)4-methylaspartate; VII-96: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-((R)-2-amino-3-methylbutanamido)butanoate; VII-97: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl 4-(2-amino-3-methylbutanamido)butanoate; VII-98: isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)-D-alaninate; VII-99: isopropyl(((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)(phenoxy)phosphoryl)alaninate; VII-100: (2R,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid; VII-101: (2S,3R)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid; VII-102: (2S,3S)-2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid; VII-103: 2,3-diacetoxy-4-((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methoxy)-4-oxobutanoic acid; VII-104: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide phosphate; VII-105: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide gentisate; or VII-106: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide succinate.

[0141] III.Synthesis A. Synthesis of pyrimidinediamine compounds represented by formula I The 2,4-pyrimidinediamine compounds described herein can be synthesized by a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods.Suitable exemplary methods that can be routinely adapted to synthesize the 2,4-pyrimidinediamine compounds and prodrugs described herein can be found in U.S. Patent No. 5,958,935, the disclosure of which is incorporated herein by reference.Specific examples illustrating the synthesis of many 2,4-pyrimidinediamine compounds and prodrugs, as well as their intermediates, are described in U.S. Patent Application No. 10 / 355,543, filed January 31, 2003 (U.S. Patent Application Publication No. 2004 / 0029902A1), the contents of which are incorporated herein by reference. Suitable exemplary methods that may be routinely used and / or adapted to synthesize active 2,4-substituted pyrimidinediamine compounds are also found in International Application No. PCT / US03 / 03022 (WO 03 / 063794), filed January 31, 2003, U.S. Patent Application No. 10 / 631,029, filed July 29, 2003, International Application No. PCT / US03 / 24087 (WO 2004 / 014382), U.S. Patent Application No. 10 / 903,263, filed July 30, 2004, and International Application No. PCT / US2004 / 24716 (WO 005 / 016893), the disclosures of which are incorporated herein by reference. All of the compounds described herein (including prodrugs) can be prepared by routine adaptation of these methods.

[0142] Certain exemplary synthetic methods for the 2,4-substituted pyrimidinediamines described herein are also described below in Example 1. One of skill in the art could also readily adapt these examples for the synthesis of additional 2,4-substituted pyrimidinediamines described herein.

[0143] Various exemplary synthetic routes that can be used to synthesize the 2,4-pyrimidinediamine compounds described herein are shown in Schemes (I)-(VII) below. These methods can be routinely adapted to synthesize the 2,4-substituted pyrimidinediamine compounds described herein. After each reaction step, the product can be purified or, depending on its chemical nature, can be used in the next step without purification.

[0144] For example, the compounds can be synthesized from substituted or unsubstituted uracil as shown in Scheme (I) below. In Scheme (I), rings A, R 5 , (R 2 ) p , X, Y, Z 1 , and Z 2 is as defined for pyrimidinediamine compounds. According to scheme (I), uracil A-1 can be reacted with a standard halogenating agent, such as POCl, under standard conditions. 3 (or other standard halogenating agents) to give 2,4-dichloropyrimidine A-2. 5 Depending on the substituents, the chloride at the C4 position is more reactive towards nucleophiles than the chloride at the C2 position. This difference in reactivity can be exploited by first reacting 2,4-dichloropyrimidine A-2 with one equivalent of amine A-3 to give 4N-substituted-2-chloro-4-pyrimidineamine A-4, which is subsequently reacted with amine A-5 to give 2,4-pyrimidinediamines of formula A-6 (compounds of formula I, where R 3 and R 4 where each of is H. Compounds of formula I, where either or both of the NH groups at C2 and C4 of the pyrimidine are substituted, can be made, for example, by alkylation of the NH groups. TIFF0007682155000057.tif77136

[0145] Typically, C4 halides are more reactive towards nucleophiles, as shown in the scheme. However, as will be appreciated by those skilled in the art, R 5 The properties of the substituents can change their reactivity. For example, R 5 When is trifluoromethyl, a 50:50 mixture of 4N-substituted-4-pyrimidinamine A-4 and the corresponding 2N-substituted-2-pyrimidinamine A-5 is obtained. The regioselectivity of the reaction can also be controlled by adjusting the solvent and other synthetic conditions (such as temperature), as is well known in the art.

[0146] The reaction shown in Scheme (I) may proceed more rapidly if the reaction mixture is heated by microwaves. When heating in this manner, the following conditions may be used: heat to 175° C. in ethanol for 5-20 minutes in a sealed tube (at 20 bar pressure) in a Smith Reactor (Personal Chemistry, Uppsala, Sweden).

[0147] The uracil A-1 starting material can be purchased from commercial sources or prepared using standard techniques of organic chemistry. Commercially available uracils that can be used as starting materials in Scheme (I) include, by way of example and without limitation, uracil (Aldrich #13,078-8; CAS Registry 66-22-8); 5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7; 5-fluorouracil (Aldrich #85,847-1; CAS Registry 51-21-8); 5-iodouracil (Aldrich #85,785-8; CAS Registry 696-07-1); 5-nitrouracil (Aldrich #85,276-7; CAS Registry 611-08-5); 5-(trifluoromethyl)-uracil (Aldrich #22,327-1; CAS Registry 611-08-5); 54-20-6). Additional 5-substituted uracils are available from common intermediates from Canada, Inc. (Edmonton, Calif.) and / or Interchim (Cedex, France) or can be prepared using standard techniques. References to Myriad textbooks teaching suitable synthetic methods are provided below.

[0148] Amines A-3 and A-5 can be purchased from commercial sources or, alternatively, can be synthesized using standard techniques. For example, suitable amines can be synthesized from nitro precursors using standard chemistry. Specific exemplary reactions are shown in the Examples section. See also Vogel, 1989, Practical Organic Chemistry, Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

[0149] Those skilled in the art will recognize that in some cases, the substituent X in the amines A-3 and A-5 and / or the uracil A-1 may contain functional groups that require protection during synthesis. The identity of any protecting groups used will depend on the identity of the functional group being protected and will be apparent to those skilled in the art. Guidance for selecting appropriate protecting groups and synthetic methods for their attachment and removal can be found, for example, in Green & Wuts.

[0150] Thus, a protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed as needed during the course of a synthesis. Examples of protecting groups can be found in Green & Wuts and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), etc. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated to form acetates and benzoates or alkylated to form benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups), and allyl ethers.

[0151] A particular embodiment of Scheme (I) using 5-fluorouracil (Aldrich #32,937-1) as the starting material is shown below in Scheme (Ia). In Scheme (Ia), Ring A, (R 2 )p , X, Y, Z 1 , and Z 2 is as previously defined for Scheme (I). Compound A-10, a 2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine, can be prepared by the synthesis of 2,4-dichloro-5-fluoropyrimidine A-8 (commercially available or, for example, starting from uracil, e.g., POCl 3 The amine A-7 is preferably reacted with one equivalent of amine A-3 to give 2-chloro-N4-substituted-5-fluoro-4-pyrimidineamine A-9, followed by reaction with one or more equivalents of amine A-5, typically about 1.1 equivalents of A-5 to about 2 equivalents of A-5. TIFF0007682155000058.tif73138

[0152] While many of the synthetic schemes described above do not show the use of protecting groups, those of skill in the art will recognize that in some cases, certain substituents, e.g., R 2 It will be appreciated that the protecting groups may include functional groups requiring protection, and / or other groups. The exact identity of the protecting group used will depend, inter alia, on the identity of the functional group being protected and the reaction conditions used in the particular synthetic scheme, and will be apparent to one of skill in the art. Guidance for selecting protecting groups suitable for a particular application, their attachment and removal can be found, for example, in Green & Wuts.

[0153] The prodrugs described herein can be prepared by routine adjustment of the above method. Alternatively, such prodrugs can be prepared by reacting a suitably protected 2,4-pyrimidinediamine with a suitable reagent to add the desired progroup. The conditions for carrying out such reactions and for deprotecting the product to obtain the prodrugs described herein are well known.

[0154] In general, the Myriad references which teach methods useful for synthesizing pyrimidines, as well as the starting materials described in Schemes (I)-(VII), are known in the art. For specific guidance, the reader is directed to Brown, DJ, “The Pyrimidines”, The Chemistry of Heterocyclic Compounds, Volume 16 (Weissberger, A., Ed.), 1962, Interscience Publishers, (A Division of John Wiley & Sons), New York ("Brown I"); Brown, DJ, “The Pyrimidines”, The Chemistry of Heterocyclic Compounds, Volume 16, Supplement I (Weissberger, A. and Taylor, EC, Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), New York (Brown II"); Brown, DJ, “The Pyrimidines”, The Chemistry of Heterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. and Taylor, EC, Ed.), 1985, An Interscience Publication (John Wiley & Sons), New York ("Brown III”);Brown, DJ, “The Pyrimidines”The Chemistry of Heterocyclic Compounds,Volume 52(Weissberger,A.and Taylor,EC,Ed.),1994,John Wiley&Sons,Inc.,New York,pp.1-1509(Brown IV”);Kenner, GWand Todd,A.,Heterocyclic Compounds,Volume 6, (Elderfield, RC, Ed.), 1957, John Wiley, New York, Chapter 7 (pyrimidines); Paquette, LA,Principles of Modern Heterocyclic Chemistry,1968,WABenjamin,Inc.,New York,pp.1-401(uracil synthesis pp.313,315;pyrimidineamine synthesis pp.313-316;amino pyrimidineamine synthesis pp.315);Joule,JA,Mills,K.and Smith,GF,Heterocyclic Chemistry,3. rd Edition,1995,Chapman and Hall,London,UK,pp.1-516;Vorbrueggen,H.and Ruh-Pohlenz,C.,Handbook of Nucleoside Synthesis,John Wiley&Sons,New York,2001,pp.1-631(protection of pyrimidines by acylation pp.90-91;silylation of pyrimidines pp.91-93);Joule, JA, Mills, K. and Smith, GF, Heterocyclic Chemistry, 4 th Edition, 2000, Blackwell Science, Ltd, Oxford, UK, pp. 1-589; and Comprehensive Organic Chemistry, Volumes 1-9 (Trost, BM and Fleming, I., Ed.), 1991, Pergamon Press, Oxford, UK.

[0155] B. Synthesis of Compounds BI and B-II Compounds BI and B-II, as well as exemplary salts B-III through B-VII, are synthesized as described below, or by methods analogous to the syntheses described below. Alternative syntheses will be appreciated by those skilled in the art. TIFF0007682155000059.tif74140

[0156] BI: N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine 4-Nitrophenol (1.00 g, 7.19 mmol), propargyl bromide (80 wt% in toluene; 0.788 mL, 7.09 mmol), and K 2 CO 3 (1.08 g, 7.84 mmol) were combined and stirred in acetone (16.0 mL) at 60 °C for 18 h. The reaction mixture was cooled to room temperature and diluted with water (200 mL). 4-(prop-2-ynyloxy)nitrobenzene was isolated by suction filtration as a white solid (1.12 g). 1H NMR (CDCl3): δ 8.22 (d, J = 9.0 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 4.80 (d, J = 2.4 Hz, 2H), 2.59 (t, J = 2.4 Hz, 1H).

[0157] 4-(prop-2-ynyloxy)nitrobenzene (0.910 g, 5.13 mmol), iron (1.42 g, 25.3 mmol), and NH 4 Cl (0.719 g, 12.8 mmol) was vigorously stirred in EtOH / water (1:1, 55 mL) at 70 °C for 15 min. The reaction mixture was filtered hot through diatomaceous earth and concentrated under reduced pressure. The residue was suspended in 10% 2N ammoniacal methanol in dichloromethane, sonicated, and filtered through diatomaceous earth. Concentration gave 4-(prop-2-ynyloxy)aniline as an oil, which was used without further purification. 1H NMR (CDCl3): δ 6.82 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 8.7 Hz, 2H), 4.61 (d, J = 2.4 Hz, 2H), 2.50 (t, J = 2.4 Hz, 1H).

[0158] 4-(Prop-2-ynyloxy)aniline (0.750 g, 5.10 mmol) and 2,4-dichloro-5-fluoropyrimidine (1.27 g, 0.760 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wisconsin, USA) were stirred in MeOH / water (4:1, 35 mL) at room temperature for 18 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with 1N HCl (50 mL) and brine (50 mL). The organic layer was dried (MgSO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes with gradient to EtOAc:hexanes (1:10)) to give 2-chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidinamine as a light brown solid (0.514 g). 1H NMR (CDCl3): δ 8.03 (d,J=2.7 Hz, 1H), 7.53 (d,J=8.7 Hz, 2H), 7.02 (d,J=8.7 Hz, 2H), 6.86 (s, 1H), 4.71 (d,J=2.4 Hz, 2H), 2.55 (t,J=2.4 Hz, 1H); LCMS: purity: 99%; MS (m / e): 279 (MH + ).

[0159] 2-Chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidinamine (0.514 g, 1.85 mmol), 3-(aminosulfonyl)-4-methylaniline (0.689 g, 3.70 mmol, made by reaction of commercially available 2-methyl-5-nitrobenzenesulfonamide or synthesized as described below), and trifluoroacetic acid (0.186 mL, 2.41 mmol) were combined with iPrOH (6.0 mL) in a sealed vial and heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine (BI) was isolated by suction filtration as a white solid (0.703 g). 1H NMR (DMSO-d6): δ 10.08(bs,2H), 8.19(d,J=4.5Hz, 1H), 7.89(s,1H), 7.74(dd,J=2.4 and 8.4Hz, 1H), 7.58(d,J=8.7Hz, 2H), 7.32(bs,2H), 7.23(d,J=8.4Hz, 1H), 6.97(d,J=8.4Hz, 2H), 4.79(d,J=2.1Hz, 2H), 3.59-3.55(m,1H), 2.53(s,3H); LCMS: Purity: 97%; MS(m / e): 428(MH + ).

[0160] B-II: 5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine N2-(3-aminosulfonyl-4-methylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine, BI, (0.200 g, 0.467 mmol), DMAP (40 mg, 0.33 mmol)) and triethylamine (0.118 mL, 0.847 mmol) were stirred in THF (6.0 mL). Propionic anhydride (0.180 mL, 1.40 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature overnight. The solution was diluted with ethyl acetate (50 mL) and washed with water (5×25 mL) and brine (10 mL). The organic layer was dried (MgSO 4 ), filtered and evaporated. The residue was suspended in ethyl acetate (25 mL), sonicated and the solid collected by filtration to give 5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine, B-II, (0.20 g). 1H NMR (DMSO-d6): δ 12.01 (s, 1H), 9.44 (s, 1H), 9.26 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 0.3 and 3.3 Hz, 1H), 8.00 (dd, J = 2.1 and 7.8Hz, 1H), 7.69(d,J=8.7Hz, 2H), 7.19(d,J=8.4Hz, 1H), 6.95(d,J=8.7Hz, 2H), 4.77(d,J=2.1Hz, 2H), 3.56 (t,J=2.1Hz, 1H), 2.49(s,3H), 2.24(q,J=7.2Hz, 2H), 0.89(t,J=7.2Hz, 3H); LCMS: Purity: 98%; MS(m / e): 484(MH + ).

[0161] B-III: 5-fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine monosodium salt 5-Fluoro-N2-(4-methyl-3-propionylaminosulfonylphenyl)-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine, B-II, (0.125 g, 0.258 mmol) was suspended in acetonitrile (1.5 mL) and water (1.5 mL) and cooled in an ice bath. 1N aqueous NaOH solution (0.260 mL) was added dropwise. The reaction mixture was stirred until clear, filtered through glass wool, and lyophilized to give the sodium salt of B-II. 1 H NMR (DMSO-d 6 ):δ 9.17(bs,2H), 8.01(d,J=3.6Hz, 1H), 7.89(s,1H), 7.78-7.69(m,3H), 6.99-6.92(m,3H), 4.76(d,J=2. 1Hz, 1H), 2.43(s,3H), 1.95(q,J=7.2Hz, 2H), 0.86(t,J=7.2Hz, 3H); LCMS: Purity: 98%; MS(m / e): 484(MH+).

[0162] The following compounds were made in a similar manner to those described above.

[0163] B-IV: 5-fluoro-N2-[4-methyl-3-(N-propionylaminosulfonyl)phenyl]-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine potassium salt 1H NMR(DMSO-d6):δ 9.16(s,1H), 9.14(s,1H), 8.01(d,J=3.6Hz, 1H), 7.85(d,J=2.1Hz, 1H), 7.75-7.70(m,3H), 6.97-6.92(m,3H), 4.76(d,J=1. 8Hz, 2H), 3.55(t,J=2.4Hz, 1H), 2.42(s,3H), 1.91(q,J=7.5Hz, 2H), 0.85(t,J=7.5Hz, 3H); LCMS: Purity: 97%; MS(m / z): 484 (parent, MH + ).

[0164] BV: 5-fluoro-N2-[4-methyl-3-(N-propionylaminosulfonyl)phenyl]-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine calcium salt 1H NMR(DMSO-d6):δ 9.16(s,2H), 8.00(d,J=3.6Hz, 1H), 7.88(d,J=1.8Hz, 1H), 7.75-7.69(m,3H), 6.97-6.92(m,3H), 4.76(d,J=1.8Hz, 2H) ), 3.55(t,J=2.1Hz, 1H), 2.43(s,3H), 1.94(q,J=7.5Hz, 2H), 0.87(t,J=7.5Hz, 3H);LCMS: Purity: 98%;MS(m / z):484(Parent, MH + ).

[0165] B-VI: 5-fluoro-N2-[4-methyl-3-(N-propionylaminosulfonyl)phenyl]-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine arginine salt 1H NMR(D 2 O):δ 7.61(d,J=3.9Hz, 1H), 7.57-7.55(m,1H), 7.36-7.31(m,1H), 7.12(d,J=8.7Hz, 2H), 6. 88(d,J=8.7Hz, 1H), 6.72(d,J=9.0Hz, 2H), 4.77-4.75(m,2H), 3.60(t,J=6.0Hz, 1H), 3 .09(t,J=6.9Hz, 2H), 2.84-2.81(m,1H), 2.35(s,3H), 2.03(q,J=5.7Hz, 2H), 1.80-1.7 2(m,2H), 1.61-1.48(m,2H), 0.855(t,J=7.5Hz, 3H); LCMS: Purity: 98%; MS(m / z): 484 (parent, MH + ).

[0166] B-VII: 5-fluoro-N2-[4-methyl-3-(N-propionylaminosulfonyl)phenyl]-N4-[4-(2-propynyloxy)phenyl]-2,4-pyrimidinediamine choline salt 1H NMR(DMSO-d6):δ 9.16(s,2H), 8.00(d,J=3.6Hz, 1H), 7.85(d,J=1.8Hz, 1H), 7.75-7.69(m,3H), 6.97-6.90(m,3H), 5.27(t,J=4.8Hz, 1H), 4.76(d,J =1.8Hz, 2H), 3.86-3.77(m,2H), 3.56-3.54(m,1H), 3.40-3.54(m,2H), 3.08(s,9H), 2.42(s,3H); LCMS: Purity: 99%; MS(m / z): 484 (Parent, MH + ).

[0167] Synthesis of 5-amino-2-methylbenzenesulfonamide TIFF0007682155000060.tif161324-Methylnitrobenzene (20 mmol) was treated with chlorosulfonic acid (5.29 mL, 80 mmol) at 0° C., then the homogeneous solution was allowed to come to room temperature and then stirred at 110° C. for 24 hours. The resulting slurry was then poured into ice water (100 gm), extracted with diethyl ether (3×75 mL), the organic phase was washed with water (75 mL) and then dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to give the crude sulfonyl chloride, which was taken up in ethyl acetate and stirred with ammonium hydroxide at room temperature overnight. After separation of the ethyl acetate layer, the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and then the solvent was removed under reduced pressure. The resulting oil was purified by column chromatography (silica gel, hexane, then 10%, 20%, up to 50% ethyl acetate in hexane) to give 3-aminosulfonyl-4-methylnitrobenzene, LCMS: purity: 95%; MS (m / e): 217 (MH + ) was obtained.

[0168] To a solution of 3 - aminosulfonyl - 4 - methylnitrobenzene in dichloromethane and methanol, 10% Pd / C was added and the mixture was shaken at 50 psi for 15 minutes under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth and the filter cake was washed with methanol. The combined organic solvents were concentrated under reduced pressure to obtain a crude product, which was further purified by flash column chromatography (ethyl acetate:hexane 1:1) to give 5 - amino - 2 - methylbenzenesulfonamide, LCMS: purity: 87%; MS(m / e): 187(MH + ) was obtained.

[0169] C. Synthesis of Pyrazole Compounds The disclosed pyrazole compounds can be prepared as exemplified below, as understood by those skilled in the art of organic synthesis. An exemplary synthesis can include the following first reaction step according to Scheme VIII: The acetyl compound 2 is reacted with dimethylformamide dimethylacetal 4 at a temperature suitable for promoting the reaction to form the intermediate compound 6. A suitable temperature is typically 85 °C to 130 °C. Next, the intermediate compound 6 is reacted with hydrazine hydrate 8 to form the pyrazole compound 10. The reaction is carried out in a suitable solvent, such as an alcohol like ethanol, methanol or isopropanol, and is typically heated, for example, to reflux.

[0170] The second reaction step of the exemplary synthesis is shown below according to Scheme IX: TIFF0007682155000062.tif42133 Compound 10 is nitrated using a suitable nitration reagent or mixture of reagents 12 to form compound 14. Suitable nitration conditions include reacting compound 10 with nitric acid, e.g., fuming nitric acid, optionally in the presence of sulfuric acid. Typically, compound 10 and nitric acid are added slowly one after the other. Cooling, such as with an ice bath, can be used to maintain the reaction temperature within a suitable range, such as about 0°C to less than 50°C, 0°C to 20°C, or 0°C to 10°C. After the addition is complete, the reaction can be allowed to proceed until substantially complete and warmed to room temperature to facilitate the reaction. Optionally, additional nitration reagent or mixture of nitration reagents can be added to facilitate the reaction proceeding to completion. The reaction is then quenched, such as by addition of water and / or ice, and the product is separated or extracted from the aqueous solution and purified as necessary. Suitable purification techniques for purifying the products from any of the reactions disclosed herein include, but are not limited to, crystallization, distillation, and / or chromatography.

[0171] Continuing with reference to Scheme IX, compound 14 is then reacted with compound 16 to form compound 18. Compound 16 can be used to obtain the desired R 1 The moiety and a suitable leaving group, LG, are also suitable for the coupling of R 1The leaving group may be any group that acts as a leaving group to facilitate the addition of a moiety. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro, or iodo, and tosylate or mesylate groups. Compound 14 is reacted with compound 16 in a suitable solvent and typically in the presence of a base. Suitable solvents include any solvent that facilitates the reaction, such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that facilitates the reaction, such as hydrides, typically sodium hydride, or carbonates, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction may be heated to 50° C., 100° C., or higher, if necessary, or the reaction may proceed at room temperature. Compound 18 is then isolated from the reaction mixture and purified as necessary.

[0172] Compound 18 is then reacted with a suitable reducing agent 20 to reduce the nitro moiety to an amine. Suitable reducing agents include, but are not limited to: hydrogen gas in the presence of a catalyst, such as a palladium catalyst; borohydride, such as sodium borohydride, optionally in the presence of a catalyst, such as a nickel catalyst; zinc metal in acetic acid; or iron powder in water or water and acid. In certain embodiments, hydrogen gas is used in the presence of a palladium carbon catalyst and in a suitable solvent, such as ethyl acetate or methanol. In some embodiments, a combination of reducing agents and / or techniques is used. For example, the reduction may be first performed using a first method involving a first reducing agent and / or technique, but resulting in a mixture of products. The first method may be repeated and / or a second method involving a second reducing agent and / or technique may be performed. Once the reaction is complete, as indicated by analytical techniques such as LC-MS, TLC or HPLC, the product compound 22 is isolated and purified as necessary.

[0173] The third step of an exemplary reaction sequence is shown below according to Scheme X: TIFF0007682155000063.tif38133 Compound 22 is reacted with carboxylic acid 24 to form compound 26. Carboxylic acid 24 is activated by any suitable method and then reacted with the amine in compound 22. Suitable activation methods include, but are not limited to, forming an acid chloride by treatment with thionyl chloride; by treatment with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and a base such as diisopropylethylamine (DIPEA); by treatment with carbonyldiimidazole (CDI); or by treatment with a carbodiimide such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).

[0174] Compound 26 is then coupled with compound 28 to form compound 30 using any suitable coupling reaction to form a bond between two rings. In the above example, a boronic acid coupling is shown, where the leaving group LG in compound 26 is typically bromo or iodo. Other suitable coupling functional groups include trialkyltin or boronic esters. The coupling reaction typically proceeds in the presence of a suitable catalyst. For boronic acid coupling, the catalyst is typically a palladium catalyst, such as PdCl 2 (dppf) 2 , Pd[P(Ph) 3 ] 2 Cl 2, palladium acetate and triphenylphosphine, or tetrakis(triphenylphosphine)palladium(0). The reaction is carried out in the presence of a base, such as sodium, potassium or cesium carbonate, and in a suitable solvent or solvent mixture, such as dioxane, dioxane / water or DME / ethanol / water. The reaction may be heated at a suitable temperature, such as 50° C. to 125° C., typically about 100° C., and / or stirred for a suitable period of time, such as 1 hour to 3 days, 6 hours to 24 hours, or 12 hours to 18 hours, to facilitate the reaction proceeding to completion. Compound 30 is then isolated from the reaction mixture and purified by a suitable technique.

[0175] An alternative exemplary synthesis can include the following first reaction step according to Scheme XI: TIFF0007682155000064.tif34133 Compound 32 is nitrated with a suitable nitration reagent or mixture of reagents 34 to form compound 36. Suitable nitration conditions include reacting compound 32 with nitric acid, e.g., fuming nitric acid, optionally in the presence of sulfuric acid. Typically, compound 32 and nitric acid are added slowly one after the other. Cooling, such as with an ice bath, can be used to maintain the reaction temperature within a suitable range, such as about 0°C to less than 50°C, 0°C to 20°C, or 0°C to 10°C. After the addition is complete, the reaction can be allowed to proceed until substantially complete and warmed to room temperature to facilitate the reaction. Optionally, additional nitration reagent or mixture of nitration reagents can be added to facilitate the reaction proceeding to completion. The reaction is then quenched, such as by addition of water and / or ice, and the product is separated or extracted from the aqueous solution and purified as necessary. Suitable purification techniques for purifying the products from any of the reactions disclosed herein include, but are not limited to, crystallization, distillation, and / or chromatography.

[0176] Continuing with reference to Scheme XI, compound 36 is then reacted with compound 38 to form compound 40. Compound 38 contains a desired ring, such as a cyclobutyl, cyclopentyl, or cyclohexyl ring, and a suitable leaving group, LG. Suitable leaving groups include any group that acts as a leaving group to facilitate the addition of a ring to compound 36. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro, or iodo, and tosylate or mesylate groups. Compound 36 is reacted with compound 38 in the presence of a suitable solvent and typically a base. Suitable solvents include any solvent that facilitates the reaction, such as an aprotic solvent. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents, such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that will facilitate the reaction, such as a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can be heated to 50° C., 100° C. or higher, if desired, or the reaction can proceed at room temperature. Compound 40 is then isolated from the reaction mixture and purified as necessary.

[0177] Compound 40 is then reacted with a suitable reducing agent 42 to reduce the carbonyl moiety to a hydroxyl. Suitable reducing agents include, but are not limited to, sodium borohydride, di-isobutylaluminum hydride, or lithium aluminum hydride. The reaction is carried out in a suitable solvent to facilitate the reaction, such as an alcohol, particularly methanol or ethanol; THF; or diethyl ether. The reaction can be optionally heated, for example to 50° C., 100° C. or higher, and cooled, for example, below 20° C., below 10° C., below 0° C. or lower, or the reaction can proceed at room temperature. Upon completion of the reaction, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product compound 44 is isolated and, if necessary, purified by a suitable technique, for example, column chromatography.

[0178] Optionally, compound 44 is reacted with compound 46 to form compound 48. Compound 46 can be used to obtain the desired R x The moiety and a suitable leaving group, LG, are included. Suitable leaving groups include R x The leaving group may be any group that acts as a leaving group to facilitate the addition of the moiety. Suitable leaving groups include, but are not limited to, halogens, typically bromo, chloro, or iodo, and tosylate or mesylate groups. Compound 44 is reacted with compound 46 in the presence of a suitable solvent and typically a base or one or more other reagents that facilitate the reaction. Suitable solvents include any solvent that facilitates the reaction, such as aprotic solvents. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases or reagents that facilitate the reaction include, but are not limited to, silver trifluoromethanesulfonate, 2,6-di-t-butylpyridine, sodium hydride, or combinations thereof. Typically, compound 46 is slowly combined with the reactants. Cooling, such as with an ice bath, can be used to maintain the reaction temperature within a suitable range, such as from about 0° C. to less than 50° C., 0° C. to 20° C., or 0° C. to 10° C. After the addition is complete, the reaction can be allowed to proceed and warm to room temperature until the reaction is substantially complete, or the reaction can be heated, for example to 50° C., 100° C. or higher, to facilitate the reaction. Upon completion of the reaction, as indicated by analytical techniques such as LC-MS, TLC, or HPLC, the product compound 48 is isolated and, if necessary, purified by a suitable technique, such as column chromatography.

[0179] Alternatively, compound 40 can be prepared by the exemplary synthetic route according to Scheme XII: TIFF0007682155000065.tif44128 Referring to Scheme XII, compound 36 is reacted with compound 50 to form compound 52. Compound 50 contains a desired ring, such as a cyclobutyl, cyclopentyl, or cyclohexyl ring, a suitable leaving group, LG, and a protected carbonyl moiety, such as an acetal or ketal. In the above example, a cyclic ketal moiety is shown. Suitable leaving groups include any group that acts as a leaving group to facilitate the addition of a ring to compound 36, including but not limited to halogen, typically bromo, chloro, or iodo, and a tosylate or mesylate group. Compound 36 is reacted with compound 50 in the presence of a suitable solvent and typically a base. Suitable solvents include any solvent that facilitates the reaction, such as an aprotic solvent. Suitable solvents include, but are not limited to, DMF, THF, DMSO, acetonitrile, chlorinated solvents such as dichloromethane and chloroform, DMA, dioxane, N-methylpyrrolidone, or combinations thereof. Suitable bases include any base that facilitates the reaction, such as a hydride, typically sodium hydride, or a carbonate, such as potassium carbonate, sodium carbonate, or cesium carbonate. The reaction can be heated to 50° C., 100° C. or higher, if necessary, or the reaction can proceed at room temperature. Compound 52 is then isolated from the reaction mixture and, if necessary, purified by a suitable technique, such as column chromatography.

[0180] Compound 52 is then reacted with a suitable reagent 54 to form compound 40. Reagent 54 can be any suitable reagent for removing a protecting group and / or forming a carbonyl moiety. In the exemplary synthesis shown in Scheme 5, the protecting group is a cyclic ketal and suitable reagents 54 include, but are not limited to, pyridinium tosylate (PPTS), para-toluenesulfonic acid, hydrochloric acid, or acetic acid. The reaction is carried out in a suitable solvent or mixture of solvents to facilitate the reaction, such as acetone, THF, acetic acid, water, or combinations thereof. The reaction can be heated, for example, to 50° C., 100° C. or higher, or at reflux, if desired, or the reac...

Claims

1. A pharmaceutical composition for use in a method for treating and / or preventing cytokine release syndrome (CRS) in a subject suffering from or at risk of developing CRS, comprising a compound having a structure represented by Formula VII, or a salt, solvate, or N-oxide thereof. (In the formula, R is an alkyl phosphate; or R is H) 13. A pharmaceutical composition comprising:

2. The compound is selected from the group consisting of: VI-176: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VI-177: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,4s)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; VII-2: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate; VII-3: di-tert-butyl((4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl)phosphate; VII-4: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate disodium salt; VII-11: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hemitartrate; VII-18: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate; VII-20: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl phosphate disodium salt; VII-49: 1-(4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)ethyl dihydrogen phosphate tris salt; VII-63: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate tris salt; VII-64: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hydrochloride; VII-65: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide benzenesulfonate; VII-66: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide tartrate; VII-67: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide sodium salt; VII-68: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide hemicitrate; VII-69: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)thiazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate ditris salt; VII-104: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide phosphate; VII-105: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide gentisate; or VII-106: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide succinate The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is selected from the group consisting of

3. The compound is or a pharma- ceutically acceptable salt thereof.

4. The pharmaceutical composition of any one of claims 1 to 3, which ameliorates a sign or symptom of CRS compared to the severity of the sign or symptom prior to administration of the pharmaceutical composition.

5. The pharmaceutical composition of claim 4, wherein the sign or symptom is fever.

6. The object is The subject has previously been treated with a first therapy for which CRS is a known, possible, or potential side effect; or are about to receive or are currently receiving a first treatment for which CRS is a known, possible, or potential side effect; The pharmaceutical composition according to any one of claims 1 to 5.

7. The pharmaceutical composition of claim 6 , wherein the first treatment comprises a cell therapy.

8. 8. The pharmaceutical composition of claim 7, wherein the cell therapy comprises chimeric antigen receptor (CAR) expression therapy, transgenic receptor therapy, or a combination thereof.

9. The pharmaceutical composition of any one of claims 1 to 8, administered in combination with a second therapeutic agent.

10. 10. The pharmaceutical composition of claim 9, wherein the second therapeutic agent is a steroid, an anti-inflammatory agent, an immunosuppressant, or a combination thereof.

11. The steroid may be alclometasone, algestone, beclomethasone, betamethasone, budesonide, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, fludrocortisone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin, fluocortolone, fluorometh ... bromine, fluperolone, fluprednidene, fluprednisolone, flurandrenolide, fluticasone, formocortal, halcinonide, halobetasol, halometasone, halopredone, hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone, paramethasone, prednicarbate, prednisolone, prednisone, prednibal, prednylidene, rimexolone, tixocortol, triamcinolone, or any combination thereof; the anti-inflammatory agent is an aminosalicylate, a cyclooxygenase inhibitor, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof; or 11. The pharmaceutical composition of claim 10, wherein the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inhibitor of inosine monophosphate dehydrogenase (IMPDH), or a combination thereof.

12. 11. The pharmaceutical composition of claim 10, wherein the second therapeutic agent is dexamethasone or prednisone, or a combination thereof.

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