TYK2 INHIBITORS AND COMPOSITIONS AND METHODS THEREOF

Abstract

Provided are safe and effective TYK2 inhibitors and pharmaceutical compositions, as well as methods for their preparation and use for various TYK2-mediated diseases and disorders.

Description

[Technical Field]

[0001] Priority claims and related patent applications This application claims the benefit of priority to PCT International Application No. PCT / CN2022 / 106876, filed July 20, 2022, and PCT / CN2021 / 138744, filed December 16, 2021, the entire contents of each of which are incorporated herein by reference for all purposes.

[0002] The present invention relates generally to novel compounds and methods for their therapeutic use. More particularly, the present invention provides a novel class of tyrosine kinase 2 inhibitors, as well as pharmaceutical compositions and methods of preparation of these compounds and their use for various diseases and conditions. [Background technology]

[0003] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transmit cytokine-mediated signals via the Janus kinase-signaling activator of transcription (JAK-STAT) pathway. The JAK family of enzymes in humans includes four members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). The family is defined by the presence of two adjacent kinase domains, JH1 and JH2; JH1 performs phosphorylation, which is involved in pathway activation, while JH2 regulates JH1 function (Thomas et al., 2015 British Journal of Cancer 113, 365-371).

[0004] These cytoplasmic tyrosine kinases associate with membrane cytokine receptors, such as the common gamma chain receptor and glycoprotein 130 (gp130) transmembrane protein (Murray et al., 2007 Immunol. 178(5):2623-2629). Approximately 40 cytokine receptors signal through a combination of these four JAKs and their seven downstream substrates: STAT family members (Ghoreschi et al., 2009 Immunol Rev. 228(1):273-287).

[0005] TYK2 is a key component of the JAK-STAT signaling pathway, regulating INFα, IL12, and IL23 (Ihle et al., 1995 Annu Rev Immunol. 13:369-398; Leonard et al., 1998 Annu Rev Immunol. 16:293-322; Liu et al., 1998 Curr Opin Immunol. 10:271-278). Cytokines implicated in TYK2 activation include interferons (e.g., IFN-a, IFN-b, IFN-k, IFN-d, IFN-e, IFN-t, IFN-w, and IFN-z) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin-1, cardiotrophin-like cytokine, and LIF). Activated TYK2 then phosphorylates additional signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6. Selective inhibition of TYK2 can be used to treat various autoimmune inflammatory diseases, such as psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), as well as cancer and diabetes.

[0006] Selectivity against other JAK family subtypes is considered essential for increasing the intended pharmacological effect and reducing side effects. Identifying kinase inhibitors with a high degree of TYK2 selectivity has posed a significant challenge, in part due to the high sequence homology of the active sites among JAK family kinases. TYK2 specificity is crucial for the clinical use of TYK2 kinase inhibitors because Tyk2 knockout mice are viable with normal blood cell counts, whereas JAK3 deficiency results in severe combined immunodeficiency in mice, and JAK1 or JAK2 knockout mice exhibit perinatal lethality (Ghoreschi et al., 2009 Immunol Rev. 228:273-287; Karaghiosoff et al., 2000 Immunity. 13:549-560; Shimoda et al., 2000 Immunity. 13:561-571). Genetic evidence suggests that pharmacological inhibition of TYK2 should not result in acute toxicity in human patients, but careful monitoring for viral or mycobacterial infections is warranted in patients treated long-term (Akahane et al., 2017 Br J Haematol. 177(2):271-282).

[0007] There is an urgent need for selective TYK2 inhibitors with improved efficacy and minimal side effects, and this remains a challenge across a broad therapeutic area. Summary of the Invention

[0008] The present invention provides novel, selective, and potent compounds that are orally available. These therapeutic agents are safe and effective TYK2 inhibitors that exhibit fewer and / or fewer side effects than currently available drugs. The present invention also provides pharmaceutical compositions of these compounds and methods for their preparation and use.

[0009] In one aspect, the present invention generally provides compounds of structural formula (I):

[0010] [ka] (In the formula, X 1 and X 2 are independently selected from CH and N; X 4 and X 5 are independently selected from CH, CF and N; X 3 is NR, O, CH2 or CF2, R 11 is H, F, C1-C3 alkyl or CD3, provided that X 3 If is NR or O, then R 11 is not F, R 12 is C(=O)R 12’ or R 12’ where R 12’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 12a where R 12a is selected from the group consisting of halogen, CF, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 13 is C1-C3 alkyl, CD3 or CF3, R 14 is H, C1-C6 alkyl or heteroalkyl, or C3-C6 cycloalkyl or heterocycloalkyl, or a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, or R 14 is OR 14’ where R 14’ is a C1-C6 alkyl or heteroalkyl or a C3-C6 cycloalkyl or heterocycloalkyl, each of which is selected from 0 to 2 R 14a where R 14a is selected from the group consisting of halogen, R, OR, amino, CF3, and CN; R 15is, at each occurrence, independently selected from F, Cl, CN, OR, NRR′, and C1-C3 alkyl; R in each occurrence is independently H or C1-C6 alkyl; k is 0, 1, 2, or 3. or a pharmaceutically acceptable form or isotopic derivative thereof.

[0011] In another aspect, the present invention generally provides compounds of structural formula (II):

[0012] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 21 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is N or O, then R 21 is not F, R 22 teeth, R 22’ (where R 22’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 22a where R 22a is selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, and heterocyclic; Each has 0 to 2 R 22a an aryl or heteroaryl group substituted with (C=O)R 27 and R 23 teeth,

[0013] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are O, C, CH, S, N and NR 26 are independently selected from R 24 is H and 0 to 3 R 24a C is replaced by 1~6 Alkyl, or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 24b is replaced by R 24a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 24b represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl, C 3~10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of which may contain 0 to 3 R 24a substituted with), C 1~6 Haloalkyl, 0 to 3 R 24a C is replaced by 2~6 Alkenyl, 0 to 3 R 24a C is replaced by 2~6 is alkynyl, R 25 is F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl, C3-C5 cycloalkyl, and 0-2 R 24b is replaced by R26 is H, C1-C6 alkyl, CD3, or C3-C6 cycloalkyl, and 0 to 3 R 24a is replaced by R 27 is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 24b is replaced by each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; p is 1 or 2] or a pharmaceutically acceptable form or isotopic derivative thereof.

[0014] In yet another aspect, the present invention generally provides compounds of structural formula (III):

[0015] [ka] (In the formula, Ring A is a 5- or 6-membered aryl or heteroaryl; X 1 is selected from NR, O, CH2 and CF2; Z 1 is CH or N, Z 2 is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 6 is NR 36 , CH2, O, S, SO or SO2, R 32 is R 32’ OR 32’where R 32’ is C 1~12 alkyl, a 3- to 6-membered cycloalkyl or heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- or 6-membered aryl or heteroaryl group, each of which is selected from 0 to 3 R 32a is replaced by R 32a is independently, at each occurrence, H, OCF3, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , (CH2) r NR g R g , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O) v NR g R g , -NR b S(O) v R c , -S(O) v R c , 0 to 3 R a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a C is replaced by 2~6 Alkenyl, 0 to 3 R a 3- to 6-membered cycloalkyl substituted with 0 to 3 R ais a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R 33 and R 34 Each of these is H, F, Cl, CN, OR g , CH3, CD3, CF3, OCD3, OCF3 and -(CH2) p - selected independently from Q, R 35 is H, F, C1-C3 alkyl and CD3, provided that X 1 is O or N, then R 35 is not F, R 36 is 0 to 3 R d is R substituted with R a represents, at each occurrence, independently, H, F, Cl, Br, OCF3, CF3, CHF2, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , -(CH2) r NR g R g , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O) v NR g R g , -NR b S(O) v R c , -S(O)R c , -S(O)2R c, 0 to 3 R f C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R f 3- to 6-membered cycloalkyl substituted with 0 to 3 R f is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R b is H, 0 to 3 R d C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C is replaced by 3~6 Cycloalkyl or 0 to 3 R f a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with 0-3 R d (CH2) r -phenyl, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 R f (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, R d independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C3~6 cycloalkyl, or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6 alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R d C1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; v is 0, 1, or 2; r is 0, 1, 2, 3, 4, or 5) or a pharmaceutically acceptable form or isotopic derivative thereof.

[0016] In yet another aspect, the present invention generally provides compounds of structural formula (IV):

[0017] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 41 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is NR or O, then R 41 is not F, R 42 teeth, R 42’ (where R 42’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is substituted with 0-2 of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; 0 to 2 R 42a an aryl or heteroaryl group substituted with (C=O)R 42b and R 43 teeth,

[0018] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 10 are independently selected from C, CH, O, N, and NH; R 42a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 42b is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 42c is replaced by R 42c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 42a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 42a C is replaced by 2~6 Alkenyl, 0 to 3 R 42a C is replaced by 2~6 is alkynyl, R 45 represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl (0 to 3 R 42a substituted with ), or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 42c and optionally two R 45 form, together with the C or N atom to which they are attached, a 4- to 6-membered ring, R 46 is, at each occurrence, independently F, Cl, CN, OR, C1-C3 alkyl, C3-C5 cycloalkyl, CD3, CH2CF3, or CF3; R 47 is H, OCF3, C1-C3 alkyl, C1-C3 alkoxy or OCD3, each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; j is 0, 1, or 2. or a pharmaceutically acceptable form or isotopic derivative thereof.

[0019] In yet another aspect, the present invention generally provides compounds of structural formula (V):

[0020] [ka] (In the formula, Ring B is a 5- or 6-membered aryl or heteroaryl; Z 1 is CH or N, Z 2 is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 5 is selected from NR, O, CH2 and CF2; Z 6 is NR 56 , CH2, O, S, SO or SO2, X 4 , X 7 , X 8 and X 9 are independently selected from CH, N, and NH; R 51 is H, F, C1-C3 alkyl and CD3, provided that Z 5 If is N or O, then R 51 is not F, R 52 are H, F, Cl, CN, OR g, CH3, CF3, OCF3 and -(CH2) p - selected independently from Q, R 52a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 52c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 52a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 52a C is replaced by 2~6 Alkenyl, 0 to 3 R 52a C is replaced by 2~6 is alkynyl, R 55 Each occurrence of is independently H, 0 to 3 R 52a C is replaced by 1~6 Alkyl, or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 52c is replaced by R 56 is 0 to 3 R d is R substituted with R 57 is H, C1-C3 alkyl, C1-C3 alkoxy, OCD3 or OCF3, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 R f (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, Rd independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6 alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R dC1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with i is 0, 1, 2, and 3; m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4) or a pharmaceutically acceptable form or isotopic derivative thereof.

[0021] In yet another aspect, the present invention generally relates to pharmaceutical compositions comprising the compounds disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent effective for treating or reducing one or more diseases or disorders in mammals, including humans.

[0022] In yet another aspect, the present invention provides a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans, generally comprising: (I) a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans;

[0023] [ka] (In the formula, X 1 and X 2 are independently selected from CH and N; X 4 and X 5 are independently selected from CH, CF and N; X 3 is NR, O, CH2 or CF2, R 11 is H, F, C1-C3 alkyl or CD3, provided that X 3 If is NR or O, then R 11 is not F, R 12 is C(=O)R 12’ or R 12’where R 12’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 12a where R 12a is selected from the group consisting of halogen, CF, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 13 is C1-C3 alkyl, CD3 or CF3, R 14 is H, C1-C6 alkyl or heteroalkyl, or C3-C6 cycloalkyl or heterocycloalkyl, or a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, or R 14 is OR 14’ where R 14’ is a C1-C6 alkyl or heteroalkyl or a C3-C6 cycloalkyl or heterocycloalkyl, each of which is selected from 0 to 2 R 14a where R 14a is selected from the group consisting of halogen, R, OR, amino, CF3, and CN; R 15 is, at each occurrence, independently selected from F, Cl, CN, OR, NRR′, and C1-C3 alkyl; R in each occurrence is independently H or C1-C6 alkyl; k is 0, 1, 2, or 3. or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0024] In yet another aspect, the present invention provides a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans, generally comprising: (II) a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans;

[0025] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 21 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is N or O, then R 21 is not F, R 22 teeth, R 22’ (where R 22’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 22a where R 22a is selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, and heterocyclic; Each has 0 to 2 R 22a an aryl or heteroaryl group substituted with (C=O)R 27 and R 23 teeth,

[0026] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are O, C, CH, S, N and NR 26 are independently selected from R 24 is H and 0 to 3 R 24a C is replaced by 1~6 Alkyl, or C 3~10Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 24b is replaced by R 24a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 24b represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl, C 3~10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of which may contain 0 to 3 R 24a substituted with), C 1~6 Haloalkyl, 0 to 3 R 24a C is replaced by 2~6 Alkenyl, 0 to 3 R 24a C is replaced by 2~6 is alkynyl, R 25 is F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl, C3-C5 cycloalkyl, and 0-2 R 24b is replaced by R 26 is H, C1-C6 alkyl, CD3, or C3-C6 cycloalkyl, and 0 to 3 R 24a is replaced by R 27 is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 24b is replaced by each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; p is 1 or 2] or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0027] In yet another aspect, the present invention provides compounds of structural formula (III):

[0028] [ka] (In the formula, Ring A is a 5- or 6-membered aryl or heteroaryl; X 1 is selected from NR, O, CH2 and CF2; Z 1 is CH or N, Z 2 is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 6 is NR 36 , CH2, O, S, SO or SO2, R 32 is R 32’ OR 32’ where R 32’ is C 1~12alkyl, a 3- to 6-membered cycloalkyl or heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- or 6-membered aryl or heteroaryl group, each of which is selected from 0 to 3 R 32a is replaced by R 32a is independently, at each occurrence, H, OCF3, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , (CH2) r NR g R g , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O) v NR g R g , -NR b S(O) v R c , -S(O) v R c , 0 to 3 R a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a C is replaced by 2~6 Alkenyl, 0 to 3 R a 3- to 6-membered cycloalkyl substituted with 0 to 3 R a is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R 33 and R 34 Each of these is H, F, Cl, CN, OR g , CH3, CD3, CF3, OCD3, OCF3 and -(CH2) p - selected independently from Q, R 35 is H, F, C1-C3 alkyl and CD3, provided that X 1 is O or N, then R 35 is not F, R 36 is 0 to 3 R d is R substituted with R a represents, at each occurrence, independently, H, F, Cl, Br, OCF3, CF3, CHF2, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , -(CH2) r NR g R g , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O) v NR g R g , -NR b S(O) v R c , -S(O)R c , -S(O)2R c , 0 to 3 R f C is replaced by 1~6 Alkyl, C1~6 Haloalkyl, 0 to 3 R f 3- to 6-membered cycloalkyl substituted with 0 to 3 R f is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R b is H, 0 to 3 R d C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C is replaced by 3~6 Cycloalkyl or 0 to 3 R f a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with 0-3 R d (CH2) r -phenyl, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 R f (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, R d independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, or (CH2) r-phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6 alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R d C1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; v is 0, 1, or 2; r is 0, 1, 2, 3, 4, or 5) or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0029] In yet another aspect, the present invention provides a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans, generally comprising: (IV):

[0030] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 41 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is NR or O, then R 41 is not F, R 42 teeth, R 42’ (where R 42’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is substituted with 0-2 of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; 0 to 2 R 42a an aryl or heteroaryl group substituted with (C=O)R 42b and R 43 teeth,

[0031] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X10 are independently selected from C, CH, O, N, and NH; R 42a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 42b is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 42c is replaced by R 42c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 42a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 42a C is replaced by 2~6 Alkenyl, 0 to 3 R 42a C is replaced by 2~6 is alkynyl, R 45 represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl (0 to 3 R 42a substituted with ), or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 42c and optionally two R 45 form, together with the C or N atom to which they are attached, a 4- to 6-membered ring, R 46 is, at each occurrence, independently F, Cl, CN, OR, C1-C3 alkyl, C3-C5 cycloalkyl, CD3, CH2CF3, or CF3; R 47is H, OCF3, C1-C3 alkyl, C1-C3 alkoxy or OCD3, each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; j is 0, 1, or 2. or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0032] In yet another aspect, the present invention provides a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans, generally comprising: (V) a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans;

[0033] [ka] (In the formula, Ring B is a 5- or 6-membered aryl or heteroaryl; Z 1 is CH or N, Z 2 is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 5 is selected from NR, O, CH2 and CF2; Z 6 is NR 56 , CH2, O, S, SO or SO2, X 4 , X 7 , X 8 and X 9 are independently selected from CH, N, and NH; R 51is H, F, C1-C3 alkyl and CD3, provided that Z 5 If is N or O, then R 51 is not F, R 52 are H, F, Cl, CN, OR g , CH3, CF3, OCF3 and -(CH2) p - selected independently from Q, R 52a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 52c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 52a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 52a C is replaced by 2~6 Alkenyl, 0 to 3 R 52a C is replaced by 2~6 is alkynyl, R 55 Each occurrence of is independently H, 0 to 3 R 52a C is replaced by 1~6 Alkyl, or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 52c is replaced by R 56 is 0 to 3 R d is R substituted with R 57 is H, C1-C3 alkyl, C1-C3 alkoxy, OCD3 or OCF3, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 Rf (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, R d independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6 alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R d C1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with i is 0, 1, 2, and 3; m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4) or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0034] In yet another aspect, the invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0035] In yet another aspect, the present invention generally provides compounds of structural formula (I):

[0036] [ka] (In the formula, X 1 and X 2 are independently selected from CH and N; X 4 and X 5 are independently selected from CH, CF and N; X 3 is NR, O, CH2 or CF2, R 11 is H, F, C1-C3 alkyl or CD3, provided that X3 If is NR or O, then R 11 is not F, R 12 is C(=O)R 12’ or R 12’ where R 12’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 12a where R 12a is selected from the group consisting of halogen, CF, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 13 is C1-C3 alkyl, CD3 or CF3, R 14 is H, C1-C6 alkyl or heteroalkyl, or C3-C6 cycloalkyl or heterocycloalkyl, or a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, or R 14 is OR 14’ where R 14’ is a C1-C6 alkyl or heteroalkyl or a C3-C6 cycloalkyl or heterocycloalkyl, each of which is selected from 0 to 2 R 14a where R 14a is selected from the group consisting of halogen, R, OR, amino, CF3, and CN; R 15 is, at each occurrence, independently selected from F, Cl, CN, OR, NRR′, and C1-C3 alkyl; R in each occurrence is independently H or C1-C6 alkyl; k is 0, 1, 2, or 3. or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in a mammal, including a human.

[0037] In yet another aspect, the present invention generally provides compounds of structural formula (II):

[0038] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 21 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is N or O, then R 21 is not F, R 22 teeth, R 22’ (where R 22’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 22a where R 22a is selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, and heterocyclic; Each has 0 to 2 R 22a an aryl or heteroaryl group substituted with (C=O)R 27 and R 23 teeth,

[0039] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are O, C, CH, S, N and NR 26 are independently selected from R 24 is H and 0 to 3 R 24a C is replaced by 1~6 Alkyl, or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 24b is replaced by R 24a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 24b represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl, C 3~10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of which may contain 0 to 3 R 24a substituted with), C 1~6 Haloalkyl, 0 to 3 R 24a C is replaced by 2~6 Alkenyl, 0 to 3 R 24a C is replaced by 2~6 is alkynyl, R 25 is F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl, C3-C5 cycloalkyl, and 0-2 R 24b is replaced by R26 is H, C1-C6 alkyl, CD3, or C3-C6 cycloalkyl, and 0 to 3 R 24a is replaced by R 27 is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 24b is replaced by each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; p is 1 or 2] or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in a mammal, including a human.

[0040] In yet another aspect, the present invention generally provides compounds of structural formula (III):

[0041] [ka] (In the formula, Ring A is a 5- or 6-membered aryl or heteroaryl; X 1 is selected from NR, O, CH2 and CF2; Z 1 is CH or N, Z 2 is CH, CF or N, Z 3 and Z 4are independently selected from NR, CH2, and CF2; Z 6 is NR 36 , CH2, O, S, SO or SO2, R 32 is R 32’ OR 32’ where R 32’ is C 1~12 alkyl, a 3- to 6-membered cycloalkyl or heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- or 6-membered aryl or heteroaryl group, each of which is selected from 0 to 3 R 32a is replaced by R 32a is independently, at each occurrence, H, OCF3, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , (CH2) r NR g R g , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O) v NR g R g , -NR b S(O) v R c , -S(O) v R c , 0 to 3 R a C is replaced by 1~6 Alkyl, C1~6 Haloalkyl, 0 to 3 R a C is replaced by 2~6 Alkenyl, 0 to 3 R a 3- to 6-membered cycloalkyl substituted with 0 to 3 R a is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R 33 and R 34 Each of these is H, F, Cl, CN, OR g , CH3, CD3, CF3, OCD3, OCF3 and -(CH2) p - selected independently from Q, R 35 is H, F, C1-C3 alkyl and CD3, provided that X 1 is O or N, then R 35 is not F, R 36 is 0 to 3 R d is R substituted with R a represents, at each occurrence, independently, H, F, Cl, Br, OCF3, CF3, CHF2, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , -(CH2) r NR g R g , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O)v NR g R g , -NR b S(O) v R c , -S(O)R c , -S(O)2R c , 0 to 3 R f C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R f 3- to 6-membered cycloalkyl substituted with 0 to 3 R f is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R b is H, 0 to 3 R d C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C is replaced by 3~6 Cycloalkyl or 0 to 3 R f a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with 0-3 R d (CH2) r -phenyl, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 R f (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, R d independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6 alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R d C1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; v is 0, 1, or 2; r is 0, 1, 2, 3, 4, or 5) or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in a mammal, including a human.

[0042] In yet another aspect, the present invention generally provides compounds of structural formula (IV):

[0043] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 41 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is NR or O, then R 41 is not F, R 42 teeth, R 42’ (where R 42’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is substituted with 0-2 of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; 0 to 2 R 42a an aryl or heteroaryl group substituted with (C=O)R 42b and R 43 teeth,

[0044] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 10 are independently selected from C, CH, O, N, and NH; R 42a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 42b is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 42c is replaced by R 42c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 42a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 42a C is replaced by 2~6 Alkenyl, 0 to 3 R 42a C is replaced by 2~6 is alkynyl, R 45 represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl (0 to 3 R 42a substituted with ), or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 42c and optionally two R 45 form, together with the C or N atom to which they are attached, a 4- to 6-membered ring, R 46 is, at each occurrence, independently F, Cl, CN, OR, C1-C3 alkyl, C3-C5 cycloalkyl, CD3, CH2CF3, or CF3; R 47 is H, OCF3, C1-C3 alkyl, C1-C3 alkoxy or OCD3, each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; j is 0, 1, or 2. or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in a mammal, including a human.

[0045] In yet another aspect, the present invention generally provides compounds of structural formula (V):

[0046] [ka] (In the formula, Ring B is a 5- or 6-membered aryl or heteroaryl; Z 1 is CH or N, Z 2is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 5 is selected from NR, O, CH2 and CF2; Z 6 is NR 56 , CH2, O, S, SO or SO2, X 4 , X 7 , X 8 and X 9 are independently selected from CH, N, and NH; R 51 is H, F, C1-C3 alkyl and CD3, provided that Z 5 If is N or O, then R 51 is not F, R 52 are H, F, Cl, CN, OR g , CH3, CF3, OCF3 and -(CH2) p - selected independently from Q, R 52a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 52c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 52a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 52a C is replaced by 2~6 Alkenyl, 0 to 3 R 52a C is replaced by 2~6 is alkynyl, R 55 Each occurrence of is independently H, 0 to 3 R 52a C is replaced by 1~6 Alkyl, or C 3~10Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 52c is replaced by R 56 is 0 to 3 R d is R substituted with R 57 is H, C1-C3 alkyl, C1-C3 alkoxy, OCD3 or OCF3, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 R f (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, R d independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R d C1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with i is 0, 1, 2, and 3; m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4) or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in a mammal, including a human.

[0047] In yet another aspect, the invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a medicament for treating a disease or disorder.

[0048] definition Unless otherwise defined, all technical and chemical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. General principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2006.

[0049] The following terms are intended to have the following meanings unless otherwise indicated according to the context in which the term is found.

[0050] Ranges provided herein are understood to be shorthand for all values ​​within the range, for example, a range of 1 to 16 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0051] As used herein, "at least" a particular value is understood to be that value and all values ​​greater than that value.

[0052] As used herein, "greater than 1" is understood to mean 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 100, etc., or any value in between.

[0053] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0054] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to mean within a certain range of normal tolerance in the art, for example, within two standard deviations of the mean. About can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the specified value. Unless otherwise clear from the context, all numerical values ​​provided herein can be modified by the term about.

[0055] Unless specifically stated otherwise or apparent from the context, the term "or" as used herein is understood to be inclusive.

[0056] Any composition or method disclosed herein can be combined with one or more of any of the other compositions and methods provided herein.

[0057] The recitation of a list of chemical groups in any definition of a variable herein includes a definition of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0058] The term "comprising," when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements but do not exclude other elements. The term "essentially consisting of," when used to define compositions and methods, means that the compositions and methods include the recited elements but exclude other elements of any essential importance to the compositions and methods. For example, "essentially consisting of" refers to the administration of specifically recited pharmacologically active agents and excludes pharmacologically active agents not specifically recited. The term "essentially consisting of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "consisting of," when used to define compositions and methods, means excluding trace elements and substantial method steps of other components. Embodiments defined by each of these transition terms are within the scope of this invention.

[0059] Certain compounds of the present invention can exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, atropisomers, R and S enantiomers, diastereomers, (d) isomers, (l) isomers, racemic mixtures thereof, and other mixtures, as being within the scope of the present invention. Additional asymmetric carbon atoms can be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be encompassed by this invention. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess of either the R or S configuration. Of optically active compounds, it is often preferable to use one enantiomer to the substantial exclusion of the other enantiomer.

[0060] Isomeric mixtures containing any of a variety of isomeric ratios can be utilized in accordance with the present invention. For example, when only two isomers are combined, mixtures containing isomeric ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are contemplated by the present invention. Those skilled in the art will readily recognize that similar ratios are contemplated for more complex isomeric mixtures.

[0061] For example, if a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers so formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

[0062] Mixtures of isomers can be separated on the basis of the physical chemical differences of the constituents, into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0063] Definitions of specific functional groups and chemical terms are described in more detail below. When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6, C 3~5 , C 3~4 , C 4~6 , C 4-5 , and C 5~6 Alkyl is intended to be included.

[0064] Where substituents are specified by their conventional chemical formula written from left to right, they equally encompass the chemically identical substituents that result from writing the structure from right to left, e.g., -C(=O)-O- is equivalent to -OC(=O)-.

[0065] The structure of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art. Thus, when a group may be substituted with one or more of a number of substituents, such substitutions are selected to obtain compounds that comply with the principles of chemical bonding and are known to those skilled in the art to be inherently unstable and / or likely to be unstable under environmental conditions (e.g., aqueous, neutral, and some known physiological conditions).

[0066] Solvates and polymorphs of the compounds of the invention are also contemplated herein. Solvates of the compounds of the invention include, for example, hydrates.

[0067] As used herein, the term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 10 carbon atoms (e.g., C 1~10 Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range, for example, "1 to 10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on up to and including 10 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, "alkyl" refers to C 1~6It can be an alkyl group. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight-chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl, while saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The alkyl is attached to the parent molecule by a single bond. Unless stated otherwise in the specification, alkyl groups are optionally substituted by one or more of substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a)2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R a are independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. In non-limiting embodiments, the substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0068] As used herein, the term "alkoxy" refers to alkyl groups of 1 to 10 carbon atoms (C) of a linear, branched, saturated cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. 1~10 "Alkoxy" refers to an -O-alkyl group containing 1 to 6 carbons. Unless otherwise specified in the specification, the term is intended to include both substituted and unsubstituted alkoxy groups. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy, and the like. "Lower alkoxy" refers to an alkoxy group containing 1 to 6 carbons. In some embodiments, C 1~3Alkoxy is an alkoxy group, including straight- and branched-chain alkyl of 1 to 3 carbon atoms. Unless stated otherwise in the specification, the alkoxy group can be optionally substituted by one or more substituents independently including: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R ais independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein.

[0069] As used herein, the term "aromatic" or "aryl" refers to an aromatic ring having 6 to 14 ring atoms (e.g., C 6~14 Aromatic or C 6~14 Aryl) refers to a group having at least one ring with a conjugated pi-electron system that is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Unless otherwise specified herein, the term is intended to include both substituted and unsubstituted aryl groups. In some embodiments, aryl ... 6~10It is an aryl group. For example, a divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is called a substituted phenylene group. In another embodiment, a divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends in "-yl" by removing one hydrogen atom from the carbon atom having a free valence is called by adding "-yden" to the name of the corresponding monovalent group, for example, a naphthyl group having two attachment points is called naphthylidene. Whenever it appears herein, a numerical range such as "6 to 14 aryl" refers to each integer in the given range, for example, "6 to 14 ring atoms" means that the aryl group can consist of 6 ring atoms, 7 ring atoms, and up to 14 ring atoms, including 14 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings sharing adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In polycyclic groups, only one ring is required to be aromatic, thus groups such as indanyl are encompassed by the aryl definition. Non-limiting examples of aryl groups include phenyl, phenalenyl, naphthalenyl, tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl, indanyl, and the like. Unless stated otherwise in the specification, an aryl moiety can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a , -OC(O)-Ra , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein.

[0070] As used herein, the terms "cycloalkyl" and "carbocyclyl" refer to monocyclic or polycyclic groups containing only carbon and hydrogen, respectively, and may be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or "cycloalkynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C 3~13Cycloalkyl). Unless otherwise specified herein, the term is intended to include both substituted and unsubstituted cycloalkyl groups. Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and so on, up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused ring structures that do not contain heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" refers to C 3~8 In some embodiments, "cycloalkyl" can be a C 3~5 Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties: 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3~7 An example of a carbocyclyl group is norbornyl (C7). 3~8 Examples of carbocyclyl groups include the previously mentioned C 3~7 Examples include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. 3~13 Examples of carbocyclyl groups include the previously mentioned C 3~8Examples include carbocyclyl groups, as well as octahydro-1H indenyl, decahydronaphthalenyl, spiro[4.5]decanyl, and the like. Unless stated otherwise in the specification, cycloalkyl groups can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R a )3, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(R a )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R aare independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein. The terms "cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl," where the prefix "alk" is replaced with "alkene" or "alkyn," respectively, and the original terms "alkenyl" and "alkynyl" are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, e.g., 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

[0071] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). As used herein, the term "halide" or "halo" means fluoro, chloro, bromo, or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halo groups, or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Each of the alkyl, alkenyl, alkynyl, and alkoxy groups is as defined herein and is optionally further substituted as defined herein.

[0072] As used herein, the term "heteroatom" refers to oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

[0073] As used herein, the term "heteroalkyl" refers to an alkyl group having one or more skeletal atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. Unless otherwise specified herein, the term is intended to include both substituted and unsubstituted heteroalkyl groups. Numerical ranges may be given that refer to the total chain length, for example, C 1~4 The heteroalkyl, in this example, is four atoms long. For example, the group -CHOCHCH is referred to as a "C" heteroalkyl, which includes the heteroatom center in the atom chain length description. The connection to the parent molecular structure can be through either a heteroatom or a carbon in the heteroalkyl chain. For example, an N-containing heteroalkyl moiety refers to a group in which at least one of the backbone atoms is a nitrogen atom. One or more heteroatoms in a heteroalkyl group can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. For example, heteroalkyl also includes a backbone chain substituted with one or more nitrogen oxide (-O-) substituents. Illustrative heteroalkyl groups include, without limitation, ethers, such as methoxyethanyl (-CH2CHOCH3), ethoxymethanyl (-CHOCH2CH3), (methoxymethoxy)ethanyl (-CH2CHOCH2OCH3), (methoxymethoxy)methanyl (-CH2CHOCH2CH3), and (methoxyethoxy)methanyl (-CHOCH2CH2OCH3); amines, such as (-CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2NHCH2CH3, -CH2N(CH2CH3)(CH3)), and the like.

[0074] As used herein, the term "heterocycloalkyl" refers to a cycloalkyl group having one or more skeletal atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. Unless otherwise specified herein, the term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Illustrative examples of heterocycloalkyl include 2-hydroxyaziridin-1-yl, 3-oxo-1-oxacyclobutan-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, 3-carboxy-morpholin-4-yl, 1-cyclopropyl-4-methyl-piperazin-2-yl, 2-pyrrolinyl, 3-pyrrolinyl, dihydro-2H-pyranyl, 1,2,3,4-tetrahydropyridine, 3,4-dihydro-2H-[1,4]oxazine, and the like.

[0075] As used herein, the term "heteroaryl" or alternatively "heteroaromatic" refers to a 5- to 18-membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., having 6, 10, or 14 π-electrons shared in a cyclic arrangement) having ring carbon atoms and 1 to 6 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 18-membered heteroaryl"). Unless otherwise specified herein, the term is intended to include both substituted and unsubstituted heteroaryl groups. Heteroaryl polycyclic ring systems can contain one or more heteroatoms in one or both rings. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range; for example, "5 to 18 ring atoms" means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, and up to and including 18 ring atoms. In some cases, heteroaryl can have 5 to 14 ring atoms. In some embodiments, heteroaryl has a divalent group derived from a monovalent heteroaryl group whose name ends in "-yl" by removing one hydrogen atom from the atom having the free valence, e.g., named by adding "-ene" to the name of the corresponding monovalent group; e.g., a pyridyl group having two points of attachment is pyridylene.

[0076] For example, an N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. One or more heteroatoms in a heteroaryl group can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. Heteroaryl also includes ring systems substituted with one or more nitrogen oxide (-O-) substituents, such as pyridinyl N-oxide. A heteroaryl is attached to the parent molecular structure through any atom of the ring.

[0077] "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, with the point of attachment to the parent molecular structure being on either the aryl or heteroaryl ring, or in which a heteroaryl ring, as defined above, is fused to one or more cycloalkyl or heterocyclyl groups, with the point of attachment to the parent molecular structure being on the heteroaryl ring. For polycyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment to the parent molecular structure can be on either ring, i.e., on either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl). In some embodiments, a heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5-8 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl groups are 5-6 membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryls have 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, 5-6 membered heteroaryls have 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, 5-6 membered heteroaryls have 1 ring heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0078] Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzopyranonyl, benzofurazanyl, benzothiazolyl, benzyl, Benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2 -c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazinyl Zolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3 -d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, a heteroaryl moiety can be optionally substituted by one or more substituents which independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, -Si(R, a )3, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, -N(Ra )C(NR a )N(R a )2, -N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a )(R a ), or -OP(=O)(OR a )2, where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, each of which moieties can be optionally substituted as defined herein.

[0079] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration to a subject, or implantation of a slow-release device, such as a mini-osmotic pump. The preferred route of administration for a particular patient will depend on the nature and severity of the disease or condition being treated, or the nature of the therapy being used, and the nature of the active compound.

[0080] Administration can be by any suitable route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0081] By "co-administered" is meant that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies.

[0082] The compounds of the present invention can be administered alone or simultaneously to patients. Simultaneous administration is meant to include simultaneous or sequential administration of compounds individually or in combination (more than one compound or drug).Therefore, the preparation can also be combined with other active substances if desired (for example, to reduce metabolic degradation).

[0083] The compositions of the present invention can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols, and can be delivered by topical routes, such as transdermal routes. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for oral ingestion by patients. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, gels, for example, water or water / propylene glycol solutions.

[0084] The compositions of the present invention can additionally contain components for providing sustained release and / or comfort. Such components include high molecular weight anionic mucosomimetic polymers, gelling polysaccharides, and finely divided drug carrier substrates. These components are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of slow-releasing drug-containing microspheres subcutaneously (see Rao, 1995 J. Biomater Sci. Polym. Ed. 7:623-645), as biodegradable and injectable gel formulations (see, e.g., Gao 1995 Pharm. Res. 12:857-863), or as microspheres for oral administration (see, e.g., Eyles 1997 J. Pharm. Pharmacol. 49:669-674).

[0085] As used herein, the terms "disease," "condition," and "disorder" are used interchangeably herein and refer to a physical condition or state of health of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein.

[0086] As used herein, the term "effective amount" of an active agent refers to an amount sufficient to elicit a desired biological response.As recognized by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.

[0087] As used herein, the terms "inhibition," "inhibit," and "inhibiting," etc., in reference to biological target (e.g., TYK2)-inhibitor interaction, refer to negatively affecting (e.g., decreasing) the activity or function of a protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition means negatively affecting (e.g., decreasing) the concentration or level of a protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to the reduction of a disease or disease symptom. In embodiments, inhibition refers to the reduction of the activity of a particular protein target. Inhibition includes at least partially, partially, or fully blocking stimulation; reducing, preventing, or delaying activation; or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to the reduction of the activity of a target protein due to direct interaction (e.g., an inhibitor binds to the target protein). In embodiments, inhibition refers to a reduction in the activity of a target protein from an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).

[0088] As used herein, the terms "isolated" or "purified" refer to material that is substantially or essentially free from components that normally accompany it in its natural state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography.

[0089] As used herein, the term "modulate" refers to the production, either directly or indirectly, of an increase or decrease, stimulation, inhibition, interference, or blockage in a measured activity when compared to a suitable control. A "modulator" of a polypeptide or polynucleotide refers to a substance that affects, e.g., increases, decreases, stimulates, inhibits, interferes, or blocks, the measured activity of the polypeptide or polynucleotide when compared to a suitable control. For example, a "modulator" can bind to and / or activate or inhibit a target with measurable affinity, or directly or indirectly affect the normal regulation of receptor activity.

[0090] As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable salts, esters, prodrugs, and isotopically labeled derivatives thereof. In some embodiments, "pharmaceutically acceptable forms" include, but are not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs, and isotopically labeled derivatives thereof.

[0091] In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of a subject, does not cause excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethylethanesulfonate, and the like. Examples of the salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, p-toluenesulfonate, undecanoate, and valerate.In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0092] Salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, such as by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt can be selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0093] In certain embodiments, the pharmaceutically acceptable form is a "solvate" (e.g., a hydrate). As used herein, the term "solvate" refers to a compound that further comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. The solvate may be the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate." Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. The term "compound," as used herein, is understood to encompass compounds and solvates of compounds, as well as mixtures thereof.

[0094] In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term "prodrug" (or "prodrug") refers to a compound that is converted in vivo to yield a pharmaceutically acceptable form of the disclosed compound or compounds. A prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis (e.g., hydrolysis in the blood). In certain cases, a prodrug has improved physical and / or delivery properties than the parent compound. A prodrug can increase the bioavailability of a compound when administered to a subject (e.g., by enabling enhanced absorption into the blood following oral administration), or can enhance delivery to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of the disclosed compounds that have enhanced water solubility or active transport through intestinal membranes relative to the parent compound.

[0095] Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi, T. et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties.

[0096] Prodrug forms often offer advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985; and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992). Commonly known prodrugs in the art include well-known acid derivatives, such as esters prepared by reacting the parent acid with a suitable alcohol, amides prepared by reacting the parent acid with an amine, and base groups reacted to form acylated base derivatives. Other prodrug derivatives can be combined with other features disclosed herein to enhance bioavailability. Thus, those skilled in the art will recognize that certain disclosed compounds having free amino, amido, hydroxy, or carboxyl groups can be converted into prodrugs. Prodrugs include compounds with a carbonate, carbamate, amide, or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.

[0097] Illustrative advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, or it can enhance absorption from the gastrointestinal tract, or it can enhance drug stability from long-term storage.

[0098] As used herein, the term "pharmaceutically acceptable" excipient, carrier, or diluent refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a subject pharmaceutical agent from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic, compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0099] As used herein, the term "subject" refers to any animal (e.g., mammal), including but not limited to, a human, a non-human primate, a rodent, etc., that will be the recipient of a particular treatment. Subjects to which administration is contemplated include, but are not limited to, humans (e.g., male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or other non-human animals, e.g., non-human mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), commercially relevant mammals, e.g., cows, pigs, horses, sheep, goats, cats, and / or dogs), rodents (e.g., rats and / or mice), etc. In certain embodiments, the non-human animal is a mammal. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic animal. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject.

[0100] As used herein, the term "treatment" or "treating" a disease or disorder refers to a method of reducing, delaying, or ameliorating such a condition before or after its appearance. Treatment can target one or more effects or symptoms of the disease and / or underlying condition. Treatment can be any reduction, including, but not limited to, the complete disappearance of the disease or disease symptoms. Treating or treatment therefore refers to any indicia of success in treating or ameliorating an injury, disease, condition, or condition, including any objective or subjective parameter, such as remission, remission, alleviation of symptoms, or making the injury, condition, or condition more tolerable to the patient, slowing the rate of regression or decline, making the endpoint of decline less debilitating, or improving the patient's physical or mental well-being. Treatment or amelioration of symptoms can be based on objective or subjective parameters, for example, the results of a physical examination, a neuropsychiatric examination, and / or a psychiatric evaluation. Compared to comparable untreated controls, the degree of such reduction or amelioration can be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100% as measured by any standard technique.

[0101] The treatment method includes administering a therapeutically effective amount of a compound described herein to a subject. The administration step can be a single administration or can include a series of administrations. The length of the treatment period depends on various factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of the agent used for treatment can increase or decrease over the course of a particular treatment plan. Changes in dosage can occur and be identified by standard diagnostic assays known in the art. In some cases, chronic administration may be required. For example, the composition is administered to the subject in an amount and for a duration sufficient to treat the patient. DETAILED DESCRIPTION OF THE INVENTION

[0102] The present invention is based on the unexpected discovery of novel, selective, and potent compounds that are TYK2 inhibitors. The present invention also provides pharmaceutical compositions of these compounds and methods for their preparation and use. The compounds are orally available and exhibit fewer and / or fewer side effects than currently available drugs.

[0103] The new class of TYK2 inhibitors disclosed herein exhibit exceptional efficacy profiles and are useful in treating one or more TYK2-mediated diseases and conditions, such as allergic, autoimmune, inflammatory, metabolic, neurological, and proliferative diseases and conditions. Without wishing to be bound by theory, the compounds of the present invention are modulators of interleukins (e.g., IL-12, IL-23) and interferons (e.g., IFN-α) by inhibiting TYK2-mediated signaling.

[0104] These compounds are designed to exhibit good efficacy against TYK2 with good oral absorption and good in vivo stability. The present invention also provides pharmaceutical compositions of these compounds and methods for their preparation and use. The TYK2 inhibitors disclosed herein exhibit advantageous pharmacokinetic profiles and drug properties suitable for target indications.

[0105] In one aspect, the present invention generally provides compounds of structural formula (I):

[0106] [ka] (In the formula, X 1 and X 2 are independently selected from CH and N; X 4 and X 5 are independently selected from CH, CF and N; X 3 is NR, O, CH2 or CF2, R 11is H, F, C1-C3 alkyl or CD3, provided that X 3 If is NR or O, then R 11 is not F, R 12 is C(=O)R 12’ or R 12’ where R 12’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 12a where R 12a is selected from the group consisting of halogen, CF, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 13 is C1-C3 alkyl, CD3 or CF3, R 14 is H, C1-C6 alkyl or heteroalkyl, or C3-C6 cycloalkyl or heterocycloalkyl, or a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, or R 14 is OR 14’ where R 14’ is a C1-C6 alkyl or heteroalkyl or a C3-C6 cycloalkyl or heterocycloalkyl, each of which is selected from 0 to 2 R 14a where R 14a is selected from the group consisting of halogen, R, OR, amino, CF3, and CN; R 15 is, at each occurrence, independently selected from F, Cl, CN, OR, NRR′, and C1-C3 alkyl; R in each occurrence is independently H or C1-C6 alkyl; k is 0, 1, 2, or 3. or a pharmaceutically acceptable form or isotopic derivative thereof.

[0107] In certain embodiments of Formula (I), R 12is C(=O)R 12’ is.

[0108] In certain embodiments of Formula (I), R 12 is R 12’ is.

[0109] In certain embodiments of Formula (I), R 12 is aryl.

[0110] In certain embodiments of Formula (I), R 12 is heteroaryl.

[0111] In certain embodiments of Formula (I), R 12 is an unsubstituted or substituted phenyl, pyridinyl, pyrazolyl or pyrimidinyl group.

[0112] In certain embodiments of Formula (I), X 1 and X 2 Each of these is CH.

[0113] In certain embodiments of Formula (I), X 4 and X 5 Each of these is CH.

[0114] In certain embodiments of Formula (I), X 4 is CF.

[0115] In certain embodiments of Formula (I), X 4 is CH and X 5 is N.

[0116] In certain embodiments of Formula (I), X 1 and X 2 Each of these is CH.

[0117] In certain embodiments of Formula (I), X 4 and X 5 Each of these is CH.

[0118] In certain embodiments of Formula (I), X 4 is CH and X 5 is N.

[0119] In certain embodiments of Formula (I), X 4 is N and X 5 is CH and the compound has the structural formula:

[0120] [ka] It has.

[0121] Formula (I) to (I a In certain embodiments of 3 is NR. In certain embodiments, X 3 is NH.

[0122] Formula (I) to (I a In certain embodiments of 3 is O.

[0123] Formula (I) to (I a In certain embodiments of 12 is R 12’ and R 12’ is an aryl group (e.g., unsubstituted or substituted phenyl).

[0124] Formula (I) to (I a In certain embodiments of 12 is R 12’ and R 12’ is a heteroaryl group (eg, an unsubstituted or substituted pyrazolyl, pyridinyl, or pyrimidyl group).

[0125] Formula (I) to (I a In certain embodiments of 12 is C(=O)R 12’ and R 12’ is unsubstituted or substituted C-C cycloalkyl. In certain embodiments, R12’ is cyclopropyl. In certain embodiments, R 12’ is cyclobutyl.

[0126] Formula (I) to (I a In certain embodiments of 12’ is a C1-C6 alkyl substituted with an amino group or a morpholino group.

[0127] Formula (I) to (I a In certain embodiments of 13 is CH3.

[0128] Formula (I) to (I a In certain embodiments of 13 is CD3.

[0129] Formula (I) to (I a In certain embodiments of 13 is CF3.

[0130] Formula (I) to (I a In certain embodiments of 14 is a 5-membered heteroaryl group (eg, 1,2,4-triazole).

[0131] Formula (I) to (I a In certain embodiments of 14 is OR 14’ In certain embodiments, R 14’ is heterocycloalkyl (e.g., tetrahydropyran).

[0132] Formula (I) to (I a In certain embodiments of 14 is H.

[0133] Formula (I) to (I a In certain embodiments of R 15 does not exist).

[0134] Formula (I) to (I a In certain embodiments of ), k is 1.

[0135] Formula (I) to (I a In certain embodiments of ), k is 2.

[0136] Formula (I) to (I a In certain embodiments of), the compound has the structural formula:

[0137] [ka] (In the formula, each R 16 is CN, Cl, F, C1-C3 alkyl, C 3~6 heterocyclic, and OR, and j is 0, 1, 2, 3, 4, or 5.

[0138] Formula (I) to (I b In certain embodiments of R 16 does not exist).

[0139] Formula (I) to (I b In certain embodiments of ), j is 1.

[0140] Formula (I) to (I b In certain embodiments of ), j is 2.

[0141] Formula (I b In certain embodiments of ), j is 1 and R 16 is in meta position:

[0142] [ka]

[0143] Formula (I b In certain embodiments of), the compound has the structural formula:

[0144] [ka] (In the formula, Each R 16 are independently selected from CN, Cl, F, C1-C3 alkyl, and OR; j is 0, 1, 2, 3, 4 or 5).

[0145] Formula (I) to (I d In certain embodiments of 11 is CH3.

[0146] Formula (I) to (I d In certain embodiments of 11 is CD3.

[0147] Formula (I) to (I d In certain embodiments of 15 is F.

[0148] Formula (I d In certain embodiments of ), j is 1.

[0149] Formula (I d In certain embodiments of ), j is 2.

[0150] Formula (I) to (I d In certain embodiments of 16 are independently selected from F, Cl, CN and CF3.

[0151] Formula (I) to (I d In certain embodiments of ), a substituted or unsubstituted morpholino group.

[0152] In another aspect, the present invention generally comprises: Structural formula (II):

[0153] [ka] [In the formula, Y1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 21 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is N or O, then R 21 is not F, R 22 teeth, R 22’ (where R 22’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 22a where R 22a is selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, and heterocyclic; Each has 0 to 2 R 22a an aryl or heteroaryl group substituted with (C=O)R 27 and R 23 teeth,

[0154] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are O, C, CH, S, N and NR 26 are independently selected from R 24 is H and 0 to 3 R 24a C is replaced by 1~6 Alkyl, or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 24b is replaced by R 24a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 24b represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl, C 3~10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of which may contain 0 to 3 R 24a substituted with), C 1~6 Haloalkyl, 0 to 3 R 24a C is replaced by 2~6 Alkenyl, 0 to 3 R 24a C is replaced by 2~6 is alkynyl, R 25 is F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl, C3-C5 cycloalkyl, and 0-2 R 24b is replaced by R 26 is H, C1-C6 alkyl, CD3, or C3-C6 cycloalkyl, and 0 to 3 R 24a is replaced by R 27 is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 24b is replaced by each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; p is 1 or 2] or a pharmaceutically acceptable form or isotopic derivative thereof.

[0155] In certain embodiments of Formula (II), p is 1 and R 23 teeth,

[0156] [ka] is.

[0157] In certain embodiments of Formula (II), p is 2.

[0158] In certain embodiments of Formula (II), Y 1 is CH and Y 2 is CH and the compound has the structural formula:

[0159] [ka] It has.

[0160] In certain embodiments of Formula (II), Y 1 is CH and Y 2 is N and the compound has the structural formula:

[0161] [ka] It has.

[0162] In certain embodiments of Formula (II), Y 1 is N and Y 2 is CH and the compound has the structural formula:

[0163] [ka] It has.

[0164] In certain embodiments of Formula (II), Y 1 is N and Y 2 is N and the compound has the structural formula:

[0165] [ka] It has.

[0166] Formula (II) to (II d In certain embodiments of 1 is CF.

[0167] Formula (II) to (II d In certain embodiments of 3 is NR. In certain embodiments, Y 3 is NH.

[0168] Formula (II) to (II d In certain embodiments of 3 is CH2.

[0169] Formula (II) to (II d In certain embodiments of 3 is CF2.

[0170] Formula (II) to (II d In certain embodiments of 23 is a group selected from:

[0171] [ka]

[0172] In certain embodiments, R 23 teeth,

[0173] [ka] is.

[0174] In certain embodiments, R 23 teeth,

[0175] [ka] is.

[0176] In certain embodiments, R 26 is optionally substituted with OCH3 1~3 It is alkyl.

[0177] In certain embodiments, R 26 is methyl.

[0178] In certain embodiments, R 23 teeth,

[0179] [ka] is.

[0180] In certain embodiments, R 23 teeth,

[0181] [ka] is.

[0182] Formula (II) to (II d In certain embodiments of 21 is F.

[0183] Formula (II) to (II d In certain embodiments of 21 is CH3.

[0184] Formula (II) to (II d In certain embodiments of 21 is CD3.

[0185] Formula (II) to (II d In certain embodiments of 22 is aryl (eg, phenyl) optionally substituted with one or two halogen (eg, F, Cl) atoms.

[0186] Formula (II) to (II d In certain embodiments of 22 is a heteroaryl group (eg, pyridinyl) optionally substituted with one or two halogen (eg, F, Cl) atoms.

[0187] Formula (II) to (II d In certain embodiments of 22 is (C=O)R 27 where R 27 is 0~2R 24b C1-C6 alkyl, cyclopropyl or cyclobutyl, substituted with

[0188] Formula (II) to (II d In certain embodiments of 22 is 0 to 2 R 24b is a pyridine substituted with

[0189] In certain embodiments, the compound has the structural formula:

[0190] [ka] It has.

[0191] In certain embodiments, the compound has the structural formula:

[0192] [ka] It has.

[0193] In certain embodiments, the compound has the structural formula:

[0194] [ka] It has.

[0195] In certain embodiments, the compound has the structural formula:

[0196] [ka] It has.

[0197] In certain embodiments, the compound has the structural formula:

[0198] [ka] It has.

[0199] In certain embodiments, the compound has the structural formula:

[0200] [ka] It has.

[0201] In certain embodiments, the compound has the structural formula:

[0202] [ka] It has.

[0203] In certain embodiments, the compound has the structural formula:

[0204] [ka] It has.

[0205] Formula (II) to (II l In certain embodiments of 27is cyclopropyl.

[0206] Formula (II) to (II l In certain embodiments of 27 is cyclobutyl.

[0207] Formula (II) to (II l In certain embodiments of 24 is optionally substituted with one or more of F, Cl, CN, OR, CH3, CF3 and OCF3; 12 It is alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0208] Formula (II) to (II l In certain embodiments of 24 is a C1-C optionally substituted with one or more of F, Cl, CN, OR, NRR', CH3, CF3 and OCF3; 12 In certain embodiments, R 24 is CH3. In certain embodiments, R 24 is ethyl.

[0209] Formula (II) to (II l In certain embodiments of 24 is a C3-C optionally substituted with one or more of F, Cl, CN, OR, NRR', CH3, CF3 and OCF3; 12 It is cycloalkyl or heterocycloalkyl.

[0210] Formula (II) to (II l In certain embodiments of 24 is a C4-C optionally substituted with one or more of F, Cl, CN, OR, NRR', CH3, CF3 and OCF3 12 It is aryl.

[0211] Formula (II) to (II lIn certain embodiments of 24 is a C-C group optionally substituted with one or more of F, Cl, CN, OR, NRR', CH, CF, and OCF; 12 It is heteroaryl.

[0212] Formula (II) to (II l In certain embodiments of 25 is H.

[0213] Formula (II) to (II l In certain embodiments of 25 is F or Cl.

[0214] Formula (II) to (II l In certain embodiments of 25 is CH3, CHF2 or CF3.

[0215] Formula (II) to (II l In certain embodiments of 25 is CN.

[0216] Formula (II) to (II l In certain embodiments of 25 is an OR.

[0217] Formula (II) to (II l In certain embodiments of , i is 0 (i.e., R 25 does not exist).

[0218] Formula (II) to (II l In certain embodiments of ), i is 1.

[0219] Formula (II) to (II l In certain embodiments of ), i is 2.

[0220] In yet another aspect, the present invention generally provides compounds of structural formula (III):

[0221] [ka] (In the formula, Ring A is a 5- or 6-membered aryl or heteroaryl; X 1 is selected from NR, O, CH2 and CF2; Z 1 is CH or N, Z 2 is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 6 is NR 36 , CH2, O, S, SO or SO2, R 32 is R 32’ OR 32’ where R 32’ is C 1~12 alkyl, a 3- to 6-membered cycloalkyl or heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- or 6-membered aryl or heteroaryl group, each of which is selected from 0 to 3 R 32a is replaced by R 32a is independently, at each occurrence, H, OCF3, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , (CH2) r NR g R g , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)Rc , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O) v NR g R g , -NR b S(O) v R c , -S(O) v R c , 0 to 3 R a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a C is replaced by 2~6 Alkenyl, 0 to 3 R a 3- to 6-membered cycloalkyl substituted with 0 to 3 R a is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R 33 and R 34 Each of these is H, F, Cl, CN, OR g , CH3, CD3, CF3, OCD3, OCF3 and -(CH2) p - selected independently from Q, R 35 is H, F, C1-C3 alkyl and CD3, provided that X 1 is O or N, then R 35 is not F, R 36 is 0 to 3 R d is R substituted with R a represents, at each occurrence, independently, H, F, Cl, Br, OCF3, CF3, CHF2, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2)r OC(O)R b , -(CH2) r NR g R g , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O) v NR g R g , -NR b S(O) v R c , -S(O)R c , -S(O)2R c , 0 to 3 R f C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R f 3- to 6-membered cycloalkyl substituted with 0 to 3 R f is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R b is H, 0 to 3 R d C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C is replaced by 3~6 Cycloalkyl or 0 to 3 R f a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with 0-3 R d (CH2) r -phenyl, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 R f(CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, R d independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6 alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R d C1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; v is 0, 1, or 2; r is 0, 1, 2, 3, 4, or 5) or a pharmaceutically acceptable form or isotopic derivative thereof.

[0222] In certain embodiments of formula (III), X 1 is NH and has the structural formula (III1):

[0223] [ka] It has.

[0224] In certain embodiments of Formulae (III)-(III1), ring A is a 6-membered aryl.

[0225] In certain embodiments of Formulae (III)-(III1), ring A is a 6-membered heteroaryl.

[0226] In certain embodiments of Formulas (III)-(III1), the compound has structural formula (III2):

[0227] [ka] (In the formula, Z 5 and Z 8 each of which is CH or N.

[0228] In certain embodiments of Formula (III2), Z 8 is CH and the compound has the structural formula (III3):

[0229] [ka] It has.

[0230] In certain embodiments of Formula (III3), Z 2 and Z 5 are not both CH.

[0231] In certain embodiments of formula (III) or (III3), Z 7 is NR. In certain embodiments, R is H and Z 7 is NH.

[0232] In certain embodiments of formula (III) or (III3), Z 7 is CH2.

[0233] In certain embodiments of formula (III) or (III3), Z 7 is CF2.

[0234] In certain embodiments of formula (III) or (III3), Z 3 and Z 4 Each of the is NH.

[0235] In certain embodiments of Formula (III3), Z 1 is CH and Z 2 is CH and Z 3 and Z 4 Each of the is NH and Z 5 is N.

[0236] In certain embodiments of formula (III3), (CRR') m (CH2) m and (CRR') n (CH2) n is.

[0237] In certain embodiments of Formula (III3), the compound has the structural formula:

[0238] [ka] It has.

[0239] In certain embodiments of Formula (III3), Z 1 is N and Z 2 is CH and Z 5 is N.

[0240] In certain embodiments of Formula (III3), the compound has the structural formula:

[0241] [ka] It has.

[0242] In certain embodiments of Formula (III3), Z 1 is CH and Z 2 is N and Z 5 is N.

[0243] In certain embodiments of Formula (III3), the compound has the structural formula:

[0244] [ka] It has.

[0245] In certain embodiments of Formula (III3), Z 1 is CH and Z 2 is N and Z 5 is CH.

[0246] In certain embodiments of Formula (III3), the compound has the structural formula:

[0247] [ka] It has.

[0248] In certain embodiments of Formula (III3), Z 1 is N and Z 2 is N and Z 5 is N.

[0249] In certain embodiments of Formula (III3), the compound has the structural formula:

[0250] [ka] It has.

[0251] Formula (III3)~(III3 e In certain embodiments of 32 is a 6-membered aryl or heteroaryl group containing 0, 1 or 2 nitrogen atoms and 0 or 1 oxygen atoms.

[0252] Formula (III3)~(III3 e In certain embodiments of 32 is selected from:

[0253] [ka]

[0254] Formula (III3)~(III3 e In certain embodiments of 32 is 0 to 3 R 32a is a 3- to 6-membered cycloalkyl or heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S, substituted with

[0255] Formula (III3)~(III3 e In certain embodiments of 32 is 0 to 3 R 32a is a 3-membered cycloalkyl substituted with

[0256] Formula (III3)~(III3 e In certain embodiments of 32 is 0 to 3 R 32a is cyclopropyl substituted with

[0257] Formula (III3)~(III3 e In certain embodiments of 32 is a 5-membered heteroaryl group containing 1, 2 or 3 nitrogen atoms and 0 or 1 oxygen atom.

[0258] Formula (III3)~(III3 e In certain embodiments of 32 is 0 to 3 R 32a and n is 0 or 1. The group is a triazole, oxadiazole, thiazole, oxazole or pyrazole substituted with

[0259] Formula (III3)~(III3 e In certain embodiments of 32 is selected from:

[0260] [ka]

[0261] In certain embodiments, R 32 is N-methyl-1,2,4-triazole.

[0262] Formula (III3)~(III3 e In certain embodiments of R 34 does not exist).

[0263] Formula (III3)~(III3 e In certain embodiments of ), q is 1.

[0264] Formula (III3)~(III3 e In certain embodiments of ), q is 2.

[0265] In certain embodiments of Formula (III3), the compound has the structural formula:

[0266] [ka] It has.

[0267] In certain embodiments of Formula (III2), the compound has the structural formula:

[0268] [ka] It has.

[0269] In certain embodiments of Formula (III2), the compound has the structural formula:

[0270] [ka] It has.

[0271] In certain embodiments of Formula (III2), the compound has the structural formula:

[0272] [ka] It has.

[0273] Formula (III3)~(III3 i In certain embodiments of 6 is NR 36 In certain embodiments, R 36 is CH3.

[0274] Formula (III3)~(III3 i In certain embodiments of 6 is O.

[0275] Formula (III3)~(III3 i In certain embodiments of 6 is S.

[0276] Formula (III3)~(III3 i In certain embodiments of 6 is CH2.

[0277] Formula (III3)~(III3 i In certain embodiments of ), m=1.

[0278] Formula (III3)~(III3 i In certain embodiments of ), m=2.

[0279] Formula (III3)~(III3 i In certain embodiments of ), n=1.

[0280] Formula (III3)~(III3 i In certain embodiments of ), n=2.

[0281] Formula (III3)~(III3 i In certain embodiments of ), m=n=1.

[0282] Formula (III3)~(III3 i In certain embodiments of ), m=n=2.

[0283] In certain embodiments of Formula (III3), the compound has the structural formula:

[0284] [ka] It has.

[0285] In certain embodiments of Formula (III3), the compound has the structural formula:

[0286] [ka] It has.

[0287] In certain embodiments of Formula (III3), the compound has the structural formula:

[0288] [ka] It has.

[0289] In certain embodiments of Formula (III3), the compound has the structural formula:

[0290] [ka] It has.

[0291] In certain embodiments of Formula (III3), the compound has the structural formula:

[0292] [ka] It has.

[0293] In certain embodiments of Formula (III3), the compound has the structural formula:

[0294] [ka] It has.

[0295] In certain embodiments of Formula (III3), the compound has the structural formula:

[0296] [ka] It has.

[0297] In certain embodiments of Formula (III3), the compound has the structural formula:

[0298] [ka] It has.

[0299] In certain embodiments of Formula (III3), the compound has the structural formula:

[0300] [ka] It has.

[0301] In certain embodiments of Formula (III3), the compound has the structural formula:

[0302] [ka] It has.

[0303] In certain embodiments of Formula (III3), the compound has the structural formula:

[0304] [ka] It has.

[0305] In certain embodiments of Formula (III3), the compound has the structural formula:

[0306] [ka] It has.

[0307] In certain embodiments of Formula (III3), the compound has the structural formula:

[0308] [ka] It has.

[0309] In certain embodiments of Formula (III3), the compound has the structural formula:

[0310] [ka] It has.

[0311] In certain embodiments of Formula (III3), the compound has the structural formula:

[0312] [ka] It has.

[0313] In certain embodiments of Formula (III3), the compound has the structural formula:

[0314] [ka] It has.

[0315] In certain embodiments of Formula (III1), Z 5 is N and Z 8 is N.

[0316] In certain embodiments of Formula (III1), the compound has structural formula (III4):

[0317] [ka] It has.

[0318] In certain embodiments of Formula (III4), the compound has the structural formula (III4 a ):

[0319] [ka] It has.

[0320] In certain embodiments of Formula (III4), the compound has the structural formula (III4 b ):

[0321] [ka] It has.

[0322] In certain embodiments of Formula (III4), the compound has the structural formula (III4 c ):

[0323] [ka] It has.

[0324] In certain embodiments of Formula (III4), the compound has the structural formula (III4 d ):

[0325] [ka] It has.

[0326] In certain embodiments of Formula (III4), the compound has the structural formula (III4 e ):

[0327] [ka] It has.

[0328] Formula (III)~(III4 e In certain embodiments of 33 is OR. In certain embodiments, R is CH3 and R 33 is OCH. In certain embodiments, R is CD and R 33 is OCD3.

[0329] Formula (III)~(III4 eIn certain embodiments of 34 is H.

[0330] Formula (III)~(III4 e In certain embodiments of 34 is selected from F or Cl.

[0331] Formula (III)~(III4 e In certain embodiments of 34 is selected from CN.

[0332] Formula (III)~(III4 e In certain embodiments of 34 is selected from CH3 and CF3.

[0333] Formula (III)~(III4 e In certain embodiments of 34 is selected from OCF3.

[0334] Formula (III)~(III4 e In certain embodiments of 34 Ha-(CH2) p In certain embodiments, p is 1 or 2 and Q is OH, OR, or NRR′ (e.g., N(CH)). In certain embodiments, Q is a heterocyclic (e.g., morpholine) or heteroaryl group.

[0335] Formula (III)~(III4 e In certain embodiments of 34 Ha-(CH2) p -Q, where Q is an amino group or a morpholino group.

[0336] Formula (III)~(III4 e In certain embodiments of 35 is CH3.

[0337] Formula (III)~(III4e In certain embodiments of 35 is CD3.

[0338] In certain embodiments of Formulae (III)-(III1), ring A is a 5-membered aryl.

[0339] In certain embodiments of Formulae (III)-(III1), ring A is a 5-membered heteroaryl.

[0340] In certain embodiments of Formulas (III)-(III1), the compound has structural formula (III5):

[0341] [ka] It has.

[0342] In certain embodiments of formula (III5), (CRR') m (CH2) m and (CRR') n (CH2) n is.

[0343] In certain embodiments of Formula (III5), the compound has the structural formula:

[0344] [ka] It has.

[0345] In certain embodiments of Formula (III5), the compound has the structural formula:

[0346] [ka] It has.

[0347] Formula (III5) or (III5 b In certain embodiments of 35 is CH3.

[0348] Formula (III5) or (III5 b In certain embodiments of 35 is CD3.

[0349] Formula (III5) or (III5 b In certain embodiments of 33 is OCH3.

[0350] Formula (III5) or (III5 b In certain embodiments of ), m is 1 and n is 2.

[0351] In yet another aspect, the present invention generally provides compounds of structural formula (IV):

[0352] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 41 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is NR or O, then R 41 is not F, R 42 teeth, R 42’ (where R 42’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is substituted with 0-2 of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; 0 to 2 R 42a an aryl or heteroaryl group substituted with (C=O)R 42b and R 43 teeth,

[0353] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 10 are independently selected from C, CH, O, N, and NH; R 42a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 42b is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 42c is replaced by R 42c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 42a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 42a C is replaced by 2~6 Alkenyl, 0 to 3 R 42a C is replaced by 2~6 is alkynyl, R 45 represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl (0 to 3 R 42a substituted with ), or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 42c and optionally two R 45 form, together with the C or N atom to which they are attached, a 4- to 6-membered ring, R 46 is, at each occurrence, independently F, Cl, CN, OR, C1-C3 alkyl, C3-C5 cycloalkyl, CD3, CH2CF3, or CF3; R 47 is H, OCF3, C1-C3 alkyl, C1-C3 alkoxy or OCD3, each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; j is 0, 1, or 2. or a pharmaceutically acceptable form or isotopic derivative thereof.

[0354] In certain embodiments of Formula (IV), R 43 is selected from:

[0355] [ka] (In the formula, R 44 or R 45 When bonded to N, H, C 1~6 Alkyl, CD3, C 3~8 cycloalkyl, 3- to 7-membered heterocycloalkyl, or C-C aryl or heteroaryl, and 0 to 3 R 52a is replaced by R 44 or R 45When bonded to C, H, F, Cl, CN, C 1~6 Alkyl, CD3, or C 1~6 Alkoxy, C 3~8 cycloalkyl, 3- to 7-membered heterocycloalkyl, or C-C aryl or heteroaryl, and 0 to 3 R 42a is replaced by ).

[0356] In certain embodiments of Formula (IV), R 43 is selected from:

[0357] [ka] (In the formula, R 44 or R 45 When bonded to N, H, C 1~6 Alkyl, CD3, C 3~8 cycloalkyl, 3- to 7-membered heterocycloalkyl, or C-C aryl or heteroaryl, and 0 to 3 R 52a is replaced by R 44 or R 45 When bonded to C, H, F, Cl, CN, C 1~6 Alkyl, CD3, or C 1~6 Alkoxy, C 3~8 cycloalkyl, 3- to 7-membered heterocycloalkyl, or C-C aryl or heteroaryl, and 0 to 3 R 42a is replaced by ).

[0358] In certain embodiments, R 47 is C1-C3 alkoxy.

[0359] In certain embodiments, R 47 is OCH3.

[0360] In certain embodiments, R 47 is OCD3.

[0361] In certain embodiments, j is 0.

[0362] In certain embodiments, j is 1.

[0363] In certain embodiments, R 46 is F.

[0364] In certain embodiments, R 46 is Cl.

[0365] In certain embodiments of formula (IV), Y 1 is CH and Y 2 is CH:

[0366] [ka]

[0367] In certain embodiments of formula (IV), Y 1 is CH and Y 2 is N:

[0368] [ka]

[0369] In certain embodiments of formula (IV), Y 1 is N and Y 2 is CH:

[0370] [ka]

[0371] In certain embodiments of formula (IV), Y 1 is N and Y 2 is N:

[0372] [ka]

[0373] In certain embodiments of formula (IV), Y 1 is CF.

[0374] Formula (IV)~(IV d In certain embodiments of 3 is NR.

[0375] Formula (IV)~(IV d In certain embodiments of 3 is NH.

[0376] In certain embodiments of Formula (IV), the compound has the structural formula:

[0377] [ka] It has.

[0378] In certain embodiments of Formula (IV), the compound has the structural formula:

[0379] [ka] It has.

[0380] In certain embodiments of Formula (IV), the compound has the structural formula:

[0381] [ka] It has.

[0382] In certain embodiments of Formula (IV), the compound has the structural formula:

[0383] [ka] It has.

[0384] In certain embodiments of Formula (IV), the compound has the structural formula:

[0385] [ka] It has.

[0386] In certain embodiments of Formula (IV), the compound has the structural formula:

[0387] [ka] It has.

[0388] In certain embodiments of Formula (IV), the compound has the structural formula:

[0389] [ka] It has.

[0390] In certain embodiments of Formula (IV), the compound has the structural formula:

[0391] [ka] It has.

[0392] In certain embodiments of Formula (IV), the compound has the structural formula:

[0393] [ka] It has.

[0394] In certain embodiments of Formula (IV), the compound has the structural formula:

[0395] [ka] It has.

[0396] In certain embodiments of Formula (IV), the compound has the structural formula:

[0397] [ka] It has.

[0398] In certain embodiments of Formula (IV), the compound has the structural formula:

[0399] [ka] It has.

[0400] In certain embodiments of Formula (IV), the compound has the structural formula:

[0401] [ka] It has.

[0402] In certain embodiments of Formula (IV), the compound has the structural formula:

[0403] [ka] It has.

[0404] In certain embodiments of Formula (IV), the compound has the structural formula:

[0405] [ka] It has.

[0406] In certain embodiments of Formula (IV), the compound has the structural formula:

[0407] [ka] It has.

[0408] In certain embodiments of Formula (IV), the compound has the structural formula:

[0409] [ka] It has.

[0410] In certain embodiments of Formula (IV), the compound has the structural formula:

[0411] [ka] It has.

[0412] In certain embodiments of Formula (IV), the compound has the structural formula:

[0413] [ka] It has.

[0414] In certain embodiments of Formula (IV), the compound has the structural formula:

[0415] [ka] It has.

[0416] Formula (IV)~(IV x In certain embodiments of 41 is CH3.

[0417] Formula (IV)~(IV x In certain embodiments of 41 is CD3.

[0418] Formula (IV)~(IV x In certain embodiments of 42 is (C=O)R 42b where R 42b is 0 to 2 R 42cC1-C6 alkyl, cyclopropyl or cyclobutyl, substituted with

[0419] In certain embodiments, R 42 is (C=O)R 42b where R 42b is cyclopropyl optionally substituted with one or more of F, Cl, CH3, CF3 and CN.

[0420] In certain embodiments, R 42 is (C=O)R 42b where R 42b is cyclobutyl optionally substituted with one or more of F, Cl, CH3, CF3 and CN.

[0421] In certain embodiments, R 42 is (C=O)R 42b where R 42b is C1-C6 alkyl optionally substituted with one or more of F, Cl, CH3, CF3, CN, NRR' and OR.

[0422] In certain embodiments, R 42 is 0 to 2 R 42c is a pyridine substituted with

[0423] In certain embodiments, R 42 is 0 to 2 R 42c is phenyl substituted with

[0424] In certain embodiments, R 42 is 0 to 2 R 42c and pyrazolyl substituted with

[0425] In certain embodiments, R 42 is 0 to 2 R 42c and pyrimidyl substituted with

[0426] In certain embodiments, R 42c is CH3.

[0427] In certain embodiments of Formula (IV), the compound has the structural formula:

[0428] [ka] (In the formula, R 44 Halo, CN, CD3, OC 1~3 Alkyl, C 1~3 alkyl or cyclopropyl, optionally substituted with 0-3 halo, OH, NRR′, or CN; R 42 is phenyl, pyridinyl, pyrazole, or pyrimidyl, each of which is 0 to 2 R 42c substituted with ).

[0429] In certain embodiments of Formula (IV), the compound has the structural formula:

[0430] [ka] (In the formula, R 44 Halo, CN, CD3, OC 1~3 Alkyl, or C 1~3 alkyl or cyclopropyl, optionally substituted with 0-3 halo, OH, NRR′, or CN; R 42 is phenyl, pyridinyl, pyrazole, or pyrimidyl, each of which is 0 to 2 R 42c substituted with ).

[0431] In certain embodiments of Formula (IV), the compound has the structural formula:

[0432] [ka] (In the formula, R44 is CD3, CD2CD3, or C 1~3 alkyl or cyclopropyl, optionally substituted with 0-3 halo, OH, NRR′, or CN; R 42 is phenyl, pyridinyl, pyrazole, or pyrimidyl, each of which is 0 to 2 R 42c substituted with ).

[0433] In certain embodiments of Formula (IV), the compound has the structural formula:

[0434] [ka] (In the formula, R 44 is CD3, CD2CD3, or C 1~3 alkyl or cyclopropyl, optionally substituted with 0-3 halo, OH, NRR′, or CN; R 42 is phenyl, pyridinyl, pyrazole, or pyrimidyl, each of which is 0 to 2 R 42c substituted with ).

[0435] In certain embodiments of Formula (IV), the compound has the structural formula:

[0436] [ka] (In the formula, R 44 Halo, CN, CD3, OC 1~3 Alkyl, or C 1~3 alkyl or cyclopropyl, optionally substituted with 0-3 halo, OH, NRR′, or CN; R 42c is H, F or CF3).

[0437] In certain embodiments of Formula (IV), the compound has the structural formula:

[0438] [ka] (In the formula, R 44 Halo, CN, CD3, OC 1~3 Alkyl, or C 1~3 alkyl or cyclopropyl, optionally substituted with 0-3 halo, OH, NRR′, or CN; R 42c is H, F or CF3).

[0439] In certain embodiments of Formula (IV), the compound has the structural formula:

[0440] [ka] (In the formula, R 44 CD3, or C 1~3 alkyl or cyclopropyl, optionally substituted with 0-3 halo, OH, NRR′, or CN; R 42c is H, F or CF3).

[0441] In certain embodiments of Formula (IV), the compound has the structural formula:

[0442] [ka] (In the formula, R 44 CD3, CD2CD3, C 1~3 alkyl or cyclopropyl, optionally substituted with 0-3 halo, OH, NRR′, or CN; R 42c is H, F or CF3).

[0443] Formula (IV c1 )~(IV f1 In certain embodiments of 42c is H.

[0444] Formula (IV c1 )~(IV f1 In certain embodiments of 42c is F.

[0445] R 44 In certain embodiments where R is attached to N, 44 is CD3, methyl or ethyl, (optionally substituted with F, Cl or CN).

[0446] R 44 In certain embodiments where R is attached to C, 44 is Cl, CN, CD3, methyl or ethyl, optionally substituted with F, Cl or CN.

[0447] In yet another aspect, the present invention generally provides compounds of structural formula (V):

[0448] [ka] (In the formula, Ring B is a 5- or 6-membered aryl or heteroaryl; Z 1 is CH or N, Z 2 is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 5 is selected from NR, O, CH2 and CF2; Z 6 is NR 56 , CH2, O, S, SO or SO2, X 4 , X 7 , X 8 and X 9 are independently selected from CH, N, and NH; R 51is H, F, C1-C3 alkyl and CD3, provided that Z 5 If is N or O, then R 51 is not F, R 52 are H, F, Cl, CN, OR g , CH3, CF3, OCF3 and -(CH2) p - selected independently from Q, R 52a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 52c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 52a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 52a C is replaced by 2~6 Alkenyl, 0 to 3 R 52a C is replaced by 2~6 is alkynyl, R 55 Each occurrence of is independently H, 0 to 3 R 52a C is replaced by 1~6 Alkyl, or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 52c is replaced by R 56 is 0 to 3 R d is R substituted with R 57 is H, C1-C3 alkyl, C1-C3 alkoxy, OCD3 or OCF3, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 Rf (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, R d independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6 alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R d C1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with i is 0, 1, 2, and 3; m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4) or a pharmaceutically acceptable form or isotopic derivative thereof.

[0449] In certain embodiments of formula (V), Z 3 , Z 4 and Z 5 each of which is NH and has structural formula (V1):

[0450] [ka] It has.

[0451] In certain embodiments of Formulas (V)-(V1), ring B is a 6-membered aryl.

[0452] In certain embodiments of Formulae (V)-(V1), Ring B is a 6-membered heteroaryl.

[0453] In certain embodiments of Formulas (V)-(V1), the compound has structural formula (V2):

[0454] [ka] (In the formula, Z 7 and Z 8 each of which is independently CH or N.

[0455] In certain embodiments of Formula (V2), the compound has structural formula (V3):

[0456] [ka] (In the formula, R 54 is H, C1-C6 alkyl or C 1~6 alkoxy, CD3, or C3-C5 cycloalkyl, and 0 to 3 R 52a is replaced by R 55 is H or 0 to 3 R 52a C is replaced by 1~6 Alkyl or C 1~6 alkoxy).

[0457] In certain embodiments of Formula (V2), the compound has structural formula (V4):

[0458] [ka] (In the formula, R 54 is H, C1-C6 alkyl or C 1~6 alkoxy, CD3, or C3-C5 cycloalkyl, and 0 to 3 R 52a is replaced by R 55 is H or 0 to 3 R 52a C is replaced by 1~6 Alkyl or C 1~6 alkoxy).

[0459] In certain embodiments of Formulas (V)-(V4), Z 6 is O or S.

[0460] In certain embodiments of Formulas (V)-(V4), Z 6 is NR.

[0461] In certain embodiments of Formulas (V)-(V4), each of m and n is 1.

[0462] In certain embodiments of Formulas (V)-(V4), R 51 is CH3.

[0463] In certain embodiments of Formulas (V)-(V4), R 51 is CD3.

[0464] In certain embodiments of Formulas (V)-(V4), R 57 is C1-C3 alkoxy.

[0465] In certain embodiments of Formulas (V)-(V4), R 57 is OCH3.

[0466] In certain embodiments of Formulas (V)-(V4), R 57 is OCD3.

[0467] In certain embodiments of Formulas (V)-(V4), R 57 is OCF3.

[0468] In certain embodiments of Formulas (V)-(V4), q is 1 and R 52 is F, Cl, CN, CH3, CF3, OCF3 or morpholino.

[0469] Non-limiting examples of compounds of the present invention include:

[0470] [Table 1-1]

[0471] [Table 1-2]

[0472]

Table 1-3

[0473]

Table 1-4

[0474]

Table 1-5

[0475]

Table 1-6

[0476]

Table 1-7

[0477]

Table 1-8

[0478]

Table 1-9

[0479]

Table 1-10

[0480]

Table 1-11

[0481]

Table 1-12

[0482]

Table 1-13

[0483]

Table 1-14

[0484]

Table 1-15

[0485]

Table 1-16

[0486]

Table 1-17

[0487]

Table 1-18

[0488]

Table 1-19

[0489]

Table 1-20

[0490]

Table 1-21

[0491]

Table 1-22

[0492]

Table 1-23

[0493]

Table 1-24

[0494]

Table 1-25

[0495]

Table 1-26

[0496]

Table 1-27

[0497]

Table 1-28

[0498]

Table 1-29

[0499]

Table 1-30

[0500]

Table 1-31

[0501]

Table 1-32

[0502]

Table 1-33

[0503]

Table 1-34

[0504]

Table 1-35

[0505]

Table 1-36

[0506]

Table 1-37

[0507]

Table 1-38

[0508]

Table 1-39

[0509]

Table 1-40

[0510]

Table 1-41

[0511]

Table 1-42

[0512]

Table 1-43

[0513]

Table 1-44

[0514]

Table 1-45

[0515]

Table 1-46

[0516]

Table 1-47

[0517]

Table 1-48

[0518]

Table 1-49

[0519]

Table 1-50

[0520]

Table 1-51

[0521]

Table 1-52

[0522]

Table 1-53

[0523] [Table 1-54]

[0524] [Table 1-55]

[0525] [Table 1-56]

[0526] [Table 1-57]

[0527] [Table 1-58]

[0528] [Table 1-59]

[0529] In yet another aspect, the present invention relates generally to methods for preparing the compounds disclosed herein, as exemplified by the synthetic schemes and experimental procedures disclosed herein.

[0530] In yet another aspect, the present invention generally relates to pharmaceutical compositions comprising the compounds disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent, effective for treating or reducing one or more diseases or disorders in mammals, including humans.

[0531] In yet another aspect, the present invention provides a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans, generally comprising: (I) a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans;

[0532] [ka] (In the formula, X 1 and X 2 are independently selected from CH and N; X 4 and X 5 are independently selected from CH, CF and N; X 3 is NR, O, CH2 or CF2, R 11 is H, F, C1-C3 alkyl or CD3, provided that X 3 If is NR or O, then R 11 is not F, R 12 is C(=O)R 12’ or R 12’ where R 12’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 12a where R 12a is selected from the group consisting of halogen, CF, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 13 is C1-C3 alkyl, CD3 or CF3, R 14 is H, C1-C6 alkyl or heteroalkyl, or C3-C6 cycloalkyl or heterocycloalkyl, or a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, or R 14 is OR 14 and ’ , where R 14’is a C1-C6 alkyl or heteroalkyl or a C3-C6 cycloalkyl or heterocycloalkyl, each of which is selected from 0 to 2 R 14a where R 14a is selected from the group consisting of halogen, R, OR, amino, CF3, and CN; R 15 is, at each occurrence, independently selected from F, Cl, CN, OR, NRR′, and C1-C3 alkyl; R in each occurrence is independently H or C1-C6 alkyl; k is 0, 1, 2, or 3. or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0533] In yet another aspect, the present invention provides a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans, generally comprising: (II) a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans;

[0534] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 21 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is N or O, then R 21 is not F, R 22 teeth, R 22’ (where R 22’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 22a where R 22ais selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, and heterocyclic; Each has 0 to 2 R 22a an aryl or heteroaryl group substituted with (C=O)R 27 and R 23 teeth,

[0535] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are O, C, CH, S, N and NR 26 are independently selected from R 24 is H and 0 to 3 R 24a C is replaced by 1~6 Alkyl, or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 24b is replaced by R 24a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 24b represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl, C 3~10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of which may contain 0 to 3 R 24a substituted with), C1~6 Haloalkyl, 0 to 3 R 24a C is replaced by 2~6 Alkenyl, 0 to 3 R 24a C is replaced by 2~6 is alkynyl, R 25 is F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl, C3-C5 cycloalkyl, and 0-2 R 24b is replaced by R 26 is H, C1-C6 alkyl, CD3, or C3-C6 cycloalkyl, and 0 to 3 R 24a is replaced by R 27 is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 24b is replaced by each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; p is 1 or 2] or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0536] In yet another aspect, the present invention provides a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans, generally comprising: (III):

[0537] [ka] (In the formula, Ring A is a 5- or 6-membered aryl or heteroaryl; X 1 is selected from NR, O, CH2 and CF2; Z 1 is CH or N, Z 2 is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 6 is NR 36 , CH2, O, S, SO or SO2, R 32 is R 32’ OR 32’ where R 32’ is C 1~12 alkyl, a 3- to 6-membered cycloalkyl or heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- or 6-membered aryl or heteroaryl group, each of which is selected from 0 to 3 R 32a is replaced by R 32a is independently, at each occurrence, H, OCF3, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , (CH2) r NR g R g , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O)v NR g R g , -NR b S(O) v R c , -S(O) v R c , 0 to 3 R a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a C is replaced by 2~6 Alkenyl, 0 to 3 R a 3- to 6-membered cycloalkyl substituted with 0 to 3 R a is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R 33 and R 34 Each of these is H, F, Cl, CN, OR g , CH3, CD3, CF3, OCD3, OCF3 and -(CH2) p - selected independently from Q, R 35 is H, F, C1-C3 alkyl and CD3, provided that X 1 is O or N, then R 35 is not F, R 36 is 0 to 3 R d is R substituted with R a represents, at each occurrence, independently, H, F, Cl, Br, OCF3, CF3, CHF2, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , -(CH2) r NR g R g , -(CH2) r C(O)NR g Rg , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O) v NR g R g , -NR b S(O) v R c , -S(O)R c , -S(O)2R c , 0 to 3 R f C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R f 3- to 6-membered cycloalkyl substituted with 0 to 3 R f is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R b is H, 0 to 3 R d C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C is replaced by 3~6 Cycloalkyl or 0 to 3 R f a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with 0-3 R d (CH2) r -phenyl, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 R f (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, R dindependently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6 alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R dC1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; v is 0, 1, or 2; r is 0, 1, 2, 3, 4, or 5) or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0538] In yet another aspect, the present invention provides a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans, generally comprising: (IV):

[0539] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 41 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is NR or O, then R 41 is not F, R 42 teeth, R 42’ (where R 42’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is substituted with 0-2 of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; 0 to 2 R 42a an aryl or heteroaryl group substituted with (C=O)R 42b and R 43 teeth,

[0540] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 10 are independently selected from C, CH, O, N, and NH; R 42a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 42b is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 42c is replaced by R 42c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 42a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 42a C is replaced by 2~6 Alkenyl, 0 to 3 R 42a C is replaced by 2~6 is alkynyl, R 45 represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl (0 to 3 R42a substituted with ), or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 42c and optionally two R 45 form, together with the C or N atom to which they are attached, a 4- to 6-membered ring, R 46 is, at each occurrence, independently F, Cl, CN, OR, C1-C3 alkyl, C3-C5 cycloalkyl, CD3, CH2CF3, or CF3; R 47 is H, OCF3, C1-C3 alkyl, C1-C3 alkoxy or OCD3, each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; j is 0, 1, or 2. or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0541] In yet another aspect, the present invention provides a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans, generally comprising: (V) a compound useful in treating or reducing one or more diseases or disorders in mammals, including humans;

[0542] [ka] (In the formula, Ring B is a 5- or 6-membered aryl or heteroaryl; Z 1 is CH or N, Z2 is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 5 is selected from NR, O, CH2 and CF2; Z 6 is NR 56 , CH2, O, S, SO or SO2, X 4 , X 7 , X 8 and X 9 are independently selected from CH, N, and NH; R 51 is H, F, C1-C3 alkyl and CD3, provided that Z 5 If is N or O, then R 51 is not F, R 52 are H, F, Cl, CN, OR g , CH3, CF3, OCF3 and -(CH2) p - selected independently from Q, R 52a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 52c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 52a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 52a C is replaced by 2~6 Alkenyl, 0 to 3 R 52a C is replaced by 2~6 is alkynyl, R 55 Each occurrence of is independently H, 0 to 3 R 52a C is replaced by 1~6 Alkyl, or C 3~10Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 52c is replaced by R 56 is 0 to 3 R d is R substituted with R 57 is H, C1-C3 alkyl, C1-C3 alkoxy, OCD3 or OCF3, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 R f (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, R d independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R d C1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with i is 0, 1, 2, and 3; m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4) or a pharmaceutically acceptable form or isotopic derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

[0543] In certain embodiments, the pharmaceutical compositions disclosed herein are suitable for oral administration.

[0544] In certain embodiments, the pharmaceutical compositions disclosed herein are suitable for topical administration.

[0545] In certain embodiments, the pharmaceutical compositions disclosed herein are suitable for GI restricted administration.

[0546] In certain embodiments, the pharmaceutical compositions disclosed herein are useful for treating or reducing one or more of inflammatory diseases, immune-mediated diseases, and cancer, or related diseases or disorders. In certain embodiments, the disease or disorder is an inflammatory disease. In certain embodiments, the disease or disorder is an immune-mediated disease. In certain embodiments, the disease or disorder is cancer. In certain embodiments, the disease or disorder is selected from inflammatory bowel disease, psoriasis, vitiligo vulgaris, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0547] In yet another aspect, the invention generally relates to unit dosage forms comprising the pharmaceutical compositions disclosed herein.

[0548] In certain embodiments, the unit dosage form is a tablet.

[0549] In certain embodiments, the unit dosage form is a capsule.

[0550] In certain embodiments, the unit dosage form is a topical formulation.

[0551] In yet another aspect, the present invention generally relates to methods for treating, reducing, or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0552] In yet another aspect, the present invention generally provides a method for treating a skin condition comprising: (I):

[0553] [ka] (In the formula, X 1 and X 2 are independently selected from CH and N; X 4 and X 5 are independently selected from CH, CF and N; X 3 is NR, O, CH2 or CF2, R 11 is H, F, C1-C3 alkyl or CD3, provided that X 3 If is NR or O, then R 11 is not F, R 12 is C(=O)R 12’ or R 12’ where R 12’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 12a where R 12a is selected from the group consisting of halogen, CF, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R 13 is C1-C3 alkyl, CD3 or CF3, R 14 is H, C1-C6 alkyl or heteroalkyl, or C3-C6 cycloalkyl or heterocycloalkyl, or a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S, or R 14 is OR 14’ where R 14’ is a C1-C6 alkyl or heteroalkyl or a C3-C6 cycloalkyl or heterocycloalkyl, each of which is selected from 0 to 2 R 14awhere R 14a is selected from the group consisting of halogen, R, OR, amino, CF3, and CN; R 15 is, at each occurrence, independently selected from F, Cl, CN, OR, NRR′, and C1-C3 alkyl; R in each occurrence is independently H or C1-C6 alkyl; k is 0, 1, 2, or 3. or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in a mammal, including a human.

[0554] In yet another aspect, the present invention generally comprises: (II):

[0555] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 21 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is N or O, then R 21 is not F, R 22 teeth, R 22’ (where R 22’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is selected from 0 to 2 R 22a where R 22ais selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, and heterocyclic; Each has 0 to 2 R 22a an aryl or heteroaryl group substituted with (C=O)R 27 and R 23 teeth,

[0556] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 and X 9 are O, C, CH, S, N and NR 26 are independently selected from R 24 is H and 0 to 3 R 24a C is replaced by 1~6 Alkyl, or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 24b is replaced by R 24a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 24b represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl, C 3~10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each of which may contain 0 to 3 R 24a substituted with), C1~6 Haloalkyl, 0 to 3 R 24a C is replaced by 2~6 Alkenyl, 0 to 3 R 24a C is replaced by 2~6 is alkynyl, R 25 is F, Cl, CN, CD3, CH2CF3, CF3, OR, NRR', C1-C3 alkyl, C3-C5 cycloalkyl, and 0-2 R 24b is replaced by R 26 is H, C1-C6 alkyl, CD3, or C3-C6 cycloalkyl, and 0 to 3 R 24a is replaced by R 27 is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 24b is replaced by each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; p is 1 or 2] or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in a mammal, including a human.

[0557] In yet another aspect, the present invention generally provides compounds of structural formula (III):

[0558] [ka] (In the formula, Ring A is a 5- or 6-membered aryl or heteroaryl; X 1 is selected from NR, O, CH2 and CF2; Z 1 is CH or N, Z 2 is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 6 is NR 36 , CH2, O, S, SO or SO2, R 32 is R 32’ OR 32’ where R 32’ is C 1~12 alkyl, a 3- to 6-membered cycloalkyl or heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S, or a 5- or 6-membered aryl or heteroaryl group, each of which is selected from 0 to 3 R 32a is replaced by R 32a is independently, at each occurrence, H, OCF3, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , (CH2) r NR g R g , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c, -NR b C(O)NR g R g , -S(O) v NR g R g , -NR b S(O) v R c , -S(O) v R c , 0 to 3 R a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R a C is replaced by 2~6 Alkenyl, 0 to 3 R a 3- to 6-membered cycloalkyl substituted with 0 to 3 R a is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R 33 and R 34 Each of these is H, F, Cl, CN, OR g , CH3, CD3, CF3, OCD3, OCF3 and -(CH2) p - selected independently from Q, R 35 is H, F, C1-C3 alkyl and CD3, provided that X 1 is O or N, then R 35 is not F, R 36 is 0 to 3 R d is R substituted with R a represents, at each occurrence, independently, H, F, Cl, Br, OCF3, CF3, CHF2, CN, -(CH2) r OR b , -(CH2) r SR b , -(CH2) r C(O)R b , -(CH2) r C(O)OR b , -(CH2) r OC(O)R b , -(CH2) r NR g Rg , -(CH2) r C(O)NR g R g , -(CH2) r NR b C(O)R c , -(CH2) r NR b C(O)OR c , -NR b C(O)NR g R g , -S(O) v NR g R g , -NR b S(O) v R c , -S(O)R c , -S(O)2R c , 0 to 3 R f C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R f 3- to 6-membered cycloalkyl substituted with 0 to 3 R f is a 3- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with R b is H, 0 to 3 R d C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 2 R d C is replaced by 3~6 Cycloalkyl or 0 to 3 R f a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with 0-3 R d (CH2) r -phenyl, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 R f (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f(CH2) r -phenyl, R d independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2) r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6 alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R d C1-C6 alkyl substituted with R' is H or 0 to 3 R d C1-C6 alkyl substituted with m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; v is 0, 1, or 2; r is 0, 1, 2, 3, 4, or 5) or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in a mammal, including a human.

[0559] In yet another aspect, the present invention generally provides compounds of structural formula (IV):

[0560] [ka] [In the formula, Y 1 is CH, CF or N, Y 2 is CH or N, Y 3 is NR, O, CH2 or CF2, R 41 is H, F, C1-C3 alkyl and CD3, provided that Y 3 If is NR or O, then R41 is not F, R 42 teeth, R 42’ (where R 42’ is C1-C6 alkyl, C3-C6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is substituted with 0-2 of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; 0 to 2 R 42a an aryl or heteroaryl group substituted with (C=O)R 42b and R 43 teeth,

[0561] [ka] and During the ceremony, X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 10 are independently selected from C, CH, O, N, and NH; R 42a is, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3, CN, C(O)NR, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 42b is C 1~6 Alkyl or C 3~6 cycloalkyl, aryl, or heteroaryl, each of which is 0 to 2 R 42c is replaced by R 42c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 42a C is replaced by 1~6Alkyl, C 1~6 Haloalkyl, 0 to 3 R 42a C is replaced by 2~6 Alkenyl, 0 to 3 R 42a C is replaced by 2~6 is alkynyl, R 45 represents, at each occurrence independently, H, halo, CN, OR, NRR', OCF3, CF3, C 1~6 Alkyl (0 to 3 R 42a substituted with ), or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 42c and optionally two R 45 form, together with the C or N atom to which they are attached, a 4- to 6-membered ring, R 46 is, at each occurrence, independently F, Cl, CN, OR, C1-C3 alkyl, C3-C5 cycloalkyl, CD3, CH2CF3, or CF3; R 47 is H, OCF3, C1-C3 alkyl, C1-C3 alkoxy or OCD3, each of R and R' is independently H or C1-C6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO2; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; j is 0, 1, or 2. or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in a mammal, including a human.

[0562] In yet another aspect, the present invention generally provides compounds of structural formula (V):

[0563] [ka] (In the formula, Ring B is a 5- or 6-membered aryl or heteroaryl; Z 1 is CH or N, Z 2 is CH, CF or N, Z 3 and Z 4 are independently selected from NR, CH2, and CF2; Z 5 is selected from NR, O, CH2 and CF2; Z 6 is NR 56 , CH2, O, S, SO or SO2, X 4 , X 7 , X 8 and X 9 are independently selected from CH, N, and NH; R 51 is H, F, C1-C3 alkyl and CD3, provided that Z 5 If is N or O, then R 51 is not F, R 52 are H, F, Cl, CN, OR g , CH3, CF3, OCF3 and -(CH2) p - selected independently from Q, R 52ais, at each occurrence, independently H, D, halo, OH, OR, CH3, CF3, CH2CF3 or CN, NRR', (CH2) n NRR' or a 4- to 6-membered heterocycle having 1 to 4 heteroatoms selected from N, O and S; R 52c is, at each occurrence, independently H, halo, CN, OR, NRR', OCF3, CF3, or 0 to 3 R 52a C is replaced by 1~6 Alkyl, C 1~6 Haloalkyl, 0 to 3 R 52a C is replaced by 2~6 Alkenyl, 0 to 3 R 52a C is replaced by 2~6 is alkynyl, R 55 Each occurrence of is independently H, 0 to 3 R 52a C is replaced by 1~6 Alkyl, or C 3~10 Cycloalkyl or heterocycloalkyl, C 5~10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1 to 4 heteroatoms selected from N, O, and S, each group having 0 to 4 R 52c is replaced by R 56 is 0 to 3 R d is R substituted with R 57 is H, C1-C3 alkyl, C1-C3 alkoxy, OCD3 or OCF3, R c is 0 to 3 R f C is replaced by 1~6 Alkyl, 0 to 3 R f (CH2) r -C 3~6 Cycloalkyl or 0 to 3 R f (CH2) r -phenyl, R d independently, at each occurrence, represent hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, -OR e , -(CH2)r C(O)R c , -NR e R e , -NR e C(O)OR c , C 1~6 Alkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R e independently, at each occurrence, hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl or (CH2) r -phenyl, and 0 to 3 R f is replaced by R f independently, at each occurrence, represent hydrogen, halo, CN, NH, OH, C 3~6 Cycloalkyl, CF3, O(C 1~6 alkyl), or a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S; R g Each occurrence of is independently H, 0 to 3 R f C is replaced by 1~4 Alkyl, CF3, 0-1 R f C is replaced by 3~10 Cycloalkyl, 0 to 3 R d (CH) r -phenyl, or 0 to 3 R d is a 5- to 7-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, substituted with Q is a water solubilizing group optionally selected from OH, OR, NRR′, heterocyclic and heteroaryl groups, where R and R′ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S and SO; R is H or 0 to 3 R d C1-C6 alkyl substituted with R' is H or 0 to 3 R dC1-C6 alkyl substituted with i is 0, 1, 2, and 3; m is 0, 1, 2, and 3; n is 0, 1, 2, and 3; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4) or a pharmaceutically acceptable form or isotopic derivative thereof to a subject in need thereof, wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or related diseases or disorders in a mammal, including a human.

[0564] In certain embodiments, the method is used to treat an inflammatory disease. In certain embodiments, the method is used to treat an immune-mediated disease. In certain embodiments, the method is used to treat cancer. In certain embodiments, the method is used to treat a disease or disorder selected from the following: inflammatory bowel disease, psoriasis, vitiligo vulgaris, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0565] In certain embodiments, administration of the compound is via oral administration.

[0566] In certain embodiments, administration of the compound is via topical administration.

[0567] In certain embodiments, administration of the compound is via GI restricted administration.

[0568] In yet another aspect, the invention generally relates to the use of a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent in the preparation of a medicament for treating a disease or disorder.

[0569] In certain embodiments, the compound is used to treat one or more of an inflammatory disease, an immune-mediated disease, and cancer. In certain embodiments, the compound is used to treat an inflammatory disease. In certain embodiments, the compound is used to treat an immune-mediated disease. In certain embodiments, the compound is used to treat cancer. In certain embodiments, the compound is used to treat a disease or disorder selected from the following: inflammatory bowel disease, psoriasis, vitiligo vulgaris, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0570] In certain embodiments, the use of the compound is via oral administration. In certain embodiments, the use of the compound is via topical administration. In certain embodiments, the use of the compound is via GI restricted administration.

[0571] A non-limiting list of exemplary compounds of the present invention is provided in Table #. Certain illustrative data for select compounds is provided in Table #.

[0572] As discussed herein, isotopically derivatized compounds having one or more hydrogen atoms (e.g., 1, 2, 4, 5, 6, 7, 8, 9, 10, etc.) replaced with deuterium atoms are contemplated in the present invention.

[0573] The term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation, e.g., an increased level of inflammation, compared to a control, such as a healthy human not suffering from the disease. Examples of inflammatory diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include autoimmune diseases, traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune diseases, and the like. These include immune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis.These conditions are often closely intertwined with other diseases, disorders, and conditions.For example, the non-limiting list of inflammation-related diseases, disorders, and conditions that can be caused by inflammatory cytokines includes arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergy, fibrosis, surgical complications (for example, when inflammatory cytokines hinder healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infectious diseases, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczema, systemic sclerosis, transplantation and multiple sclerosis.Some of the aforementioned diseases, disorders and conditions that the compounds of the present disclosure may be particularly effective (for example, due to the limitations of current treatment) are described in more detail below.

[0574] The term "autoimmune disease" refers to a disease or condition in which a subject's immune system has an abnormal immune response to a substance that does not normally elicit an immune response in healthy subjects. Examples of autoimmune diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include acne vulgaris, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, Aicardi-Goutieres syndrome (AGS), alopecia areata, alopecia totalis, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic neuropathy, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency syndrome, and autoimmune inflammatory bowel disease. All autoimmune inner ear diseases, autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroid disease, autoimmune urticaria, axonal or neurogenic neuropathy, Barrow's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas' disease, chronic atypical neutrophilic dermatosis with lipodystrophy and fever (CANDLE), chronic active hepatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multiple myelitis , Churg-Strauss syndrome, cicatricial pemphigoid / benign mucosal pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, Crest's disease, Cushing's disease, demyelinating neuropathy, depression, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, dry eye syndrome (DES), endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, experimental allergic encephalomyelitis, Evans' syndrome, fibromyalgia Myalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, graft-versus-host disease (GVDH), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hidradenitis suppurativa, hypogammaglobulinemia, idiopathic thrombocytopenic purpura, IgA nephropathy, IgG4-related sclerosing disease, inflammatory bowel disease (IBD), immunoregulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile arthritis,Juvenile diabetes mellitus (type 1 diabetes), juvenile dermatomyositis (JDM), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear IgA disease, lupus, Lyme disease, chronic Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Much-Habermann disease, multiple sclerosis (MS), myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis, schizophrenia ... Pediatric autoimmune neuropsychiatric disorders associated with streptococcus, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, Parsonage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polycystic ovary syndrome (PCOS), autoimmune polyglandular syndrome types I, II & III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy Syndrome, Progestational Dermatitis, Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, Psoriasis, Psoriatic Arthritis, Plaque Psoriasis, Idiopathic Pulmonary Fibrosis, Pyoderma Gangrenosum, Pure Red Cell Aplasia, Raynaud's Phenomenon, Reactive Arthritis, Reflex Sympathetic Dystrophy, Reiter's Syndrome, Relapsing Polychondritis, Restless Legs Syndrome, Retroperitoneal Fibrosis, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Schmidt's Syndrome, Scleritis, Scleroderma, Sjogren's Syndrome, Sperm & Testicular Autoimmunity, Stiff Body Syndrome, Onset During Infancy These include stimulator of interferon genes (STING)-associated vasculopathy (SAVI), subacute bacterial endocarditis, Susac syndrome, sympathetic ophthalmia, systemic lupus erythematosus (SLE), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, transplant rejection (allograft rejection), transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, bullous diseases, vitiligo vulgaris, or Wegener's granulomatosis.

[0575] The term "immune-mediated disease" refers to chronic inflammatory diseases perpetuated by antibody and cell-mediated immunity. Examples of immune-mediated diseases include, but are not limited to, asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), juvenile arthritis, inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis (MS)), autism spectrum disorder, depression, Alzheimer's disease, Guillain-Barré syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjögren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Guillain-Barré syndrome, and others. Reay's syndrome, myasthenia gravis, and chronic idiopathic demyelinating diseases (CIDs), vascular diseases (e.g., autoimmune hearing loss, systemic vasculitis, and atherosclerosis), and skin diseases (e.g., acne vulgaris dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, plaque psoriasis, vasculitis, vitiligo, and alopecia), Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, transplant rejection (allograft rejection), graft versus host disease (GVDH).

[0576] The term "cancer" as used herein refers to all types of cancer, neoplasms, or malignant tumors found in mammals, such as humans, including hematological cancers, leukemias, and lymphomas, T-ALL, large B-cell lymphoma, and solid cancers, such as carcinomas and sarcomas. Exemplary cancers include blood cancer, brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, stomach cancer, ovarian cancer, lung cancer, and head cancer. Exemplary cancers include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma cancer, stomach cancer, uterus cancer, medulloblastoma cancer, colorectal cancer, and pancreatic cancer. Additional examples include penile, cutaneous - non-melanoma, anal, hepatobiliary, esophagogastric, uterine sarcoma, gastrointestinal stromal tumor, salivary gland, peripheral nervous system, soft tissue sarcoma, bone, kidney, myeloproliferative neoplasm, thyroid carcinoma, bile duct adenocarcinoma, pancreatic adenocarcinoma, cutaneous melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary These include macroglobulinemia, primary brain tumors, cancer, malignant pancreatic islet cell adenoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, metastatic leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, round cell liposarcoma, or prostate cancer.

[0577] In certain embodiments of the above uses, the disease or disorder is selected from inflammatory bowel disease, psoriasis, vitiligo vulgaris, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0578] Isotopically labeled compound is also within the scope of the present disclosure.As used herein, " isotope-labeled compound " refers to the presently disclosed compound, including its pharmaceutical salts and prodrugs as described herein, wherein one or more atoms are replaced by the atom with atomic mass or mass number that is different from the atomic mass or mass number that is usually found in nature.The examples of isotopes that can be incorporated into the presently disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Examples include Cl.

[0579] By isotopically labeling the presently disclosed compounds, the compounds may be useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) labeled compounds are particularly preferred for their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, can confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. The presently disclosed isotopically labeled compounds can be prepared by any means known in the art, including pharmaceutical salts, esters, and prodrugs thereof.

[0580] Furthermore, the normally abundant hydrogen ( 1H) substitution can confer certain therapeutic benefits, for example, due to improved absorption, distribution, metabolism and / or excretion (ADME) properties, producing drugs with improved efficacy, safety, and / or tolerability. 13 Usually abundant with C 12 C replacement (see International Publication Nos. WO2007 / 005643, WO2007 / 005644, WO2007 / 016361, and WO2007 / 016431).

[0581] Stereoisomers (e.g., cis and trans isomers) and all optical isomers of the presently disclosed compounds (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers, are within the scope of this disclosure.

[0582] The compounds of the present invention are preferably isolated and purified after their preparation to obtain a composition containing 95% or more ("substantially pure") by weight, which is then used or formulated as described herein.In certain embodiments, the compounds of the present invention are more than 99% pure.Solvates and polymorphs of the compounds of the present invention are also contemplated herein.Solvates of the compounds of the present invention include, for example, hydrates.

[0583] Any suitable route of administration may be used, for example, parenteral, intravenous, subcutaneous, intramuscular, intracerebroventricular, internal, intraperitoneal, rectal, or oral administration. The most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated, or the nature of the therapy being used, and on the nature of the active compound.

[0584] Solid dosage forms for oral administration include capsules, tablets, pills, powders, or granules. In such solid dosage forms, the compounds described herein or their derivatives are administered in a pharmaceutical composition containing at least one inert conventional excipient (or carrier), such as sodium citrate or dibasic calcium phosphate, or (i) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (ii) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (iii) humectants, such as glycerol; (iv) disintegrants, such as agar, calcium carbonate, or the like. The following additives may be added to and mixed with: (i) sodium, potato, or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (ii) dissolution retarders, such as paraffin; (iii) absorption accelerators, such as quaternary ammonium compounds; (vii) wetting agents, such as cetyl alcohol and glycerol monostearate; (viii) adsorbents, such as kaolin and bentonite; and (ix) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols. Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can be prepared with coatings and shells, such as enteric coatings and others known in the art.

[0585] The liquid dosage form for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir.In addition to active compound, liquid dosage form can contain commonly used inert diluents in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, or the mixture of these substances.In addition to these inert diluents, the composition can also contain additional agents such as wetting agent, emulsifier, suspending agent, sweetener, flavoring agent or flavoring agent.

[0586] The materials, compositions, and components disclosed herein can be used for, in conjunction with, used in preparation for, or are products of the disclosed methods and compositions. When combinations, subsets, interactions, groups, etc. of these materials are disclosed, specific references to various individual and collective combinations and permutations of each of these compounds may not be explicitly disclosed, but each is understood to be specifically contemplated and described herein. For example, if a method is disclosed and discussed, and multiple modifications that can be made to multiple molecules included in the method are discussed, each and every combination and permutation of the method and possible modifications are specifically contemplated unless specifically indicated to the contrary. Similarly, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this disclosure, including, but not limited to, steps in methods using the disclosed compositions. Thus, if there are various additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method step or combination of method steps of the disclosed method, and each such combination or subset of combinations should be considered to be specifically contemplated and disclosed.

[0587] The following examples are meant to be illustrative of the practice of this invention and not limiting in any way. [Example]

[0588] Abbreviation Methanol: MeOH Dichloromethane: DCM Petroleum Ether: PE Ethyl acetate: EtOAc Acetonitrile:CAN Isopropanol: IPA Triethylamine: TEA Sodium hydroxide: NaOH Propylphosphonic anhydride: T3P Nitrogen: N2 Thin layer chromatography: TLC High performance liquid chromatography: HPLC N,N-Diisopropylethylamine: DIPEA N,N-dimethylformamide: DMF 4-Methylbenzene-1-sulfonyl chloride: TsCl Room temperature: RT / rt Time:hrs

[0589] Representative methods for preparative HPLC: Flow rates and gradients may be varied.

[0590] An exemplary method for preparative HPLC is shown below.

[0591] Method A: NH4HCO3: Column: Gilson2-Xbridge C18 19 * 150 mm, 5 μm; mobile phase: 20%-60% CH3CN (0.1% NH4HCO3) in water, flow rate: 15 ml / min.

[0592] Method B: TFA: Column: Waters-Xbridge C18 10 * 190 mm, 5 μm; mobile phase: 15%-40% CH3CN in water (0.1% TFA), flow rate: 15 ml / min.

[0593] Method C: HCOOH: Column: Waters-Xbridge C18 10 * 190 mm, 5 μm; mobile phase: 15%-40% CH3CN (0.1% formic acid) in water, flow rate: 15 ml / min.

[0594] Method D: HCOOH: Method E: NH4HCO3 Column: Waters Xbridge® Prep C18 OBD™ (5 micron, 19 *150 mm); Mobile phase: 20%-60% CH3CN (10 mM NH4HCO3) in water, flow rate: 20 ml / min.

[0595] Column: Waters SunFire® Prep C18 OBD™ (5 micron, 19 * 150 mm); Mobile phase: 18%-38% CH3CN (0.1% formic acid) in water, flow rate: 20 ml / min.

[0596] Typical analytical HPLC methods Method 1: Analysis was performed on an Agilent 1200 Series HPLC-6120MS. UHPLC Long Gradient Equivalent 5% to 95% acetonitrile (containing 0.02% NHOAc) in water, with a run time of 6.5 minutes and a flow rate of 1.5 ml / min. A Waters Xbridge C18 column (18.5 microns, 4.6 * 50 mm) was used at a temperature of 40°C.

[0597] Method 2: Analysis was performed on an Agilent 1200 Series HPLC-6120MS. UHPLC Long Gradient Equivalent 5% to 95% acetonitrile (containing 0.1% trifluoroacetic acid) in water, with a run time of 6.5 minutes and a flow rate of 1.5 ml / min. A Waters Xbridge C18 column (18.5 microns, 4.6 * 50 mm) was used at a temperature of 40°C.

[0598] Method 3: Analysis was performed on an Agilent 1260 Series HPLC-6120MS. UHPLC Long Gradient Equivalent 5% to 95% acetonitrile (containing 0.02% NHOAc) in water, with a run time of 2.5 minutes and a flow rate of 0.5 ml / min. A diamonsil Plus C18 column (18.5 microns, 4.6 * 30 mm) was used at a temperature of 40°C.

[0599] Method 4: Analysis was performed on an Agilent 1260 Series HPLC-6125C MS. HPLC Long Gradient Equivalent 20% to 100% acetonitrile (containing 0.1% FA) in water, with a run time of 6 minutes and a flow rate of 0.8 ml / min. An Agilent ZORBAX SB-C18 column (1.8 microns, 2.1 * 50 mm) was used at a temperature of 30°C.

[0600] Typical methods for preparative chiral HPLC: Shimadzu LC-20A,Daicel Chiralpak IB N,5μm,4.6 * 250 mm; mobile phase: hexane / EtOH / diethylamine=80 / 20 / 0.3, flow rate: 25 ml / min.

[0601] [ka]

[0602] Step 1. 4-Chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (1b) To a mixture of 4-chloro-1H-pyrrolo[3,2-c]pyridine 1a (17.00 g, 111.42 mmol) in DMF (350 mL) was added NIS (37.60 g, 167.12 mmol) dropwise at 0 °C. After stirring at room temperature for 2 h, the mixture was diluted with EtOAc (2 L) and washed with brine (3 x 500 mL). The separated organic layer was concentrated under reduced pressure to give the title compound 1b (23.2 g, 75% yield) as a brown solid. 1 H NMR (400MHz, CDCl3) δ 8.89 (brs, 1H), 8.10 (d, J = 5.6 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 5.6 Hz, 1H).

[0603] Step 2. 4-Chloro-3-iodo-1,5-dimethyl-1H-pyrrolo[3,2-c]pyridin-5-ium iodide (1c) A mixture of 1b (2 g, 7.18 mmol), K2CO3 (2.97 g, 21.55 mmol), and CHCl (5.10 g, 35.91 mmol) in DMF (20 mL) was stirred at room temperature for 16 h. The reaction solution was used in the next step without workup. LC-MS (Method 1) R =1.78 min, m / z M + =307.1.

[0604] Step 3. 3-Iodo-1,5-dimethyl-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (1d) Compound 1c was dissolved in a mixture of water (10 mL) and 1,4-dioxane (10 mL). To the solution was added NaOH (1.44 g, 35.93 mmol). After stirring at room temperature for 6 hours, the reaction mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated to give the title compound 1d (1.13 g, 55% yield) as a black solid. 1 H NMR (400MHz, CDCl3) δ 7.05 (d, J = 7.6 Hz, 1H), 6.89 (s, 1H), 6.27 (d, J = 7.6 Hz, 1H), 3.68 (s, 3H), 3.56 (s, 3H).

[0605] Step 4. Tert-butyl (1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)carbamate (1e) A mixture of 1d (1.13 g, 3.92 mmol), tert-butyl carbamate (4.60 g, 39.22 mmol), N,N'-dimethylenediamine (173 mg, 1.96 mmol), CuI (374 mg, 1.96 mmol), and KPO (1.67 g, 7.84 mmol) in 1,4-dioxane / DMSO (2 mL, v / v = 10 / 1) was stirred under N at 90 °C. The reaction mixture was cooled to room temperature and concentrated, and the residue was purified by silica gel chromatography (1 / 10 to 1 / 1 PE / EtOAc) to give the title compound 1e (400 mg, 37% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.27(s,1H),7.20(d,J=7.2Hz,1H),7.13(s,1H),6.51(d,J=7.2Hz,1H),3.64(s,3H),3.43(s,3H),1.47(s,9H).

[0606] Step 5. 3-Amino-1,5-dimethyl-1H-pyrrolo[3,2-c]pyridin-4(5H)-one hydrochloride (1f) Compound 1e (279 mg, 1 mmol) was dissolved in a solution of HCl (g) in EtOAc (5 mL, 2 M). The resulting mixture was stirred at room temperature for 2 hours. The resulting solid was filtered. The filter cake was dried to give the title compound 1f (179 mg, 82% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.22(s,2H),7.45(d,J=7.6Hz,1H),7.27(s,1H),6.61(d,J=7.6Hz,1H),3.71(s,3H),3.48(s,3H).

[0607] Step 6. 2,4-Dichloro-N-methylpyrimidine-5-carboxamide (1h) To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride 1g (500 mg, 2.36 mmol) in DCM (5 mL) were added TEA (478 mg, 4.73 mmol) and methylamine (2.36 mmol, 1.2 mL, 2 M in THF) successively at −70° C. The mixture was stirred at −70° C. for 1 h. The mixture was diluted with DCM (20 mL) and washed with saturated NaHCO (20 mL). The separated organic layer was washed with brine (20 mL), dried over NaSO, and filtered. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 3 / 1) to give the title compound 1h (170 mg, 35% yield). 1 H NMR (400MHz, CDCl3) δ 8.98 (s, 1H), 6.49 (s, 1H), 3.07 (d, J = 4.8Hz, 3H).

[0608] Step 7. 2-Chloro-4-((1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-N-methylpyrimidine-5-carboxamide (1i) Compound 1f (50 mg, 0.23 mmol), 1h (58 mg, 0.28 mmol), and DIPEA (91 mg, 0.70 mmol) were dissolved in IPA (1 mL). The resulting reaction was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The solid was treated with EtOAc (5 mL). The resulting solid was collected by filtration, and the filter cake was dried to give the title compound 1i (51.5 mg, 63% yield) as a white solid. LC-MS (Method 3) R =1.30 min, m / z(M+H) + =347.2.

[0609] Step 8. 2-(Cyclopropanecarboxamide)-4-((1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-N-methylpyrimidine-5-carboxamide (1) Compound 1i (50 mg, 0.14 mmol), cyclopropanecarboxamide (61 mg, 0.72 mmol), BrettPhos (15 mg, 0.02 mmol), BrettPhos Pd G3 (26 mg, 0.02 mmol), and Cs2CO3 (94 mg, 0.29 mmol) were dissolved in 1,4-dioxane (1 mL). The mixture was stirred at 100 °C under N2 for 5 h. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was purified by preparative HPLC (Method A) to give the title compound 1 (22.5 mg, 39% yield). LC-MS (Method 2) R =2.52 min, m / z(M+H) + =396.2. 1H NMR(400MHz,DMSO-d6)δ 11.82(s,1H),10.86(s,1H),8.62(d,J=7.6Hz,2H),8.46(d,J=4.4Hz,1H),7.30(d,J=7.2Hz,1H),6.52( d,J=7.6Hz,1H),3.70(s,3H),3.46(s,3H),2.80(d,J=4.8Hz,3H),2.20-2.17(m,1H),0.93-0.83(m,4H).

[0610] [ka]

[0611] Step 1. Methyl 2-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (2b) To a solution of 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline (1.4 g, 6.86 mmol) and 2a (1.42 g, 6.86 mmol) in IPA (20 mL) was added DIPEA (1.77 g, 13.71 mmol) dropwise. The reaction mixture was stirred at 80 °C overnight. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated to dryness to give the title compound 2b (1.3 g, 51% yield) as a red oil. 1 H NMR(400MHz,DMSO-d6)δ 11.00(s,1H),8.87(s,1H),8.58(s,1H),8.47(d,J=8.0Hz,1H),7.65(d,J=8.8Hz,1H),7.31(t,J=7.6Hz 1H),3.96(s,3H),3.93(s,3H),3.81(s,3H).

[0612] Step 2. 2-Chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (2c) Compound 2b (1 g, 2.67 mmol) and NaOH (214 mg, 5.34 mmol) were dissolved in THF (8 mL) and HO (4 mL). The resulting mixture was stirred at 50° C. for 3 h. The mixture was acidified with 1N HCl to pH=2. The resulting solid was filtered, and the filter cake was dried to give the title compound 2c (840 mg, 87% yield) as a yellow solid. LC-MS (Method 3) R =1.12 min, m / z(M+H) + =361.1.

[0613] Step 3. 2-Chloro-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteromethyl)pyrimidine-5-carboxamide (2d) Compound 2c (500 mg, 1.39 mmol), methyl-d3-amine hydrochloride (127 mg, 1.80 mmol), T3P (716 mg, 5.54 mmol, 50% in DMF), and DIPEA (1.32 g, 4.16 mmol) were dissolved in DMF (8 mL). The resulting solution was stirred at room temperature for 1 h. The mixture was basified with 20% aqueous Na2CO3 to a pH above 8 and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give the title compound 2d (190 mg, 36% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.89(s,1H),8.91(s,1H),8.76(s,1H),8.57(s,1H),8.45(d,J=7.6Hz,1H ),8.60(d,J=7.6Hz,1H),7.27(t,J=8.0Hz,1H),3.95(s,3H),3.80(s,3H).

[0614] Step 4. 2-[(1-cyclopropylpyrazol-4-yl)amino]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteromethyl)pyrimidine-5-carboxamide (2) Compound 2d (20 mg, 0.53 mmol), 1-cyclopropylpyrazol-4-amine (20 mg, 0.15 mmol), DavePhos (5 mg, 0.011 mmol), CsCO (35 mg, 0.16 mmol), and Pd(dba) (5 mg, 0.005 mmol) were dissolved in a mixture of 2-methyltetrahydrofuran (1 mL) and HO (0.5 mL). The mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Method A) to give the title compound 2 (7 mg, 28% yield) as a white solid. LC-MS (Method 1) R =2.89 min, m / z(M+H) + =464.2. 1 H NMR(400MHz,DMSO-d6)δ 11.77-11.60(m,1H),9.50(s,1H),8.67-8.61(m,1H),8.55(s,1H),8.36(s,1H),8.25-8.23(m,1H),7.95-7.79(m ,1H),7.59-7.38(m,2H),7.20(t,J=8.0Hz,1H),3.95(s,3H),3.78(s,3H),3.59-3.50(m,1H),1.00-0.85(m,4H).

[0615] [ka]

[0616] Step 1. Methyl 2-((4-chlorophenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (3a) A mixture of 2b (40 mg, 0.108 mmol), 4-chloroaniline (15 mg, 0.119 mmol), CsCO (70 mg, 0.216 mmol), BINAP (13.7 mg, 0.022 mmol), and Pd(OAc) (2.5 mg, 0.011 mmol) in 1,4-dioxane (1.2 mL) was stirred overnight at 85 °C under N. The mixture was cooled to room temperature, then filtered through a Celite pad and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give product 3a (15 mg, 27% yield) as a pale yellow oil. LC-MS (Method 4) R =4.54 min, m / z(M+H) + =466.2.

[0617] Step 2. Lithium 2-((4-chlorophenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (3b) To a stirred mixture of 3a (15 mg, 0.032 mmol) in THF (0.6 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (3 mg, 0.064 mmol). The reaction was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure to give crude product 3b (18 mg, yield) as a tan solid. LC-MS (Method 4) R =3.24 min, m / z(M+H) + =452.2.

[0618] Step 3. 2-((4-chlorophenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (3) To a stirred mixture of 3b (18 mg, 0.04 mmol) in DMF (1.0 mL) was added methyl-d3-amine hydrochloride (8.5 mg, 0.12 mmol), HATU (46 mg, 0.12 mmol), and DIPEA (31 mg, 0.24 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by preparative HPLC (Method E) to give the title product 3 (3.4 mg, 18% yield) as an off-white solid. LC-MS (Method 4) R =3.56 min, m / z(M+H) + =468.3. 1 H NMR(400MHz,CDCl3)δ 11.53(s,1H),8.32(s,1H),8.15-8.07(m,2H),7.97(s,1H),7.74(dd,J=8.0,1.6Hz,1H),7.32(d,J =8.8Hz,2H),7.20(t,J=8.0Hz,1H),7.14(d,J=8.8Hz,2H),6.46(s,1H),4.05(s,3H),3.83(s,3H).

[0619] [ka]

[0620] Step 1. Ethyl 2-chloro-4-((1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)pyrimidine-5-carboxylate (4b) Compound 1f (200 mg, 0.94 mmol), DIPEA (603 mg, 4.68 mmol), and ethyl 2,4-dichloropyrimidine-5-carboxylate 4a (207 mg, 0.94 mmol) were dissolved in ACN (4 mL). The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the resulting solid was filtered. The filter cake was dried to give the title compound 4b (223 mg, 66% yield). 1H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),8.76(s,1H),7.65(s,1H),7.39(d,J=6.4Hz,1H),6.60(d,J=7. 2Hz, 1H), 4.42-4.39 (m, 2H), 3.75 (s, 3H), 3.49 (s, 3H), 1.37 (t, J=7.2Hz, 3H).

[0621] Step 2. Ethyl 4-((1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-2-((4-fluorophenyl)amino)pyrimidine-5-carboxylate (4c) Compound 4c (184 mg, 76% yield) was synthesized as a yellow solid by using 4b (200 mg, 0.55 mmol) and 4-fluoroaniline (92 mg, 0.83 mmol) as starting materials using a preparative procedure similar to that in Step 4 of Example 2. LC-MS (Method 3) R =1.46 min, m / z(M+H) + =437.2.

[0622] Step 3. 4-((1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-2-((4-fluorophenyl)amino)pyrimidine-5-carboxylic acid (4d) A mixture of 4c (150 mg, 0.34 mmol) and LiOH.HO (29 mg, 0.69 mmol) in THF (5 mL) and HO (2.5 mL) was stirred at 50 °C for 16 h. After cooling to room temperature, the mixture was adjusted to pH = 3 with 1 M HCl and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to give 4d (100 mg, 71% yield) as a yellow solid. LC-MS (Method 3) R =0.98 min, m / z(M+H) + =409.1.

[0623] Step 4. 4-((1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-2-((4-fluorophenyl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (4) Compound 4d (30 mg, 0.07 mmol), methyl-d3-amine hydrochloride (21 mg, 0.29 mmol), HATU (84 mg, 0.22 mmol), and DIPEA (47 mg, 0.37 mmol) were dissolved in DMF (2 mL). The reaction mixture was stirred at 25° C. for 2 hours and then concentrated to dryness. The residue was purified by preparative HPLC (Method A) to give the title compound 4 (9.2 mg, 29% yield). LC-MS (Method 1) R =3.31 min, m / z(M+H) + =425.1. 1 H NMR(400MHz,DMSO-d6)δ 11.80(s,1H),9.49(s,1H),8.53(s,1H),8.24(s,1H),7.68-7.64(m,3H),7.32(d,J= 7.2Hz,1H), 7.23(t,J=8.6Hz,2H),6.51(d,J=7.6Hz,1H),3.63(s,3H),3.45(s,3H).

[0624] [ka]

[0625] Step 1. Methyl 2-((5-fluoropyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (5a) Compound 5a (230 mg, 95% yield) was synthesized as a yellow solid by using a similar preparative procedure as in Step 4 of Example 2, starting from 2b (200 mg, 0.53 mmol) and 5-fluoropyridin-2-amine (60 mg, 0.53 mmol). LC-MS (Method 3) R =1.29 min, m / z(M+H) + =451.1.

[0626] Step 2. 2-((5-fluoropyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylic acid (5b) Compound 5b (222 mg, 98% yield) was synthesized as a yellow solid by using 5a (230 mg, 0.51 mmol) as the starting material and a similar preparative procedure to that in Step 3 of Example 4. LC-MS (Method 3) R =1.06 min, m / z(M+H) + =437.1.

[0627] Step 3. 2-((5-fluoropyridin-2-yl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyrimidine-5-carboxamide (5) Compound 5 (6 mg, 12% yield) was synthesized as a white solid by using 5b (50 mg, 0.11 mmol) and CH3NH2.HCl (15 mg, 0.22 mmol) as starting materials using a preparative procedure similar to that in Step 3 of Example 2. LC-MS (Method 2) R =2.84 min, m / z(M+H) + =450.0. 1 H NMR(400MHz,CDCl3)δ 11.23(s,1H),8.37(s,1H),8.33-8.27(m,2H),8.13-8.11(m,2H),7.84(s,1H),7.73(dd,J=8.0,2.0Hz,1H),7.3 5-7.28(m,1H),7.19(t,J=8.0Hz,1H),5.99(d,J=4.0,Hz,1H),4.01(s,3H),3.89(s,3H),3.01(d,J=4.8Hz,3H).

[0628] [ka]

[0629] Step 1. 4-(2-Methoxy-3-nitrophenoxy)tetrahydro-2H-pyran (6b) To a solution of 6a (2 g, 11.82 mmol), tetrahydropyran-4-ol (1.45 g, 14.18 mmol), and triphenylphosphine (6.20 g, 23.64 mmol) in THF (40 mL) was added dropwise DIAD (4.78 g, 23.64 mmol) at 0 °C. After stirring overnight at room temperature, the reaction mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with water (20 mL x 2) and brine (20 mL). The separated organic layer was dried over anhydrous NaSO and filtered. The filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 5 / 1) to give the title compound 6b (1.79 g, 60% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 7.38-7.35(m,2H),7.25-7.21(m,1H),4.49-4.45(m,1H),3.89(s,3H),3. 87-3.77(m,2H),3.39-3.33(m,2H),1.85-1.82(m,2H),1.58-1.55(m,2H).

[0630] Step 2. 2-Methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)aniline (6c) Compound 6b (1.25 g, 4.93 mmol), Fe powder (1.38 g, 24.68 mmol), and NH4Cl (1.31 g, 24.68 mmol) were dissolved in a mixture of EtOH (5 mL) and HO (5 mL). The reaction solution was stirred at 80 °C for 2 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 5 / 1) to give the title compound 6c (450 mg, 41% yield) as a red oil. LC-MS (Method 3) R =1.18 min, m / z(M+H) + =224.1.

[0631] Step 3. Ethyl 2-chloro-4-((2-methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)pyrimidine-5-carboxylate (6d) Compound 6d (80 mg, 11% yield) was synthesized as a white solid by using 6c (400 mg, 1.79 mmol) and 4a (475 mg, 2.15 mmol) as starting materials using a preparative procedure similar to that in Step 1 of Example 2. 1 H NMR(300MHz,DMSO-d6)δ 10.91(s,1H),8.87(s,1H),8.06(d,J=8.4Hz,1H),7.16(t,J=8.4Hz,1H),6.93(d,J=8.4Hz,1H),4 .48-4.40(m,4H),3.89-3.85(m,5H),3.32-3.28(m,1H),2.01-1.71(m,4H),1.39(t,J=7.2Hz,3H).

[0632] Step 4. Ethyl 2-((4-fluorophenyl)amino)-4-((2-methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)pyrimidine-5-carboxylate (6e) Compound 6e (57 mg, 66% yield) was synthesized as a white solid by using a similar preparative procedure to Step 8 of Example 1, using 6d (80 mg, 0.20 mmol) and 4-fluoroaniline (33 mg, 0.30 mmol) as starting materials. 1 H NMR(400MHz,DMSO-d6)δ 10.70(s,1H),9.94(s,1H),8.75(s,1H),8.01(brs,1H),7.67(s,2H),7.15(t,J=9.0Hz,2H),7.02(t,J=8.2Hz,1H),6.82(d,J=7. 2Hz,1H),4.41-4.30(m,3H),3.86-3.82(m,5H),3.27-3.24(m,2H),1.35-1.23(m,2H),1.19-1.03(m,2H),1.34(t,J=7.0Hz,3H).

[0633] Step 5. 2-((4-fluorophenyl)amino)-4-((2-methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-N-methylpyrimidine-5-carboxamide (6) A mixture of 6e (50 mg, 0.10 mmol) and methylamine (2 mL, 2 M in THF) was stirred at 80 °C for 2 days. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to give compound 6 (6.5 mg, 13% yield) as a white solid. LC-MS (Method 1) R =3.89 min, m / z(M+H) + =468.2. 1 H NMR(400MHz,DMSO-d6)δ 11.46(s,1H),9.62(s,1H),8.60(s,1H),8.44(s,1H),8.10(s,1H),7.68-7.66(m,2H),7.12(t,J=8.8Hz,2H),7.00(t,J=8.0Hz,1H),6 .76(d,J=7.2Hz,1H),4.30-4.28(m,1H),3.87-3.84(m,2H),3.81(s,3H),3.30-3.23(m,2H),2.79(d,J=4.4Hz,3H),1.81-1.78(m,4H).

[0634] [ka]

[0635] Step 1. 2-Chloro-4-((2-methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-N-methylpyrimidine-5-carboxamide (7a) Compound 7a (50 mg, 52% yield) was synthesized as a white solid by using 1h (50 mg, 0.24 mmol) and 6c (65 mg, 0.29 mmol) as starting materials using a preparative procedure similar to that in Step 1 of Example 2. LC-MS (Method 3) R =1.37 min, m / z(M+H) + =393.1.

[0636] Step 2. 2-(Cyclopropanecarboxamide)-4-((2-methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-N-methylpyrimidine-5-carboxamide (7) Compound 7 (10 mg, 18% yield) was synthesized as a white solid by using a preparative procedure similar to that in Step 8 of Example 1, starting with 7a (50 mg, 0.12 mmol) and cyclopropanecarboxamide (64 mg, 0.64 mmol). LC-MS (Method 1) R =3.11 min, m / z(M+H) + =442.2. 1 H NMR(400MHz,DMSO-d6)δ 11.56(s,1H),10.82(s,1H),8.77(d,J=8.4Hz,1H),8.68(s,1H),8.62(d,J=4.8Hz,1H),7.00(t,J=8.4Hz,1H),6.75(d,J=8.0Hz,1H),4.35-4. 30(m,1H),3.92-3.70(m,2H),3.76(s,3H),3.11-3.00(m,2H),2.81(t, J=4.4Hz,3H),2.33-2.32(m,1H),2.15-2.13(m,4H),0.87-0.82(m,4H).

[0637] [ka]

[0638] Step 1. 1-(2,4-Dichloropyrimidin-5-yl)propan-1-ol (8b) To a solution of 8a (1 g, 5.65 mmol) in THF (7 mL) was added EtMgBr (8 mL, 8.48 mmol, 1 M in THF) at −55° C. After stirring at −55° C. for 4 h, the reaction mixture was quenched with 1N aqueous HCl and extracted with EtOAc (2×50 mL). The combined organic phases were concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM / MeOH=50 / 1) to give the title compound 8b (256 mg, 22% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ 8.80 (s, 1H), 4.75-4.72 (m, 1H), 1.74-1.72 (m, 1H), 1.66-1.60 (m, 2H), 0.90 (t, J = 7.2Hz, 3H).

[0639] Step 2. 1-(2-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)propan-1-ol (8c) Compound 8c (50 mg, 18% yield) was synthesized as a yellow oil by using 8b (150 mg, 0.72 mmol) and 2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)aniline (221 mg, 1.09 mmol) as starting materials using a preparative procedure similar to that in Step 1 of Example 2. LC-MS (Method 3) R =1.38 min, m / z(M+H) + =375.2.

[0640] Step 3. 1-(2-((4-fluorophenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)propan-1-ol (8d) Compound 8d (50 mg, 69% yield) was synthesized as a yellow oil by using a preparative procedure similar to that in Step 4 of Example 2, starting with 8c (60 mg, 0.16 mmol) and 4-fluoroaniline (35 mg, 0.32 mmol). LC-MS (Method 3) R =1.51 min, m / z(M+H) + =450.5.

[0641] Step 4. 1-(2-((4-fluorophenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidin-5-yl)propan-1-one (8) A suspension of 8d (30 mg, 66.74 mmol) and MnO2 (29.01 mg, 0.33 mmol) in 1,2-dichloroethane (2 mL) was stirred at 100 °C for 4 h. The reaction mixture was cooled and filtered. The filter cake was purified by preparative HPLC (Method A) to give compound 8 (3 mg, 10% yield) as a white solid. LC-MS (Method 1) R =2.32 min, m / z(M+H)+ =448.2. 1 H NMR(400MHz,DMSO-d6)δ 11.90(s,1H),10.02(s,1H),8.97(s,1H),8.57(s,2H),7.69(s,2H),7.57(d,J=7.6Hz,1H),7 .17(t,J=8.8Hz,3H),3.96(s,3H),3.80(s,3H),3.02(q,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H).

[0642] [ka]

[0643] Step 1. 4-Chloro-3-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridine (9a) To a solution of 1b (15 g, 53.86 mmol) in DMF (80 mL) was added sodium hydride (2.48 g, 64.64 mmol, 60% in mineral oil) dropwise at 0° C. After stirring at this temperature for 0.5 h, iodomethane (6.88 g, 48.48 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 1 h and then poured into water (200 mL) with stirring. The resulting solid was collected by filtration, and the filter cake was dried to give the title compound 9a (11 g, 70% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ 8.04 (d, J = 6.4 Hz, 1H), 7.77 (s, 1H), 7.63 (d, J = 6.4 Hz, 1H), 3.83 (s, 3H).

[0644] Step 2. 4-Chloro-5-ethyl-3-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridin-5-ium iodide (9b) Compound 9a (5 g, 17.09 mmol) and C2H5I (10 mL) were dissolved in EtOH (10 mL) in a sealed tube. The resulting mixture was stirred at 80 °C for 18 h. After cooling to room temperature, the reaction mixture was cooled and concentrated to dryness. The residue was used in the next step without purification. LC-MS (Method 3) R =1.48 min, m / z M+ =321.1.

[0645] Step 3. 5-Ethyl-3-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (9c) Compound 9c (2.0 g, 40% yield) was synthesized as a brown solid by using a similar preparative procedure as in Step 3 of Example 1, using 9b (5.4 g, 16.79 mmol) and NaOH (2.02 g, 50.38 mmol) as starting materials. 1 H NMR(300MHz,DMSO-d6)δ 7.32(d,J=7.5Hz,1H),7.16(s,1H),6.49(d,J=7.5Hz,1H),3.84(q,J=6.6Hz,2H),3.61(s,3H),1.12(t,J=6.6Hz,3H).

[0646] Step 4. Tert-butyl (5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)carbamate (9d) Compound 9d (1.5 g, 71% yield) was synthesized as a white solid by using 9c (2.19 g, 7.25 mmol) and tert-butyl carbamate (8.49 g, 72.49 mmol) as starting materials using a similar preparative procedure to Step 4 of Example 1. 1 H NMR(400MHz,DMSO-d6)δ 8.32(s,1H),7.31(d,J=7.2Hz,1H),7.14(s,1H),6.54(d,J=7.2Hz,1H),3.92(q,J=7.2Hz,2H),3.65(s,3H),1.47(s,9H),1.18(t,J=7.2Hz,3H).

[0647] Step 5. 3-Amino-5-ethyl-1-methyl-1H-pyrrolo[3,2-c]pyridin-4(5H)-one hydrochloride (9e) Compound 9e (1.3 g, 83% yield) was synthesized as a white solid by using a similar preparative procedure to step 5 of Example 1 using 9d (2.0 g, 6.86 mmol) as the starting material. 1H NMR(400MHz,DMSO-d6)δ 10.21(brs,3H),7.46(d,J=7.6Hz,1H),7.27(s,1H),6.53(d,J=7.6Hz,1H),3.97(q,J=7.6Hz,2H),3.71(s,3H),1.22(t,J=7.6Hz,3H).

[0648] Step 6. Ethyl 2-chloro-4-((5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)pyrimidine-5-carboxylate (9f) Compound 9f (160 mg, 63% yield) was synthesized as a white solid by using 9e (130 mg, 0.86 mmol) and 2,4-dichloropyrimidine-5-carboxylate (150 mg, 0.86 mmol) as starting materials using a similar preparative procedure to Step 1 of Example 2. 1 H NMR(400MHz,DMSO-d6)δ 8.75(s,1H),7.63(s,1H),7.39(d,J=7.6Hz,1H),6.58(d,J=7.6Hz,1H),4.40(q,J=7.2H) z,2H),3.97(t,J=7.2Hz,2H),3.75(s,3H),1.37(t,J=7.2Hz,3H),1.25(t,J=7.2Hz,3H).

[0649] Step 7. Ethyl 2-((2,4-difluorophenyl)amino)-4-((5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)pyrimidine-5-carboxylate (9g) Compound 9g (30 mg, 70% yield) was synthesized as a yellow solid by using a preparative procedure similar to that in Step 8 of Example 1, starting with 9f (50 mg, 0.13 mmol) and 2,4-difluoroaniline (35 mg, 0.26 mmol). LC-MS (Method 3) R =1.57 min, m / z(M+H) + =469.3.

[0650] Step 8. 2-((2,4-Difluorophenyl)amino)-4-((5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-N-methylpyrimidine-5-carboxamide (9) Compound 9 (6 mg, 18% yield) was synthesized as a yellow solid by using 9g (35 mg, 0.07 mmol) as the starting material and a similar preparative procedure as in Step 5 of Example 6. The crude product was purified by preparative HPLC (Method C). LC-MS (Method 2) R =3.10 min, m / z(M+H) + =454.1. 1 H NMR(400MHz,DMSO-d6)δ 11.77(s,1H),9.18(s,1H),8.49(s,1H),8.25-8.20(m,1H),7.60-7.58(m,1H),7.43(t,J=8.4Hz,1H),7.30(d,J=7.2Hz,1H),7 .19(t,J=7.6Hz,1H),6.49(d,J=7.2Hz,1H),3.93(q,J=6.4Hz,2H),3.50(s,3H),2.77(d,J=4.4Hz,3H),1.20(t,J=6.8Hz,3H).

[0651] [ka]

[0652] Step 1. Methyl 6-chloro-4-((5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)nicotinate (10a) Compound 9e (100 mg, 0.43 mmol), methyl 4,6-dichloropyridine-3-carboxylate (136 mg, 0.66 mmol), and concentrated HCl (0.1 mL) were dissolved in EtOH (1 mL). The resulting mixture was stirred at 90 °C for 4 h. The suspension was cooled and filtered. The filter cake was dried to give 10a (120 mg, 69% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 10.74(s,1H),8.66(s,1H),7.43(s,1H),7.39(d,J=7.2Hz,1H),7.15(s,1H), 6.57(d,J=7.2Hz,1H),3.99-3.89(m,5H),3.72(s,3H),1.20(t,J=6.8Hz,3H).

[0653] Step 2. Methyl 4-((5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-6-((5-fluoropyridin-2-yl)amino)nicotinate (10b) Compound 10b (61 mg, 56% yield) was synthesized as a yellow solid by using 10a (100 mg, 0.25 mmol) and 5-fluoropyridin-2-amine (34 mg, 0.30 mmol) as starting materials using a preparative procedure similar to that in Step 8 of Example 1. 1 H NMR(400MHz,DMSO-d6)δ 10.88(s,1H),10.04(s,1H),8.65(s,1H),8.32(s,1H),7.80(s,1H),7.71-7.68(m,2H),7.38(d,J=7.2Hz,1H) ,7.28(s,1H),6.59(d,J=7.2Hz,1H),3.94(d,J=7.6Hz,2H),3.87(s,3H),3.78(s,3H),1.22(t,J=7.6Hz,3H).

[0654] Step 3. 4-((5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methylnicotinamide (10) Compound 10 (15 mg, 30% yield) was synthesized as a white solid by using 10b (50 mg, 0.11 mmol) as the starting material and a similar preparative procedure to that in Step 5 of Example 6. The crude product was purified by preparative HPLC (Method C). LC-MS (Method 3) R =3.26 min, m / z(M+H) + =436.1. 1H NMR(400MHz,DMSO-d6)δ 11.00(s,1H),9.80(s,1H),8.39(s,1H),8.30-8.29(m,1H),8.26(d,J=2.8Hz,1H),7.77-7.74(m,1H),7.68-7.65(m,2H),7.35(d,J =7.6Hz,1H),7.22(s,1H),6.55(d,J=7.2Hz,1H),3.94(q,J=7.6Hz,2H),3.76(s,3H),2.77(d,J=4.4Hz,3H),1.21(t,J=7.6Hz,3H).

[0655] [ka]

[0656] Step 1. 4,6-Dichloronicotinic acid (11b) Compound 11a (10 g, 48.54 mmol) and LiOH.HO (6.12 g, 145.61 mmol) were dissolved in THF / HO (100 mL, v / v = 1 / 1). The mixture was stirred at room temperature for 2 h. The reaction mixture was acidified with 1 N HCl to a pH above 7 and extracted with EtOAc (2 x 10 mL). The combined organic phase was concentrated to give 11b (9.2 g, 99% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 13.95 (brs, 1H), 8.82 (s, 1H), 7.93 (s, 1H).

[0657] Step 2. 4,6-Dichloro-N-methylnicotinamide (11c) Compound 11b (4.15 g, 21.61 mmol), methylamine hydrochloride (1.90 g, 28.10 mmol), DIPEA (11.17 g, 86.46 mmol), and T3P (27.51 g, 86.46 mmol, 50 wt % in DMF) were dissolved in DMF (20 mL). The resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was diluted with EtOAc (60 mL), washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 2 / 1) to give 11c (3.9 g, 88% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 8.62 (s, 1H), 7.42 (s, 1H), 6.38 (brs, 1H), 3.03 (d, J = 4.4Hz, 3H).

[0658] Step 3. 6-chloro-4-((1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-N-methylnicotinamide (11d) Compound 1f (90 mg, 0.51 mmol), 11c (156 mg, 0.76 mmol), and concentrated HCl (0.2 mL) were dissolved in EtOH (1 mL), and the resulting reaction mixture was stirred at 90 °C for 6 h. The suspension was cooled and filtered. The filter cake was dried to give 11d (100 mg, 52% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.81(s,1H),8.68(d,J=4.4Hz,1H),8.44(s,1H),7.36(d,J=7.6Hz,1H),7.33(s,1H) ,7.04(s,1H),6.53(d,J=7.6Hz,1H),3.71(s,3H),3.42(s,3H),2.79(d,J=3.6Hz,3H).

[0659] Step 4. 4-((1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methylnicotinamide (11) Compound 11 (9 mg, 15% yield) was synthesized as a white solid by using 11d (50 mg, 0.14 mmol) and 5-fluoropyridin-2-amine (24 mg, 0.21 mmol) as starting materials using a preparative procedure similar to that in Step 8 of Example 1. LCMS (Method 1) R =3.01 min, m / z(M+H) + =422.2. 1 H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),9.77(s,1H),8.38(s,1H),8.28-8.28(m,2H),7.78-7.75(m,1H),7.67-7.62(m,2H),7.33 (d,J=7.6Hz,1H),7.21(s,1H),6.52(d,J=7.6Hz,1H),3.75(s,3H),3.44(s,3H),2.77(d,J=4.4Hz,3H).

[0660] [ka]

[0661] Step 1. 6-(Cyclopropanecarboxamido)-4-((1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-N-methylnicotinamide (12) Compound 12 (12.5 mg, 22% yield) was synthesized as a white solid by using 11d (50 mg, 0.14 mmol) and cyclopropanecarboxamide (61 mg, 0.72 mmol) as starting materials using a preparative procedure similar to that in Step 8 of Example 1. LCMS (Method 1) R =2.18 min, m / z(M+H) + =395.1. 1H NMR(400MHz,DMSO-d6)δ 10.88(s,1H),10.73(s,1H),8.42-8.40(m,2H),7.98(s,1H),7.34(d,J=7.2Hz,1H),7.01(s,1H),6.51( d,J=7.2Hz,1H),3.68(s,3H),3.42(s,3H),2.78(d,J=4.4Hz,3H),2.02-2.00(m,1H),0.83-0.79(m,4H).

[0662] [ka]

[0663] Step 1. 6-chloro-4-((2-methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-N-methylnicotinamide (13a) Compound 13a (8.6 mg, 35% yield) was synthesized as a white solid by using 6c (200 mg, 0.90 mmol) and 11c (202 mg, 0.99 mmol) as starting materials using a preparative procedure similar to that in Step 1 of Example 10. (Method 3) R =1.49 min, m / z(M+H) + =392.3.

[0664] Step 2. 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-N-methylnicotinamide (13) Compound 13 (35 mg, 45% yield) was synthesized as a white solid by using 13a (70 mg, 0.18 mmol) and cyclopropanecarboxamide (76 mg, 0.90 mmol) as starting materials using a preparative procedure similar to that in Step 8 of Example 1. LCMS (Method 1) R =3.24 min, m / z(M+H) + =441.2. 1H NMR(400MHz,DMSO-d6)δ 10.70(s,1H),10.40(s,1H),8.54(d,J=4.4Hz,1H),8.45(s,1H),8.04(s,1H),7.08-7.00(m,2H),6.81(d,J=7.6Hz,1H),4.24-4.20(m,1H) ,3.82-3.80(m,5H),3.30-3.24(m,2H),2.78(d,J=4.4Hz,2H),1.98-1.95(m,2H),1.79-1.77(m,2H),1.68-1.60(m,2H),0.78-0.75(m,4H).

[0665] [ka]

[0666] Step 1. 4-Chloro-7-fluoro-3-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridine (14b) To a mixture of 14a (450 mg, 2.64 mmol) and KOH (296 mg, 5.28 mmol) in DMF (5 mL) was added I2 (668 mg, 2.64 mmol) at 0 °C. After stirring at this temperature for 1 h, CHI (418 mg, 2.95 mmol) was added to the reaction mixture. The black reaction mixture was stirred at 0 °C for 1 h. The mixture was poured into ice water (30 mL) and the resulting solid was filtered. The filter cake was dried to give 14b (550 mg, 72% yield) as a brown solid. 1 H NMR (300MHz, CDCl3) δ 7.97(d,J=3.0Hz,1H),7.24(s,1H),4.05(s,3H).

[0667] Step 2. 4-Chloro-7-fluoro-3-iodo-1,5-dimethyl-1H-pyrrolo[3,2-c]pyridin-5-ium iodide (14c) Compound 14c (570 mg, yield obtained) was synthesized as a yellow solid by using 14b (550 mg, 1.77 mmol) as the starting material and utilizing a preparative procedure similar to that in Step 2 of Example 1. LC-MS (Method 3) R =1.13min,m / z M+ =325.1.

[0668] Step 3. 7-Fluoro-3-iodo-1,5-dimethyl-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (14d) Compound 14d (460 mg, 86% yield) was synthesized as a yellow solid by using a similar preparative procedure to step 3 of Example 1, using 14c (570 mg, 1.75 mmol) as the starting material. 1 H NMR (400MHz, DMSO-d6) δ 7.58 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 3.83 (d, J = 2.0 Hz, 3H), 3.36 (s, 3H).

[0669] Step 4. Tert-butyl (7-fluoro-1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)carbamate (14e) Compound 14e (110 mg, 50% yield) was synthesized as a yellow solid by using 14d (230 mg, 0.75 mmol) and tert-butyl carbamate (880 mg, 7.51 mmol) as starting materials using a preparative procedure similar to that in Step 4 of Example 1. 1 H NMR(400MHz,DMSO-d6)δ 8.35(s,1H),7.53(d,J=8.0Hz,1H),7.23(s,1H),3.80(s,3H),3.38(s,3H),1.47(s,9H).

[0670] Step 5. 3-Amino-7-fluoro-1,5-dimethyl-1H-pyrrolo[3,2-c]pyridin-4(5H)-one hydrochloride (14f) Compound 14f (80 mg, 93% yield) was synthesized as a white solid by using a similar preparative procedure to step 5 of Example 1, starting with 14e (110 mg, 0.37 mmol). 1 H NMR(400MHz,DMSO-d6)δ 10.10(brs,2H),7.69(d,J=8.0Hz,1H),7.33(s,1H),3.86(s,3H),3.42(s,3H).

[0671] Step 6. 6-chloro-4-((7-fluoro-1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-N-methylnicotinamide (14 g) Compound 14g (68 mg, 46% yield) was synthesized as a brown solid by using 14f (80 mg, 0.41 mmol) and 11c (126 mg, 0.61 mmol) as starting materials using a preparative procedure similar to that in Step 1 of Example 10. LC-MS (Method 3) R =1.32 min, m / z(M+H) + =364.3.

[0672] Step 7. 6-(Cyclopropanecarboxamido)-4-((7-fluoro-1,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-N-methylnicotinamide (14) Compound 14 (10 mg, 18% yield) was synthesized as a white solid by using a preparative procedure similar to that in Step 8 of Example 1, starting with 14g (50 mg, 0.14 mmol) and cyclopropanecarboxamide (47 mg, 0.55 mmol). LC-MS (Method 1) R =2.69 min, m / z(M+H) + =413.1. 1 H NMR(400MHz,DMSO-d6)δ 10.88(s,1H),10.73(s,1H),8.42(s,1H),8.40(s,1H),7.99(s,1H),7.56(d,J=8.0Hz,1H),7.10 (s,1H),3.84(s,3H),3.59(s,3H),2.78(d,J=4.4Hz,3H),2.03-2.11(m,1H),0.85-0.88(m,4H).

[0673] [ka]

[0674] Step 1. Tert-butyl (5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)carbamate (15b) Compound 15b (92 mg, 27% yield) was synthesized as a white solid by using 15a (300 mg, 1.23 mmol) and tert-butyl carbamate (719 mg, 6.14 mmol) as starting materials using a preparative procedure similar to that in Step 4 of Example 1. 1 H NMR(400MHz,DMSO-d6)δ 9.88(s,1H),7.58(d,J=7.2Hz,1H),7.38(s,1H),6.94(d,J=7.2Hz,1H),3.50(s,3H),1.49(s,9H).

[0675] Step 2. 3-Amino-5-methylthieno[3,2-c]pyridin-4(5H)-one hydrochloride (15c) Compound 15c (71 mg, yield obtained) was synthesized as a white solid by using 15b (59 mg, 0.33 mmol) as the starting material and utilizing a preparative procedure similar to that in Step 5 of Example 1. LCMS (Method 3) R =1.15 min, m / z(M+H) + =181.2.

[0676] Step 3. 6-Chloro-N-methyl-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)nicotinamide (15d) A mixture of 15c (71 mg, 0.33 mmol) and 11c (67 mg, 0.33 mmol) in EtOH (2 mL) and concentrated HCl (0.2 mL) was stirred overnight at 80° C. After cooling to room temperature, the resulting solid was filtered, and the filter cake was dried to give 15d (60 mg, 53% yield) as a yellow solid.

[0677] Step 4. 6-((5-fluoropyridin-2-yl)amino)-N-methyl-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)nicotinamide (15) Compound 15 (5.6 mg, 9% yield) was synthesized as a white solid by using 15d (50 mg, 0.14 mmol) and 5-fluoropyridin-2-amine (48 mg, 0.43 mmol) as starting materials using a preparative procedure similar to that in Step 8 of Example 1. LCMS (Method 1) R =3.34 min, m / z(M+H) + =425.1. 1 H NMR(400MHz,DMSO-d6)δ 11.44(s,1H),9.84(s,1H),8.40(s,1H),8.33(d,J=4.4Hz,1H),8.24(d,J=2.8Hz,1H),7.99(s,1H),7.78(dd,J=8.8,3.6Hz,1H ),7.65(td,J=8.4,2.8Hz,1H),7.58(d,J=7.6Hz,1H),7.20(s,1H),6.87(d,J=7.6Hz,1H),3.52(s,3H),2.77(d,J=4.4Hz,3H).

[0678] [ka]

[0679] Step 1. 6-(Cyclopropanecarboxamido)-N-methyl-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)nicotinamide (16) Compound 16 (4 mg, 7% yield) was synthesized as a white solid by using 15d (50 mg, 0.14 mmol) and cyclopropanecarboxamide (85 mg, 0.61 mmol) as starting materials using a preparative procedure similar to that in Step 8 of Example 1. LCMS (Method 1) R =3.07 min, m / z(M+H) + =398.1. 1H NMR(400MHz,DMSO-d6)δ 11.44(s,1H),10.85(s,1H),8.45(s,2H),8.40(s,1H),7.58(d,J=7.6Hz,1H),7.05(s,1H),6. 85(d,J=7.6Hz,1H),3.50(s,3H),2.77(d,J=4.8Hz,3H),2.12-1.99(m,1H),0.83-0.80(m,4H).

[0680] [ka]

[0681] Step 1. 3-Bromo-5-ethylthieno[3,2-c]pyridin-4(5H)-one (17b) To a solution of 17a (1 g, 4.35 mmol) in DMF (10 mL) was added NaH (150 mg, 6.52 mmol, 60% in mineral oil) at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h. Then CH3CH2I (813 mg, 5.22 mmol) was added to the mixture. After stirring at room temperature overnight, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by silica gel flash chromatography (PE / EtOAc = 4 / 1) to give 17b (810 mg, 72%) as a black oil. LCMS (Method 3) R =1.43 min, m / z(M+H) + =260.1.

[0682] Step 2. Tert-butyl (5-ethyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)carbamate (17c) Compound 17c (500 mg, 71% yield) was synthesized as a yellow oil by using a preparative procedure similar to that in Step 4 of Example 1, starting with 17b (620 mg, 2.40 mmol) and tert-butyl carbamate (2.81 g, 24.02 mmol). LCMS (Method 3) R =1.70 min, m / z(M+H) +=295.3.

[0683] Step 3. 3-Amino-5-ethylthieno[3,2-c]pyridin-4(5H)-one hydrochloride (17d) Compound 17d (390 mg, yield obtained) was synthesized as a yellow solid by using 17c (500 mg, 1.7 mmol) as the starting material and utilizing a preparative procedure similar to that in Step 5 of Example 1. LCMS (Method 3) R =1.31 min, m / z(M+H) + =195.1.

[0684] Step 4. 6-Chloro-4-((5-ethyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)-N-methylnicotinamide (17e) Compound 17e (160 mg, 43% yield) was synthesized as a brown solid by using 17d (200 mg, 1.03 mmol) and 11c (316 mg, 1.54 mmol) as starting materials using a preparative procedure similar to that in Step 1 of Example 10. LCMS (Method 3) R =1.31 min, m / z(M+H) + =363.0.

[0685] Step 5. 6-(Cyclopropanecarboxamido)-4-((5-ethyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)-N-methylnicotinamide (17) Compound 17 (18 mg, 26% yield) was synthesized as a white solid by using a preparative procedure similar to that in Step 8 of Example 1, starting with 17e (60 mg, 0.17 mmol) and cyclopropanecarboxamide (28 mg, 0.33 mmol). LCMS (Method 1) R =3.28 min, m / z(M+H) + =412.1. 1H NMR(400MHz,DMSO-d6)δ 11.45(s,1H),10.85(s,1H),8.46(s,2H),8.42(s,1H),7.61(d,J=7.2Hz,1H),7.08(s,1H),6.91(d,J=7.2Hz,1 H),4.02(q,J=6.4Hz,2H),2.80(d,J=4.4Hz,3H),2.02-1.98(m,1H),1.27(t,J=6.8Hz,3H),0.85-0.82(m,4H).

[0686] [ka]

[0687] Step 1. 4-((5-ethyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-methylnicotinamide (18) Compound 18 (3.5 mg, 5% yield) was synthesized as a white solid by using 17e (60 mg, 0.17 mmol) and 5-fluoropyridin-2-amine (37 mg, 0.33 mmol) as starting materials using a preparative procedure similar to that in Step 8 of Example 1. LCMS (Method 1) R =2.99 min, m / z(M+H) + =439.1. 1 H NMR(400MHz,DMSO-d6)δ 11.46(s,1H),9.86(s,1H),8.43(s,1H),8.36(s,1H),8.26(s,1H),8.03(s,1H),7.79-7.61(m,3H),7. 23(s,1H),6.92(d,J=9.2Hz,1H),4.04(q,J=6.4Hz,2H),2.81(d,J=4.4Hz,3H),1.29(t,J=6.8Hz,3H).

[0688] [ka]

[0689] Step 1. 2-(3-cyanoanilino)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyrimidine-5-carboxamide (19) Compound 19 (8.6 mg, 35% yield) was synthesized as a white solid by using a preparative procedure similar to that in Step 8 of Example 1, starting with 2d (20 mg, 0.05 mmol) and 3-aminobenzonitrile (7 mg, 0.05 mmol). LCMS (Method 2) R =4.10 min, m / z(M+H) + =459.2. 1 H NMR(400MHz,DMSO-d6)δ 11.82(s,1H),10.01(s,1H),8.72(s,1H),8.55-8.51(m,3H),8.27(s,1H),7.91(d, J=8.4Hz,1H),7.54-7.42(m,3H),7.22(t,J=8.0Hz,1H),3.95(s,3H),3.79(s,3H).

[0690] [ka]

[0691] Step 1. 2-(4-fluoroanilino)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyrimidine-5-carboxamide (20) Compound 2d (50 mg, 0.13 mmol), 4-fluoroaniline (15 mg, 0.13 mmol), and CsF (18 mg, 0.26 mmol) were dissolved in DMSO (1 mL). The reaction was stirred at 60 °C for 3 days. The mixture was cooled, diluted with HO (5 mL), and extracted with EtOAc (5 mL). The organic layer was concentrated to dryness. The residue was purified by preparative HPLC (Method A) to give 20 (1.4 mg, 2% yield) as a white solid. LCMS (Method 1) R =3.77 min, m / z(M+H) + =452.3. 1H NMR(400MHz,DMSO-d6)δ 11.78(s,1H),9.68(s,1H),8.65(s,1H),8.58(s,2H),8.44(s,1H),7.70-7.67(m ,2H),7.51(dd,J=9.2,4.4Hz,1H),7.17-7.12(m,3H),3.94(s,3H),3.78(s,3H).

[0692] [ka]

[0693] Step 1. 2-[(6-cyano-2-pyridyl)amino]-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyrimidine-5-carboxamide (21) Compound 21 (3.4 mg, 7% yield) was synthesized as a white solid by using a preparative procedure similar to that in Step 8 of Example 1, starting with 2d (40 mg, 0.1 mmol) and 6-aminopicolinonitrile (25 mg, 0.21 mmol). LCMS (Method 1) R =3.44 min, m / z(M+H) + =460.2. 1 H NMR(400MHz,DMSO-d6)δ 11.82(s,1H),10.63(s,1H),8.84(d,J=8.4Hz,1H),8.72(s,1H),8.59(s,1H),8.55(s,1H),8.44(d,J=8.4Hz,1H),7.95 (t,J=8.0Hz,1H),7.63(dd,J=7.6Hz,1H),7.51(t,J=7.6,1.2Hz,1H),7.22(t,J=7.6Hz,1H),3.95(s,3H),3.79(s,3H).

[0694] [ka]

[0695] Step 1. 3-(2-Methoxy-5-methyl-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (22b) Compound 22a (15.49 g, 52.84 mmol), 3-bromo-1-methyl-1H-1,2,4-triazole (9.42 g, 58.13 mmol), Pd(dppf)Cl.CHCl (2.16 g, 2.64 mmol), and KCO (21.88 g, 158.53 mmol) were mixed in 1,4-dioxane (160 mL) and HO (16 mL). The reaction mixture was stirred at 110 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were concentrated to dryness. The residue was purified by flash chromatography on silica gel (3 / 1 PE / EtOAc to EtOAc) to give the title compound 22b (8.3 g, 63% yield) as a brown solid. 1 H NMR(400MHz, CDCl3)δ 8.12(s,1H),8.02(d,J=2.0Hz,1H),7.60(d,J=1.6Hz,1H),4.02(s,3H),3.91(s,3H),2.42(s,3H).

[0696] Step 2. 3-(5-(bromomethyl)-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (22c) To a mixture of 22b (2.0 g, 8.06 mmol) in CCl (20 mL) was added BPO (199 mg, 3.22 mmol) and NBS (1.58 g, 8.86 mmol). The mixture was irradiated for 16 h. The mixture was diluted with HO (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 2 / 1) to give the title compound 22c (1.1 g, 42% yield) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ 8.27(d,J=2.0Hz,1H),8.16(s,1H),7.84(d,J=2.0Hz,1H),4.51(s,2H),4.04(s,3H),3.95(s,3H).

[0697] Step 3. 1-(4-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrophenyl)-N-methylmethanamine (22d) Compound 22c (1.32 g, 4.04 mmol) was dissolved in a solution of methanamine in THF (2.0 M, 20 mL) and stirred at room temperature overnight. The mixture was concentrated to dryness. The residue was purified by flash chromatography on silica gel (DCM / MeOH=10 / 1) to give the title compound 22d (500 mg, 45% yield) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ 8.17(d,J=2.0Hz,1H),8.13(s,1H),7.81(d,J=2.0Hz,1H),4.02(s,3H),3.92(s,3H),3.83(s,2H),2.47(s,3H).

[0698] Step 4. Tert-butyl (3-(((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrobenzyl)(methyl)amino)methyl)phenyl)carbamate (22e) Compound 22d (128 mg, 0.46 mmol), tert-butyl (3-(bromomethyl)phenyl)carbamate (139 mg, 0.48 mmol), and K2CO3 (191 mg, 1.38 mmol) were dissolved in ACN (3 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated to dryness. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 2 / 1) to give the title compound 22e (160 mg, 72% yield) as a yellow oil. LC-MS (Method 3) R =1.67 min, m / z(M+H) + =483.3.

[0699] Step 5. Tert-butyl (3-(((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)(methyl)amino)methyl)phenyl)carbamate (22f) Compound 22f (135 mg, 90% yield) was synthesized as a yellow solid by using 22e (160 mg, 0.33 mmol) as the starting material and utilizing a preparative procedure similar to that in Step 2 of Example 6. LC-MS (Method 3) R =1.49 min, m / z(M+H) + =453.3.

[0700] Step 6. Ethyl 4-((5-(((3-((tert-butoxycarbonyl)amino)benzyl)(methyl)amino)methyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-chloropyrimidine-5-carboxylate (22g) A mixture of 22f (156 mg, 0.35 mmol), ethyl 2,4-dichloropyrimidine-5-carboxylate (80 mg, 0.36 mmol), and DIPEA (89 mg, 0.69 mmol) in ACN (3 mL) was stirred at 85 °C for 2 h. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel (DCM / MeOH = 30 / 1) to give 22g (144 mg, 66% yield) as a yellow solid. LC-MS (Method 3) R =1.77 min, m / z(M+H) + =637.6.

[0701] Step 7. Ethyl 10-methoxy-15-methyl-11-(1-methyl-1,2,4-triazol-3-yl)-2,4,8,15,23-pentaazatetracyclo[15.3.1.13,7.19,13]tricosa-1(21),3(23),4,6,9,11,13(22),17,19-nonaene-6-carboxylate (22h) Compound 22g (124 mg, 0.19 mmol) was dissolved in a solution of HCl (g) in 1,4-dioxane (40 mL, 2.0 M). The reaction was stirred at 60° C. for 2 h. The mixture was concentrated to give the title compound 22h (120 mg, 40% purity, 46% yield) as a yellow oil. LC-MS (Method 3) R =1.56 min, m / z(M+H) + =501.5.

[0702] Step 8. 10-Methoxy-N,15-dimethyl-11-(1-methyl-1,2,4-triazol-3-yl)-2,4,8,15,23-pentaazatetracyclo[15.3.1.13,7.19,13]tricosa-1(21),3(23),4,6,9,11,13(22),17,19-nonaene-6-carboxamide (22) A mixture of 22h (120 mg, 0.24 mmol) and methanamine (18 mL, 40% in water) was stirred at 100° C. for 18 h. The mixture was concentrated to dryness. The residue was purified by preparative HPLC (Method A) to give the title compound 22 (11 mg, 9% yield) as a yellow solid. LC-MS (Method 2) R =2.53 min, m / z(M+H) + =486.2. 1 H NMR(400MHz,DMSO-d6)δ 11.70(s,1H),9.73(s,1H),8.86(d,J=1.6Hz,1H),8.68(s,1H),8.54(s,1H),8.47-8.44(m,2H),7.37(d,J=2.0Hz,1H),7.21(t,J=8.0Hz,1 H),7.02(d,J=8.0Hz,1H),6.92(d,J=7.6Hz,1H),3.94(s,3H),3.78(s,3H),3.50(s,2H),3.42(s,2H),2.80(d,J=4.4Hz,3H),2.40(s,3H).

[0703] [ka]

[0704] Step 1. Methyl 6-chloro-4-((5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)pyridazine-3-carboxylate (23a) Compound 23a (120 mg, 50% yield) was synthesized as a yellow solid by using a similar preparative procedure to Step 1 of Example 2, starting with 9e (150 mg, 0.66 mmol) and methyl 4,6-dichloropyridazine-3-carboxylate (136 mg, 0.66 mmol). LC-MS (Method 3) R =1.22 min, m / z(M+H) + =362.1.

[0705] Step 2. 6-Chloro-4-((5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-N-methylpyridazine-3-carboxamide (23b) Compound 23a (100 mg, 0.28 mmol) was dissolved in methanamine solution (5 mL, 2 M in THF). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 23b (80 mg, 80% yield). LC-MS (Method 3) R =1.25 min, m / z(M+H) + =361.1.

[0706] Step 3. 6-(Cyclopropanecarboxamide)-4-((5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)amino)-N-methylpyridazine-3-carboxamide (23) Compound 23 (4.2 mg, 19% yield) was synthesized as a pale yellow solid by using 23b (20 mg, 0.06 mmol) and cyclopropanecarboxamide (24 mg, 0.28 mmol) as starting materials using a preparative procedure similar to that in Step 8 of Example 1. LC-MS (Method 1) R =3.12 min, m / z(M+H) + =410.1. 1H NMR(400MHz,DMSO-d6)δ 11.28-11.26(m,2H),8.98(s,1H),8.09-8.07(m,1H),7.38(d,J=7.6Hz,1H),7.06(s,1H),6.58-6.55(m,1H),3.92 (q,J=7.2Hz,2H),3.71(s,3H),2.85(d,J=4.4Hz,3H),2.11-2.08(m,1H),1.23(t,J=7.2Hz,3H),0.95-0.73(m,4H).

[0707] [ka]

[0708] Step 1. Methyl 6-chloro-4-((2-methyl-1-oxo-1,2-dihydroisoquinolin-8-yl)amino)pyridazine-3-carboxylate (24b) Compound 24b (100 mg, 21% yield) was synthesized as a yellow solid by using a similar preparative procedure to Step 1 of Example 2, using 24a (240 mg, 1.38 mmol) and methyl 4,6-dichloropyridazine-3-carboxylate (342 mg, 1.65 mmol) as starting materials. 1 H NMR(400MHz,DMSO-d6)δ 12.39(s,1H),7.78(s,1H),7.69-7.63(m,2H),7.53(d,J=8.4Hz,1H),7.3 9(dd,J=2.0,6.8Hz,1H),6.67(d,J=7.2Hz,1H),4.00(s,3H),3.50(s,3H).

[0709] Step 2. 6-Chloro-N-methyl-4-((2-methyl-1-oxo-1,2-dihydroisoquinolin-8-yl)amino)pyridazine-3-carboxamide (24c) Compound 24c (100 mg, 63% yield, 50% purity) was synthesized as a yellow solid by using 24b (80 mg, 0.23 mmol) as the starting material and a similar preparative procedure to that in Step 2 of Example 23. LC-MS (Method 3) R =1.39 min, m / z(M+H)+ =344.8.

[0710] Step 3. 6-(Cyclopropanecarboxamido)-N-methyl-4-((2-methyl-1-oxo-1,2-dihydroisoquinolin-8-yl)amino)pyridazine-3-carboxamide (24) Compound 24 (11.6 mg, 20% yield) was synthesized as a yellow solid by using a preparative procedure similar to that in Step 8 of Example 1, starting with 24c (50 mg, 0.15 mmol) and cyclopropanecarboxamide (25 mg, 0.29 mmol). LC-MS (Method 1) R =3.64 min, m / z(M+H) + =393.2. 1 H NMR(400MHz,DMSO-d6)δ 12.40(s,1H),11.31(s,1H),8.95-8.92(m,1H),8.48(s,1H),7.62-7.58(m,1H),7.52(d,J=8.0Hz,1H),7.48(d,J=6.8Hz,1 H),7.30(d,J=7.6Hz,1H),6.60(d,J=7.2Hz,1H),3.47(s,3H),2.85(d,J=4.8Hz,3H),2.09-2.05(m,1H),0.87-0.80(m,4H).

[0711] [ka]

[0712] Step 1. Methyl 6-chloro-4-((2-methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)pyridazine-3-carboxylate (25a) Compound 25a (100 mg, 13% yield) was synthesized as a yellow solid by using a similar preparative procedure to Step 1 of Example 2, using 6c (450 mg, 2.02 mmol) and methyl 4,6-dichloropyridazine-3-carboxylate (500 mg, 2.42 mmol) as starting materials. 1H NMR(400MHz,CDCl3)δ 9.82(s,1H),7.14-7.10(m,2H),6.92(d,J=8.0Hz,1H),6.86(d,J=7.6Hz,1H),4.37-4.32(m,1H),4. 09(s,3H),3.98-3.91(m,2H),3.90(s,3H),3.43-3.37(m,2H),1.89-1.84(m,2H),1.77-1.68(m,2H).

[0713] Step 2. 6-Chloro-4-((2-methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-N-methylpyridazine-3-carboxamide (25b) Compound 25b (60 mg, 60% yield) was synthesized as a white solid by using 25a (100 mg, 0.25 mmol) as the starting material and a similar preparative procedure to that in Step 2 of Example 23. LC-MS (Method 3) R =1.58 min, m / z(M+H) + =393.4.

[0714] Step 3. 6-((5-fluoropyridin-2-yl)amino)-4-((2-methoxy-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)amino)-N-methylpyridazine-3-carboxamide (25) Compound 25 (12.5 mg, 23% yield) was synthesized as an off-white solid by using 25b (45 mg, 0.11 mmol) and 5-fluoropyridin-2-amine (39 mg, 0.34 mmol) as starting materials using a preparative procedure similar to that in Step 8 of Example 1. LC-MS (Method 1) R =3.85 min, m / z(M+H) + =469.2. 1H NMR(400MHz,DMSO-d6)δ 10.79(s,1H),10.18(s,1H),9.08-9.04(m,1H),8.20-8.18(m,1H),8.00(s,1H),7.70-7.68(m,2H),7.03-7.14(m,2H),6.88(dd,J=2.0,7.6 Hz,1H),4.30-4.25(m,1H),3.84(s,3H),3.83-3.79(m,2H),3.29-3.25(m,2H),2.84(d,J=4.8Hz,3H),1.82-1.77(m,2H),1.69-1.60(m,2H).

[0715] [ka]

[0716] Step 1. 8-Bromo-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (26b) A mixture of 26a (1 g, 4.46 mmol), 1-(chloromethyl)-4-methoxybenzene (1.05 g, 6.69 mmol), and K2CO3 (1.23 g, 8.93 mmol) in DMF (10 mL) was stirred at 50 °C overnight. After cooling to room temperature, the mixture was poured into water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were concentrated, and the residue was purified by flash chromatography on silica gel (PE / EtOAc = 3 / 1) to give 26b (1.54 g, 97% yield) as a yellow oil. LC-MS (Method 3) R =1.61 min, m / z(M+H) + =344.2.

[0717] Step 2. 8-((diphenylmethylene)amino)-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (26c) A mixture of 26b (1.5 g, 4.36 mmol), diphenylmethanamine (2.37 g, 13.07 mmol), Pd(dba) (399 mg, 0.44 mmol), BINAP (814 mg, 1.31 mmol), and CsCO (2.83 g, 8.72 mmol) in toluene (15 mL) was stirred overnight at 100 °C under N. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were concentrated, and the residue was purified by flash chromatography on silica gel (PE / EtOAc = 1 / 1) to give 26c (870 mg, 45% yield) as a red solid. LC-MS (Method 3) R =1.78 min, m / z(M+H) + =445.3.

[0718] Step 3. 8-Amino-2-(4-methoxybenzyl)isoquinolin-1(2H)-one hydrochloride (26d) A mixture of 26c (830 mg, 1.87 mmol) in HCl / EtOAc (10 mL, 1 M) was stirred at room temperature for 3 h. The resulting solid was filtered and the filter cake was dried to give 26d (380 mg, 64% yield) as a yellow solid. LC-MS (Method 3) R =1.55 min, m / z(M+H) + =281.1.

[0719] Step 4. Methyl 6-chloro-4-((2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-8-yl)amino)pyridazine-3-carboxylate (26e) of 26d (310 mg, 0.98 mmol), methyl 4,6-dichloropyridazine-3-carboxylate (304 mg, 1.47 mmol), and DIPEA (379 mg, 2.94 mmol). i The mixture was stirred at 80° C. for 12 h. After cooling to room temperature, the resulting solid was filtered and dried to give 26e (100 mg, 23% yield) as a yellow solid. LC-MS (Method 3) R =1.56 min, m / z(M+H) + =451.2.

[0720] Step 5. 6-Chloro-4-((2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-8-yl)amino)-N-methylpyridazine-3-carboxamide (26f) A mixture of 26e (90 mg, 0.20 mmol) and CHNH (2 mmol, 2 mL, 1 M in THF) was stirred at room temperature for 1 h. The solid was filtered and dried to give 26f (80 mg, 89% yield) as a yellow solid. LC-MS (Method 3) R =1.61 min, m / z(M+H) + =450.2.

[0721] Step 6. 6-(Cyclopropanecarboxamide)-4-((2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-8-yl)amino)-N-methylpyridazine-3-carboxamide (26g) A mixture of 26f (90 mg, 0.20 mmol), cyclopropanecarboxamide (51 mg, 0.60 mmol), BrettPhos Pd G3 (18 mg, 0.02 mmol), BrettPhos (21 mg, 0.04 mmol), and Cs2CO3 (130 mg, 0.40 mmol) in 1,4-dioxane (1 mL) was stirred at 100 °C under a N2 atmosphere for 3 h. After cooling to room temperature, the mixture was concentrated, and the residue was purified by flash chromatography on silica gel (DCM / MeOH = 20 / 1) to give 26g (25 mg, 32% yield) as a white solid. LC-MS (Method 3) R =1.50 min, m / z(M+H) + =499.5.

[0722] Step 7. 6-(Cyclopropanecarboxamido)-N-methyl-4-((1-oxo-1,2-dihydroisoquinolin-8-yl)amino)pyridazine-3-carboxamide (26) A mixture of 26g (50 mg, 0.10 mmol) and TFA (2 mL) was stirred at 110° C. for 18 h. The mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to give 26 (3 mg, 8% yield) as a white solid. LC-MS (Method 1) R =2.81 min, m / z(M+H) + =379.2. 1 H NMR(400MHz,DMSO-d6)δ 12.30(s,1H),11.32(s,1H),11.20(d,J=6.4Hz,1H),8.92(d,J=4.0Hz,1H),8.49(s,1H),7.57(t,J=8.0Hz,1H),7.50(d,J=8.0Hz,1H) ),7.29(d,J=8.0Hz,1H),7.15(t,J=6.8Hz,1H),6.53(d,J=6.8Hz,1H),2.83(d,J=4.8Hz,3H),2.09-2.05(m,1H),0.87-0.80(m,4H).

[0723] [ka]

[0724] Step 1. Methyl 6-chloro-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)pyridazine-3-carboxylate (27a) Compound 27a (100 mg, 34% yield) was synthesized as a blue solid by using 15c (150 mg, 0.83 mmol) and methyl 4,6-dichloropyridazine-3-carboxylate (258 mg, 1.25 mmol) as starting materials using a preparative procedure similar to that in Step 1 of Example 2. 1 H NMR (400MHz, DMSO-d6) δ 11.50(s,1H),7.81(s,1H),7.67-7.65(m,2H),6.96(d,J=7.6Hz,1H),4.01(s,3H),3.54(s,3H).

[0725] Step 2. Methyl 6-(cyclopropanecarboxamido)-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)pyridazine-3-carboxylate (27b) Compound 27b (100 mg, 59% yield) was synthesized as a yellow solid by using 27a (150 mg, 0.43 mmol) and cyclopropanecarboxamide (73 mg, 0.86 mmol) as starting materials using a preparative procedure similar to that in Step 8 of Example 1. LC-MS (Method 3) R =1.36 min, m / z(M+H) + =400.2.

[0726] Step 3. 6-(Cyclopropanecarboxamido)-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)pyridazine-3-carboxylic acid (27c) A mixture of 27b (30 mg, 0.08 mmol) and LiOH.HO (10 mg, 0.24 mmol) in THF / MeOH / HO (0.6 mL, v / v / v = 1 / 1 / 1) was stirred at room temperature for 3 h. The mixture was diluted with water (5 mL), acidified with 1N HCl to pH = 4, and concentrated to give compound 27c (28 mg, 97% yield) as a white solid. LC-MS (Method 3) R =1.04 min, m / z(M+H) + =386.1.

[0727] Step 4. 6-(Cyclopropanecarboxamido)-N-methyl-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)pyridazine-3-carboxamide (27) A mixture of 27c (28 mg, 0.07 mmol), methanamine hydrochloride (15 mg, 0.22 mmol), HATU (138 mg, 0.36 mmol), and DIPEA (94 mg, 0.73 mmol) in DMF (1 mL) was stirred at room temperature for 2 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL). The organic layer was concentrated. The residue was purified by preparative HPLC (Method A) to give 27 (1.2 mg, 4% yield) as a white solid. LC-MS (Method 1) R =3.03 min, m / z(M+H) + =399.1. 1 H NMR(400MHz,CD3OD)δ 8.62(s,1H),7.47(d,J=7.2Hz,1H),7.23(s,1H),6.85(d,J=6.8Hz,1H),3.62( s,3H),3.00(s,3H),2.00-1.92(m,1H),1.03-1.01(m,2H),0.96-0.93(m,2H).

[0728] [ka]

[0729] Step 1. Methyl 2-((4-cyanophenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (28a) A mixture of 2b (50 mg, 0.133 mmol), 4-aminobenzonitrile (17 mg, 0.146 mmol), CsCO (87 mg, 0.266 mmol), BINAP (16.2 mg, 0.026 mmol), and Pd(OAc) (2.9 mg, 0.013 mmol) in 1,4-dioxane (1.4 mL) was stirred overnight at 85 °C under N. The mixture was cooled to room temperature, then filtered through a Celite pad and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give compound 28a (21 mg, 35% yield) as a tan solid. LC-MS (Method 4) R =4.16 min, m / z(M+H) + =457.3.

[0730] Step 2. Lithium 2-((4-cyanophenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyrimidine-5-carboxylate (28b) To a stirred solution of 28a (21 mg, 0.046 mmol) in THF (0.6 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (4 mg, 0.092 mmol) over 12 h at room temperature. The mixture was concentrated under reduced pressure to give crude compound 28b (27 mg, yield) as a tan solid. LC-MS (Method 4) R =3.34 min, m / z(M+H) + =443.2.

[0731] Step 3. 2-((4-cyanophenyl)amino)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyrimidine-5-carboxamide (28) To a stirred mixture of 28b (27 mg, 0.06 mmol) in DMF (1.0 mL) was added methyl-d3-amine hydrochloride (13 mg, 0.18 mmol), HATU (70 mg, 0.18 mmol), and DIPEA (47 mg, 0.36 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by preparative HPLC (Method E) to give compound 28 (8.5 mg, 31% yield) as an off-white solid. LC-MS (Method 4) R =3.20 min, m / z(M+H) + =459.3. 1 H NMR (400MHz, DMSO-d6)δ 11.76(s,1H),10.17(s,1H),8.72(s,1H),8.57-8.54(m,3H),7.94(d,J=8.8Hz,2H),7.72(d, J=8.8Hz,2H),7.57(dd,J=8.0,1.6Hz,1H),7.26(t,J=8.0Hz,1H),3.95(s,3H),3.79(s,3H).

[0732] [ka]

[0733] Step 1. Methyl 2-chloro-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)pyrimidine-5-carboxylate (29b) To a mixture of 15c (36 mg, 0.167 mmol) and methyl 2,4-dichloropyrimidine-5-carboxylate (37 mg, 0.184 mmol) in THF (0.8 mL) was added DIPEA (43 mg, 0.334 mmol) at room temperature. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated and purified by preparative TLC (PE / EtOAc = 1 / 4) to give product 29b (16 mg, 27% yield) as a pale yellow solid. LC-MS (Method 4) R =4.46 min, m / z(M+H) + =351.1.

[0734] Step 2. Methyl 2-((4-fluorophenyl)amino)-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)pyrimidine-5-carboxylate (29c) A mixture of 29b (32 mg, 0.091 mmol), 4-fluoroaniline (12 mg, 0.11 mmol), CsCO (59 mg, 0.182 mmol), BINAP (16.2 mg, 0.026 mmol), and Pd(OAc) (2.9 mg, 0.013 mmol) in 1,4-dioxane (1.0 mL) was stirred overnight at 85 °C under N. The mixture was cooled to room temperature, then filtered through a Celite pad and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give product 29c (30 mg, 77% yield) as a tan solid. LC-MS (Method 4) R =4.53 min, m / z(M+H) + =426.2.

[0735] Step 3. Lithium 2-((4-fluorophenyl)amino)-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)pyrimidine-5-carboxylate (29d) To a stirred solution of 29c (30 mg, 0.07 mmol) in THF (0.6 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (8 mg, 0.21 mmol) at room temperature over 12 h. The mixture was concentrated under reduced pressure to give crude compound 29d (35 mg, yield) as a tan solid. LC-MS (Method 4) R =3.63 min, m / z(M+H) + =412.1.

[0736] Step 4. 2-((4-fluorophenyl)amino)-N-(methyl-d3)-4-((5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridin-3-yl)amino)pyrimidine-5-carboxamide (29) To a stirred mixture of 29d (35 mg, 0.08 mmol) in DMF (1.0 mL) was added methyl-d3-amine hydrochloride (17 mg, 0.24 mmol), HATU (91 mg, 0.24 mmol), and DIPEA (62 mg, 0.48 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by preparative HPLC (Method E) to give the title product 29 (2.7 mg, 8% yield) as a pale yellow solid. LC-MS (Method 4) R =3.48 min, m / z(M+H) + =428.1. 1 H NMR(400MHz,DMSO-d6)δ 12.46(s,1H),9.67(s,1H),8.56(s,1H),8.30(s,1H),7.72-7.70(m,2H),7. 58(d,J=7.2Hz,1H),7.20-7.16(m,2H),6.88(d,J=7.2Hz,1H),3.53(s,3H).

[0737] [ka]

[0738] Step 1. 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide (30) Compound 30 (32.2 mg, 48% yield) was synthesized as an off-white solid by using 2d (50 mg, 0.13 mmol) and 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (33 mg, 0.20 mmol) as starting materials using a preparative procedure similar to that in Step 4 of Example 2. LC-MS (Method 4) R =3.48 min, m / z(M+H) + =508.2. 1 H NMR(400MHz,CDCl3)δ 11.22(s,1H),8.31(s,1H),8.10(s,1H),7.75-7.73(m,2H),7.46-7.44(m,1H),7.17(t,J=8.0Hz,1H),6.92-6.90(m,1H) ),5.93(s,1H),4.22-4.20(m,1H),4.09-4.06(m,2H),4.01(s,3H),3.89(s,3H),3.52-3.50(m,2H),2.05-1.92(m,4H).

[0739] [ka]

[0740] Step 1. 4-((2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)-2-((1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidine-5-carboxamide (31) Compound 31 (6 mg, 9% yield) was synthesized as an off-white solid by using 2d (50 mg, 0.13 mmol) and 1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-amine (31 mg, 0.20 mmol) as starting materials using a preparative procedure similar to that in Step 4 of Example 2. LC-MS (Method 4) R =3.33 min, m / z(M+H) + =494.2. 1 H NMR(400MHz,CDCl3)δ 11.27(s,1H),8.32(s,1H),8.11(s,1H),7.71-7.69(m,2H),7.48(s,1H),7.16(t,J=8.0Hz,1 H),6.11(s,1H),4.83-4.81(m,1H),4.07-4.00(m,6H),3.93-3.82(m,4H),2.39-2.34(m,2H).

[0741] [ka]

[0742] Step 1. (6-((Tert-butoxycarbonyl)amino)pyridin-2-yl)methyl methanesulfonate (32b) To a solution of 32a (300 mg, 1.34 mmol) and TEA (406 mg, 4.01 mmol) in DCM (3 mL) was added MsCl (161 mg, 1.40 mmol) at 0° C. After stirring at this temperature for 2 h, the mixture was used in the next step without workup. LC-MS (Method 3) R =1.12 min, m / z(M+H) + =303.2.

[0743] Step 2. Tert-butyl (6-(((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrobenzyl)(methyl)amino)methyl)pyridin-2-yl)carbamate (32c) To a solution of 32b (400 mg, 1.32 mmol) and TEA (402 mg, 3.97 mmol) in DCM (5 mL) was added 22d (275 mg, 0.99 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by flash chromatography on silica gel (DCM / MeOH = 30 / 1) to give the title compound 32c (213 mg, 33% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 9.62(s,1H),8.63(s,1H),8.22(d,J=2.0Hz,1H),7.89(d,J=2.0Hz,1H),7.71-7.64(m,2H),7.11 (d,J=6.4Hz,1H),3.97(s,3H),3.82(s,3H),3.66(s,2H),3.57(s,2H),2.18(s,3H),1.46(s,9H).

[0744] Step 3. 6-(((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)(methyl)amino)methyl)pyridin-2-amine (32d) Compound 32d (300 mg, 35% purity, 62% yield) was synthesized as a yellow solid by using 32c (230 mg, 0.48 mmol) as the starting material and a similar preparative procedure to that in Step 2 of Example 6. LC-MS (Method 3) R =1.12 min, m / z(M+H) + =354.2.

[0745] Step 4. Methyl 4-((5-((((6-aminopyridin-2-yl)methyl)(methyl)amino)methyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloropyridazine-3-carboxylate (32e) Compound 32e (45 mg, 24% yield) was synthesized as a yellow oil by using a similar preparative procedure as in Step 1 of Example 2, using 32d (270 mg, 60% purity, 0.36 mmol) and methyl 4,6-dichloropyridazine-3-carboxylate (89 mg, 0.43 mmol) as starting materials. 1 H NMR(400MHz,DMSO-d6)δ 9.87(s,1H),8.82(s,1H),8.00-7.97(m,1H),7.76-7.73(m,1H),7.53-7.50(m,1H),7.25-7.23(m,1H),6. 69(s,1H),6.56(brs,2H),4.25(s,2H),4.08(s,2H),4.00(s,3H),3.96(s,3H),3.72(s,3H),3.14(s,3H).

[0746] Step 5. 4-((5-((((6-aminopyridin-2-yl)methyl)(methyl)amino)methyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide (32f) Compound 32f (25 mg, 83% yield) was synthesized as a yellow oil by using a preparative procedure similar to that in Step 2 of Example 23, starting with 32e (30 mg, 0.06 mmol) and methylamine (2.36 mmol, 1.2 mL, 2M in THF). LC-MS (Method 3) R =1.27 min, m / z(M+H) + =523.5.

[0747] Step 6. 10-Methoxy-N,15-dimethyl-11-(1-methyl-1,2,4-triazol-3-yl)-2,4,5,8,15,21-hexaazatetracyclo[15.3.1.13,7.19,13]tricosa-1(21),3(23),4,6,9,11,13(22),17,19-nonaene-6-carboxamide (32) Compound 32f (25 mg, 0.05 mmol), BrettPhos (3 mg, 0.005 mmol), BrettPhos Pd G3 (4 mg, 0.005 mmol), and Cs2CO3 (47 mg, 0.14 mmol) were dissolved in 1,4-dioxane (15 mL). The resulting mixture was stirred at 100 °C under N2 for 3 h. The mixture was filtered. The filtrate was concentrated. The residue was purified by preparative HPLC (Method A) to give the title compound 32 (4 mg, 17% yield) as a yellow solid. LC-MS (Method 2) R =2.80 min, m / z(M+H) + =487.2. 1 H NMR(400MHz,DMSO-d6)δ 10.67(s,1H),10.44(brs,1H),9.89(s,1H),9.06-9.03(m,1H),8.56(s,1H),8.27(s,1H),7.63(t,J=8.0Hz,1H),7.44(d,J=2.0Hz,1H) ,7.05(d,J=8.0Hz,1H),6.84(d,J=7.2Hz,1H),3.95(s,3H),3.78(s,3H),3.69(s,2H),3.19(s,2H),2.87(d,J=4.8Hz,3H),2.30(s,3H).

[0748] [ka]

[0749] Step 1. (3-(bis(2,4-dimethoxybenzyl)amino)phenyl)methanol (33b) Compound 33a (2.0 g, 16.24 mmol), 2,4-dimethoxybenzaldehyde (8.10 g, 48.72 mmol), and AcOH (975 mg, 16.24 mmol) were dissolved in MeOH (30 mL). The above reaction was stirred at room temperature for 10 minutes. Then, NaBHCN (5.10 g, 81.20 mmol) was added to the mixture. The mixture was stirred at room temperature for 4 hours. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were concentrated to dryness. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 30 / 1) to give the title compound 33b (1.1 g, 16% yield) as a yellow oil. LC-MS (Method 3) R =1.66 min, m / z(M+H) + =424.3.

[0750] Step 2. N,N-bis(2,4-dimethoxybenzyl)-3-(((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrobenzyl)oxy)methyl)aniline (33c) To a mixture of 33b (311 mg, 0.73 mmol) in DMF (2 mL) was added NaH (35 mg, 0.88 mmol, 60% in mineral oil) at 0 °C. The mixture was stirred at room temperature for 30 min. Then 22c (200 mg, 0.61 mmol) was added at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was quenched with H2O (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (EtOAc) to give the title compound 33c (150 mg, 37% yield) as a yellow solid. LC-MS (Method 3) R =1.78 min, m / z(M+H) + =670.4.

[0751] Step 3. 3-(((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)oxy)methyl)-N,N-bis(2,4-dimethoxybenzyl)aniline (33d) Compound 33d (150 mg, 50% purity, 52% yield) was synthesized as a yellow solid by using 33c (150 mg, 0.22 mmol) as the starting material and a similar preparative procedure to that in Step 2 of Example 6. LC-MS (Method 3) R =1.67 min, m / z(M+H) + =640.8.

[0752] Step 4. Ethyl 4-((5-(((3-(bis(2,4-dimethoxybenzyl)amino)benzyl)oxy)methyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-chloropyrimidine-5-carboxylate (33e) A mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (45 mg, 0.20 mmol), 33d (100 mg, 0.16 mmol), and DIPEA (61 mg, 0.47 mmol) in ACN (4 mL) was stirred at 80 °C for 3 h. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel (PE / EtOAc = 1 / 1) to give 33e (37 mg, 29% yield) as a yellow solid. LC-MS (Method 3) R = 1.92 min, m / z (M−H) - =822.6.

[0753] Step 5. Ethyl 4-((5-(((3-aminobenzyl)oxy)methyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-chloropyrimidine-5-carboxylate (33f) Compound 33e (37 mg, 0.05 mmol) was dissolved in TFA (3 mL), and the resulting mixture was stirred at 50° C. for 3 h. The mixture was concentrated to give crude compound 33f (30 mg, yield) as a red solid. LC-MS (Method 3) R=1.55 min, m / z(M+H) + =524.5.

[0754] Step 6. Ethyl 10-methoxy-11-(1-methyl-1,2,4-triazol-3-yl)-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.13,7.19,13]tricosa-1(21),3(23),4,6,9,11,13(22),17,19-nonaene-6-carboxylate (33 g) To a mixture of 33f (20 mg, 0.04 mmol) in EtOH (6 mL) was added one drop of concentrated HCl. The mixture was stirred at 60° C. for 2 h. The mixture was concentrated to give the crude title compound 33g (20 mg, 99% yield) as a yellow solid. LC-MS (Method 3) R = 1.56 min, m / z (M−H) - =486.5.

[0755] Step 7. 10-Methoxy-N-methyl-11-(1-methyl-1,2,4-triazol-3-yl)-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.13,7.19,13]tricosa-1(21),3(23),4,6,9,11,13(22),17,19-nonaene-6-carboxamide (33) A mixture of 33g (25 mg, 0.05 mmol) and methylamine (4 mL, 30 wt % in ethanol solution) was stirred at 90°C for 16 h. The mixture was concentrated. The residue was purified by preparative HPLC (Method A) to give 33 (3.2 mg, 13% yield) as a yellow solid. LC-MS (Method 1) R =2.94 min, m / z(M+H) + =473.2. 1 H NMR(400MHz,CD3OD)δ 8.92(d,J=1.2Hz,1H),8.52(s,1H),8.47(s,1H),8.41(d,J=1.6Hz,1H),7.46(d,J=1.6Hz,1H),7.33 -7.27(m,1H),7.06-7.03(m,2H),4.59(s,2H),4.51(s,2H),4.01(s,3H),3.78(s,3H),2.91(s,3H).

[0756] [ka]

[0757] Step 1. 2-Bromo-6-(((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrobenzyl)oxy)methyl)pyridine (34a) Compound 34a (269 mg, 34% yield) was synthesized as a yellow solid by using a preparative procedure similar to that in Step 2 of Example 33, starting with 22c (600 mg, 1.83 mmol) and (6-bromopyridin-2-yl)methanol (517 mg, 2.75 mmol). LC-MS (Method 3) R =1.56 min, m / z(M+H) + =436.3.

[0758] Step 2. Tert-butyl (6-(((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrobenzyl)oxy)methyl)pyridin-2-yl)carbamate (34b) Compound 34a (269 mg, 0.62 mmol), tert-butyl carbamate (363 mg, 3.10 mmol), XantPhos (72 mg, 0.12 mmol), Pd(dba) (57 mg, 0.06 mmol), and CsCO (404 mg, 1.24 mmol) were dissolved in 1,4-dioxane (4 mL). The reaction was stirred at 90 °C for 3 h. The mixture was concentrated. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 1 / 1) to give the title compound 34b (266 mg, 91% yield) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 8.33(d,J=2.0Hz,1H),8.17(s,1H),7.86-7.82(m,2H),7.67(t,J=8.0Hz,1H),7.48(brs,1H ),7.08(d,J=7.6Hz,1H),4.65(s,2H),4.56(s,2H),4.03(s,3H),3.94(s,3H),1.53(s,9H).

[0759] Step 3. Tert-butyl (6-(((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)oxy)methyl)pyridin-2-yl)carbamate (34c) Compound 34c (241 mg, 97% yield) was synthesized as a white solid by using 34b (266 mg, 0.57 mmol) as the starting material and a similar preparative procedure to that in Step 2 of Example 6. LC-MS (Method 3) R =1.50 min, m / z(M+H) + =441.5.

[0760] Step 4. 4-((5-(((6-aminopyridin-2-yl)methoxy)methyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-methylnicotinamide (34d) Compound 34d (36 mg, 62% yield) was synthesized as a yellow solid by using 34c (50 mg, 0.11 mmol) and 11c (35 mg, 0.17 mmol) as starting materials using a preparative procedure similar to that in Step 1 of Example 10. 1H NMR(400MHz,DMSO-d6)δ 10.60(s,1H),8.86-8.76(m,1H),8.56(s,1H),8.51(s,1H),7.67(d,J=2.0Hz,1H),7.48(d,J=2.0Hz,1H),7.36(t,J=8.0Hz,1H),6.95(s,1 H),6.59(d,J=7.2Hz,1H),6.33(d,J=8.0Hz,1H),5.87(s,2H),4.60(s,2H),4.40(s,2H),3.95(s,3H),3.71(s,3H),2.81(d,J=4.8Hz,3H).

[0761] Step 5. 10-Methoxy-N-methyl-11-(1-methyl-1,2,4-triazol-3-yl)-15-oxa-2,4,8,21-tetraazatetracyclo[15.3.1.13,7.19,13]tricosa-1(21),3(23),4,6,9,11,13(22),17,19-nonaene-6-carboxamide (34) Compound 34 (8 mg, 36% yield) was synthesized as a yellow solid by using 34d (24 mg, 0.05 mmol) as the starting material and a similar preparative procedure to that in Step 6 of Example 32. LC-MS (Method 1) R =3.40 min, m / z(M+H) + =473.2. 1 H NMR(400MHz,DMSO-d6)δ 10.72(s,1H),9.92(s,1H),9.46(s,1H),8.56(s,1H),8.52-8.49(m,2H),8.23(d,J=2.0Hz,1H),7.61(t,J=7.6Hz,1H),7.41(d,J=2 .0Hz,1H),7.00(d,J=8.0Hz,1H),6.91(d,J=7.2Hz,1H),4.65(s,2H),4.35(s,2H),3.95(s,3H),3.79(s,3H),2.80(d,J=4.0Hz,3H).

[0762] [ka]

[0763] Step 1. Methyl 4-((5-(((6-((tert-butoxycarbonyl)amino)pyridin-2-yl)methoxy)methyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloropyridazine-3-carboxylate (35a) Compound 35a (25 mg, 30% yield) was synthesized as a yellow solid by using a preparative procedure similar to that in Step 7 of Example 1, starting with 34c (60 mg, 0.14 mmol) and methyl 4,6-dichloropyridazine-3-carboxylate (56 mg, 0.27 mmol). LC-MS (Method 3) R =1.23 min, m / z(M+H) + =611.1.

[0764] Step 2. Tert-butyl (6-(((3-((6-chloro-3-(methylcarbamoyl)pyridazin-4-yl)amino)-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)oxy)methyl)pyridin-2-yl)carbamate (35b) Compound 35b (50 mg, yield obtained) was synthesized as a yellow solid by using 35a (50 mg, 0.08 mmol) as the starting material and a similar preparative procedure to that in Step 2 of Example 23. LC-MS (Method 3) R =1.55 min, m / z(M+H) + =610.3.

[0765] Step 3. 4-((5-(((6-aminopyridin-2-yl)methoxy)methyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-chloro-N-methylpyridazine-3-carboxamide formate (35c) Compound 35b (50 mg, 0.08 mmol) was dissolved in a solution consisting of TFA (0.5 mL) and DCM (0.5 mL). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by preparative HPLC (Method C) to give the title compound 35c (45 mg, 99% yield) as a yellow solid. LC-MS (Method 3)R =1.31 min, m / z(M+H) + =510.5.

[0766] Step 4. 10-Methoxy-N-methyl-11-(1-methyl-1H-1,2,4-triazol-3-yl)-15-oxa-2,4,5,8,21-pentaazatetracyclo[15.3.1.1^{3,7}.1^{9,13}]tricosa-1(21),3,5,7(23),9(22),10,12,17,19-nonaene-6-carboxamide (35) Compound 35 (10 mg, 26% yield) was synthesized as a white solid by using 35c (50 mg, 0.08 mmol) as the starting material and a similar preparative procedure to that in Step 6 of Example 32. LC-MS (Method 1) R =3.18 min, m / z(M+H) + =474.0. 1 H NMR(400MHz,DMSO-d6)δ 10.77(s,1H),10.47(s,1H),9.74(s,1H),9.07(d,J=4.8Hz,1H),8.57(s,1H),8.22(s,1H),7.68(t,J=7.6Hz,1H),7.48(s,1 H),7.11(d,J=8.4Hz,1H),6.98(d,J=7.2Hz,1H),4.67(s,2H),4.39(s,2H),3.96(s,3H),3.81(s,3H),2.87(d,J=4.8Hz,3H).

[0767] [ka]

[0768] Step 1. 3-(5-(((5-bromo-2-fluorobenzyl)oxy)methyl)-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (36a) Compound 36a (160 mg, 29% yield) was synthesized as a brown solid by using 22c (400 mg, 1.22 mmol) and (5-bromo-2-fluorophenyl)methanol (376 mg, 1.83 mmol) as starting materials using a preparative procedure similar to that in Step 2 of Example 33. LC-MS (Method 3) R =1.60 min, m / z(M+H) + =451.5.

[0769] Step 2. Tert-butyl (4-fluoro-3-(((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrobenzyl)oxy)methyl)phenyl)carbamate (36b) Compound 36b (80 mg, 74% yield) was synthesized as a brown solid by using 36a (100 mg, 0.22 mmol) as the starting material and a similar preparative procedure to that in Step 2 of Example 34. LC-MS (Method 3) R =1.59 min, m / z(M+H) + =488.3.

[0770] Step 3. Tert-butyl (3-(((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)oxy)methyl)-4-fluorophenyl)carbamate (36c) Compound 36c (30 mg, 40% yield) was synthesized as a yellow solid by using 36b (80 mg, 0.16 mmol) as the starting material and a similar preparative procedure to that in Step 2 of Example 6. LC-MS (Method 3) R = 1.53 min, m / z (M−H) - =456.7.

[0771] Step 4. Tert-butyl (3-(((3-((2-chloro-5-(methylcarbamoyl)pyrimidin-4-yl)amino)-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)oxy)methyl)-4-fluorophenyl)carbamate (36d) Compound 36d (48 mg, 92% yield) was synthesized as a yellow solid by using 36c (38 mg, 0.08 mmol) and 1h (26 mg, 0.12 mmol) as starting materials using a preparative procedure similar to that in Step 7 of Example 1. LC-MS (Method 3) R =1.59 min, m / z(M+H) + =627.7.

[0772] Step 5. 4-((5-(((5-amino-2-fluorobenzyl)oxy)methyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-chloro-N-methylpyrimidine-5-carboxamide formate (36e) A solution of 36d (103 mg, 0.16 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at room temperature for 1 h. The reaction was completed and the residue was purified by preparative HPLC (Method C) to give 36e (87 mg, 92% yield) as a yellow solid. LC-MS (Method 3) R =1.40 min, m / z(M+H) + =527.5.

[0773] Step 6. 18-Fluoro-10-methoxy-N-methyl-11-(1-methyl-1H-1,2,4-triazol-3-yl)-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1^{3,7}.1^{9,13}]tricosa-1(20),3,5,7(23),9(22),10,12,17(21),18-nonaene-6-carboxamide (36) Compound 36 (18 mg, 28% yield) was synthesized as an off-white solid by using 36e (70 mg, 0.13 mmol) as the starting material and a similar preparative procedure to that in Step 6 of Example 33. LC-MS (Method 1) R =3.07 min, m / z(M+H) + =491.3. 1H NMR(400MHz,DMSO-d6)δ 11.76(s,1H),9.81(s,1H),8.74(d,J=2.0Hz,1H),8.69(s,1H),8.55(s,1H),8.49-8.45(m,2H),7.47(d,J= 2.0Hz,1H),7.13-7.11(m,2H),4.60(s,2H),4.51(s,2H),3.95(s,3H),3.79(s,3H),2.80(d,J=4.4Hz,3H).

[0774] [ka]

[0775] Step 1. 3-(5-(((3-bromo-5-(trifluoromethyl)benzyl)oxy)methyl)-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (37a) Compound 37a (16 mg, 10% yield) was synthesized as a yellow solid by using a preparative procedure similar to that in Step 2 of Example 33, starting with 22c (100 mg, 0.31 mmol) and (3-bromo-5-(trifluoromethyl)phenyl)methanol (117 mg, 0.46 mmol). LC-MS (Method 3) R =1.67 min, m / z(M+H) + =503.1.

[0776] Step 2. Tert-butyl (3-(((4-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-5-nitrobenzyl)oxy)methyl)-5-(trifluoromethyl)phenyl)carbamate (37b) Compound 37b (85 mg, 56% purity, 37% yield) was synthesized as a brown solid by using 37a (120 mg, 0.24 mmol) as the starting material and a similar preparative procedure to that in Step 2 of Example 34. LC-MS (Method 3) R =1.68 min, m / z(M+H) + =538.3.

[0777] Step 3. Tert-butyl (3-(((3-amino-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)oxy)methyl)-5-(trifluoromethyl)phenyl)carbamate (37c) Compound 37c (36 mg, 45% yield) was synthesized as a yellow solid by using 37b (85 mg, 0.16 mmol) as the starting material and a similar preparative procedure to that in Step 2 of Example 6. LC-MS (Method 3) R =1.62 min, m / z(M+H) + =508.6.

[0778] Step 4. Tert-butyl (3-(((3-((2-chloro-5-(methylcarbamoyl)pyrimidin-4-yl)amino)-4-methoxy-5-(1-methyl-1H-1,2,4-triazol-3-yl)benzyl)oxy)methyl)-5-(trifluoromethyl)phenyl)carbamate (37d) Compound 37d (40 mg, 85% yield) was synthesized as a white solid by using 37c (36 mg, 0.07 mmol) and 1h (22 mg, 0.11 mmol) as starting materials using a preparative procedure similar to that in Step 7 of Example 1. LC-MS (Method 3) R =1.64 min, m / z(M+H) + =677.3.

[0779] Step 5. 4-((5-(((3-amino-5-(trifluoromethyl)benzyl)oxy)methyl)-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-2-chloro-N-methylpyrimidine-5-carboxamide formate (37e) Compound 37e (30 mg, 64% yield) was synthesized as a white solid by using 37d (51 mg, 0.08 mmol) as the starting material and a similar preparative procedure to that in Step 3 of Example 35. LC-MS (Method 3) R =1.19 min, m / z(M+H) + =577.1.

[0780] Step 6. 10-Methoxy-N-methyl-11-(1-methyl-1H-1,2,4-triazol-3-yl)-19-(trifluoromethyl)-15-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1^{3,7}.1^{9,13}]tricosa-1(20),3,5,7(23),9(22),10,12,17(21),18-nonaene-6-carboxamide (37) Compound 37 (15 mg, 53% yield) was synthesized as an off-white solid by using 37e (30 mg, 0.05 mmol) as the starting material and a similar preparative procedure to that in Step 6 of Example 33. LC-MS (Method 2) R =3.04 min, m / z(M+H) + =541.2. 1 H NMR(400MHz,DMSO-d6)δ 11.77(s,1H),10.07(s,1H),8.86(s,1H),8.72(s,1H),8.66(d,J=2.0Hz,1H),8.56-8.54(m,2H),7.49(d,J=2. 0Hz,1H),7.44(s,1H),7.29(s,1H),4.60(s,2H),4.56(s,2H),3.95(s,3H),3.79(s,3H),2.81(d,J=4.4Hz,3H).

[0781] [ka]

[0782] Step 1. Tert-butyl (5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-3-yl)carbamate (38b) Compound 38b (447 mg, 48% yield) was synthesized as a white solid by using a similar preparative procedure to Step 4 of Example 1, starting with 38a (800 mg, 3.51 mmol) and tert-butyl carbamate (822 mg, 7.02 mmol). 1H NMR (400MHz, DMSO-d6) δ 7.99(s,1H),7.90(s,1H),7.67(d,J=7.6Hz,1H),6.71(d,J=7.6Hz,1H),3.52(s,3H),1.51(s,9H).

[0783] Step 2. 3-Amino-5-methylfuro[3,2-c]pyridin-4(5H)-one trifluoromethanesulfonate (38c) Compound 38b (100 mg, 0.38 mmol) was dissolved in a mixture of TFA and DCM (2 mL, v / v=1 / 3). The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give 38c (105 mg, yield) as a brown oil. LC-MS (Method 3) R =0.29 min, m / z(M+H) + =165.1.

[0784] Step 3. 2-Chloro-N-methyl-4-((5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-3-yl)amino)pyrimidine-5-carboxamide (38d) A mixture of 1h (78 mg, 0.38 mmol), 38c (105 mg, 0.37 mmol), and DIPEA (244 mg, 1.89 mmol) in IPA (2 mL) was stirred at 40° C. for 6 h. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel (EtOAc) to give 38d (38 mg, 30% yield) as a yellow solid. LCMS (Method 3) R =1.03 min, m / z(M+H) + =334.3.

[0785] Step 4. 2-((4-fluorophenyl)amino)-N-methyl-4-((5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-3-yl)amino)pyrimidine-5-carboxamide (38) Compound 38 (9 mg, 19% yield) was synthesized as a yellow solid by using a similar preparative procedure to Step 8 of Example 1, starting with 38d (38 mg, 0.11 mmol) and 4-fluoroaniline (63 mg, 0.60 mmol). LCMS (Method 1) R =3.13 min, m / z(M+H) + =408.9. 1 H NMR(400MHz,DMSO-d6)δ 11.74(s,1H),9.69(s,1H),8.63(s,1H),8.38(d,J=4.4Hz,1H),7.71-7.64(m,2H),7.63(d,J= 7.2Hz,1H), 7.19(t,J=8.8Hz,2H),6.67(d,J=7.6Hz,1H),3.49(s,3H),2.79(d,J=4.4Hz,3H).

[0786] [ka]

[0787] Step 1. (E)-4-Bromo-2-(2-nitrovinyl)thiophene (39a) To a mixture of 4-bromothiophene-2-carbaldehyde (5 g, 26.2 mmol) in ethanol (100 mL) was added nitromethane (2 g, 32.7 mmol) dropwise. The reaction was stirred at 0 °C, followed by the dropwise addition of NaOH (10 N, 2.6 mL, 27.4 mmol) at the same temperature. After stirring at room temperature for 2 h, the mixture was quenched with 6 N HCl (100 mL). The resulting solid was collected and dried under reduced pressure to give compound 39a (2.3 g, 37% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ 8.04 (d, J = 13.6 Hz, 1H), 7.49-7.43 (m, 2H), 7.36-7.35 (m, 1H). LC-MS (Method 4) R =3.67 min, m / z(M+H-46) + =188.0.

[0788] Step 2. 2-(4-Bromothiophen-2-yl)ethan-1-amine (39b) A solution of LiBH4 (4.1 mL, 8.2 mmol, 2 M in THF) in THF (3.0 mL) was treated dropwise with trimethylchlorosilane (1.78 g, 16.4 mmol) at room temperature under a nitrogen atmosphere, followed by the dropwise addition of 39a (480 mg, 2.05 mmol) in THF (6 mL). The resulting mixture was stirred at room temperature overnight. The mixture was quenched with MeOH, basified with 4 N NaOH to pH = 8-9, and extracted with EA. The organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure to give compound 39b (280 mg, 68% yield) as a pale yellow oil. LC-MS (Method 4) R =1.25 min, m / z(M+H) + =206.1.

[0789] Step 3. 4-Bromo-2-(2-isocyanatoethyl)thiophene (39c) A solution of 39b (210 mg, 1.01 mmol) in DCM (9 mL) was treated with the dropwise addition of triphosgene (120 mg, 0.4 mmol) in DCM (0.5 mL) at 0 °C, followed by the dropwise addition of saturated sodium bicarbonate solution (2.5 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h, dried over Na SO , and concentrated to give crude compound 39c (250 mg, yield obtained). The crude was used in the next step without purification.

[0790] Step 4. 3-Bromo-6,7-dihydrothieno[3,2-c]-pyridin-4(5H)-one (39d) To a stirred solution of 39c (250 mg, 1.08 mmol) in DCM (9 mL) was added FeCl3 (192.18 mg, 1.18 mmol) at room temperature. The mixture was stirred at 50 °C for 3 h. The residue was purified by preparative TLC (PE / EtOAc = 1 / 1) to give compound 39d (80 mg, 32% yield) as a pale yellow oil. LC-MS (Method 4) R =2.63 min, m / z(M+H) + =231.9.

[0791] Step 5. 3-Bromo-5-ethyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (39e) To a stirred solution of 39d (75 mg, 0.323 mmol) in DMF (6 mL), NaH (26 mg, 0.646 mmol, 60% purity in mineral oil) and iodomethane (76 mg, 0.485 mmol) were added dropwise at room temperature. The mixture was stirred at 65° C. overnight. The residue was purified by preparative TLC (PE / EtOAc=1 / 3) to give compound 39e (50 mg, 59% yield) as a pale yellow oil. LC-MS (Method 4) R =3.40 min, m / z(M+H) + =259.9.

[0792] Step 6. Tert-butyl (5-ethyl-4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-3-yl)carbamate (39f) A mixture of 39e (50 mg, 0.19 mmol), tert-butyl carbamate (45 mg, 0.38 mmol), N,N-dimethylenediamine (7 mg, 0.076 mmol), CuI (8 mg, 0.04 mmol), and KPO (81 mg, 0.38 mmol) in 1,4-dioxane (1 mL) and DMSO (0.4 mL) was stirred at 90 °C under N. The reaction mixture was cooled to room temperature and concentrated, and the residue was purified by preparative TLC (PE / EtOAc = 1 / 2) to give compound 39f (21 mg, 37% yield) as a pale yellow oil. LC-MS (Method 4) R =4.82 min, m / z(M+H) + =297.1.

[0793] Step 7. 3-Amino-5-ethyl-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-one (39g) To a stirred solution of 39f (20 mg, 0.067 mmol) in DCM (0.5 mL) was added TFA (148.00 mg, 1.30 mmol, 0.1 mL) dropwise at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM and concentrated under reduced pressure to give crude compound 39g (25 mg, yield obtained). The crude was used in the next step without purification. LC-MS (Method 4) R =1.83 min, m / z(M+H) +=197.1.

[0794] Step 8. Methyl 4-chloro-6-(cyclopropanecarboxamido)nicotinate (39h) A solution of 11a (42 mg, 0.2 mmol), Pd(OAc) (4.58 mg, 0.02 mmol), DPPF (33 mg, 0.06 mmol), KPO (85 mg, 0.4 mmol), and cyclopropanecarboxamide (85 mg, 0.2 mmol) in 1,4-dioxane (1 mL) was stirred at 75 °C overnight. The reaction mixture was cooled to room temperature and concentrated, and the residue was purified by preparative TLC (PE / EtOAc = 1 / 2) to give compound 39h (40 mg, 78% yield) as an off-white solid. LC-MS (Method 4) R =3.80 min, m / z(M+H) + =255.1.

[0795] Step 9. Methyl 6-(cyclopropanecarboxamido)-4-((5-ethyl-4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-3-yl)amino)nicotinate (39i) A mixture of 39g (239 mg, 0.068 mmol), 39h (23 mg, 0.088 mmol), K2CO3 (40 mg, 0.136 mmol), XantPhos (8 mg, 0.014 mmol), and Pd(OAc)2 (2.0 mg, 0.007 mmol) in 1,4-dioxane (0.8 mL) was stirred overnight at 85 °C under N2. The mixture was cooled to room temperature, then filtered through a Celite pad and concentrated. The residue was concentrated and purified by preparative TLC (PE / EtOAc = 1 / 1) to give compound 39i (12 mg, 43% yield) as a tan solid. LC-MS (Method 4) R =3.56 min, m / z(M+H) + =415.1.

[0796] Step 10. Lithium 6-(cyclopropanecarboxamido)-4-((5-ethyl-4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-3-yl)amino)nicotinate (39j) To a stirred solution of 39i (12 mg, 0.029 mmol) in THF (0.9 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (8 mg, 0.21 mmol). The reaction was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure to give crude compound 39j (19 mg, yield) as a tan solid. LC-MS (Method 4) R =2.89 min, m / z(M+H) + =401.1.

[0797] Step 11. 6-(Cyclopropanecarboxamido)-4-((5-ethyl-4-oxo-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-3-yl)amino)-N-methyl-nicotinamide (39) To a stirred mixture of 39j (19 mg, 0.05 mmol) in DMF (1.0 mL) was added methyl-d3-amine hydrochloride (10 mg, 0.14 mmol), HATU (54 mg, 0.14 mmol), and DIEA (37 mg, 0.28 mmol). The mixture was stirred at room temperature overnight. The mixture was purified by preparative HPLC (Method E) to give the title product 39 (1.6 mg, 8% yield) as a yellow solid. LC-MS (Method 4) R =2.90 min, m / z(M+H) + =414.1.

[0798] 1 H NMR(400MHz,CDCl3)δ 11.47(s,1H),8.63(s,1H),8.36(s,1H),8.24(s,1H),6.95(s,1H),6.27(s,1H),3.65-3.59(m,4H), 3.06-2.99(m,5H),1.55-1.53(m,1H),1.19(t,J=7.2Hz,3H),1.10-1.08(m,2H),0.92-0.88(m,2H).

[0799] [ka]

[0800] Step 1. 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-methylpyridazine-3-carboxamide (40) Compound 40a (35 mg, 0.09 mmol), cyclopropanecarboxamide (16 mg, 0.19 mmol), Pd(dba) (9 mg, 0.009 mmol), XantPhos (7 mg, 0.014 mmol), and CsCO (61 mg, 0.19 mmol) were dissolved in 1,4-dioxane (1 mL). The reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were concentrated to dryness. The residue was purified by preparative HPLC (Method A) to give the title compound 40 (9 mg, 16% yield) as a white solid. LC-MS (Method 1) R =3.16 min, m / z(M+H) + =423.1. 1 H NMR(400MHz,CDCl3)δ 11.10(s,1H),9.12(brs,1H),8.18(s,1H),8.10-8.04(m,2H),7.82(d,J=6.8Hz,1H),7.50(d,J=7.6Hz,1H),7.30-7. 23(m,1H),4.00(s,3H),3.81(s,3H),3.04(d,J=5.2Hz,3H),1.27-1.23(m,1H),1.12-1.08(m,2H),0.95-0.88(m,2H).

[0801] [ka]

[0802] Step 1. 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (41) To a mixture of 41a (100 mg, 0.28 mmol) and DIPEA (108 mg, 0.84 mmol) in THF (2 mL) was added cyclopropanecarbonyl chloride (59 mg, 0.56 mmol) at room temperature. The mixture was stirred at room temperature for 2 h and then concentrated to dryness. The residue was dissolved in MeOH (4 mL), and then K2CO3 (116 mg, 0.84 mmol) was added to the mixture. The mixture was stirred at room temperature for 40 min. The mixture was diluted with H2O (8 mL) and extracted with DCM (2 x 15 mL). The combined organic layers were concentrated to dryness. The residue was purified by preparative HPLC (Method A) to give the title compound 41 (40 mg, 33% yield) as a white solid. LC-MS (Method 2) R =3.21 min, m / z(M+H) + =426.3. 1 H NMR(400MHz,CDCl3)δ 11.05(s,1H),9.25(brs,1H),8.19(s,1H),8.11(s,1H),8.06(brs,1H),7.81(dd,J=8.0,1.6Hz,1H),7.50(dd,J=8.0 ,1.6Hz,1H),7.29-7.25(m,1H),4.01(s,3H),3.80(s,3H),1.72-1.68(m,1H),1.12-1.08(m,2H),0.94-0.89(m,2H).

[0803] [ka]

[0804] Step 1. 4,6-Dichloro-N-(methyl-d3)nicotinamide (42b) To a solution of 42a (1.1 g, 5.23 mmol) in DCM (20 mL) was added methan-d3-amine hydrochloride (406 mg, 5.75 mmol) and TEA (2.64 g, 26.14 mmol) at 0 °C. The mixture was then stirred at room temperature for 1 h. The mixture was diluted with HO (20 mL) and extracted with DCM (20 mL). The organic layer was separated, washed with brine (20 mL), dried over NaSO, and filtered. The filtrate was concentrated to dryness to give the title compound 42b (800 mg, 74% yield) as an off-white solid. LC-MS (Method 4) R =2.18 min, m / z(M+H) + =208.0.

[0805] Step 2. 2-Bromo-3-(dimethoxymethyl)phenol (42d) To a solution of 42c (2 g, 9.95 mmol) and trimethoxymethane (5.28 g, 49.75 mmol, 5.45 mL) in MeOH (30 mL) was added pTSA (172 mg, 1.00 mmol). The mixture was stirred at 100 °C for 16 h. The solvent was removed in vacuo to give crude product 42d (2.5 g, yield) as a yellow oil. LC-MS (Method 4) R =3.54 min, m / z(M+H) + =215.0.

[0806] Step 3. 2,4-Dibromo-3-hydroxybenzaldehyde (42e) To a solution of 42d (500 mg, 2.02 mmol) in CHCl (5 mL) was added a solution of molecular bromine (323 mg, 2.02 mmol) in CHCl (5 mL) at 0 °C. The reaction was stirred at 25 °C for 16 h. The reaction was quenched with aqueous NaSO (40 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (PE / EtOAc = 10 / 1 to 3 / 1) to give the title compound 42e (300 mg, 53% yield) as a white solid. LC-MS (Method 4) R =2.915 min, m / z(M+H)+ =280.9. 1 H NMR (400MHz, DMSO-d6) δ 10.44 (s, 1H), 10.17 (d, J = 0.8 Hz, 1 H), 7.83-7.65 (m, 1 H), 7.27 (d, J = 8.4 Hz, 1 H).

[0807] Step 4. 2,4-Dibromo-3-methoxybenzaldehyde (42f) To a solution of 42e (300 mg, 1.07 mmol) and K2CO3 (296 mg, 2.14 mmol) in DMF (3 mL) was added iodomethane (228 mg, 1.61 mmol). The mixture was stirred at 25 °C for 2 h, then poured into water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title product 42f (300 mg, 95% yield) as a yellow solid. LC-MS (Method 4) R =4.00 min, m / z(M+H) + =294.9.

[0808] Step 5. (E)-1-(2,4-dibromo-3-methoxybenzylidene)-2-ethylhydrazine hydrochloride (42 g) Compound 42f (300 mg, 1.02 mmol) and ethyl hydrazine hydrochloride (128 mg, 1.33 mmol) were dissolved in EtOH (5 mL). The resulting mixture was stirred at 25° C. for 1 hour and then cooled to 0° C. The cloudy mixture was filtered and the solid was washed with EtOH (1 mL) to give the title compound 42g (270 mg, 71% yield) as an off-white solid. LC-MS (Method 4) R =4.62 min, m / z(M+H) + =337.0.

[0809] Step 6. 6-Bromo-1-ethyl-7-methoxy-1H-indazole (42h) To a solution of 42g (270 mg, 0.72 mmol) in DMF (2.5 mL) was added K2CO3 (300 mg, 2.17 mmol) and CuI (14 mg, 0.072 mmol). The mixture was stirred at 100 °C for 16 h. To this mixture was added water (40 mL). The solution was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give crude compound 42h (150 mg, 81% yield) as a pale yellow solid. LC-MS (Method 4) R =3.99 min, m / z(M+H) + =255.0.

[0810] Step 7. Tert-butyl (1-ethyl-7-methoxy-1H-indazol-6-yl)carbamate (42i) Compound 42h (45 mg, 0.18 mmol), tert-butyl carbamate (41 mg, 0.35 mmol), Pd(dba) (16 mg, 0.018 mmol), XantPhos (21 mg, 0.035 mmol), and CsCO (144 mg, 0.44 mmol) were dissolved in dioxane (1 mL). The resulting mixture was stirred at 100 °C under N for 16 h. The mixture was diluted with H0, extracted with EtOAc, washed with brine, dried over NaSO, and filtered. The filtration was concentrated to dryness. The residue was purified by flash chromatography (PE / EtOAc = 10 / 1 to 1 / 1) to give the title compound 42i (35 mg, 68% yield) as a pale yellow solid. LC-MS (Method 4) R =3.99 min, m / z(M+H) + =292.3.

[0811] Step 8. 1-Ethyl-7-methoxy-1H-indazol-6-amine (42j) To a solution of 42i (31 mg, 0.1 mmol) in dioxane (0.5 mL) was added a solution of HCl (g) in dioxane (4 M, 0.5 mL). The mixture was stirred at room temperature for 30 min. The mixture was concentrated to dryness. The residue was diluted with H2O (10 mL), and the pH was adjusted to above 7 with aqueous Na2CO3, then extracted with EtOAc (3 x 10 mL). The organic layer was washed with aqueous Na2CO3 (15 mL) and brine (15 mL) and separated. The solution was dried over Na2SO4 and filtered. The filtrate was concentrated to give the title compound 42j (20 mg, 98% yield) as a yellow solid. LC-MS (Method 4) R =1.73 min, m / z(M+H) + =192.3.

[0812] Step 9. 6-chloro-4-((1-ethyl-7-methoxy-1H-indazol-6-yl)amino)-N-(methyl-d3)nicotinamide (42k) To a solution of 42j (20 mg, 0.10 mmol) and 42b (26 mg, 0.13 mmol) in THF (1 mL) was added NaHMDS (0.35 mL, 0.7 mmol, 2 M in THF) at 0 °C, and the mixture was stirred at room temperature for 30 min. The mixture was diluted with HO (20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried over NaSO, and filtered. The filtrate was concentrated to dryness to give the title compound 42k (30 mg, 79% yield) as a yellow solid. LC-MS (Method 4) R =3.52 min, m / z(M+H) + =363.2.

[0813] Step 10. 4-((1-ethyl-7-methoxy-1H-indazol-6-yl)amino)-6-((5-fluoropyridin-2-yl)amino)-N-(methyl-d3)nicotinamide (42) Compound 42k (30 mg, 0.082 mmol), 5-fluoropyridin-2-amine (19 mg, 0.17 mmol), XantPhos (9.7 mg, 0.016 mmol), CsCO (67 mg, 0.20 mmol), and Pd(dba) (7.6 mg, 0.008 mmol) were dissolved in DMA (1 mL). The resulting mixture was stirred at 145 °C for 2 h. The mixture was concentrated to dryness and purified by preparative HPLC (Method D) to give the title compound 42 (2.2 mg, 6% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.54(s,1H),9.71(s,1H),8.47(s,1H),8.44(s,1H),8.03(d,J=1.6Hz,1H),8.01(s,1H),7.68-7.65(m,1H),7.60-7.56(m ,1H),7.54(d,J=8.8Hz,1H),7.46(m,1H),7.21(d,J=8.8Hz,1H),4.52(q,J=7.2Hz,2H),3.78(s,3H),1.37(t,J=7.2Hz,3H). LC-MS (Method 4) R =2.66 min, m / z(M+H) + =439.2.

[0814] [ka]

[0815] Step 1. 4-((1-ethyl-7-methoxy-1H-indazol-6-yl)amino)-N-(methyl-d3)-6-((1-methyl-1H-pyrazol-3-yl)amino)nicotinamide (43) Compound 42k (20 mg, 55.1 μmol), 1-methyl-1H-pyrazol-3-amine (11 mg, 0.11 mmol), XantPhos (6 mg, 0.011 mmol), CsCO (44.9 mg, 0.14 mmol), and Pd(dba) (5 mg, 0.005 mmol) were dissolved in DMA (1 mL). The resulting mixture was stirred at 160 °C under a N atmosphere for 1 h. The mixture was concentrated to dryness and purified by preparative HPLC (Method D) to give compound 43 (2.0 mg, 9% yield) as an off-white solid. LC-MS (Method 4) R =2.42 min, m / z(M+H) + =424.3. 1 H NMR(400MHz,DMSO-d6)δ 10.57(s,1H),9.20(s,1H),8.40(s,1H),8.03(s,1H),7.53(d,J=8.4Hz,1H),7.45(d,J=1.6Hz,1H),7.24(d,J=8.4H) z,1H),7.20(s,1H),6.06(d,J=1.6Hz,1H),4.55(q,J=7.2Hz,2H),3.81(s,3H),3.62(s,3H),1.40(t,J=7.2Hz,3H).

[0816] [ka]

[0817] Step 1. Lithium 4-chloro-6-(cyclopropanecarboxamido)nicotinate (44a) To a solution of 39h (500 mg, 1.96 mmol) in a solvent containing MeOH (2 mL), THF (2 mL), and water (1 mL) was added LiOH.HO (165 mg, 3.93 mmol). The mixture was then stirred at room temperature overnight. The mixture was concentrated to dryness to give compound 44a (480 mg, 99% yield) as a white solid. LC-MS (Method 4) R =3.81 min, m / z(M+H) + =241.1.

[0818] Step 2. 4-Chloro-6-(cyclopropanecarboxamido)-N-(methyl-d3)nicotinamide (44b) To a solution of 44a (480 mg, 1.95 mmol) in DCM (15 mL) were added methane-d3-amine hydrochloride (275 mg, 3.89 mmol), DIPEA (1.51 g, 11.68 mmol), and T3P (1.86 g, 2.92 mmol, 50% in EtOAc) successively at 0 °C. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with HO (30 mL) and extracted with DCM (3 x 30 mL). The organic layer was washed with brine (50 mL), dried over NaSO, and filtered. The filtrate was concentrated to dryness to give 44b (300 mg, 60% yield) as a white solid. LC-MS (Method 4) R =2.25 min, m / z(M+H) + =257.1.

[0819] Step 3. 6-(Cyclopropanecarboxamido)-4-((1-ethyl-7-methoxy-1H-indazol-6-yl)amino)-N-(methyl-d3)nicotinamide (44) A mixture of 42j (20 mg, 0.10 mmol), 44b (27 mg, 0.10 mmol), and pTSA (18 mg, 0.1 mmol) in dioxane (1 mL) was stirred at 100 °C for 15 h. The mixture was concentrated to dryness. The residue was purified by preparative HPLC (Method E) to give compound 44 (8.5 mg, 20% yield) as a pale yellow solid. LC-MS (Method 4) R =2.16 min, m / z(M+H) + =412.2. 1 H NMR(400MHz,DMSO-d6)δ 10.67(s,1H),10.49(s,1H),8.57(s,1H),8.47(s,1H),.8.00(s,1H),7.78(s,1H),7.47(d,J=8.4Hz,1H),7.05(d ,J=8.4Hz,1H),4.50(q,J=7.2Hz,2H),3.74(s,3H),1.91-1.88(s,1H),1.35(t,J=7.2Hz,3H),0.71-0.66(m,4H).

[0820] [ka]

[0821] Step 1. Methyl 6-chloro-4-((4-methoxybenzyl)amino)nicotinate (45a) To a solution of 11a (5 g, 24.27 mmol) in ACN (8 mL) were added (4-methoxyphenyl)methanamine (3.33 g, 24.27 mmol, 3.17 mL) and TEA (4.91 g, 48.54 mmol, 6.77 mL), and the mixture was stirred at room temperature for 24 h. The mixture was diluted with HO (100 mL), extracted with EA (3 x 50 mL), washed with brine, dried over NaSO, concentrated, and purified by flash chromatography (PE / EtOAc = 20 / 1 to 5 / 1) to give compound 45a (6.5 g, 87% yield) as an off-white solid. LC-MS (Method 4) R =4.18 min, m / z(M+H) + =307.1.

[0822] Step 2. Methyl 6-(cyclopropanecarboxamido)-4-((4-methoxybenzyl)amino)nicotinate (45b) A mixture of 45a (2 g, 6.52 mmol), cyclopropanecarboxamide (1.11 g, 13.04 mmol), XantPhos (754 mg, 1.30 mmol), Pd(dba) (597 mg, 0.65 mmol), and CsCO (5.31 g, 16.30 mmol) in 1,4-dioxane (30 mL) was stirred at 110 °C for 2 h. The mixture was then diluted with HO (100 mL), extracted with EA (3 x 60 mL), washed with brine, dried over NaSO, and concentrated to give crude compound 45b (2.3 g, 99% yield) as a yellow solid. LC-MS (Method 4) R =2.91 min, m / z(M+H) + =356.2.

[0823] Step 3. Methyl 4-amino-6-(cyclopropanecarboxamido)nicotinate 2,2,2-trifluoroacetate (45c) A solution of 45b (2.1 g, 5.91 mmol) in TFA (10 mL) was stirred at 80 °C for 16 h. The mixture was then concentrated, diluted with EA (10 mL), filtered, washed with EA (2 x 5 mL), and the solid was dried to give compound 45c (1.8 g, 87% yield, TFA salt) as an off-white solid. LC-MS (Method 4) R =1.28 min, m / z(M+H) + =236.2.

[0824] Step 4. 4-Bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide (45e) To a stirred solution of 45d (1 g, 5.24 mmol) in DCM (30 mL), TEA (2.65 g, 26.18 mmol, 3.65 mL) and 2,2-dimethoxyethanamine (826 mg, 7.85 mmol) were added at room temperature. The reaction mixture was cooled to 0 °C, and T3P (4.7 mL, 7.85 mmol, 50% in ethyl acetate) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (60 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (PE / EtOAc = 10 / 1 to 1 / 1) to give compound 45e (500 mg, 34% yield) as a white solid. LC-MS (Method 4) R = 2.28 min, m / z (M−H) - =276.0.

[0825] Step 5. 3-Bromo-7-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (45f) and 3-bromo-7-methoxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (45g) To a solution of 45e (500 mg, 1.80 mmol) in DCM (2 mL) was added TFA (266 mg, 2.34 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was concentrated to give a mixture of compound 45f (300 mg, 72% yield) and 45g (120 mg, 27% yield) as a yellow oil. 45f: LC-MS (Method 4) R =1.32 min, m / z(M+H) + =232.0;45g:LC-MS(Method 4)t R =2.12 min, m / z(M+H) + =246.0.

[0826] Step 6. 3-Bromopyrazolo[1,5-a]pyrazin-4(5H)-one (45h) A mixture of 45f (300 mg, 1.29 mmol) and 45g (120 mg, 0.49 mmol) in PPA (1 mL) was stirred at 145 °C for 4 h. The mixture was diluted with HO (50 mL), extracted with DCM (3...

Claims

1. Structural formula (I): 【Chemistry 1】 (In the formula, X １ and X ２ are independently selected from CH and N; X ４ and X ５ are independently selected from CH, CF and N; X ３ is NR, O, CH ２ or CF ２ and R １１ is H, F, C １ ~C ３ Alkyl or CD ３ where X ３ is NR or O, then R １１ is not F, R １２ is C(=O)R １２’ or R １２’ where R １２’ is C １ ~C ６ Alkyl, C ３ ~C ６ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is 0 to 2 R １２ａ where R １２ａ is a halogen, CF ３ , CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R １３ is C １ ~C ３ Alkyl, CD ３ or CF ３ and R １４ is H, C １ ~C ６ Alkyl or heteroalkyl or C ３ ~C ６ a cycloalkyl or heterocycloalkyl, or a 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms selected from N, O, and S, or R １４ is OR １４’ where R １４’ is C １ ~C ６ Alkyl or heteroalkyl or C ３ ~C ６ cycloalkyl or heterocycloalkyl, each of which is 0 to 2 R １４ａ where R １４ａ is halogen, R, OR, amino, CF ３ and CN; R １５ represents, at each occurrence, F, Cl, CN, OR, NRR′, and C １ ~C ３ independently selected from alkyl, R, in each occurrence, is independently H or C １ ~C ６ is alkyl, k is 0, 1, 2 or 3. or a pharmaceutically acceptable form or isotopic derivative thereof.

2. R １２ is C(=O)R １２’ 2. The compound of claim 1, wherein:

3. R １２ is R １２’ 2. The compound of claim 1, wherein:

4. The compound of claim 1, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 12 is an unsubstituted or substituted phenyl, pyridinyl, pyrazolyl, or pyrimidinyl group.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein each of X 1 and X 2 is CH.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein each of X 4 and X 5 is CH.

7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein X 4 is CF.

8. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein X 4 is CH and X 5 is N.

9. A compound represented by the formula: 【Chemistry 2】 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable form or isotopic derivative thereof, having the formula:

10. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein X 3 is NR.

11. Structural formula: 【Transformation 3】 (In the formula, each R 16 is independently selected from CN, Cl, F, C 1 -C 3 alkyl, C 3-6 heterocyclic, and OR; j is 0, 1, 2, 3, 4 or 5.

10. The compound of claim 1, or a pharmaceutically acceptable form or isotopic derivative thereof, having the formula:

12. The compound of claim 11, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein j is 1 and R 16 is in the meta position: 【Chemistry 4】

13. Structural formula: 【Transformation 5】 (In the formula, each R 16 is independently selected from CN, Cl, F, C 1 -C 3 alkyl, and OR; and j is 0, 1, 2, 3, 4, or 5, or a pharmaceutically acceptable form or isotopic derivative thereof.

14. The compound of claim 13, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein j is 1.

15. Structural formula (II): 【Transformation 6】 [In the formula, Y 1 is CH, CF or N; Y 2 is CH or N; Y 3 is NR, O, CH 2 or CF 2 ; R 21 is H, F, C 1 -C 3 alkyl and CD 3 , with the proviso that when Y 3 is N or O, then R 21 is not F; R 22 is R 22' , where R 22' is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R 22a , where R 22a is selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic; an aryl or heteroaryl group, each of which is substituted with 0-2 R 22a ; or (C=O)R 27 and R23 is 【Transformation 7】 and During the ceremony, each of X 4 , X 5 , X 6 , X 7 , X 8 and X 9 is independently selected from O, C, CH, S, N and NR 26 ; R 24 is H and C 1-6 alkyl substituted with 0-3 R 24a , or C 3-10 cycloalkyl or heterocycloalkyl, C 5-10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1-4 heteroatoms selected from N, O and S, each group substituted with 0-4 R 24b ; R 24a in each occurrence is independently H, D, halo, OH, OR, CH 3 , CF 3 , CH 2 CF 3 or CN, NRR′, (CH 2 ) n NRR′, or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S; R 24b in each occurrence is independently H, halo, CN, OR, NRR', OCF 3 , CF 3 , C 1-6 alkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (each substituted with 0-3 R 24a ), C 1-6 haloalkyl, C 2-6 alkenyl substituted with 0-3 R 24a , C 2-6 alkynyl substituted with 0-3 R 24a ; R 25 is F, Cl, CN, CD 3 , CH 2 CF 3 , CF 3 , OR, NRR′, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, substituted with 0-2 R 24b ; R 26 is H, C 1 -C 6 alkyl, CD 3 , or C 3 -C 6 cycloalkyl, substituted with 0-3 R 24a ; R 27 is C 1-6 alkyl or C 3-6 cycloalkyl, aryl or heteroaryl, each of which is substituted with 0-2 R 24b ; each of R and R' is independently H or C 1 -C 6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO 2 ; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; p is 1 or 2. or a pharmaceutically acceptable form or isotopic derivative thereof.

16. p is 1, and R 23 is 【Transformation 8】 16. The compound of claim 15, wherein:

17. The compound of claim 15, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein p is 2.

18. The compound of any one of claims 15 to 17, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 1 is CH and Y 2 is CH: 【Chemistry 9】 19. The compound of any one of claims 15 to 17, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 1 is CH and Y 2 is N: 【Chemistry 10】 20. The compound of any one of claims 15 to 17, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 1 is N and Y 2 is CH: 【Chemistry 11】 21. The compound of any one of claims 15 to 17, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 1 is N and Y 2 is N: 【Chemistry 12】 22. The compound of any one of claims 15 to 17, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 1 is CF.

23. The compound of any one of claims 15 to 17, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 3 is NR.

24. The compound of claim 23, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 3 is NH.

25. R 23 is 【Chemistry 13】 16. The compound of claim 15, or a pharmaceutically acceptable form or isotopic derivative thereof, selected from:

26. Structural formula: 【Chemistry 14】 16. The compound of claim 15, or a pharmaceutically acceptable form or isotopic derivative thereof, having the formula:

27. ​​Structural formula: 【Chemistry 15】 16. The compound of claim 15, or a pharmaceutically acceptable form or isotopic derivative thereof, having the formula:

28. Structural formula: 【Chemistry 16】 16. The compound of claim 15, or a pharmaceutically acceptable form or isotopic derivative thereof, having the formula:

29. Structural formula: 【Chemistry 17】 16. The compound of claim 15, or a pharmaceutically acceptable form or isotopic derivative thereof, having the formula:

30. Structural formula (IV): [Chemistry 18] [In the formula, Y 1 is CH, CF or N; Y 2 is CH or N; Y 3 is NR, O, CH 2 or CF 2 ; R 41 is H, F, C 1 -C 3 alkyl and CD 3 , with the proviso that when Y 3 is NR or O, then R 41 is not F; R42 is R 42′ , where R 42′ is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each of which is substituted with 0-2 of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; an aryl or heteroaryl group substituted with 0-2 R 42a , or (C=O)R 42b and R43 is 【Chemistry 19】 (In the formula, Each of X 4 , X 5 , X 6 , X 7 , X 8 , X 9 and X 10 is independently selected from C, CH, O, N and NH. and R 42a in each occurrence is independently H, D, halo, OH, OR, CH 3 , CF 3 , CH 2 CF 3 , CN, C(O)NR, NRR′, (CH 2 ) n NRR′, or a 4- to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S; R 42b is C 1-6 alkyl or C 3-6 cycloalkyl, aryl or heteroaryl, each of which is substituted with 0-2 R 42c ; R 42c at each occurrence is independently H, halo, CN, OR, NRR', OCF 3 , CF 3 , C 1-6 alkyl substituted with 0-3 R 42a , C 1-6 haloalkyl, C 2-6 alkenyl substituted with 0-3 R 42a , C 2-6 alkynyl substituted with 0-3 R 42a ; R 45 in each occurrence is independently H, halo, CN, OR, NRR', OCF 3 , CF 3 , C 1-6 alkyl (substituted with 0-3 R 42a ), or C 3-10 cycloalkyl or heterocycloalkyl, C 5-10 aryl or heteroaryl, or a 4- to 10-membered heterocycle having 1-4 heteroatoms selected from N, O and S, each group being substituted with 0-4 R 42c , and optionally two R 45 together with the C or N atom to which they are attached form a 4- to 6-membered ring; R 46 at each occurrence is independently F, Cl, CN, OR, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, CD 3 , CH 2 CF 3 or CF 3 ; R 47 is H, OCF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy or OCD 3 ; each of R and R' is independently H or C 1 -C 6 alkyl, or R and R' together with the nitrogen atom to which they are attached form a 4- to 7-membered ring containing 0-2 heteroatoms selected from O, NR, S, and SO 2 ; n is 0, 1, 2, 3 or 4; i is 0, 1 or 2; j is 0, 1 or 2. or a pharmaceutically acceptable form or isotopic derivative thereof.

31. R 43 is 【Chemistry 20】 (In the formula, R 44 or R 45 , when attached to N, is H, C 1-6 alkyl, CD 3 , C 3-8 cycloalkyl, 3- to 7-membered heterocycloalkyl, or C 5 -C 6 aryl or heteroaryl, substituted with 0-3 R 52a ; 31. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 44 or R 45, when attached to C, is selected from H, F, Cl, CN, C 1-6 alkyl, CD 3 , or C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 7-membered heterocycloalkyl, or C 5 -C 6 aryl or heteroaryl, substituted with 0-3 R 42a .

32. R 43 is 【Chemistry 21】 (In the formula, R 44 or R 45 , when attached to N, is H, C 1-6 alkyl, CD 3 , C 3-8 cycloalkyl, 3- to 7-membered heterocycloalkyl, or C 5 -C 6 aryl or heteroaryl, substituted with 0-3 R 52a ; 31. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 44 or R 45, when attached to C, is selected from H, F, Cl, CN, C 1-6 alkyl, CD 3 , or C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 7-membered heterocycloalkyl, or C 5 -C 6 aryl or heteroaryl, substituted with 0-3 R 42a .

33. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 47 is C 1 -C 3 alkoxy.

34. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 47 is OCH 3 .

35. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 47 is OCD 3 .

36. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein j is 0.

37. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein j is 1.

38. The compound of claim 37, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 46 is F or Cl.

39. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 1 is CH and Y 2 is CH: 【Chemistry 22】 40. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 1 is CH and Y 2 is N: 【Chemistry 23】 41. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 1 is N and Y 2 is CH: 【Chemistry 24】 42. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 1 is N and Y 2 is N: 【Chemistry 25】 43. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 1 is CF.

44. The compound of claim 30, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 3 is NR.

45. The compound of claim 44, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein Y 3 is NH.

46. ​​The compound of any one of claims 30 to 45, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 41 is CH 3 .

47. The compound of any one of claims 30 to 45, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 41 is CD 3 .

48. The compound of any one of claims 30 to 45, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 42 is (C═O)R 42b , where R 42b is selected from C 1 -C 6 alkyl, cyclopropyl, or cyclobutyl, substituted with 0 to 2 R 42c .

49. The compound of claim 48, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 42 is (C═O)R 42b , where R 42b is cyclopropyl optionally substituted with one or more of F, Cl, CH 3 , CF 3 and CN.

50. The compound of claim 48, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 42 is (C═O)R 42b , where R 42b is cyclobutyl optionally substituted with one or more of F, Cl, CH 3 , CF 3 and CN.

51. The compound of claim 48, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 42 is (C═O)R 42b , where R 42b is C 1 -C 6 alkyl optionally substituted with one or more of F, Cl, CH 3 , CF 3 , CN, NRR′ and OR.

52. The compound of any one of claims 30 to 45, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 42 is pyridinyl substituted with 0 to 2 R 42c .

53. The compound of any one of claims 30 to 45, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 42 is phenyl substituted with 0 to 2 R 42c .

54. The compound of any one of claims 30 to 45, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 42 is pyrazolyl substituted with 0 to 2 R 42c .

55. The compound of any one of claims 30 to 45, or a pharmaceutically acceptable form or isotopic derivative thereof, wherein R 42 is pyrimidyl substituted with 0 to 2 R 42c .

56. A compound selected from Table 1, or a pharmaceutically acceptable excipient, carrier, or diluent.

57. A pharmaceutical composition comprising a compound of any one of claims 1, 15, 30, or 56, and a pharmaceutically acceptable excipient, carrier, or diluent, for treating one or more diseases or disorders in a mammal, including a human.

58. Use of a compound of any one of claims 1, 15, 30, or 56, and a pharmaceutically acceptable excipient, carrier, or diluent, in the preparation of a pharmaceutical preparation for treating a disease or disorder.

59. The use of claim 58, wherein the disease or disorder is one or more of an inflammatory disease, an immune-mediated disease, and cancer.

60. A method for preparing a compound according to any one of claims 1, 15, 30 and 56.

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