WO2023109120A1

WO2023109120A1 - Tyk2 inhibitors and compositions and methods thereof

Info

Publication number: WO2023109120A1
Application number: PCT/CN2022/106876
Authority: WO
Inventors: Zhaokui WAN; Xiaodong Li; Michael Lawrence Vazquez
Original assignee: Lynk Pharmaceuticals Co. Ltd.
Priority date: 2021-12-16
Filing date: 2022-07-20
Publication date: 2023-06-22
Also published as: WO2023108536A1

Abstract

TYK2 inhibitors, pharmaceutical compositions of these compounds,methods of preparation and the use thereof against various TYK2-mediated diseases and disorders.

Description

TYK2 INHIBITORS AND COMPOSITIONS AND METHODS THEREOF

Technical Fields of the Invention

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

Background of the Invention

Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the Janus kinase -Signal Transduction Activators of Transcription (JAK-STAT) pathway. There are four members in the JAK family of enzymes in humans, i.e., JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) . The family is defined by the presence of two adjacent kinase domains, JH1 and JH2, of which JH1 performs the phosphorylation involved in pathway activation whereas JH2 regulates JH1 function. (Thomas, et al., 2015 British Journal of Cancer 113, 365–371. )

These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors such as common gamma-chain receptors and the glycoprotein 130 (gp130) transmembrane proteins. (Murray, et al. 2007 Immunol. 178 (5) : 2623-2629. ) About 40 cytokine receptors signal through combinations of these four JAKs and their 7 downstream substrates: the STAT family members. (Ghoreschi et al. 2009 Immunol Rev. 228 (l) : 273-287. )

TYK2 is a key component of the JAK-STAT signaling pathway. TYK2 regulates 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, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF) . The activated TYK2 goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6. Selective inhibition of TYK2 can be utilized to treat a variety of autoimmune inflammatory diseases, such as psoriasis, systemic lupus erythematosus (SLE) , inflammatory bowel disease (IBD) , rheumatoid arthritis (RA) , as well as cancer and diabetes.

The selectivity against other JAK family subtypes is regarded as crucial in order to increase the intended pharmacological effects and to reduce side effects. Identifying kinase inhibitors with a high degree of TYK2 selectivity has posed a significant challenge partly due to the high sequence homology of the active site among the JAK family kinases. TYK2 specificity is critical for clinical application of TYK2 kinase inhibitors, because Tyk2 knockout mice are viable with normal blood cell counts, whereas deficiency of JAK3 results in severe combined immunodeficiency in mice, and JAK1 or JAK2 knockout mice show 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 would be warranted in patients treated for prolonged periods. (Akahane, et al. 2017 Br J Haematol. 177 (2) : 271–282. )

An urgent need exists and challenges remain across broad therapeutic areas for selective TYK2 inhibitors with improved potency and minimal side effects.

Summary of the Invention

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

In one aspect, the invention generally relates to a compound having the structural formula (I) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of X ¹ and X ² is independently selected from CH and N;

each of X ⁴ and X ⁵ is independently selected from CH, CF and N;

X ³ is NR, O, CH ₂ or CF ₂;

R ¹¹ is a H, F, C ₁-C ₃ alkyl or CD ₃;

R ¹² is C (=O) R ^12’ or R ^12’, wherein R ^12’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^12a, wherein R ^12a is selected from the group consisting of halogen, CF ₃, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ¹³ is a C ₁-C ₃ alkyl, CD ₃ or CF ₃;

R ¹⁴ is H, C ₁-C ₆ alkyl or heteroalkyl or a C ₃-C ₆ cycloalkyl or heterocycloalkyl, or a 5-or 6-membered heteroaryl group comprising 1, 2 or 3 hetero atoms selected from N, O and S, or R ¹⁴ is OR ^14’, wherein R ^14’ is C ₁-C ₆ alkyl or heteroalkyl or a C ₃-C ₆ cycloalkyl or heterocycloalkyl, each substituted with 0-2 R ^14a, wherein R ^14a is selected from the group consisting of halogen, R, OR, amino, CF ₃ and CN;

R ¹⁵ at each occurrence is independently selected from F, Cl, CN, OR, and a C ₁-C ₃ alkyl;

R at each occurrence is independently H or a C ₁-C ₆ alkyl; and

k is 0, 1, 2 or 3.

In another aspect, the invention generally relates to a compound having the structural formula (II) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ²¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ²² is

R ^22’, wherein R ^22’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^22a, wherein R ^22a is selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

an aryl or heteroaryl group, each substituted with 0-2 R ^24a; or

(C=O) R ²⁷;

R ²³ is

wherein

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 is substituted with 0-4 R ^24b;

R ^24a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^24b at 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, OR, C ₁-C ₃ alkyl, C ₃-C ₅ cycloalkyl, CD ₃, CH ₂CF ₃ or CF ₃;

R ²⁶ is H, a C ₁-C ₆ alkyl, CD ₃, or C ₃-C ₆ cycloalkyl, substituted with 0-3 R ^24a;

R ²⁷ is a C _1-6 alkyl or C _3-6 cycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^24b;

each of R and R’ is independently H or a C ₁-C ₆ alkyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 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; and

p is 1 or 2.

In yet another aspect, the invention generally relates to a compound having the structural formula (III) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring A is a 5-or 6-membered aryl or heteroaryl;

X ¹ is selected from NR, O, CH ₂ and CF ₂;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁶ is NR ³⁶, CH ₂, O, S, SO or SO ₂;

R ³² is R ^32’ or OR ^32’, wherein R ^32’ is a C _1-12 alkyl, 3-to 6-membered cycloalkyl or heterocycloalkyl comprising 1, 2 or 3 heteroatoms selected from N, O and S, or a 5-or 6-membered aryl or heteroaryl group, each substituted with 0-3 R ^32a;

R ^32a is independently at each occurrence, H, OCF ₃, CN, NO ₂, - (CH ₂) _rOR ^b, - (CH ₂) _rSR ^b, - (CH ₂) _rC (O) R ^b, - (CH ₂) _rC (O) OR ^b, - (CH ₂) _rOC (O) R ^b, (CH ₂) _rNR ^gR ^g, - (CH ₂) _rC (O) NR ^gR ^g, - (CH ₂) _rNR ^bC (O) R ^c, - (CH ₂) _rNR ^bC (O) OR ^c, -NR ^bC (O) NR ^gR ^g, -S (O) _vNR ^gR ^g, -NR ^bS (O) _vR ^c, -S (O) _vR ^c, C _1-6 alkyl substituted with 0-3 R ^a, C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a, 3-to 6-membered cycloalkyl substituted with 0-3 R ^a, or 3-to 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^a;

each of R ³³ and R ³⁴ is independently selected from H, F, Cl, CN, OR ^g, CH ₃, CD ₃, CF ₃, OCD ₃, OCF ₃ and - (CH ₂) _p-Q;

R ³⁵ is H, F, a C ₁-C ₃ alkyl and CD ₃;

R ³⁶ is R substituted with 0-3 R ^d;

R ^a at each occurrence is independently H, F, Cl, Br, OCF ₃, CF ₃, CHF ₂, CN, NO ₂, - (CH ₂) _rOR ^b, - (CH ₂) _rSR ^b, - (CH ₂) _rC (O) R ^b, - (CH ₂) _rC (O) OR ^b, - (CH ₂) _rOC (O) R ^b, - (CH ₂) _rNR ^gR ^g, - (CH ₂) _rC (O) NR ^gR ^g, - (CH ₂) _rNR ^bC (O) R ^c, - (CH ₂) _rNR ^bC (O) OR ^c, -NR ^bC (O) NR ^gR ^g, -S (O) _vNR ^gR ^g, -NR ^bS (O) _vR ^c, -S (O) R ^c, -S (O) ₂R ^c, C _1-6 alkyl substituted with 0-3 R ^f, C _1-6 haloalkyl, 3-to 6-membered cycloalkyl substituted with 0-3 R ^f, or 3-to 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^f;

R ^b is H, C _1-6 alkyl substituted with 0-3 R ^d, C _1-6 haloalkyl, C _3-6 cycloalkyl substituted with 0-2 R ^d, or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^d;

R ^c is C _1-6 alkyl substituted with 0-3 R ^f, (CH ₂) _r-C _3-6 cycloalkyl substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^d is independently at each occurrence, hydrogen, F, Cl, Br, OCF ₃, CF ₃, CN, NO ₂, -OR ^e, - (CH ₂) _rC (O) R ^c, -NR ^eR ^e, -NR ^eC (O) OR ^c, C _1-6 alkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^e is independently at each occurrence, hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^f is independently at each occurrence, hydrogen, halo, CN, NH ₂, OH, C _3-6 cycloalkyl, CF ₃, O (C _1-6 alkyl) or a 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S;

R ^g at each occurrence is independently H, C _1-4 alkyl substituted with 0-3 R ^f, CF ₃, C _3-10 cycloalkyl substituted with 0-1 R ^f, (CH) _r-phenyl substituted with 0-3 R ^d or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^d;

Q is a water solubilizing group, optionally selected from OH, OR, NRR’, heterocyclic and heteroaryl groups, wherein R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO ₂;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

r is 0, 1, 2, 3, 4 or 5.

In yet another aspect, the invention generally relates to a compound having the structural formula (IV) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ⁴¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁴² is

R ^42’, wherein R ^42’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each 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;

R ⁴³ is

wherein

each of X ⁴, X ⁵, X ⁶, X ⁷, X ⁸, X ⁹ and X ¹⁰ is independently selected from C, CH, N and NH;

R ^42a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^42b is a C _1-6 alkyl or C _3-6 cycloalkyl, aryl or heteroaryl, each 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 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 is substituted with 0-4 R ^42c;

R ⁴⁶ each occurrence is independently F, Cl, CN, OR, C ₁-C ₃ alkyl, C ₃-C ₅ cycloalkyl, CD ₃, CH ₂CF ₃ or CF ₃;

R ⁴⁷ is H, OCF ₃, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy or OCD ₃;

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

j is 0, 1 or 2.

In yet another aspect, the invention generally relates to a compound having the structural formula (V) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring B is a 5-or 6-membered aryl or heteroaryl;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁵ is selected from NR, O, CH ₂ and CF ₂;

Z ⁶ is NR ⁵⁶, CH ₂, O, S, SO or SO ₂;

each of X ⁴, X ⁷, X ⁸ and X ⁹ is independently selected from CH, N and NH;

R ⁵¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁵² is independently selected from H, F, Cl, CN, OR ^g, CH ₃, CF ₃, OCF ₃ and - (CH ₂) _p-Q;

R ^52a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^52c at each occurrence is independently H, halo, CN, OR, NRR’, OCF ₃, CF ₃, C _1-6 alkyl substituted with 0-3 R ^52a, C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^52a , C _2-6 alkynyl substituted with 0-3 R ^52a;

R ⁵⁵ each occurrence is independently H, C _1-6 alkyl, substituted with 0-3 R ^52a, 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 is substituted with 0-4 R ^52c;

R ⁵⁶ is R substituted with 0-3 R ^d;

R ⁵⁷ is H, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, OCD ₃ or OCF ₃;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

q is 0, 1, 2, 3 or 4.

In yet another aspect, the invention generally relates to a pharmaceutical composition comprising a compound disclosed herein, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

In yet another aspect, the invention generally relates to a pharmaceutical composition comprising an amount of a compound having the structural formula of (I) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of X ¹ and X ² is independently selected from CH and N;

each of X ⁴ and X ⁵ is independently selected from CH, CF and N;

X ³ is NR, O, CH ₂ or CF ₂;

R ¹¹ is a H, F, C ₁-C ₃ alkyl or CD ₃;

R ¹³ is a C ₁-C ₃ alkyl, CD ₃ or CF ₃;

R at each occurrence is independently H or a C ₁-C ₆ alkyl; and

k is 0, 1, 2 or 3,

or a pharmaceutically acceptable form or an isotope derivative thereof, effective to treat, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

In yet another aspect, the invention generally relates to a pharmaceutical composition comprising an amount of a compound having the structural formula of (II) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ²¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ²² is

an aryl or heteroaryl group, each substituted with 0-2 R ^24a; or

(C=O) R ²⁷;

R ²³ is

wherein

R ^24b at 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;

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

p is 1 or 2,

effective to treat, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.

In yet another aspect, the invention generally relates to a pharmaceutical composition comprising an amount of a compound having the structural formula (III) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring A is a 5-or 6-membered aryl or heteroaryl;

X ¹ is selected from NR, O, CH ₂ and CF ₂;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁶ is NR ³⁶, CH ₂, O, S, SO or SO ₂;

R ³⁵ is H, F, a C ₁-C ₃ alkyl and CD ₃;

R ³⁶ is R substituted with 0-3 R ^d;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

r is 0, 1, 2, 3, 4 or 5,

In yet another aspect, the invention generally relates to a pharmaceutical composition comprising an amount of a compound having the structural formula of (IV) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ⁴¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁴² is

an aryl or heteroaryl group substituted with 0-2 R ^42a; or

(C=O) R ^42b;

R ⁴³ is

wherein

R ⁴⁷ is H, OCF ₃, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy or OCD ₃;

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

j is 0, 1 or 2,

In yet another aspect, the invention generally relates to a pharmaceutical composition comprising an amount of a compound having the structural formula of (V) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring B is a 5-or 6-membered aryl or heteroaryl;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁵ is selected from NR, O, CH ₂ and CF ₂;

Z ⁶ is NR ⁵⁶, CH ₂, O, S, SO or SO ₂;

R ⁵¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁵⁶ is R substituted with 0-3 R ^d;

R ⁵⁷ is H, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, OCD ₃ or OCF ₃,

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

q is 0, 1, 2, 3 or 4,

In yet another aspect, the invention generally relates to a unit dosage form comprising a pharmaceutical composition disclosed herein.

In yet another aspect, the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula (I) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of X ¹ and X ² is independently selected from CH and N;

each of X ⁴ and X ⁵ is independently selected from CH, CF and N;

X ³ is NR, O, CH ₂ or CF ₂;

R ¹¹ is a H, F, C ₁-C ₃ alkyl or CD ₃;

R ¹³ is a C ₁-C ₃ alkyl, CD ₃ or CF ₃;

R at each occurrence is independently H or a C ₁-C ₆ alkyl; and

k is 0, 1, 2 or 3,

wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.

In yet another aspect, the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula (II) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ²¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ²² is

an aryl or heteroaryl group, each substituted with 0-2 R ^24a; or

(C=O) R ²⁷;

R ²³ is

wherein

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

p is 1 or 2,

In yet another aspect, the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula (III) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring A is a 5-or 6-membered aryl or heteroaryl;

X ¹ is selected from NR, O, CH ₂ and CF ₂;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁶ is NR ³⁶, CH ₂, O, S, SO or SO ₂;

R ³⁵ is H, F, a C ₁-C ₃ alkyl and CD ₃;

R ³⁶ is R substituted with 0-3 R ^d;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

r is 0, 1, 2, 3, 4 or 5,

In yet another aspect, the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula (IV) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ⁴¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁴² is

R ^42’, wherein R ^42’ is R ^42’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each 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;

R ⁴³ is

wherein

R ⁴⁷ is H, OCF ₃, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy or OCD ₃;

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

j is 0, 1 or 2,

In yet another aspect, the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula (V) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring B is a 5-or 6-membered aryl or heteroaryl;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁵ is selected from NR, O, CH ₂ and CF ₂;

Z ⁶ is NR ⁵⁶, CH ₂, O, S, SO or SO ₂;

R ⁵¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁵⁶ is R substituted with 0-3 R ^d;

R ⁵⁷ is H, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, OCD ₃ or OCF ₃;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

q is 0, 1, 2, 3 or 4,

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

Definitions

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

The following terms, unless indicated otherwise according to the context wherein the terms are found, are intended to have the following meanings.

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

As used herein, “at least” a specific value is understood to be that value and all values greater than that value.

As used herein, “more than one” is understood as 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 therebetween.

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

Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01%of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.

Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive.

Any compositions or methods disclosed herein can be combined with one or more of any of the other compositions and methods provided herein.

The recitation of a listing of chemical groups in any definition of a variable herein includes definitions 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 embodiments or portions thereof.

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 “consisting essentially of” , when used to define compositions and methods, shall mean that the compositions and methods include the recited elements and exclude other elements of any essential significance to the compositions and methods. For example, “consisting essentially of” refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The term consisting essentially of does not exclude pharmacologically inactive or inert agents, e.g., pharmaceutically acceptable excipients, carriers or diluents. The term “consisting of” , when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

Certain compounds of the present invention may 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, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in 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. For optically active compounds, it is often preferred to use one enantiomer to the substantial exclusion of the other enantiomer.

Isomeric mixtures containing any of a variety of isomer ratios may be utilized in accordance with the present invention. For example, where only two isomers are combined, mixtures containing 50: 50, 60: 40, 70: 30, 80: 20, 90: 10, 95: 5, 96: 4, 97: 3, 98: 2, 99: 1, or 100: 0 isomer ratios are contemplated by the present invention. Those of ordinary skill in the art will readily appreciate that analogous ratios are contemplated for more complex isomer mixtures.

If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic methods well known in the art, and subsequent recovery of the pure enantiomers.

A mixture of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

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 sub-range within the range. For example, “C _1-6 alkyl” is intended to encompass, C ₁, C ₂, C ₃, C ₄, C ₅, C ₆, 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.

Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -C (=O) -O-is equivalent to -O-C (=O) -.

Structures of compounds of the invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds that are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions (e.g., aqueous, neutral, and several known physiological conditions) .

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

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, having from one to ten carbon atoms (e.g., C _1-10 alkyl) . Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; e.g., "1 to 10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, “alkyl” can be a C _1-6 alkyl group. In some embodiments, alkyl groups have 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, an alkyl group is 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) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. In a non-limiting embodiment, a substituted alkyl can be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

As used herein, the term “alkoxy” refers to the group -O-alkyl, including from 1 to 10 carbon atoms (C _1-10) of a straight, branched, saturated cyclic configuration and combinations thereof, attached to the parent molecular structure through an oxygen. Unless stated otherwise 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 alkoxy groups containing one to six carbons. In some embodiments, C _1-3 alkoxy is an alkoxy group that encompasses both straight and branched chain alkyls of from 1 to 3 carbon atoms. Unless stated otherwise in the specification, an alkoxy group 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) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

As used herein, the terms “aromatic” or “aryl” refer to a radical with 6 to 14 ring atoms (e.g., C _6-14 aromatic or C _6-14 aryl) that has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl) . Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted aryl groups. In some embodiments, the aryl is a C _6-10 aryl group. For example, bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. In other embodiments, bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as "6 to 14 aryl" refers to each integer in the given range; e.g., "6 to 14 ring atoms" means that the aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 14 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In a multi-ring group, only one ring is required to be aromatic, so 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) -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) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

As used herein, the terms “cycloalkyl” and “carbocyclyl” each refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and can be saturated or partially unsaturated. Partially unsaturated cycloalkyl groups can be termed "cycloalkenyl" if the carbocycle contains at least one double bond, or "cycloalkynyl" if the carbocycle contains at least one triple bond. Cycloalkyl groups include groups having from 3 to 13 ring atoms (i.e., C _3-13 cycloalkyl) . Unless stated otherwise in the specification, 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; e.g., "3 to 13 carbon atoms" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridged and spiro-fused cyclic structures containing no heteroatoms. The term also includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicycles, tricycles, tetracycles, and the like. In some embodiments, “cycloalkyl” can be a C _3-8 cycloalkyl radical. In some embodiments, “cycloalkyl” can be a C _3-5 cycloalkyl radical. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: C _3-6 carbocyclyl groups include, without limitation, cyclopropyl (C ₃) , cyclobutyl (C ₄) , cyclopentyl (C ₅) , cyclopentenyl (C ₅) , cyclohexyl (C ₆) , cyclohexenyl (C ₆) , cyclohexadienyl (C ₆) and the like. Examples of C _3-7 carbocyclyl groups include norbornyl (C ₇) . Examples of C _3-8 carbocyclyl groups include the aforementioned C _3-7 carbocyclyl groups as well as cycloheptyl (C ₇) , cycloheptadienyl (C ₇) , cycloheptatrienyl (C ₇) , cyclooctyl (C ₈) , bicyclo [2.2.1] heptanyl, bicyclo [2.2.2] octanyl, and the like. Examples of C _3-13 carbocyclyl groups include the aforementioned C _3-8 carbocyclyl groups as well as octahydro-1H indenyl, decahydronaphthalenyl, spiro [4.5] decanyl and the like. Unless stated otherwise in the specification, a cycloalkyl group 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) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein. The terms “cycloalkenyl" and "cycloalkynyl" mirror the above description of "cycloalkyl" wherein the prefix "alk" is replaced with "alken" or "alkyn" respectively, and the parent "alkenyl" or "alkynyl" terms are as described herein. For example, a cycloalkenyl group can have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloalkynyl group can have 5 to 13 ring atoms.

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 that are substituted with one or more halo groups or with 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 are as defined herein and can be optionally further substituted as defined herein.

As used herein, the term “heteroatom” refers to oxygen (O) , nitrogen (N) , sulfur (S) , and phosphorus (P) .

As used herein, the term "heteroalkyl" refers to an alkyl radical, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heteroalkyl groups. A numerical range can be given, e.g., C _1-4 heteroalkyl, which refers to the chain length in total, which in this example is 4 atoms long. For example, a -CH ₂OCH ₂CH ₃ radical is referred to as a "C ₄" heteroalkyl, which includes the heteroatom center in the atom chain length description. 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 skeletal atoms is a nitrogen atom. One or more heteroatom (s) in the heteroalkyl radical can be optionally oxidized. One or more nitrogen atoms, if present, can also be optionally quaternized. For example, heteroalkyl also includes skeletal chains substituted with one or more nitrogen oxide (-O-) substituents. Exemplary heteroalkyl groups include, without limitation, ethers such as methoxyethanyl (-CH ₂CH ₂OCH ₃) , ethoxymethanyl (-CH ₂OCH ₂CH ₃) , (methoxymethoxy) ethanyl (-CH ₂CH ₂OCH ₂OCH ₃) , (methoxymethoxy) methanyl (-CH ₂OCH ₂OCH ₃) and (methoxyethoxy) methanyl (-CH ₂OCH ₂CH ₂OCH ₃) and the like; amines such as (-CH ₂CH ₂NHCH ₃, -CH ₂CH ₂N (CH ₃) ₂, -CH ₂NHCH ₂CH ₃, -CH ₂N (CH ₂CH ₃) (CH ₃) ) and the like.

As used herein, the term “heterocycloalkyl” refers to a cycloalkyl radical, which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heterocycloalkyl groups. Illustrative examples of heterocycloalkyl include 2-hydroxy-aziridin-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, etc.

As used herein, the term “heteroaryl” or, alternatively, “heteroaromatic” refers to a radical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic and the like) aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-6 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous and sulfur ( "5-18 membered heteroaryl" ) . Unless stated otherwise in the specification, the term is intended to include both substituted and unsubstituted heteroaryl groups. Heteroaryl polycyclic ring systems can include 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; e.g., "5 to 18 ring atoms" means that the heteroaryl group can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some instances, a heteroaryl can have 5 to 14 ring atoms. In some embodiments, the heteroaryl has, for example, bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-ene" to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylene.

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 heteroatom (s) in the heteroaryl radical 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-oxides. The heteroaryl is attached to the parent molecular structure through any atom of the ring (s) .

“Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment to the parent molecular structure is either on the aryl or on the heteroaryl ring, or wherein the heteroaryl ring, as defined above, is fused with one or more cycloalkyl or heterocycyl groups wherein the point of attachment to the parent molecular structure is on the heteroaryl ring. For polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl and the like) , the point of attachment to the parent molecular structure can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl) . In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ( "5-10 membered heteroaryl" ) . In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ( “5-8 membered heteroaryl” ) . In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorous, and sulfur ( "5-6 membered heteroaryl" ) . In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, phosphorous, and sulfur.

Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1, 3-benzodioxolyl, benzofuranyl, benzooxazolyl, 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, 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-tetrahydroquinazolinyl, naphthyridinyl, 1, 6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5, 6, 6a, 7, 8, 9, 10, 10a-octahydrobenzo [h] quinazolinyl, 1-phenyl-lH-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] pyrimdinyl, 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 (R ^a) C (NR ^a) N (R ^a) ₂, -N (R ^a) S (O) _tN (R ^a) ₂ (where t is 1 or 2) , -P (=O) (R ^a) (R ^a) , or -O-P (=O) (OR ^a) ₂ where each R ^a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each of these moieties can be optionally substituted as defined herein.

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, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Suitable routes 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.

Administration may be by any suitable route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal) . Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, 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.

By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies.

The compound of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent) . Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation) .

The compositions of the present invention can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. 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.

The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. 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 drug-containing microspheres, which slowly release 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) .

As used herein, the terms “disease, ” “condition, ” and “disorder” are used interchangeably herein and refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein.

As used herein, the term “effective amount” of an active agent refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.

As used herein, the terms “inhibition, ” “inhibit” and “inhibiting” and the like in reference to a biological target (e.g., TYK2) inhibitor interaction refers to negatively affecting (e.g., decreasing) the activity or function of the 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 levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to reduction of a disease or symptoms of disease. In embodiments, inhibition refers to a reduction in the activity of a particular protein target. Inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g., an inhibitor binds to the target protein) . In embodiments, inhibition refers to a reduction of 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) .

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

As used herein, the term “modulate” refers to the production, either directly or indirectly, of an increase or a decrease, a 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, for example, increases, decreases, stimulates, inhibits, interferes with, or blocks a measured activity of the polypeptide or polynucleotide, when compared to a suitable control. For example, a “modulator” may bind to and /or activate or inhibit the target with measurable affinity, or directly or indirectly affect the normal regulation of a receptor activity.

As used herein, a “pharmaceutically acceptable form” of a disclosed compound includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable salts, esters, prodrugs and isotopically labeled derivatives thereof. In some embodiments, a "pharmaceutically acceptable form" includes, but is not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs and isotopically labeled derivatives thereof.

In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes 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, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchlorate 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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, valerate salts, and the like. 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.

The 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 a parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4alkyl) ₄ salts. 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, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring 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 chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

In certain embodiments, the pharmaceutically acceptable form is a “solvate” (e.g., a hydrate) . As used herein, the term “solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a “hydrate. ” Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4, solvent or water molecules. It will be understood that the term “compound” as used herein encompasses the compound and solvates of the compound, as well as mixtures thereof.

In certain embodiments, the pharmaceutically acceptable form is a prodrug. As used herein, the term “prodrug” (or “pro-drug” ) refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood) . In certain cases, a prodrug has improved physical and/or delivery properties over the parent compound. Prodrugs can increase the bioavailability of the compound when administered to a subject (e.g., by permitting enhanced absorption into the blood following oral administration) or which 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 a disclosed compound with enhanced aqueous solubility or active transport through the gut membrane, relative to the parent compound.

The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (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., "Pro-drugs as Novel Delivery Systems, " A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.

Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism. (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. ) Prodrugs commonly known in the art include well-known acid derivatives, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, amides prepared by reaction of the parent acid compound with an amine, basic groups reacted to form an acylated base derivative, etc. Other prodrug derivatives may be combined with other features disclosed herein to enhance bioavailability. As such, those of skill in the art will appreciate that certain of the presently disclosed compounds having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds having a carbonate, carbamate, amide or alkyl ester moiety covalently bonded to any of the above substituents disclosed herein.

Exemplary 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 digestive tract, or it can enhance drug stability for long-term storage.

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, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body. 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 carboxymethyl cellulose, ethyl cellulose 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; buffering agents, 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 employed in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

As used herein, the term “subject” refers to any animal (e.g., a mammal) , including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment. A subject to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult) ) and/or other non-human animals, for example, non-human mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys) ; commercially relevant mammals such as cattle, 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 a male or female at any stage of development. A non-human animal may be a transgenic animal. Typically, the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.

As used herein, the terms “treatment” or “treating” a disease or disorder refers to a method of reducing, delaying or ameliorating such a condition before or after it has occurred. Treatment may be directed at one or more effects or symptoms of a disease and/or the underlying pathology. The treatment can be any reduction and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. Treating or treatment thus refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, for example, the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. As compared with an equivalent untreated control, such reduction or degree of amelioration may be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%as measured by any standard technique.

Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein. The administering step may be a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the patient’s age, the concentration of the compound, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.

Detailed Description of the Invention

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

The new class of TYK2 inhibitors disclosed herein exhibit exceptional potency 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 the theory, compounds of the invention are modulators of interleukins (e.g., IL-12, IL-23) and interferons (e.g., IFN-a) by inhibiting TYK2-mediated signal transduction.

These compounds are designed to show good potency against TYK2 with good oral absorption and good in vivo stability. The invention also provides pharmaceutical compositions of these compounds and methods of preparation and use thereof. The TYK2 inhibitors disclosed herein exhibit favorable pharmacokinetic profiles and drug properties that are suitable for the target indications.

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of X ¹ and X ² is independently selected from CH and N;

each of X ⁴ and X ⁵ is independently selected from CH, CF and N;

X ³ is NR, O, CH ₂ or CF ₂;

R ¹¹ is a H, F, C ₁-C ₃ alkyl or CD ₃;

R ¹³ is a C ₁-C ₃ alkyl, CD ₃ or CF ₃;

R at each occurrence is independently H or a C ₁-C ₆ alkyl; and

k is 0, 1, 2 or 3.

In certain embodiments of formula (I) , R ¹² is C (=O) R ^12’.

In certain embodiments of formula (I) , R ¹² is R ^12’.

In certain embodiments of formula (I) , each of X ¹ and X ² is CH.

In certain embodiments of formula (I) , each of X ⁴ and X ⁵ is CH.

In certain embodiments of formula (I) , one or both of X ⁴ and X ⁵ is CF.

In certain embodiments of formula (I) , X ⁴ is CH and X ⁵ is N.

In certain embodiments of formula (I) , each of X ¹ and X ² is CH.

In certain embodiments of formula (I) , each of X ⁴ and X ⁵ is CH.

In certain embodiments of formula (I) , X ⁴ is CH and X ⁵ is N.

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

In certain embodiments of formulae (I) - (I ^a) , X ³ is NR. In certain embodiments, X ³ is NH.

In certain embodiments of formulae (I) - (I ^a) , X ³ is O.

In certain embodiments of formulae (I) - (I ^a) , R ¹² is R ^12’ and R ^12’ is an aryl group (e.g., an unsubstituted or substituted phenyl) .

In certain embodiments of formulae (I) - (I ^a) , R ¹² is R ^12’ and R ^12’ is a heteroaryl group (e.g., an unsubstituted or substituted pyrazolyl or pyridinyl) .

In certain embodiments of formulae (I) - (I ^a) , R ¹² is C (=O) R ^12’ and R ^12’ is an unsubstituted or substituted C ₃-C ₆ cycloalkyl. In certain embodiments, R ^12’ is cyclopropyl. In certain embodiments, R ^12’ is cyclobutyl.

In certain embodiments of formulae (I) - (I ^a) , R ^12’ is a C ₁-C ₆ alkyl substituted with an amino or morpholino group.

In certain embodiments of formulae (I) - (I ^a) , R ¹³ is CH ₃.

In certain embodiments of formulae (I) - (I ^a) , R ¹³ is CD ₃.

In certain embodiments of formulae (I) - (I ^a) , R ¹³ is CF ₃.

In certain embodiments of formulae (I) - (I ^a) , R ¹⁴ is 5-membered heteroaryl group (e.g., 1, 2, 4-triazole) .

In certain embodiments of formulae (I) - (I ^a) , R ¹⁴ is OR ^14’. In certain embodiments, R ^14’ is a heterocycloalkyl (e.g., tetrahydropyran) .

In certain embodiments of formulae (I) - (I ^a) , R ¹⁴ is H.

In certain embodiments of formulae (I) - (I ^a) , k is 0 (i.e., R ¹⁵ is absent) .

In certain embodiments of formulae (I) - (I ^a) , k is 1.

In certain embodiments of formulae (I) - (I ^a) , k is 2.

In certain embodiments of formulae (I) - (I ^a) , the compound has the structural formula:

wherein each R ¹⁶ is independently selected from CN, Cl, F, a C ₁-C ₃ alkyl and OR, and j is 0, 1, 2, 3, 4 or 5.

In certain embodiments of formulae (I) - (I ^b) , j is 0 (i.e., R ¹⁶ is absent) .

In certain embodiments of formulae (I) - (I ^b) , j is 1.

In certain embodiments of formulae (I) - (I ^b) , j is 2.

In certain embodiments of formula (I ^b) , j is 1 and R ¹⁶ is at the meta position:

In certain embodiments of formulae (I) - (I ^c) , R ¹¹ is CH ₃.

In certain embodiments of formulae (I) - (I ^c) , R ¹¹ is CD ₃.

In certain embodiments of formulae (I) - (I ^c) , R ¹⁵ is F.

In certain embodiments of formulae (I) - (I ^c) , R ¹⁶ is CN.

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ²¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ²² is

an aryl or heteroaryl group, each substituted with 0-2 R ^24a; or

(C=O) R ²⁷;

R ²³ is

wherein

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

p is 1 or 2.

In certain embodiments of formula (II) , p is 1 and R ²³ is

In certain embodiments of formula (II) , p is 2.

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

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

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

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

In certain embodiments of formulae (II) - (II ^d) , one or both of Y ¹ and Y ² is CF.

In certain embodiments of formulae (II) - (II ^d) , Y ³ is NR. In certain embodiments, Y ³ is NH.

In certain embodiments of formulae (II) - (II ^d) , Y ³ is CH ₂.

In certain embodiments of formulae (II) - (II ^d) , Y ³ is CF ₂

In certain embodiments of formulae (II) - (II ^d) , R ²³ is a group selected from:

In certain embodiments, R ²³ is:

In certain embodiments, R ²³ is:

In certain embodiments, R ²³ is:

In certain embodiments, R ²³ is:

In certain embodiments of formulae (II) - (II ^d) , R ²¹ is F.

In certain embodiments of formulae (II) - (II ^d) , R ²¹ is CH ₃.

In certain embodiments of formulae (II) - (II ^d) , R ²¹ is CD ₃.

In certain embodiments of formulae (II) - (II ^d) , R ²² is an aryl (e.g., phenyl) , optionally substituted with 1 or 2 halogen (e.g., F, Cl) atoms.

In certain embodiments of formulae (II) - (II ^d) , R ²² is a heteroaryl group (e.g., pyridinyl) , optionally substituted with 1 or 2 halogen (e.g., F, Cl) atoms.

In certain embodiments of formulae (II) - (II ^d) , R ²² is (C=O) R ²⁷, wherein R ²⁷ is selected from C ₁-C ₆ alkyl, cyclopropyl or cyclobutyl, substituted with 0-2 R ^24b.

In certain embodiments of formulae (II) - (II ^d) , R ²² is pyridine substituted with 0-2 R ^24b.

In certain embodiments, the compound has the structural formula:

In certain embodiments, the compound has the structural formula:

In certain embodiments, the compound has the structural formula:

In certain embodiments, the compound has the structural formula:

In certain embodiments, the compound has the structural formula:

In certain embodiments, the compound has the structural formula:

In certain embodiments, the compound has the structural formula:

In certain embodiments, the compound has the structural formula:

In certain embodiments of formulae (II) - (II ^l) , R ²⁷ is cyclopropyl.

In certain embodiments of formulae (II) - (II ^l) , R ²⁷ is cyclobutyl.

In certain embodiments of formulae (II) - (II ^l) , R ²⁴ is a C ₁-C ₁₂ alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted with one or more of F, Cl, CN, OR, CH ₃, CF ₃ and OCF ₃.

In certain embodiments of formulae (II) - (II ^l) , R ²⁴ is a C ₁-C ₁₂ alkyl, optionally substituted with one or more of F, Cl, CN, OR, NRR’, CH ₃, CF ₃ and OCF ₃. In certain embodiments, R ²⁴ is CH ₃. In certain embodiments, R ²⁴ is ethyl.

In certain embodiments of formulae (II) - (II ^l) , R ²⁴ is a C ₃-C ₁₂ cycloakyl or heterocycloalkyl, optionally substituted with one or more of F, Cl, CN, OR, NRR’, CH ₃, CF ₃ and OCF ₃.

In certain embodiments of formulae (II) - (II ^l) , R ²⁴ is a C ₄-C ₁₂ aryl, optionally substituted with one or more of F, Cl, CN, OR, NRR’, CH ₃, CF ₃ and OCF ₃.

In certain embodiments of formulae (II) - (II ^l) , R ²⁴ is a C ₃-C ₁₂ heteroaryl, optionally substituted with one or more of F, Cl, CN, OR, NRR’, CH ₃, CF ₃ and OCF ₃.

In certain embodiments of formulae (II) - (II ^l) , R ²⁵ is H.

In certain embodiments of formulae (II) - (II ^l) , R ²⁵ is F or Cl.

In certain embodiments of formulae (II) - (II ^l) , R ²⁵ is CH ₃, CHF ₂ or CF ₃.

In certain embodiments of formulae (II) - (II ^l) , R ²⁵ is CN.

In certain embodiments of formulae (II) - (II ^l) , R ²⁵ is OR.

In certain embodiments of formulae (II) - (II ^l) , i is 0 (i.e., R ²⁵ is absent) .

In certain embodiments of formulae (II) - (II ^l) , i is 1.

In certain embodiments of formulae (II) - (II ^l) , i is 2.

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring A is a 5-or 6-membered aryl or heteroaryl;

X ¹ is selected from NR, O, CH ₂ and CF ₂;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁶ is NR ³⁶, CH ₂, O, S, SO or SO ₂;

R ³⁵ is H, F, a C ₁-C ₃ alkyl and CD ₃;

R ³⁶ is R substituted with 0-3 R ^d;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

r is 0, 1, 2, 3, 4 or 5.

In certain embodiments of formula (III) , X ¹ is NH, having the structural formula (III ₁) :

In certain embodiments of formulae (III) - (III ₁) , Ring A is a 6-membered aryl or heteroaryl.

In certain embodiments of formulae (III) - (III ₁) , the compound has the structural formula (III ₂) :

wherein each of Z ⁵ and Z ⁸ is CH or N.

In certain embodiments of formula (III ₂) , wherein Z ⁸ is CH and the compound has the structural formula (III ₃) :

In certain embodiments of formula (III ₃) , Z ² and Z ⁵ are not both CH.

In certain embodiments of formulae (III) or (III ₃) , Z ⁷ is NR. In certain embodiments, R is H and Z ⁷ is NH.

In certain embodiments of formulae (III) or (III ₃) , Z ⁷ is CH ₂.

In certain embodiments of formulae (III) or (III ₃) , Z ⁷ is CF ₂.

In certain embodiments of formulae (III) or (III ₃) , each of Z ³ and Z ⁴ is NH.

In certain embodiments of formula (III ₃) , Z ¹ is CH, Z ² is CH, each of Z ³ and Z ⁴ is NH, and Z ⁵ is N.

In certain embodiments of formula (III ₃) , (CRR’) _m is (CH ₂) _m and (CRR’) _n is (CH ₂) _n.

In certain embodiments of formula (III ₃) , the compound has the structural formula:

In certain embodiments of formula (III ₃) , Z ¹ is N, Z ² is CH, and Z ⁵ is N.

In certain embodiments of formula (III ₃) , Z ¹ is CH, Z ² is N, and Z ⁵ is N.

In certain embodiments of formula (III ₃) , Z ¹ is CH, Z ² is N, and Z ⁵ is CH.

In certain embodiments of formula (III ₃) , Z ¹ is N, Z ² is N, and Z ⁵ is N.

In certain embodiments of formulae (III ₃) - (III ₃ ^e) , R ³² is a 6-membered aryl or heteroaryl group comprising 0, 1 or 2 nitrogen atoms and 0 or 1 oxygen atom.

In certain embodiments of formulae (III ₃) - (III ₃ ^e) , R ³² is selected from:

In certain embodiments of formulae (III ₃) - (III ₃ ^e) , R ³² is a 3-to 6-membered cycloalkyl or heterocycloalkyl comprising 1, 2 or 3 heteroatoms wherein the heteroatoms are selected from N, O and S, substituted with 0-3 R ^32a.

In certain embodiments of formulae (III ₃) - (III ₃ ^e) , R ³² is a 3-membered cycloalkyl substituted with 0-3 R ^32a.

In certain embodiments of formulae (III ₃) - (III ₃ ^e) , R ³² is cyclopropyl substituted with 0-3 R ^32a.

In certain embodiments of formulae (III ₃) - (III ₃ ^e) , R ³² is a 5-membered heteroaryl group comprising 1, 2 or 3 nitrogen atoms and 0 or 1 oxygen atom.

In certain embodiments of formulae (III ₃) - (III ₃ ^e) , R ³² is a triazole, oxadiazole, thiazole, oxazole or pyrazole substituted with 0-3 R ^32a.

In certain embodiments, R ³² is a N-methyl-1, 2, 4-triazole.

In certain embodiments of formulae (III ₃) - (III ₃ ^e) , q is 0 (i.e., R ³⁴ is absent) .

In certain embodiments of formulae (III ₃) - (III ₃ ^e) , q is 1.

In certain embodiments of formulae (III ₃) - (III ₃ ^e) , q is 2.

In certain embodiments of formulae (III ₃) , the compound has the structural formula:

In certain embodiments of formulae (III ₂) , the compound has the structural formula:

In certain embodiments of formulae (III ₃) - (III ₃ ⁱ) , Z ⁶ is NR ³⁶. In certain embodiments, R ³⁶ is CH ₃.

In certain embodiments of formulae (III ₃) - (III ₃ ⁱ) , Z ⁶ is O.

In certain embodiments of formulae (III ₃) - (III ₃ ⁱ) , Z ⁶ is S.

In certain embodiments of formulae (III ₃) - (III ₃ ⁱ) , Z ⁶ is CH ₂.

In certain embodiments of formulae (III ₃) - (III ₃ ⁱ) , m = 1.

In certain embodiments of formulae (III ₃) - (III ₃ ⁱ) , m = 2.

In certain embodiments of formulae (III ₃) - (III ₃ ⁱ) , n = 1.

In certain embodiments of formulae (III ₃) - (III ₃ ⁱ) , n = 2.

In certain embodiments of formulae (III ₃) - (III ₃ ⁱ) , m = n = 1.

In certain embodiments of formulae (III ₃) - (III ₃ ⁱ) , m = n = 2.

In certain embodiments of formula (III ₁) , Z ⁵ is N and Z ⁸ is N.

In certain embodiments of formula (III ₁) , the compound has the structural formula (III ₄) :

In certain embodiments of formula (III ₄) , the compound has the structural formula (III ₄ ^a) :

In certain embodiments of formula (III ₄) , the compound has the structural formula (III ₄ ^b) :

In certain embodiments of formula (III ₄) , the compound has the structural formula (III ₄ ^c) :

In certain embodiments of formula (III ₄) , the compound has the structural formula (III ₄ ^d) :

In certain embodiments of formula (III ₄) , the compound has the structural formula (III ₄ ^e) :

In certain embodiments of formulae (III) - (III ₄ ^e) , R ³³ is OR. In certain embodiments, R is CH ₃ and R ³³ is OCH ₃. In certain embodiments, R is CD ₃ and R ³³ is OCD ₃.

In certain embodiments of formulae (III) - (III ₄ ^e) , R ³⁴ is H.

In certain embodiments of formulae (III) - (III ₄ ^e) , R ³⁴ is selected from F or Cl.

In certain embodiments of formulae (III) - (III ₄ ^e) , R ³⁴ is selected from CN.

In certain embodiments of formulae (III) - (III ₄ ^e) , R ³⁴ is selected from CH ₃ or CF ₃.

In certain embodiments of formulae (III) - (III ₄ ^e) , R ³⁴ is selected from OCF ₃.

In certain embodiments of formulae (III) - (III ₄ ^e) , R ³⁴ is - (CH ₂) _p-Q. In certain embodiments, p is 1 or 2 and Q is OH, OR or NRR’ (e.g., N (CH ₃) ₂) . In certain embodiments, Q is a heterocyclic (e.g., morpholine) or heteroaryl group.

In certain embodiments of formulae (III) - (III ₄ ^e) , R ³⁴ is - (CH ₂) _p-Q and Q is an amino or morpholino group.

In certain embodiments of formulae (III) - (III ₄ ^e) , R ³⁵ is CH ₃.

In certain embodiments of formulae (III) - (III ₄ ^e) , R ³⁵ is CD ₃.

In certain embodiments of formulae (III) - (III ₁) , Ring A is a 5-membered aryl or heteroaryl.

In certain embodiments of formulae (III) - (III ₁) , the compound has the structural formula (III ₅) :

In certain embodiments of formula (III ₅) , (CRR’) _m is (CH ₂) _m and (CRR’) _n is (CH ₂) _n.

In certain embodiments of formula (III ₅) , the compound has the structural formula:

In certain embodiments of formulae (III ₅) or (III ₅ ^b) , R ³⁵ is CH ₃.

In certain embodiments of formulae (III ₅) or (III ₅ ^b) , R ³⁵ is CD ₃.

In certain embodiments of formulae (III ₅) or (III ₅ ^b) , wherein R ³³ is OCH ₃.

In certain embodiments of formulae (III ₅) or (III ₅ ^b) , m is 1 and n is 2.

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ⁴¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁴² is

an aryl or heteroaryl group substituted with 0-2 R ^42a; or

(C=O) R ^42b;

R ⁴³ is

wherein

R ⁴⁷ is H, OCF ₃, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy or OCD ₃;

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

j is 0, 1 or 2.

In certain embodiments of formula (IV) , R ⁴³ is selected from:

wherein

R ⁴⁴, when bond to N, is H, a C ₁-C ₃ alkyl, CD ₃, or C ₃-C ₅ cycloalkyl, substituted with 0-3 R ^52a;

R ⁴⁴, when bond to C, is H, C _1-6 alkyl or C _1-6 alkoxy, substituted with 0-3 R ^42a; and

R ⁴⁵ is H, C _1-6 alkyl or C _1-6 alkoxy, substituted with 0-3 R ^42a.

In certain embodiments, R ⁴⁷ is C ₁-C ₃ alkoxy.

In certain embodiments, R ⁴⁷ is OCH ₃ or OCD ₃.

In certain embodiments, j is 0.

In certain embodiments, j is 1, and R ⁴⁶ is F or Cl.

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

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

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

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

In certain embodiments of formula (IV) , one or both of Y ¹ and Y ² is CF.

In certain embodiments of formulae (IV) - (IV ^d) , Y ³ is NR.

In certain embodiments of formulae (IV) - (IV ^d) , Y ³ is NH.

In certain embodiments of formula (IV) , the compound has the structural formula:

In certain embodiments of formulae (IV) - (IV ^k) , wherein R ⁴¹ is CH ₃.

In certain embodiments of formulae (IV) - (IV ^k) , wherein R ⁴¹ is CD ₃.

In certain embodiments of formulae (IV) - (IV ^k) , wherein R ⁴² is (C=O) R ^42b, wherein R ^42b is selected from C ₁-C ₆ alkyl, cyclopropyl or cyclobutyl, substituted with 0-2 R ^42c.

In certain embodiments, R ⁴² is (C=O) R ^42b, wherein R ^42b is cyclopropyl.

In certain embodiments R ⁴² is (C=O) R ^42b, wherein R ^42b is cyclobutyl, optionally substituted with CN.

In certain embodiments R ⁴² is (C=O) R ^42b, wherein R ^42b is C ₁-C ₆ alkyl, optionally substituted with NRR’ or OR.

In certain embodiments R ⁴² is pyridine substituted with 0-2 R ^42c.

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring B is a 5-or 6-membered aryl or heteroaryl;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁵ is selected from NR, O, CH ₂ and CF ₂;

Z ⁶ is NR ⁵⁶, CH ₂, O, S, SO or SO ₂;

R ⁵¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁵⁶ is R substituted with 0-3 R ^d;

R ⁵⁷ is H, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, OCD ₃ or OCF ₃;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

q is 0, 1, 2, 3 or 4.

In certain embodiments of formula (V) , each of Z ³, Z ⁴ and Z ⁵ is NH, having the structural formula (V ₁) :

In certain embodiments of formulae (V) - (V ₁) , wherein Ring B is a 6-membered aryl or heteroaryl.

In certain embodiments of formulae (V) - (V ₁) , the compound has the structural formula (V ₂) :

wherein each of Z ⁷ and Z ⁸ is independently CH or N.

In certain embodiments of formula (V ₂) , the compound has the structural formula (V ₃) :

wherein

R ⁵⁴ is H, a C ₁-C ₆ alkyl or C _1-6 alkoxy, CD ₃, or C ₃-C ₅ cycloalkyl, substituted with 0-3 R ^52a; and

R ⁵⁵ is H or C _1-6 alkyl or C _1-6 alkoxy, substituted with 0-3 R ^52a.

In certain embodiments of formula (V ₂) , the compound has the structural formula (V ₄) :

wherein

R ⁵⁵ is H or C _1-6 alkyl or C _1-6 alkoxy, substituted with 0-3 R ^52a.

In certain embodiments of formulae (V) - (V ₄) , Z ⁶ is O or S.

In certain embodiments of formulae (V) - (V ₄) , Z ⁶ is NR.

In certain embodiments of formulae (V) - (V ₄) , each of m and n is 1.

In certain embodiments of formulae (V) - (V ₄) , R ⁵¹ is CH ₃.

In certain embodiments of formulae (V) - (V ₄) , R ⁵¹ is CD ₃.

In certain embodiments of formulae (V) - (V ₄) , R ⁵⁷ is C ₁-C ₃ alkoxy.

In certain embodiments of formulae (V) - (V ₄) , R ⁵⁷ is OCH ₃, OCD ₃ or OCF ₃

In certain embodiments of formulae (V) - (V ₄) , q is 1 and R ⁵² is F, Cl, CN, CH ₃, CF ₃ or OCF ₃.

Non-limiting examples of compounds of the invention include:

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of X ¹ and X ² is independently selected from CH and N;

each of X ⁴ and X ⁵ is independently selected from CH, CF and N;

X ³ is NR, O, CH ₂ or CF ₂;

R ¹¹ is a H, F, C ₁-C ₃ alkyl or CD ₃;

R ¹³ is a C ₁-C ₃ alkyl, CD ₃ or CF ₃;

R at each occurrence is independently H or a C ₁-C ₆ alkyl; and

k is 0, 1, 2 or 3,

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ²¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ²² is

an aryl or heteroaryl group, each substituted with 0-2 R ^24a; or

(C=O) R ²⁷;

R ²³ is

wherein

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

p is 1 or 2,

In yet another aspect, the invention generally relates to a pharmaceutical composition comprising an amount of a compound having the structural formula of (III) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring A is a 5-or 6-membered aryl or heteroaryl;

X ¹ is selected from NR, O, CH ₂ and CF ₂;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁶ is NR ³⁶, CH ₂, O, S, SO or SO ₂;

R ³⁵ is H, F, a C ₁-C ₃ alkyl and CD ₃;

R ³⁶ is R substituted with 0-3 R ^d;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

r is 0, 1, 2, 3, 4 or 5,

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ⁴¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁴² is

an aryl or heteroaryl group substituted with 0-2 R ^42a; or

(C=O) R ^42b;

R ⁴³ is

wherein

R ⁴⁷ is H, OCF ₃, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy or OCD ₃;

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

j is 0, 1 or 2,

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring B is a 5-or 6-membered aryl or heteroaryl;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁵ is selected from NR, O, CH ₂ and CF ₂;

Z ⁶ is NR ⁵⁶, CH ₂, O, S, SO or SO ₂;

R ⁵¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁵⁶ is R substituted with 0-3 R ^d;

R ⁵⁷ is H, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, OCD ₃ or OCF ₃;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

q is 0, 1, 2, 3 or 4,

In certain embodiments, a pharmaceutical composition disclosed herein is suitable for oral administration.

In certain embodiments, a pharmaceutical composition disclosed herein is suitable for topical administration.

In certain embodiments, a pharmaceutical composition disclosed herein is suitable for GI-restricted administration.

In certain embodiments, a pharmaceutical composition disclosed herein is useful to treat or reduce one or more of inflammatory diseases, immune-mediated diseases and cancers, or a related disease or disorder. 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, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myelogenous leukemia (CML) , essential thrombocythemia (ET) , polycythemia vera (PV) , myelofibrosis (MF) , breast cancer and ovarian cancer.

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

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

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

In yet another aspect, the invention generally relates to a method 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.

In yet another aspect, the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (I) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of X ¹ and X ² is independently selected from CH and N;

each of X ⁴ and X ⁵ is independently selected from CH, CF and N;

X ³ is NR, O, CH ₂ or CF ₂;

R ¹¹ is a H, F, C ₁-C ₃ alkyl or CD ₃;

R ¹³ is a C ₁-C ₃ alkyl, CD ₃ or CF ₃;

R at each occurrence is independently H or a C ₁-C ₆ alkyl; and

k is 0, 1, 2 or 3,

In yet another aspect, the invention generally relates to a method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (II) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ²¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ²² is

an aryl or heteroaryl group, each substituted with 0-2 R ^24a; or

(C=O) R ²⁷;

R ²³ is

wherein

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

p is 1 or 2,

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring A is a 5-or 6-membered aryl or heteroaryl;

X ¹ is selected from NR, O, CH ₂ and CF ₂;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁶ is NR ³⁶, CH ₂, O, S, SO or SO ₂;

R ³⁵ is H, F, a C ₁-C ₃ alkyl and CD ₃;

R ³⁶ is R substituted with 0-3 R ^d;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

r is 0, 1, 2, 3, 4 or 5,

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ⁴¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁴² is

an aryl or heteroaryl group substituted with 0-2 R ^42a; or

(C=O) R ^42b;

R ⁴³ is

wherein

R ⁴⁷ is H, OCF ₃, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy or OCD ₃;

n is 0, 1, 2, 3 or 4;

i is 0, 1 or 2; and

j is 0, 1 or 2,

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring B is a 5-or 6-membered aryl or heteroaryl;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁵ is selected from NR, O, CH ₂ and CF ₂;

Z ⁶ is NR ⁵⁶, CH ₂, O, S, SO or SO ₂;

R ⁵¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁵⁶ is R substituted with 0-3 R ^d;

R ⁵⁷ is H, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, OCD ₃ or OCF ₃;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

q is 0, 1, 2, 3 or 4,

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 is selected from: inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myelogenous leukemia (CML) , essential thrombocythemia (ET) , polycythemia vera (PV) , myelofibrosis (MF) , breast cancer and ovarian cancer.

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

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

In certain embodiments, administration of the compound administration is via GI-restricted administration.

In certain embodiments, use of the compound is for treating one or more of inflammatory diseases, immune-mediated diseases and cancer. In certain embodiments, use of the compound is for treating an inflammatory disease. In certain embodiments, use of the compound is for treating an immune-mediated disease. In certain embodiments, use of the compound is for treating cancer. In certain embodiments, use of the compound is for treating a disease or disorder is selected from: inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myelogenous leukemia (CML) , essential thrombocythemia (ET) , polycythemia vera (PV) , myelofibrosis (MF) , breast cancer and ovarian cancer.

In certain embodiments, use of the compound is via oral administration. In certain embodiments, use of the compound is via topical administration. In certain embodiments, use of the compound is via GI restriction administration.

A list of non-limiting examples of the compounds of the invention is provided in Table #. Certain exemplary data of select compounds are provided in Table #.

As discussed herein, isotope derivative 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 presented invention.

The term “inflammatory disease” refers to a disease or condition characterized by aberrant inflammation, e.g. an increased level of inflammation compared to a control such as a healthy person not suffering from a disease. Examples of inflammatory diseases that may be treated with a compound, pharmaceutical composition, or method 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, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, auto-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. Such conditions are frequently inextricably intertwined with other diseases, disorders and conditions. A non-limiting list of inflammatory-related diseases, disorders and conditions which may, for example, be caused by inflammatory cytokines, include, arthritis, kidney failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., where inflammatory cytokines prevent healing) , anemia, and fibromyalgia. Other diseases and disorders, which may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic valve stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (IBD) , allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation and multiple sclerosis. Some of the aforementioned diseases, disorders and conditions for which a compound of the present disclosure may be particularly efficacious (due to, for example, limitations of current therapies) are described in more detail hereafter.

The term “autoimmune disease” refers to a disease or condition in which a subject's immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that may be treated with a compound, pharmaceutical composition, or method described herein include acne vulgaris, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, Aicardi-Goutières syndrome (AGS) , alopecia areata, alopecia totalis, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune aplastic anemia, autoimmune dysautonomia, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathies, balo disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) , chronic active hepatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, chronic recurrent multifocal ostomyelitis, Churg-Strauss syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST disease, Cushing's disease, demyelinating neuropathies, depression, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica) , discoid lupus, Dressler's syndrome, dry eye syndrome DES (keratoconjunctivitis sicca) , endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, 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-Barre 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 (Type 1 diabetes) , juvenile dermatomyositis (JDM) , juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease, lupus, lyme disease, chronic, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mucha-Habermann disease, multiple sclerosis (MS) , myasthenia gravis, myositis, narcolepsy, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, pediatric autoimmune neuropsychiatric disorders associated with streptococcus, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria p, Parry Romberg syndrome, Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis) , pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polycystic ovary syndrome (PCOS) , Type I, II, &III autoimmune polyglandular syndromes, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, plaque psoriasis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, pure red cell aplasia, Raynauds phenomenon, reactive Arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm &testicular autoimmunity, stiff person syndrome, stimulator of interferon genes (STING) -associated vasculopathy with onset during infancy (SAVI) , subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, systemic lupus erythematosus (SLE) , Takayasu's arteritis, temporal arteritis/Giant cell arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, transplant rejection (allograft transplant rejection) , transverse myelitis, Type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vesiculobullous dermatosis, vitiligo, or Wegener's granulomatosis.

The term “immune-mediated disease” refers to chronic inflammatory diseases perpetuated by antibodies and cellular immunity. Immune-mediated diseases include, for example, but not limited to, asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) , juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease) , endocrinopathies (e.g., type 1 diabetes and Graves’ disease) , neurodegenerative diseases (e.g., multiple sclerosis (MS) ) , autistic spectrum disorder, depression, Alzheimer's disease, Guillain-Barre syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome DES, Sjogren's syndrome, amyotrophic lateral sclerosis (ALS) , Parkinson's disease, Huntington's Disease, Guillain-Barre syndrome, myasthenia gravis, and chronic idiopathic demyelinating disease (CID) ) , 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 erthematosus, scleroderma, psoriasis, plaque psoriasis, vasculitics, vitiligo and alopecias) . Hashimoto's thyroiditis, pernicious anemia, Cushing's disease, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS) , celiac disease, pemphigus, transplant rejection (allograft transplant rejection) , graft-versus-host disease (GVDH) .

The term “cancer” as used herein refers to all types of cancer, neoplasm or malignant tumors found in mammals, e.g., humans, including hematological cancers leukemia, and lymphomas, T-ALL, large B-cell lymphoma, 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, gastric cancer, ovarian cancer, lung cancer, and cancer of the head. Exemplary cancers include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head &neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, colorectal cancer, pancreatic cancer. Additional examples include penile, skin –non-melanoma, anal, hepatobiliary, esophagogastric, uterine sarcoma, gastrointestinal stromal tumor, salivary gland, peripheral nervous system, soft tissue sarcoma, bone, renal, myeloproliferative neoplasms, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach 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 macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, 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.

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

Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an "isotopically-labeled compound" refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

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

Further, substitution of normally abundant hydrogen ( ¹H) with heavier isotopes such as deuterium can afford certain therapeutic advantages, e.g., resulting from improved absorption, distribution, metabolism and/or excretion (ADME) properties, creating drugs with improved efficacy, safety, and/or tolerability. Benefits may also be obtained from replacement of normally abundant ¹²C with ¹³C. (See, WO 2007/005643, WO 2007/005644, WO 2007/016361, and WO 2007/016431. )

Stereoisomers (e.g., cis and trans isomers) and all optical isomers of a presently disclosed compound (e.g., R and S enantiomers) , as well as racemic, diastereomeric and other mixtures of such isomers are within the scope of the present disclosure.

Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% ( “substantially pure” ) , 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 invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

Any appropriate route of administration can be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intraventricular, intracorporeal, intraperitoneal, rectal, or oral administration. 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.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof are admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (i) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (ii) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (iii) humectants, as for example, glycerol, (iv) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (v) solution retarders, as for example, paraffin, (vi) absorption accelerators, as for example, quaternary ammonium compounds, (vii) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (viii) adsorbents, as for example, kaolin and bentonite, and (ix) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like. 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.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, such as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1, 3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like. Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

Materials, compositions, and components disclosed herein can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules including in the method are discussed, each and every combination and permutation of the method, and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. Likewise, 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 a variety of additional steps that can be performed, it is understood that each of these additional steps can be performed with any specific method steps or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is specifically contemplated and should be considered disclosed.

The following examples are meant to be illustrative of the practice of the invention and not limiting in any way.

Examples

Abbreviations

Methanol: MeOH

Dichloromethane: DCM

Petroleum ether: PE

Ethyl acetate: EtOAc

Acetonitrile: ACN

Isopropanol: IPA

Triethylamine: TEA

Sodium hydroxide: NaOH

Propylphosphonic Acid Anhydride: T ₃P

Nitrogen: N ₂

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

Hours: hrs

Representative methods of prep-HPLC: Flow rate and gradient may change.

Exemplary methods for prep-HPLC are provided below.

Method A: NH ₄HCO ₃:

Column: Gilson2-Xbrige C18 19*150mm, 5μm; mobile phase: CH ₃CN in water (0.1%NH ₄HCO ₃) from 20%to 60%, flow rate: 15ml/min.

Method B: TFA:

Column: waters-Xbridge C18 10*190mm, 5μm; mobile phase: CH ₃CN in water (0.1%TFA) from 15%to 40%, flow rate: 15ml/min.

Method C: HCOOH:

Column: waters-Xbridge C18 10*190mm, 5μm; mobile phase: CH ₃CN in water (0.1%formic acid) from 15%to 40%, flow rate: 15ml/min.

Method D: HCOOH:

Column: Waters

Prep C18 OBDTM (5 micron, 19*150 mm) ; mobile phase: CH3CN in water (0.1%formic acid) from 18%to 38%, flow rate: 20 ml/min.

Representative methods of analytical-HPLC

Method 1: Analysis was performed on an Agilent 1200_series HPLC-6120MS. UHPLC Long Gradient Equivalent 5%to 95%acetonitrile (containing 0.02%NH4OAc) in water run time of 6.5 minutes with a flow rate of 1.5 mL/min. A Waters Xbridge C18 column (18.5 micron, 4.6*50 mm) was used at a temperature of 40 ℃.

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 run time of 6.5 minutes with a flow rate of 1.5 mL/min. A Waters Xbridge C18 column (18.5 micron, 4.6*50 mm) was used at a temperature of 40 ℃.

Method 3: Analysis was performed on an Agilent 1260_series HPLC-6120MS. UHPLC Long Gradient Equivalent 5%to 95%acetonitrile (containing 0.02%NH4OAc) in water run time of 2.5 minutes with a flow rate of 0.5 mL/min. A diamonsil Plus C18 column (18.5 micron, 4.6*30 mm) was used at a temperature of 40 ℃.

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

Example 1

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) portionwise at 0 ℃. After stirring for 2 hrs at RT, the mixture was diluted with EtOAc (2 L) and washed with brine (500 mL*3) . The separated organic layer was concentrated under reduced pressure to give the title compound 1b (23.2 g, 75%yield) as a brown solid. ¹H NMR (400 MHz, CDCl ₃) δ: 8.89 (br s,1H) , 8.10 (d, J = 5.6 Hz, 1H) , 7.40 (d, J = 2.4 Hz, 1H) , 7.32 (d, J = 5.6 Hz, 1H) .

Step 2. 4-Chloro-3-iodo-1, 5-dimethyl-1H-pyrrolo [3, 2-c] pyridin-5-ium (1c)

Compound 1b (2 g, 7.18 mmol) , K ₂CO ₃ (2.97 g, 21.55 mmol) and CH ₃I (5.10 g, 35.91 mmol) was dissolved in DMF (20 mL) . The mixture was stirred at RT for 16 hrs. The reaction solution was used to the next step without working up. LC-MS (Method 1) : t _R = 1.78 min, m/z (M+H) ⁺ = 307.1.

Step 3. 3-Iodo-1, 5-dimethyl-1H-pyrrolo [3, 2-c] pyridin-4 (5H) -one (1d)

To a solution of 1c in water (10 mL) and 1, 4-dioxane (10 mL) was added NaOH (1.44 g, 35.93 mmol) . After stirring for 6 hrs at RT, the reaction mixture was extracted with EtOAc (30 mL*2) . The combined organic layers were washed with brine (30 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated under reduced pressure to afford the title compound 1d (1.13 g, 55%yield) as a black solid. ¹H NMR (400 MHz, CDCl ₃) : δ 7.05 (d, J = 7.6 Hz, 1H) , 6.90 (s, 1H) , 6.27 (d, J = 7.6 Hz, 1H) , 3.68 (s, 3H) , 3.56 (s, 3H) .

Step 4. Tert-butyl (1, 5-dimethyl-4-oxo-4, 5-dihydro-1H-pyrrolo [3, 2-c] pyridin-3-yl) carbamate (1e)

Compound 1d (1.13 g, 3.92 mmol) , tert-butyl carbamate (4.60 g, 39.22 mmol) , N, N-dimethyl ethylenediamine (172.88 mg, 1.96 mmol) , CuI (373.52 mg, 1.96 mmol) and K ₃PO ₄ (1.67 g, 7.84 mmol) were dissolved in Dioxane/DMSO (2 mL, v/v = 10/1) . The resulting mixture was stirred at 90 ℃ under N ₂. The reaction was cooled down to RT, concentrated to dryness and the residue was purified by chromatography on silica gel (PE/EtOAc from 1/10 to 1/1) to give the title compound 1e (400 mg, 37%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ8.27 (s, 1H) , 7.30 (d, J = 7.2 Hz, 1H) , 7.13 (s, 1H) , 6.52 (d, J = 7.2 Hz, 1H) , 3.64 (s, 3H) , 3.43 (s, 3H) , 1.47 (s, 9H) .

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 for 2 hrs at RT. The formed solid was filtered. The filter cake was dried to give the title compound 1f (179 mg, 82%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.22 (s, 2H) , 7.45 (d, J = 7.6 Hz, 1H) , 7.27 (s, 1H) , 6.61 (d, J =7.6 Hz, 1H) , 3.71 (s, 3H) , 3.48 (s, 3H) .

Step 6. 2, 4-Dichloro-N-methylpyrimidine-5-carboxamide (1i)

To a solution of 2, 4-dichloropyrimidine-5-carbonyl chloride 1g (500 mg, 2.36 mmol) in DCM (5 mL) was added TEA (478 mg, 4.73 mmol) and Methylamine (2.36 mmol, 1.2 mL, 2M in THF) sequentially at -70 ℃. The mixture was stirred at -70 ℃ for 1 hour. The mixture was diluted with DCM (20 mL) and washed with sat. NaHCO ₃ (20 mL) . The separated organic layer was washed with brine (20 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc =3/1) to give the title compound 1i (170 mg, 35%yield) . ¹H NMR (400 MHz, CDCl ₃) : δ 8.98 (s, 1H) , 6.49 (s, 1H) , 3.07 (d, J = 4.8 Hz, 3H) .

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 (1j)

Compound1f (50 mg, 0.23 mmol) , 1i (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 ℃ for 3 hrs. The reaction mixture was cooled down to RT and concentrated to dryness. The solid was triturated with EtOAc (15 mL) . The formed solid was collected by filtering and the filter cake was dried to give the title compound 1j (51.5 mg, 63%yield) as a white solid. LC-MS (Method 3) : t _R = 1.30 min, m/z (M+H) ⁺ = 347.2.

Step 8. 2- (Cyclopropanecarboxamido) -4- ( (1, 5-dimethyl-4-oxo-4, 5-dihydro-1H-pyrrolo [3, 2-c] pyridin-3-yl) amino) -N-methylpyrimidine-5-carboxamide (1)

Compound 1j (50 mg, 0.14 mmol) , cyclopropanecarboxamide (61 mg, 0.72mmol) , BrettPhos (15 mg, 0.02 mmol) , BrettphosPdG3 (26 mg, 0.02mmol) and Cs ₂CO ₃ (94 mg, 0.29mmol) were dissolved in 1, 4-dioxane (1 mL) . The mixture was stirred at 100 ℃ for 5 hrs under N ₂. The reaction mixture was cooled down to RT and evaporated to dryness. The residue was purified by prep-HPLC (Method A) to give the title compound 1 (22.5 mg, 39%yield) . LC-MS (Method 2) : t _R = 2.52 min, m/z (M+H) ⁺ = 396.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.82 (s, 1H) , 10.86 (s, 1H) , 8.62 (d, J = 7.6 Hz, 2H) , 8.46 (d, J = 4.4 Hz, 1H) , 7.30 (d, J = 7.2 Hz, 1H) , 6.52 (d, J = 7.6 Hz, 1H) , 3.70 (s, 3H) , 3.46 (s, 3H) , 2.80 (d, J = 4.8 Hz, 3H) , 2.20 -2.17 (m, 1H) , 0.93 -0.83 (m, 4H) .

Example 2

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 consisting of 2-methoxy-3- (1-methyl-1, 2, 4-triazol-3-yl) aniline (1.4 g, 6.86 mmol) and methyl 2, 4-dichloropyrimidine-5-carboxylate 2a (1.42 g, 6.86 mmol) in IPA (20 mL) was dropwise added DIPEA (1.77 g, 13.71 mmol) . The reaction mixture was stirred at 80 ℃ overnight. After cooling to RT, the reaction mixture was diluted with water (50mL) and extracted with EtOAc (50 mL*3) . The combined organic layers were dried over Na ₂SO ₄ and filtered. The filtrate was concentrated to dryness to give the title compound 2b (1.3 g, 51%yield) as red oil. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.00 (s, 1H) , 8.87 (s, 1H) , 8.58 (s, 1H) , 8.47 (d, J = 8.0 Hz, 1H) , 7.65 (d, J = 8.8 Hz, 1H) , 7.31 (t, J = 3.8 Hz, 1H) , 3.96 (s, 3H) , 3.93 (s, 3H) , 3.81 (s, 3H) .

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 (213.46 mg, 5.34 mmol) were dissolved in THF (8 mL) and H ₂O (4 mL) . The resulting mixture was stirred at 50 ℃ for 3 hrs. The mixture was acidified with HCl (1N) to pH = 2. The formed 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) : t _R = 1.12 min, m/z (M+H) ⁺ = 361.1.

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) , trideuteromethanamine hydrochloride (127.09 mg, 1.80 mmol) , T ₃P (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 RT for 1 hour. The mixture was basified with 20%aq. Na ₂CO ₃ solution to pH>8 and extracted with EtOAc (30 mL*2) . The combined organic layers were washed with water (20 mL) and brine (20 mL) , dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated to give the title compound 2d (190 mg, 36%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.89 (s, 1H) , 8.91 (s, 1H) , 8.76 (s, 1H) , 8.57 (s, 1H) , 8.45 (d, J = 7.6 Hz, 1H) , 8.60 (d, J = 7.6 Hz, 1H) , 7.27 (t, J = 8.0 Hz, 1H) , 3.95 (s, 3H) , 3.80 (s, 3H) .

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, WO2019/121691, page 211) , DavePhos (5 mg, 0.011 mmol) , Cs ₂CO ₃ (35 mg, 0.16 mmol) and Pd ₂ (dba) ₃ (5 mg, 0.005 mmol) were dissolved in a mixture of MeTHF (1 mL) and H ₂O (0.5 mL) . The mixture was stirred at 80 ℃ for 2 hrs. After cooling to RT, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by Prep-HPLC (Method A) to afford the title compound 2 (7 mg, 28 yield) as a white solid. LC-MS (Method 1) : t _R = 2.89 min, m/z (M+H) ⁺ = 464.2. ¹H NMR (400 MHz, DMSO-d ₆) : 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 = 8.0 Hz, 1H) , 3.95 (s, 3H) , 3.78 (s, 3H) , 3.59 -3.50 (m, 1H) , 1.00 -0.85 (m, 4H) .

Example 3

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) , Cs ₂CO ₃ (70 mg, 0.216 mmol) , BINAP (13.7 mg, 0.022 mmol) and Pd (OAc) ₂ (2.5 mg, 0.011 mmol) in 1, 4-dioxane (1.2 mL) was stirred at 85 ℃ under N ₂ overnight. The mixture was cooled down to RT, then filtered through a celite pad and concentrated. The residue was purified by Prep-TLC (eluent: DCM: MeOH = 10: 1) to give the product (15 mg, 27%yield) as a light-yellow oil.

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) for 12 h at RT. The mixture was concentrated under reduced pressure to give the crude product (18 mg) as a brown-yellow solid.

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) were added methyl-d3-amine hydrochloride (8.5 mg, 0.12 mmol) , O- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) and N, N-diisopropylethylamine (31 mg, 0.24 mmol) . The mixture was stirred overnight at RT. The mixture was purified by Prep-HPLC over RP-18 (eluent: CH ₃CN in H ₂O (0.05%TFA) from 20%to 60%, v/v) to afford the title product (3.4 mg) . LC-MS: m/z (M+H) ⁺ = 468.3. ¹H NMR (400 MHz, CDCl ₃) δ 11.53 (s, 1H) , 8.31 (s, 1H) , 8.09 (s, 2H) , 7.97 (s, 1H) , 7.74 (dd, J = 7.8, 1.6 Hz, 1H) , 7.32 (d, J = 8.7 Hz, 2H) , 7.20 (t, J = 7.9 Hz, 1H) , 7.17 –7.12 (m, 2H) , 6.41 (s, 1H) , 4.05 (d, J = 0.6 Hz, 3H) , 3.83 (s, 3H) .

Example 4

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 ℃ for 2 hrs. After cooling to RT, the formed solid was filtered. The filter cake was dried to give the title compound 4b (223 mg, 66%yield) . ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.63 (s, 1H) , 8.76 (s, 1H) , 7.65 (s, 1H) , 7.39 (d, J = 6.4 Hz, 1H) , 6.60 (d, J = 7.2 Hz, 1H) , 4.42-4.39 (m, 2H) , 3.75 (s, 3H) , 3.49 (s, 3H) , 1.37 (t, J = 7.2 Hz, 3H) .

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 by utilizing similar preparative procedure of the final step of compound 2 with 4b (200 mg, 0.55 mmol) and 4-fluoroaniline (92 mg, 0.83 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.46 min, m/z (M+H) ⁺ = 437.2.

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)

Compound 4d (100 mg, 71%yield) was synthesized by utilizing similar preparative procedure of the second step of compound 2 with 4c (150 mg, 0.34 mmol) as starting materials. LC-MS (Method 3) : t _R = 0.98 min, m/z (M+H) ⁺ = 409.1.

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-d ₃) pyrimidine-5-carboxamide (4)

Compound 4d (30 mg, 0.07 mmol) , trideuteromethanamine 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 ℃ for 2 hrs and then concentrated to dryness. The residue was purified by prep-HPLC (method A) to give the title compound 4 (9.2 mg, 29%yield) . LC-MS (Method 1) : t _R = 3.31 min, m/z (M+H) ⁺ = 425.1. ¹H NMR (400 MHz, DMSO-d ₆) : 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 = 7.2 Hz, 1H) , 7.23 (t, J = 8.6 Hz, 2H) , 6.51 (d, J = 7.6 Hz, 1H) , 3.63 (s, 3H) , 3.45 (s, 3H) .

Example 5

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 (5b)

Compound 5b (230 mg, 95%yield) was synthesized by utilizing similar preparative procedure of the final step of compound 2 with 2b (200 mg, 0.53 mmol) and 5-fluoropyridin-2-amine (60 mg, 0.53 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.29 min, m/z (M+H) ⁺= 451.1.

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 (5c)

Compound 5c (222 mg, 98%yield) was synthesized by utilizing similar preparative procedure of the second step of compound 2 with 5b (230 mg, 0.51 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.06 min, m/z (M+H) ⁺ = 437.1.

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 by utilizing similar preparative procedure of the third step of compound 4 with 5c (50 mg, 0.11 mmol) and CH ₃NH ₂. HCl (15 mg, 0.22 mmol) as starting materials. LC-MS (Method 2) : t _R = 2.84 min, m/z (M+H) ⁺ = 450.0. ¹H NMR (400 MHz, CDCl ₃) : 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, 2.0 Hz, 1H) , 7.35 -7.28 (m, 1H) , 7.19 (t, J = 8.0 Hz, 1H) , 5.99 (d, J = 4.0, Hz, 1H) , 4.01 (s, 3H) , 3.89 (s, 3H) , 3.01 (d, J = 4.8 Hz, 3H) .

Example 6

Step 1. 4- (2-Methoxy-3-nitrophenoxy) tetrahydro-2H-pyran (6b)

To a solution of 2-methoxy-3-nitro-phenol (1 g, 5.91 mmol) , tetrahydropyran-4-ol (725 mg, 7.09 mmol) and triphenylphosphine (3.10 g, 11.82 mmol) in THF (20 mL) was added DIAD (2.39 g, 11.84 mmol) dropwise at 0℃. After stirring at RT overnight, the reaction mixture was diluted with EtOAc (50 mL) . The resultant mixture was washed with water (10 mL *2) and brine (10 mL) . The separated organic layer was dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc = 5: 1) to give the title compound 6b (2.25 g, 40%purity, 60%yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d ₆) : δ 7.38 (s, 1H) , 7.36 (s, 1H) , 7.26-7.22 (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) .

Step 2. 2-Methoxy-3- ( (tetrahydro-2H-pyran-4-yl) oxy) aniline (6c)

Compound 6b (2.5 g, 9.87 mmol) , Fe powder (2.76 g, 49.36 mmol) and NH ₄Cl (2.62 g, 49.36 mmol) were dissolved in a mixture of EtOH (10 mL) and H ₂O (10 mL) . The reaction solution was stirred at 80 ℃ for 2 hrs. 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 (0.9 g, 41%yield) as red oil. LC-MS (Method 3) : t _R = 1.18min, m/z (M+H) ⁺ = 224.1.

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 by utilizing similar preparative procedure of the first step of compound 2 with 6c (400 mg, 1.79 mmol) and ethyl 2, 4-dichloropyrimidine-5-carboxylate (475 mg, 2.15 mmol) as starting materials. ¹H NMR (300 MHz, DMSO-d ₆) : δ 10.91 (s, 1H) , 8.87 (s, 1H) , 8.06 (d, J = 8.4 Hz, 1H) , 7.16 (t, J = 8.4 Hz, 1H) , 6.93 (d, J = 8.4 Hz, 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 = 7.2 Hz, 3H) .

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 by utilizing similar preparative procedure of the final step of compound 1 with 6d (80 mg, 0.20 mmol) and 4-fluoroaniline (33 mg, 0.30 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.70 (s, 1H) , 9.94 (s, 1H) , 8.75 (s, 1H) , 8.01 (br s, 1H) , 7.67 (s, 2H) , 7.15 (t, J = 9.0 Hz, 2H) , 7.02 (t, J = 8.2 Hz, 1H) , 6.82 (d, J = 7.2 Hz, 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 = 7.0 Hz, 3H) .

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, 0.10mmol) in methylamine (2 mL, 2M in THF) was stirred at 80℃ for 2 days. After cooling to RT, the reaction mixture was concentrated and the residue was purified by prep-HPLC (Method A) to afford 6 (6.5 mg, 13%yield) as a white solid. LC-MS (Method 1) : t _R = 3.89 min, m/z (M+H) ⁺ = 468.2. ¹H NMR (400 MHz, DMSO-d ₆) : 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 = 8.8 Hz, 2H) , 7.00 (t, J = 8.0 Hz, 1H) , 6.76 (d, J = 7.2 Hz, 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 = 4.4 Hz, 3H) , 1.81 -1.78 (m, 4H) .

Example 7

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 by utilizing similar preparative procedure of the first step of 2 with 1i (50 mg, 0.24 mmol) and 6c (65 mg, 0.29 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.37 min, m/z (M+H) ⁺ = 393.1.

Step 2. 2- (Cyclopropanecarboxamido) -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 by utilizing similar preparative procedure of the final step of compound 1 with 7a (50 mg, 0.12 mmol) and cyclopropanecarboxamide (64 mg, 0.64 mmol) as starting materials. LC-MS (Method 1) : t _R =3.11 min, m/z (M+H) ⁺ = 442.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.56 (s, 1H) , 10.82 (s, 1H) , 8.77 (d, J = 8.4 Hz, 1H) , 8.68 (s, 1H) , 8.62 (d, J = 4.8 Hz, 1H) , 7.00 (t, J = 8.4 Hz, 1H) , 6.75 (d, J = 8.0 Hz, 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 = 4.4 Hz, 3H) , 2.33 -2.32 (m, 1H) , 2.15 -2.13 (m, 4H) , 0.87 -0.82 (m, 4H) .

Example 8

Step 1. 1- (2, 4-Dichloropyrimidin-5-yl) propan-1-ol (8b)

To a solution of 2, 4-dichloropyrimidine-5-carbaldehyde (1 g, 5.65 mmol) in THF (7 mL) was added EtMgBr (8 mL, 8.48 mmol, 1M in THF) at -55℃. After stirring at -55℃ for 4 hrs, the reaction mixture was quenched with 1N aq. HCl and extracted with EtOAc (5 mL*2) . The combined organic phase was concentrated to dryness. The residue was purified by column chromatography on silica gel (DCM/MeOH = 50/1) to afford the title compound 8b (256 mg, 22%yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.80 (s, 1H) , 4.75 -4.72 (m, 1H) , 1.74 -1.72 (m, 1H) , 1.66 -1.60 (m, 1H) , 0.90 (t, J = 7.4 Hz, 3H) .

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 by utilizing similar preparative procedure of the first step of 2 with 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. LC-MS (Method 3) : t _R = 1.38 min, m/z (M+H) ⁺ = 375.2.

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 by utilizing similar preparative procedure of the final step of 2 with 8c (60 mg, 0.16 mmol) and 4-fluoroaniline (35 mg, 0.32 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.51 min, m/z (M+H) ⁺ = 450.5.

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 solution of 8d (30 mg, 66.74 mmol) and MnO ₂ (29.01 mg, 0.33 mmol) in 1, 2-dichloroethane (2 mL) was stirred at 100℃ for 4 hrs. The reaction mixture was cooled and filtered. The filtered cake was purified by prep-HPLC (Method A) to give 8 (3 mg, 10%yield) as a white solid. LC-MS (Method 1) : t _R = 2.32 min, m/z (M+H) ⁺ = 448.2. ¹H NMR (400 MHz, DMSO-d ₆) : 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 = 7.6 Hz, 1H) , 7.17 (t, J = 8.8 Hz, 3H) , 3.96 (s, 3H) , 3.80 (s, 3H) , 3.02 (q, J = 7.2 Hz, 2H) , 1.12 (t, J = 7.2 Hz, 3H) .

Example 9

Step 1. 4-Chloro-3-iodo-1-methyl-1H-pyrrolo [3, 2-c] pyridine (9b)

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) portionwise at 0℃. 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℃ for 1 hour and then poured into water (200 mL) with stirring. The formed solid was collected by filtering and the filtered cake was dried to afford the title compound 9b (11 g, 70%yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d ₆) : 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) .

Step 2. 4-Chloro-5-ethyl-3-iodo-1-methyl-1H-pyrrolo [3, 2-c] pyridin-5-ium (9c)

Compound 9b (5 g, 17.09 mmol) and C ₂H ₅I (10 mL) were dissolved in EtOH (10 mL) in a seal tube. The resulting mixture was stirred at 80℃ for 18 hrs. After cooling to RT, the reaction mixture was cooled and concentrated to dryness. The residue was used to the next step without purification. LC-MS (Method 3) : t _R = 1.48 min, m/z (M+H) ⁺ = 321.1.

Step 3. 5-Ethyl-3-iodo-1-methyl-1H-pyrrolo [3, 2-c] pyridin-4 (5H) -one (9d)

Compound 9d (2.0 g, 40%yield) was synthesized by utilizing similar preparative procedure of the third step of compound 1 with 9c (5.4 g, 16.79 mmol) and NaOH (2.02 g, 50.38 mmol) as starting materials. ¹H NMR (300 MHz, DMSO-d ₆) : δ 7.32 (d, J = 7.5 Hz, 1H) , 7.16 (s, 1H) , 6.49 (d, J = 7.5 Hz, 1H) , 3.84 (q, J = 6.4 Hz, 2H) , 3.61 (s, 3H) , 1.12 (t, J = 6.6 Hz, 3H) .

Step 4. Tert-butyl (5-ethyl-1-methyl-4-oxo-4, 5-dihydro-1H-pyrrolo [3, 2-c] pyridin-3-yl) carbamate (9e)

Compound 9e (1.5 g, 71%yield) was synthesized by utilizing similar preparative procedure of the fourth step of compound 1 with 9d (2.19 g, 7.25 mmol) and tert-butyl carbamate (8.49 g, 72.49 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.32 (s, 1H) , 7.31 (d, J = 7.2 Hz, 1H) , 7.14 (s, 1H) , 6.54 (d, J = 7.2 Hz, 1H) , 3.92 (q, J = 7.2 Hz, 2H) , 3.65 (s, 3H) , 1.47 (s, 9H) , 1.18 (t, J = 7.2 Hz, 3H) .

Step 5. 3-Amino-5-ethyl-1-methyl-1H-pyrrolo [3, 2-c] pyridin-4 (5H) -one hydrochloride (9f)

Compound 9f (1.3 g, 83%yield) was synthesized by utilizing similar preparative procedure of the fifth step of compound 1 with 9e (2.0 g, 6.86 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.21 (br s, 3H) , 7.46 (d, J = 7.6 Hz, 1H) , 7.27 (s, 1H) , 6.53 (d, J = 7.6 Hz, 1H) , 3.97 (q, J = 7.6 Hz, 2H) , 3.71 (s, 3H) , 1.22 (t, J = 7.6 Hz, 3H) .

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 (9g)

Compound 9g (160 mg, 63%yield) was synthesized by utilizing similar preparative procedure of the sixth step of compound 2 with 9f (130 mg, 0.86 mmol) and 2, 4-dichloropyrimidine-5-carboxylate (150 mg, 0.86 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.75 (s, 1H) , 7.63 (s, 1H) , 7.39 (d, J = 7.6 Hz, 1H) , 6.58 (d, J = 7.6 Hz, 1H) , 4.40 (q, J = 7.2 Hz, 2H) , 3.97 (t, J = 7.2 Hz, 2H) , 3.75 (s, 3H) , 1.37 (t, J = 7.2 Hz, 3H) , 1.25 (t, J = 7.2 Hz, 3H) .

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 (9h)

Compound 9h (30 mg, 70%yield) was synthesized by utilizing similar preparative procedure of the seventh step of compound 1 with 9g (50 mg, 0.13 mmol) and 2, 4-difluoroaniline (35 mg, 0.26 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.57 min, m/z (M+H) ⁺ =469.3.

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 by utilizing similar preparative procedure of the final step of compound 6 with 9h (35 mg, 0.07 mmol) as starting materials. The crude product was purified by prep-HPLC (Method C) . LC-MS (Method 2) : t _R = 3.10 min, m/z (M+H) ⁺ = 454.1. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.77 (s, 1H) , 9.18 (s, 1H) , 8.49 (s, 1H) , 8.25 (dd, J = 15.2, 8.8 Hz, 1H) , 7.60 -7.58 (m, 1H) , 7.43 (t, J = 8.4 Hz, 1H) , 7.30 (d, J = 7.2 Hz, 1H) , 7.19 (t, J = 7.6 Hz, 1H) , 6.49 (d, J = 7.2 Hz, 1H) , 3.93 (q, J = 6.4 Hz, 2H) , 3.50 (s, 3H) , 2.77 (d, J = 4.4 Hz, 3H) , 1.20 (t, J = 6.8 Hz, 3H) .

Example 10

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 (10b)

Compound 9f (100 mg, 0.43 mmol) , methyl 4, 6-dichloropyridine-3-carboxylate (136 mg, 0.66 mmol) and conc. HCl (0.1 mL) were dissolved in EtOH (1 mL) . The resulting mixture was stirred at 90℃ for 4 hrs. The suspension was cooled and filtered. The filtered cake was dried to afford 10b (120 mg, 69%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ10.74 (s, 1H) , 8.66 (s, 1H) , 7.43 (s, 1H) , 7.39 (d, J = 7.2 Hz, 1H) , 7.15 (s, 1H) , 6.57 (d, J = 7.2 Hz, 1H) , 3.99 -3.89 (m, 5H) , 3.72 (s, 3H) , 1.20 (t, J = 6.8 Hz, 3H) .

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 (10c)

Compound 10c (61 mg, 56%yield) was synthesized by utilizing similar preparative procedure of the final step of compound 1 with 10b (100 mg, 0.25 mmol) and 5-fluoropyridin-2-amine (34 mg, 0.30 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : 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 = 7.2 Hz, 1H) , 7.28 (s, 1H) , 6.59 (d, J = 7.2 Hz, 1H) , 3.94 (d, J = 7.6 Hz, 2H) , 3.87 (s, 3H) , 3.78 (s, 3H) , 1.22 (t, J = 7.6 Hz, 3H) .

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 by utilizing similar preparative procedure of the final step of compound 23 with 10c (50 mg, 0.11 mmol) as starting materials. The crude product was purified by prep-HPLC (Method C) . LC-MS (Method 3) : t _R = 3.26 min, m/z (M+H) ⁺ = 436.1. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.00 (s, 1H) , 9.80 (s, 1H) , 8.39 (s, 1H) , 8.30 -8.29 (m, 1H) , 8.26 (d, J = 2.8 Hz, 1H) , 7.77 -7.74 (m, 1H) , 7.68 -7.65 (m, 2H) , 7.35 (d, J = 7.6 Hz, 1H) , 7.22 (s, 1H) , 6.55 (d, J = 7.2 Hz, 1H) , 3.94 (q, J = 7.6 Hz, 2H) , 3.76 (s, 3H) , 2.77 (d, J = 4.4 Hz, 3H) , 1.21 (t, J = 7.6 Hz, 3H) .

Example 11

Step 1. 4, 6-Dichloronicotinic acid (11b)

Methyl 4, 6-dichloropyridine-3-carboxylate (10 g, 48.54 mmol) and LiOH. H ₂O (6.12 g, 145.61 mmol) were dissolved in THF/H ₂O (100 mL, v/v = 1/1) . The mixture was stirred at RT for 2 hrs. The reaction mixture was acidified with HCl (1N) to pH<7 and extracted with EtOAc (10 mL*2) . The combined organic phase was concentrated to afford 11b (9.2 g, 99%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 13.95 (br s, 1H) , 8.82 (s, 1H) , 7.93 (s, 1H) .

Step 2. 4, 6-Dichloro-N-methylnicotinamide (11c)

Compound 11b (4.15 g, 21.61 mmol) , methanamine (1.90 g, 28.10 mmol) , DIPEA (11.17 g, 86.46 mmol) and T ₃P (27.51 g, 86.46 mmol, 50%w in DMF) were dissolved in DMF (20 mL) . The resulting mixture was stirred at RT for 8 hrs. The reaction mixture was diluted with EtOAc (60 mL) , washed with brine (30 mL) , dried over anhydrous Na ₂SO ₄ and filtered. The filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE: EtOAc = 2: 1) to give 11c (3.9 g, 88 %yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.62 (s, 1H) , 7.42 (s, 1H) , 6.38 (br s, 1H) , 3.03 (d, J = 4.4 Hz, 3H) .

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 conc. HCl (0.2 mL) were dissolved in EtOH (1 mL) and the resulting reaction mixture was stirred at 90℃ for 6 hrs. The suspension was cooled and filtered. The filtered cake was dried to afford 11d (100 mg, 52%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.81 (s, 1H) , 8.68 (d, J = 4.4 Hz, 1H) , 8.44 (s, 1H) , 7.36 (d, J = 7.6 Hz, 1H) , 7.33 (s, 1H) , 7.04 (s, 1H) , 6.53 (d, J = 7.6 Hz, 1H) , 3.71 (s, 3H) , 3.42 (s, 3H) , 2.79 (d, J = 3.6 Hz, 3H) .

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 by utilizing similar preparative procedure of the final step of compound 1 with 11d (50 mg, 0.14 mmol) and 5-fluoropyridin-2-amine (24 mg, 0, 21 mmol) as starting materials. LCMS (Method 1) : t _R = 3.01 min, m/z (M+H) ⁺ =422.2. ¹H NMR (400 MHz, DMSO-d ₆) : 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 = 7.6 Hz, 1H) , 7.21 (s, 1H) , 6.52 (d, J = 7.6 Hz, 1H) , 3.75 (s, 3H) , 3.44 (s, 3H) , 2.77 (d, J = 4.4 Hz, 3H) .

Example 12

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 by utilizing similar preparative procedure of the final step of compound 1 with 11d (50 mg, 0.14 mmol) and cyclopropanecarboxamide (61 mg. 0.72 mmol) as starting materials. LCMS (Method 1) : t _R =2.18 min, m/z (M+H) ⁺ = 395.1. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.88 (s, 1H) , 10.73 (s, 1H) , 8.42 -8.40 (m, 2H) , 7.98 (s, 1H) , 7.34 (d, J = 7.2 Hz, 1H) , 7.01 (s, 1H) , 6.51 (d, J = 7.2 Hz, 1H) , 3.68 (s, 3H) , 3.42 (s, 3H) , 2.78 (d, J = 4.4 Hz, 3H) , 2.02 -2.00 (m, 1H) , 0.83 -0.79 (m, 4H) .

Example 13

Step 1. 6-Chloro-4- ( (2-methoxy-3- ( (tetrahydro-2H-pyran-4-yl) oxy) phenyl) amino) -N-methylnicotinamide (13b)

Compound 13b (8.6 mg, 35%yield) was synthesized by utilizing similar preparative procedure of the final step of compound 1 with 6c (200 mg, 0.90 mmol) and 11c (202 mg, 0.99 mmol) as starting materials. (Method 3) : t _R = 1.49 min, m/z (M+H) ⁺ = 392.3.

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 by utilizing similar preparative procedure of the final step of compound 1 with 13b (70 mg, 0.18 mmol) and cyclopropanecarboxamide (76 mg, 0.90 mmol) as starting materials. LCMS (Method 1) : t _R =3.24 min, m/z (M+H) ⁺ = 441.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.70 (s, 1H) , 10.40 (s, 1H) , 8.54 (d, J = 4.4 Hz, 1H) , 8.45 (s, 1H) , 8.04 (s, 1H) , 7.08 -7.00 (m, 2H) , 6.81 (d, J = 7.6 Hz, 1H) , 4.24 -4.20 (m, 1H) , 3.82 -3.80 (m, 5H) , 3.30 -3.24 (m, 2H) , 2.78 (d, J = 4.4 Hz, 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) .

Example 14

Step 1. 4-Chloro-7-fluoro-3-iodo-1-methyl-1H-pyrrolo [3, 2-c] pyridine (14b)

To a mixture of 4-chloro-7-fluoro-1H-pyrrolo [3, 2-c] pyridine (450 mg, 2.64 mmol) and KOH (296 mg, 5.28 mmol) in DMF (5 mL) was added I ₂ (668 mg, 2.64 mmol) at 0 ℃. After stirring at this temperature for 1 hour, CH ₃I (418 mg, 2.95 mmol) was added to the reaction mixture. The black reaction mixture was stirred at 0 ℃ for 1 hour. The mixture was poured into ice-water (30 mL) and the formed solid was filtered. The filtered cake was dried to afford 14b (550 mg, 72%yield) as a brown solid. ¹H NMR (300 MHz, CDCl ₃) : δ 7.97 (d, J = 3.0 Hz, 1H) , 7.24 (s, 1H) , 4.05 (s, 3H) .

Step 2. 4-Chloro-7-fluoro-3-iodo-1, 5-dimethyl-1H-pyrrolo [3, 2-c] pyridin-5-ium (14c)

Compound 14c (570 mg, yield given) was synthesized by utilizing similar preparative procedure of the second step of compound 1 with 14b (550 mg, 1.77 mmol) as starting material. LC-MS (Method 3) : t _R = 1.13 min, m/z (M) ⁺ = 325.1.

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 by utilizing similar preparative procedure of the second step of compound 1 with 14c (570 mg, 1.75 mmol) as starting material. ¹H NMR (400 MHz, DMSO-d ₆) : 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) .

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 by utilizing similar preparative procedure of the fourth step of compound 1 with 14d (230 mg, 0.75 mmol) and tert-butyl carbamate (880 mg, 7.51 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 8.35 (s, 1H) , 7.53 (d, J = 8.0 Hz, 1H) , 7.23 (s, 1H) , 3.80 (s, 3H) , 3.38 (s, 3H) , 1.47 (s, 9H) .

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 by utilizing similar preparative procedure of the fifth step of compound 1 with 14e (110 mg, 0.37 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.10 (brs, 2H) , 7.69 (d, J = 8.0 Hz, 1H) , 7.33 (s, 1H) , 3.86 (s, 3H) , 3.42 (s, 3H) .

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 (14g)

Compound 14g (68 mg, 46%yield) was synthesized by utilizing similar preparative procedure of the seventh step of compound 1 with 14f (80 mg, 0.41 mmol) and 11c (126 mg, 0.61 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.32 min, m/z (M+H) ⁺ = 364.3.

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 by utilizing similar preparative procedure of the final step of compound 1 with 14g (50 mg, 0.14 mmol) and cyclopropanecarboxamide (47 mg, 0.55 mmol) as starting materials. LC-MS (Method 1) : t _R =2.69 min, m/z (M+H) ⁺ = 413.1. ¹H NMR (400 MHz, DMSO-d ₆) : 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 = 8.0 Hz, 1H) , 7.10 (s, 1H) , 3.84 (s, 3H) , 3.59 (s, 3H) , 2.78 (d, J = 4.4 Hz, 3H) , 2.03 -2.11 (m, 1H) , 0.85 -0.88 (m, 4H) .

Example 15

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 by utilizing similar preparative procedure of the four step of compound 1 with 3-bromo-5-methyl-thieno [3, 2-c] pyridin-4-one (300 mg, 1.23 mmol) and tert-butyl carbamate (719 mg, 6.14 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 9.88 (s, 1H) , 7.58 (d, J = 7.2 Hz, 1H) , 7.38 (s, 1H) , 6.94 (d, J =7.2 Hz, 1H) , 3.50 (s, 3H) , 1.49 (s, 9H) .

Step 2. 3-Amino-5-methylthieno [3, 2-c] pyridin-4 (5H) -one hydrochloride (15c)

Compound 15c (71 mg, yield given) was synthesized by utilizing similar preparative procedure of the fifth step of compound 1 with 15b (59 mg, 0.33 mmol) as starting material. LCMS (Method 3) : t _R = 1.15min, m/z (M+H) ⁺ = 181.2.

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 conc. HCl (0.2 mL) was stirred overnight at 80℃. After cooling to RT, the formed solid was filtered and the filtered cake was dried to afford 15d (60 mg, 53%yield) as a yellow solid.

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 by utilizing similar preparative procedure of the final step of compound 1 with 15d (50 mg, 0.14 mmol) and 5-fluoropyridin-2-amine (48 mg, 0.43 mmol) as starting materials. LCMS (Method 1) : t _R = 3.34 min, m/z (M+H) ⁺= 425.1. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.44 (s, 1H) , 9.84 (s, 1H) , 8.40 (s, 1H) , 8.33 (d, J =4.4 Hz, 1H) , 8.24 (d, J = 2.8 Hz, 1H) , 7.99 (s, 1H) , 7.78 (dd, J = 8.8, 3.6 Hz, 1H) , 7.65 (td, J =8.4, 2.8 Hz, 1H) , 7.58 (d, J = 7.6 Hz, 1H) , 7.20 (s, 1H) , 6.87 (d, J = 7.6 Hz, 1H) , 3.52 (s, 3H) , 2.77 (d, J = 4.4 Hz, 3H) .

Example 16

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 by utilizing similar preparative procedure of the final step of compound 1 with 15d (50 mg, 0.14 mmol) and cyclopropanecarboxamide (85 mg, 0.61 mmol) as starting materials. LCMS (Method 1) : t _R =3.07 min, m/z (M+H) ⁺ = 398.1. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.44 (s, 1H) , 10.85 (s, 1H) , 8.45 (s, 2H) , 8.40 (s, 1H) , 7.58 (d, J = 7.6 Hz, 1H) , 7.05 (s, 1H) , 6.85 (d, J = 7.6 Hz, 1H) , 3.50 (s, 3H) , 2.77 (d, J = 4.8 Hz, 3H) , 2.12 -1.99 (m, 1H) , 0.83 -0.80 (m, 4H) .

Example 17

Step 1. 3-Bromo-5-ethylthieno [3, 2-c] pyridin-4 (5H) -one (17b)

To a solution of 3-bromo-5H-thieno [3, 2-c] pyridin-4-one (1 g, 4.35 mmol) in DMF (10 mL) was added NaH (149.88 mg, 6.52 mmol, 60%in mineral oil) at 0℃. The resulting mixture was stirred at RT for 0.5h. Then EtI (813.15 mg, 5.22 mmol) was added to the mixture. After stirring at RT overnight, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (50 mL*2) . The combined organic layer was dried over Na ₂SO ₄ _, filtered and evaporated under vacuum. The crude product was purified by silica gel flash column chromatography (PE: EtOAc = 4: 1) to afford 17b (810 mg, 72%) as black oil. LCMS (Method 3) : t _R = 1.43 min, m/z (M+H) ⁺ = 260.1.

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 by utilizing similar preparative procedure of the fourth step of compound 1 with 17b (620 mg, 2.40 mmol) and tert-butyl carbamate (2.81 g, 24.02 mmol) as starting materials. LCMS (Method 3) : t _R = 1.70 min, m/z (M+H) ⁺ = 295.3.

Step 3. 3-Amino-5-ethylthieno [3, 2-c] pyridin-4 (5H) -one hydrochloride (17d)

Compound 17d (390 mg, yield given) was synthesized by utilizing similar preparative procedure of the fifth step of compound 1 with 17c (500 mg, 1.7 mmol) as starting material. LCMS (Method 3) : t _R = 1.31 min, m/z (M+H) ⁺ = 195.1.

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 by utilizing similar preparative procedure of the seventh step of compound 1 with 17d (200 mg, 1.03 mmol) and 11c (316 mg, 1.54 mmol) as starting materials. LCMS (Method 3) : t _R = 1.31 min, m/z (M+H) ⁺ = 363.0.

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 by utilizing similar preparative procedure of the final step of compound 1 with 17e (60 mg, 0.17 mmol) and cyclopropanecarboxamide (28 mg, 0.33 mmol) as starting materials. LCMS (Method 1) : t _R =3.28 min, m/z (M+H) ⁺ = 412.1. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.45 (s, 1H) , 10.85 (s, 1H) , 8.46 (s, 2H) , 8.42 (s, 1H) , 7.61 (d, J = 7.2 Hz, 1H) , 7.08 (s, 1H) , 6.91 (d, J = 7.2 Hz, 1H) , 4.02 (q, J = 6.4 Hz, 2H) , 2.80 (d, J = 4.4 Hz, 3H) , 2.02 -1.98 (m, 1H) , 1.27 (t, J = 6.8 Hz, 3H) , 0.85 -0.82 (m, 4H) .

Example 18

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 (3.5mg, 5%yield) was synthesized by utilizing similar preparative procedure of the final step of compound 1 with 17e (60 mg, 0.17 mmol) and 5-fluoropyridin-2-amine (37 mg, 0.33 mmol) as starting materials. LCMS (Method 1) : t _R = 2.99 min, m/z (M+H) ⁺=439.1. ¹H NMR (400 MHz, DMSO-d ₆) : 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 = 9.2 Hz, 1H) , 4.04 (q, J =6.4 Hz, 2H) , 2.81 (d, J = 4.4 Hz, 3H) , 1.29 (t, J = 6.8 Hz, 3H) .

Example 19

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 by utilizing similar preparative procedure of the final step of compound 1 with 2d (20 mg, 0.05 mmol) and 3-aminobenzonitrile (7 mg, 0.05 mmol) as starting materials. LCMS (Method 2) : t _R = 4.10 min, m/z (M+H) ⁺ = 459.2. ¹H NMR (400 MHz, DMSO-d ₆) : 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 = 8.4 Hz, 1H) , 7.54 -7.42 (m, 3H) , 7.22 (t, J = 8.0 Hz, 1H) , 3.95 (s, 3H) , 3.79 (s, 3H) .

Example 20

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 above reaction was stirred at 60 ℃ for 3 days. The mixture was cooled, diluted with H ₂O (5 mL) and extracted with EtOAc (5 mL) . The organic layer was concentrated to dryness. The residue was purified by prep-HPLC (method A) to give 20 (1.4 mg, 2%yield) as a white solid. LCMS (Method 1) : t _R = 3.77 min, m/z (M+H) ⁺ =452.3. ¹H NMR (400 MHz, DMSO-d ₆) : 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, 4.4 Hz, 1H) , 7.17 -7.12 (m, 3H) , 3.94 (s, 3H) , 3.78 (s, 3H) .

Example 21

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 by utilizing similar preparative procedure of the final step of compound 1 with 2d (40 mg, 0.01 mmol) and 6-aminopicolinonitrile (25 mg, 0.02 mmol) as starting materials. LCMS (Method 1) : t _R = 3.44 min, m/z (M+H) ⁺ = 460.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.82 (s, 1H) , 10.63 (s, 1H) , 8.84 (d, J =8.4 Hz, 1H) , 8.72 (s, 1H) , 8.59 (s, 1H) , 8.55 (s, 1H) , 8.44 (d, J = 8.4 Hz, 1H) , 7.95 (t, J = 8.0 Hz, 1H) , 7.63 (dd, J = 7.6 Hz, 1H) , 7.51 (t, J = 7.6, 1.2 Hz, 1H) , 7.22 (t, J = 7.6 Hz, 1H) , 3.95 (s, 3H) , 3.79 (s, 3H) .

Example 22

Step 1. 3- (2-Methoxy-5-methyl-3-nitrophenyl) -1-methyl-1H-1, 2, 4-triazole (22b)

Compound 2- (2-methoxy-5-methyl-3-nitrophenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane 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 ₂-CH ₂Cl ₂ (2.16 g, 2.64 mmol) and K ₂CO ₃ (21.88 g, 158.53 mmol) were mixed in 1, 4-dioxane (160 mL) and H ₂O (16 mL) . The above reaction was stirred at 110 ℃ for 2 hrs. The mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL*2) . The combined organic layers were concentrated to dryness. The residue was purified by flash chromatography on silica gel (PE/EtOAc from 3/1 to EtOAc) to give the title compound 22b (8.3 g, 63%yield) as a brown solid. ¹H NMR (400 MHz, CDCl ₃) : δ 8.12 (s, 1H) , 8.02 (d, J = 2.0 Hz, 1H) , 7.60 (d, J = 1.6 Hz, 1H) , 4.02 (s, 3H) , 3.91 (s, 3H) , 2.42 (s, 3H) .

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 ₄ (20 mL) were added BPO (199 mg, 3.22 mmol) and NBS (1.58 g, 8.86 mmol) . The mixture was irradiated for 16 hours. The mixture was diluted with H ₂O (50 mL) and extracted with DCM (100 mL*3) . The combined organic layers were dried over Na ₂SO ₄ and filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc = 2/1) to give the title compound 22c (1.1 g, 42%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) : δ 8.27 (d, J = 2.0 Hz, 1H) , 8.16 (s, 1H) , 7.84 (d, J = 2.0 Hz, 1H) , 4.51 (s, 2H) , 4.04 (s, 3H) , 3.95 (s, 3H) .

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) was stirred at RT overnight. The mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel (DCM/MeOH = 10/1) to give the title compound 22d (500 mg, 45%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) : δ 8.17 (d, J = 2.0 Hz, 1H) , 8.13 (s, 1H) , 7.81 (d, J = 2.0 Hz, 1H) , 4.02 (s, 3H) , 3.92 (s, 3H) , 3.83 (s, 2H) , 2.47 (s, 3H) .

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)

Compound22d (128 mg, 0.46 mmol) , tert-butyl (3- (bromomethyl) phenyl) carbamate (139 mg, 0.48 mmol) and K ₂CO ₃ (191 mg, 1.38 mmol) were dissolved in ACN (3 mL) . The above mixture was stirred at RT for 16 hrs. The mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc = 2/1) to give the title compound 22e (160 mg, 72%yield) as yellow oil. LC-MS (Method 3) : t _R= 1.67 min, m/z (M+H) ⁺ = 483.3.

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 by utilizing similar preparative procedure of the second step of compound 6 with 22e (160 mg, 0.33 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.49 min, m/z (M+H) ⁺ = 453.3.

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)

Compound 22g (144 mg, 66%yield) was synthesized by utilizing similar preparative procedure of the first step of compound 2 with 22f (156 mg, 0.35 mmol) and ethyl 2, 4-dichloropyrimidine-5-carboxylate (80 mg, 0.36 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.77 min, m/z (M+H) ⁺ = 637.6.

Step 7. Ethyl 10-methoxy-15-methyl-11- (1-methyl-1, 2, 4-triazol-3-yl) -2, 4, 8, 15, 23-pentazatetracyclo [15.3.1.13, 7.19, 13] tricosa-1 (21) , 3 (23) , 4, 6, 9, 11, 13 (22) , 17, 19-nonaene-6-carboxylate (22h)

Compound22g (124 mg, 0.19 mmol) was dissolved in a mixture of HCl (g) in 1, 4-dioxane (40 mL, 2.0 M) . The above reaction was stirred at 60 ℃ for 2 hrs. The mixture was concentrated to give the title compound 22h (120 mg, purity 40%, 46%yield) as yellow oil. LC-MS (Method 3) : t _R = 1.56 min, m/z (M+H) ⁺ = 501.5.

Step 8. 10-Methoxy-N, 15-dimethyl-11- (1-methyl-1, 2, 4-triazol-3-yl) -2, 4, 8, 15, 23-pentazatetracyclo [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 ℃ for 18 hrs. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (Method A) to give the title compound 22 (11 mg, 9%yield) as a yellow solid. LC-MS (Method 2) : t _R = 2.53 min, m/z (M+H) ⁺ = 486.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.70 (s, 1H) , 9.73 (s, 1H) , 8.86 (d, J = 1.6 Hz, 1H) , 8.68 (s, 1H) , 8.54 (s, 1H) , 8.47 -8.44 (m, 2H) , 7.37 (d, J = 2.0 Hz, 1H) , 7.21 (t, J = 8.0 Hz, 1H) , 7.02 (d, J = 8.0 Hz, 1H) , 6.92 (d, J = 7.6 Hz, 1H) , 3.94 (s, 3H) , 3.78 (s, 3H) , 3.50 (s, 2H) , 3.42 (s, 2H) , 2.80 (d, J = 4.4 Hz, 3H) , 2.40 (s, 3H) .

Example 23

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 by utilizing similar preparative procedure of the sixth step of compound 1 with 9f (150 mg, 0.66 mmol) and methyl 4, 6-dichloropyridazine-3-carboxylate (136 mg, 0.66 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.22 min, m/z (M+H) ⁺ = 362.1.

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 a solution of methanamine (2.0 M) in THF (5 ml) . The reaction mixture was stirred at RT for 2 hrs. The reaction was washed with water (5 mL) and extracted with EtOAc (10 mL*3) . The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford the title compound 23b (80 mg, 80%yield) . LC-MS (Method 3) : t _R = 1.25 min, m/z (M+H) ⁺ = 361.1.

Step 3. 6- (Cyclopropanecarboxamido) -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 by utilizing similar preparative procedure of the final step of compound 1 with 23b (20 mg, 0.06 mmol) and cyclopropanecarboxamide (24 mg, 0.28 mmol) as starting materials. LC-MS (Method 1) : t _R =3.12 min, m/z (M+H) ⁺ = 410.1. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.27 (s, 2H) , 8.98 (s, 1H) , 8.08 (d, J = 4.8 Hz, 1H) , 7.38 (d, J = 7.6 Hz, 1H) , 7.06 (s, 1H) , 6.58 -6.55 (m, 1H) , 3.92 (q, J =7.2 Hz, 2H) , 3.71 (s, 3H) , 2.85 (d, J = 4.4 Hz, 3H) , 2.11 -2.08 (m, 1H) , 1.23 (t, J = 7.2 Hz, 3H) , 0.95 -0.73 (m, 4H) .

Example 24

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 by utilizing similar preparative procedure of the sixth step of compound 1 with 8-amino-2-methylisoquinolin-1 (2H) -one (240 mg, 1.38 mmol, Advanced Synthesis and Catalysis, 2018, 360, 379 -384) and methyl 4, 6-dichloropyridazine-3-carboxylate (342 mg, 1.65 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 12.39 (s, 1H) , 7.78 (s, 1H) , 7.69 -7.63 (m, 2H) , 7.53 (d, J = 8.4 Hz, 1H) , 7.39 (dd, J = 2.0, 6.8 Hz, 1H) , 6.67 (d, J = 7.2 Hz, 1H) , 4.00 (s, 3H) , 3.50 (s, 3H) .

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, purity 50%) was synthesized by utilizing similar preparative procedure of the second step of compound 23 with 24b (80 mg, 0.23 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.39 min, m/z (M+H) ⁺ = 344.8.

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 by utilizing similar preparative procedure of the final step of compound 1 with 24c (50 mg, 0.15 mmol) and cyclopropanecarboxamide (25 mg, 0.29 mmol) as starting materials. LC-MS (Method 1) : t _R =3.64 min, m/z (M+H) ⁺ = 393.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 12.40 (s, 1H) , 11.31 (s, 1H) , 8.95 -8.92 (m, 1H) , 8.48 (s, 1H) , 7.62 -7.58 (t, 1H) , 7.52 (d, J = 8.0 Hz, 1H) , 7.48 (d, J = 6.8 Hz, 1H) , 7.30 (d, J = 7.6 Hz, 1H) , 6.60 (d, J = 7.2 Hz, 1H) , 3.47 (s, 3H) , 2.85 (d, J = 4.8 Hz, 3H) , 2.09 -2.05 (m, 1H) , 0.87 -0.80 (m, 4H) .

Example 25

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 by utilizing similar preparative procedure of the sixth step of compound 1 with 6c (450 mg, 2.02 mmol) and methyl 4, 6-dichloropyridazine-3-carboxylate (500 mg, 2.42 mmol) as starting materials. ¹H NMR (400 MHz, CDCl ₃) : δ 9.82 (s, 1H) , 7.14 -7.10 (m, 2H) , 6.92 (d, J = 8.0 Hz, 1H) , 6.86 (d, J = 7.6 Hz, 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) .

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 by utilizing similar preparative procedure of the second step of compound 23 with 25a (100 mg, 0.25 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.58 min, m/z (M+H) ⁺ = 393.4.

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 by utilizing similar preparative procedure of the final step of compound 1 with 25b (45 mg, 0.11 mmol) and 5-fluoropyridin-2-amine (39 mg, 0.34 mmol) as starting materials. LC-MS (Method 1) : t _R = 3.85 min, m/z (M+H) ⁺= 469.2. ¹H NMR (400 MHz, DMSO-d ₆) : 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 =4.8 Hz, 3H) , 1.82 -1.77 (m, 2H) , 1.69 -1.60 (m, 2H) .

Example 26

Step 1. Methyl 6-chloro-4- ( (1, 5-dimethyl-4-oxo-4, 5-dihydro-1H-pyrrolo [3, 2-c] pyridin-3-yl) amino) pyridazine-3-carboxylate (26a)

Compound 26a (300 mg, 59%yield) was synthesized by utilizing similar preparative procedure of the sixth step of compound 1 with 1f (314 mg, 1.47 mmol) and methyl 4, 6-dichloropyridazine-3-carboxylate (365 mg, 1.76 mmol) as starting materials. ¹H NMR (400 MHz, CDCl ₃) : δ 11.15 (br s, 1H) , 7.18 (s, 1H) , 7.07 (d, J = 7.6 Hz, 1H) , 6.86 (s, 1H) , 6.29 (d, J =7.6 Hz, 1H) , 4.11 (s, 3H) , 3.75 (s, 3H) , 3.61 (s, 3H) .

Step 2. 6-Chloro-4- ( (1, 5-dimethyl-4-oxo-4, 5-dihydro-1H-pyrrolo [3, 2-c] pyridin-3-yl) amino) -N-methylpyridazine-3-carboxamide (26b)

Compound 26b (210 mg, 70%yield) was synthesized by utilizing similar preparative procedure of the second step of compound 23 with 26a (300 mg, 0.86 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.26 min, m/z (M+H) ⁺ = 347.0.

Step 3. 6- (Cyclopropanecarboxamido) -4- ( (1, 5-dimethyl-4-oxo-4, 5-dihydro-1H-pyrrolo [3, 2-c] pyridin-3-yl) amino) -N-methylpyridazine-3-carboxamide (26)

Compound 26 (7 mg, 12%yield) was synthesized by utilizing similar preparative procedure of the final step of compound 1 with 26b (50 mg, 0.14 mmol) and cyclopropanecarboxamide (61 mg, 0.72 mmol) as starting materials. LC-MS (Method 1) : t _R =3.09 min, m/z (M+H) ⁺ = 396.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.30 -11.22 (m, 2H) , 8.98 -8.93 (m, 1H) , 8.07 (s, 1H) , 7.37 (d, J = 7.2 Hz, 1H) , 7.06 (s, 1H) , 6.54 (d, J = 7.6 Hz, 1H) , 3.71 (s, 3H) , 3.42 (s, 3H) , 2.84 (d, J = 3.6 Hz, 3H) , 2.11 -2.07 (m, 1H) , 0.88 -0.84 (m, 4H) .

Example 27

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 by utilizing similar preparative procedure of the sixth step of compound 1 with 15c (150 mg, 0.83 mmol) and methyl 4, 6-dichloropyridazine-3-carboxylate (258 mg, 1.25 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.50 (s, 1H) , 7.81 (s, 1H) , 7.67 -7.65 (m, 2H) , 6.96 (d, J = 7.6 Hz, 1H) , 4.01 (s, 3H) , 3.54 (s, 3H) .

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 by utilizing similar preparative procedure of the final step of compound 1 with 27a (150 mg, 0.43 mmol) and cyclopropanecarboxamide (73 mg, 0.86 mmol) as starting materials. LC-MS (Method 3) : t _R =1.36 min, m/z (M+H) ⁺ = 400.2.

Step 3. 6- (Cyclopropanecarboxamido) -4- ( (5-methyl-4-oxo-4, 5-dihydrothieno [3, 2-c] pyridin-3-yl) amino) pyridazine-3-carboxylic acid (27c)

Compound 27c (28 mg, 97%yield) was synthesized by utilizing similar preparative procedure of the second step of compound 2 with 27b (30 mg, 0.08 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.04 min, m/z (M+H) ⁺ = 386.1.

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)

Compound 27 (1.2 mg, 4%yield) was synthesized by utilizing similar preparative procedure of the third step of compound 2 with 27c (28 mg, 0.07 mmol) and methanamine hydrochloride (15 mg, 0.22 mmol) as starting materials. LC-MS (Method 1) : t _R = 3.03 min, m/z (M+H) ⁺ = 399.1. ¹H NMR (400 MHz, CD ₃OD) : δ 8.62 (s, 1H) , 7.47 (d, J = 7.2 Hz, 1H) , 7.23 (s, 1H) , 6.85 (d, J = 6.8 Hz, 1H) , 5.15 (s, 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) .

Example 28

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) , Cs ₂CO ₃ (87 mg, 0.266 mmol) , BINAP (16.2 mg, 0.026 mmol) and Pd (OAc) ₂ (2.9 mg, 0.013 mmol) in 1, 4-dioxane (1.4 mL) was stirred at 85 ℃ under N ₂ overnight. The mixture was cooled down to RT, then filtered through a celite pad and concentrated. The residue was concentrated and purified by Prep-TLC (eluent: DCM: MeOH = 10: 1) give the product (21 mg, 35%yield) as a brown-yellow oil.

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 mixture 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) for 12 h at RT. The mixture was concentrated under reduced pressure to give the crude product (27 mg) as a brown-yellow solid.

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) were addedmethyl-d3-amine hydrochloride (13 mg, 0.18 mmol) , O- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluroniumxafluorophosphate (70 mg, 0.18 mmol) and N, N-diisopropylethylamine (47 mg, 0.36 mmol) . The mixture was stirred overnight at RT. The mixture was purified by Prep-HPLC over RP-18 (eluent: CH ₃CN in H ₂O (0.05%TFA) from 20%to 60%, v/v) to afford the title product (8.5 mg) . LC-MS: m/z (M+H) ⁺ = 459.3. ¹H NMR (400 MHz, DMSO-d ₆) δ 11.76 (s, 1H) , 10.17 (s, 1H) , 8.72 (s, 1H) , 8.56 (d, J = 2.8 Hz, 3H) , 8.02 –7.85 (m, 2H) , 7.75 –7.67 (m, 2H) , 7.57 (dd, J = 7.8, 1.7 Hz, 1H) , 7.26 (t, J = 8.0 Hz, 1H) , 3.95 (s, 3H) , 3.79 (s, 3H) .

Example 29

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 stirred mixture of 3-amino-5-methylthieno [3, 2-c] pyridin-4 (5H) -one 29a (30 mg, 0.167 mmol) and methyl 2, 4-dichloropyrimidine-5-carboxylate (37 mg, 0.184 mmol) in THF (0.8 mL) was added N, N-diisopropylethylamine (43 mg, 0.334 mmol) at RT. The mixture was stirred for 6 h at RT. The mixture was concentrated and purified by Prep-TLC (eluent: PE: EtOAc = 1: 4) to give the product (16 mg, 27%yield) as a light-yellow solid.

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, 0.11mmol) , Cs ₂CO ₃ (59 mg, 0.182 mmol) , BINAP (16.2 mg, 0.026 mmol) and Pd (OAc) ₂ (2.9 mg, 0.013 mmol) in 1, 4-dioxane (1.0 mL) was stirred at 85 ℃ under N ₂ overnight. The mixture was cooled down to RT, then filtered through a celite pad and concentrated. The residue was concentrated and purified by Prep-TLC (eluent: DCM: MeOH = 10: 1) give the product (30 mg, 77%yield) as a brown-yellow oil.

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 mixture of 29c (30 mg, 0.07 mmol) in THF (0.6 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (8 mg, 0.21mmol) for 12 h at RT. The mixture was concentrated under reduced pressure to give the crude product (35 mg) as a brown-yellow solid.

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) were addedmethyl-d3-amine hydrochloride (17 mg, 0.24 mmol) , O- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluroniumxafluorophosphate (91 mg, 0.24 mmol) and N, N-diisopropylethylamine (62 mg, 0.48 mmol) . The mixture was stirred overnight at RT. The mixture was purified by Prep-HPLC over RP-18 (eluent: CH ₃CN in H ₂O (0.05%TFA) from 20%to 60%, v/v) to afford the title product (2.7 mg) . LC-MS: m/z (M+H) ⁺ = 428.1. ¹H NMR (400 MHz, DMSO-d ₆) δ 12.46 (s, 1H) , 9.67 (s, 1H) , 8.56 (s, 1H) , 8.30 (s, 1H) , 7.71 (s, 2H) , 7.58 (d, J = 7.1 Hz, 1H) , 7.19 (d, J =8.8 Hz, 3H) , 6.88 (d, J = 7.1 Hz, 1H) , 4.52 (s, 1H) , 3.53 (s, 3H) .

Example 32

Step 1. Tert-butyl (6- ( ( (4-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) -5-nitrobenzyl) (methyl) amino) methyl) pyridin-2-yl) carbamate (32a)

To a solution of (6- ( (tert-butoxycarbonyl) amino) pyridin-2-yl) methyl methanesulfonate (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 ℃. The reaction mixture was stirred at RT overnight. The mixture was concentrated. The residue was purified by column chromatography on silica gel (DCM/MeOH = 30/1) to afford the title compound 32a (213 mg, 33%yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d ₆) : δ 9.62 (s, 1H) , 8.63 (s, 1H) , 8.22 (d, J = 2.0 Hz, 1H) , 7.89 (d, J = 2.0 Hz, 1H) , 7.71 -7.64 (m, 2H) , 7.11 (d, J = 6.4 Hz, 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) .

Step 2. 6- ( ( (3-Amino-4-methoxy-5- (1-methyl-1H-1, 2, 4-triazol-3-yl) benzyl) (methyl) amino) methyl) pyridin-2-amine (32b)

Compound 32b (300 mg, purity 35%, 62%yield) was synthesized by utilizing similar preparative procedure of the second step of compound 6 with 32a (230 mg, 0.48 mmol) as starting material. LC-MS (Method 3) : t _R = 1.12 min, m/z (M+H) ⁺ = 354.2.

Step 3. 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 (32c)

Compound 32c (45 mg, 24%yield) was synthesized by utilizing similar preparative procedure of the seventh step of compound 1 with 32b (270 mg, purity 60%, 0.36 mmol) and methyl 4, 6-dichloropyridazine-3-carboxylate (89 mg, 0.43 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : 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 (br s, 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) .

Step 4. 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 (32d)

Compound 32d (25 mg, 83%yield) was synthesized by utilizing similar preparative procedure of the sixth step of compound 23 with 32c (30 mg, 0.06 mmol) and methylamine (2.36 mmol, 1.2 mL, 2M in THF) as starting materials. LC-MS (Method 3) : t _R = 1.27 min, m/z (M+H) ⁺= 523.5.

Step 5. 10-Methoxy-N, 15-dimethyl-11- (1-methyl-1, 2, 4-triazol-3-yl) -2, 4, 5, 8, 15, 21-hexazatetracyclo [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 32d (25 mg, 0.05 mmol) , BrettPhos (3 mg, 0.005 mmol) , BrettPhosPdG ₃ (4 mg, 0.005 mmol) and Cs ₂CO ₃ (47 mg, 0.14 mmol) were dissolved in 1, 4-dioxane (15 mL) . The resulting mixture was stirred at 100 ℃ for 3 hrs under N ₂. The mixture was filtered. The filtrate was concentrated. The residue was purified by prep-HPLC (Method A) to give the title compound 32 (4 mg, 17%yield) as a yellow solid. LCMS (Method 2) : t _R = 2.80 min, m/z (M+H) ⁺ = 487.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.67 (s, 1H) , 10.44 (br s, 1H) , 9.89 (s, 1H) , 9.06 -9.03 (m, 1H) , 8.56 (s, 1H) , 8.27 (s, 1H) , 7.63 (t, J = 8.0 Hz, 1H) , 7.44 (d, J = 2.0 Hz, 1H) , 7.05 (d, J = 8.0 Hz, 1H) , 6.84 (d, J = 7.2 Hz, 1H) , 3.95 (s, 3H) , 3.78 (s, 3H) , 3.69 (s, 2H) , 3.19 (s, 2H) , 2.87 (d, J = 4.8 Hz, 3H) , 2.30 (s, 3H) .

Example 33

Step 1. (3- (Bis (2, 4-dimethoxybenzyl) amino) phenyl) methanol (33b)

Compound (3-aminophenyl) methanol 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 RT for 10 minutes. Then NaBH ₃CN (5.10 g, 81.20 mmol) was added to the mixture. The mixture was stirred at RT for 4 hours. The mixture was diluted with H ₂O (30 mL) and extracted with EtOAc (50 mL*2) . The combined organic layers were concentrated to dryness. The residue was purified by column chromatography on silica gel (PE/EtOAc = 30/1) to give the title compound 33b (1.1 g, 16%yield) as yellow oil. LC-MS (Method 3) : t _R = 1.66 min, m/z (M+H) ⁺ = 424.3.

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 ℃. The mixture was stirred at RT for 30 minutes. Then 22c (200 mg, 0.61 mmol) was added at 0 ℃. The mixture was stirred at RT for 3 hours. The mixture was quenched with H ₂O (5 mL) and extracted with EtOAc (15 mL*2) . The combined organic layers were washed with brine (15 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (EtOAc) to give the title compound 33c (150 mg, crude) as a yellow solid. LC-MS (Method 3) : t _R = 1.78 min, m/z (M+H) ⁺ = 670.4.

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 by utilizing similar preparative procedure of the second step of compound 6 with 33c (150 mg, 0.22 mmol) as starting material. LC-MS (Method 3) : t _R = 1.67 min, m/z (M+H) ⁺ = 640.8.

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)

Compound 33e (37 mg, 29%yield) was synthesized by utilizing similar preparative procedure of the first step of compound 2 with 33d (100 mg, 0.16 mmol) and ethyl 2, 4-dichloropyrimidine-5-carboxylate (45 mg, 0.20 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.92 min, m/z (M-H) ^-= 822.8.

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 ℃ for 3 hours. The mixture was concentrated to give the crude title compound 33f (30 mg, 60%purity, 76%yield) as a red solid. LC-MS (Method 3) : t _R = 1.55 min, m/z (M+H) ⁺ = 524.5.

Step 6. Ethyl 10-methoxy-11- (1-methyl-1, 2, 4-triazol-3-yl) -15-oxa-2, 4, 8, 23-tetrazatetracyclo [15.3.1.13, 7.19, 13] tricosa-1 (21) , 3 (23) , 4, 6, 9, 11, 13 (22) , 17, 19-nonaene-6-carboxylate (33g)

To a mixture of 33f (20 mg, 0.04 mmol) in EtOH (6 mL) was added 1 drop of conc. HCl. The mixture was stirred at 60 ℃ for 2 hours. The mixture was concentrated to give the crude title compound 33g (20 mg, 100%yield) as a yellow solid. LC-MS (Method 3) : t _R = 1.56 min, m/z (M-H) ^-= 486.5.

Step 7. 10-Methoxy-N-methyl-11- (1-methyl-1, 2, 4-triazol-3-yl) -15-oxa-2, 4, 8, 23-tetrazatetracyclo [15.3.1.13, 7.19, 13] tricosa-1 (21) , 3 (23) , 4, 6, 9, 11, 13 (22) , 17, 19-nonaene-6-carboxamide (33)

Compound 33 (3.2 mg, 13%yield) was synthesized by utilizing similar preparative procedure of the sixth step of compound 30 with 33g (25 mg, 0.05 mmol) as starting material. LC-MS (Method 1) : t _R = 2.94 min, m/z (M+H) ⁺ = 473.2. ¹H NMR (400 MHz, CD ₃OD) : δ 8.92 (d, J = 1.2 Hz, 1H) , 8.52 (s, 1H) , 8.47 (s, 1H) , 8.41 (d, J = 1.6 Hz, 1H) , 7.46 (d, J = 1.6 Hz, 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) .

Example 34

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 by utilizing similar preparative procedure of the second step of compound 33 with 22c (600 mg, 1.83 mmol) and (6-bromopyridin-2-yl) methanol (517 mg, 2.75 mmol) as starting materials. LC-MS (Method 3) : t _R =1.56 min, m/z (M+H) ⁺ = 436.3.

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 ₂ (dba) ₃ (57 mg, 0.06 mmol) and Cs ₂CO ₃ (404 mg, 1.24 mmol) were dissolved in 1, 4-dioxane (4 mL) . The above reaction was stirred at 90 ℃ for 3 hrs. The mixture was concentrated. The residue was purified by column chromatography on silica gel (PE/EtOAc = 1/1) to give the title compound 34b (266 mg, 91%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl ₃) : δ 8.33 (d, J = 2.0 Hz, 1H) , 8.17 (s, 1H) , 7.86 -7.82 (m, 2H) , 7.67 (t, J = 8.0 Hz, 1H) , 7.48 (br s , 1H) , 7.08 (d, J = 7.6 Hz, 1H) , 4.65 (s, 2H) , 4.56 (s, 2H) , 4.03 (s, 3H) , 3.94 (s, 3H) , 1.53 (s, 9H) .

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 by utilizing similar preparative procedure of the second step of compound 6 with 34b (266 mg, 0.57 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.50 min, m/z (M+H) ⁺ = 441.5.

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 by utilizing similar preparative procedure of the first step of compound 10 with 34c (50 mg, 0.11 mmol) and 4, 6-dichloro-N-methylnicotinamide (35 mg, 0.17 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.60 (s, 1H) , 8.86 -8.76 (m, 1H) , 8.56 (s, 1H) , 8.51 (s, 1H) , 7.67 (d, J = 2.0 Hz, 1H) , 7.48 (d, J = 2.0 Hz, 1H) , 7.36 (t, J = 8.0 Hz, 1H) , 6.95 (s, 1H) , 6.59 (d, J = 7.2 Hz, 1H) , 6.33 (d, J = 8.0 Hz, 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 = 4.8 Hz, 3H) .

Step 5. 10-Methoxy-N-methyl-11- (1-methyl-1, 2, 4-triazol-3-yl) -15-oxa-2, 4, 8, 21-tetrazatetracyclo [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 by utilizing similar preparative procedure of the final step of compound 32 with 34d (24 mg, 0.05 mmol) as starting material. LC-MS (Method 1) : t _R = 3.40 min, m/z (M+H) ⁺ = 473.2. ¹H NMR (400 MHz, DMSO-d ₆) : 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 = 2.0 Hz, 1H) , 7.61 (t, J = 7.6 Hz, 1H) , 7.41 (d, J = 2.0 Hz, 1H) , 7.00 (d, J = 8.0 Hz, 1H) , 6.91 (d, J = 7.2 Hz, 1H) , 4.65 (s, 2H) , 4.35 (s, 2H) , 3.95 (s, 3H) , 3.79 (s, 3H) , 2.80 (d, J = 4.0 Hz, 3H) .

Example 35

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 by utilizing similar preparative procedure of the seventh step of compound 1 with 34c (60 mg, 0.14 mmol) and methyl 4, 6-dichloropyridazine-3-carboxylate (56 mg, 0.27 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.23 min, m/z (M+H) ⁺ = 611.1.

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 given) was synthesized by utilizing similar preparative procedure of the second step of compound 23 with 35a (50 mg, 0.08 mmol) as starting material. LC-MS (Method 3) : t _R = 1.55 min, m/z (M+H) ⁺ = 610.3.

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 was stirred at RT for 1 hour. The reaction mixture was purified by prep-HPLC (Method C) to give the title compound 35c (45 mg, 99%yield) as a yellow solid. LC-MS (Method 3) : t _R = 1.31 min, m/z (M+H) ⁺ = 510.5.

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 by utilizing similar preparative procedure of the final step of compound 32 with 35c (50 mg, 0.08 mmol) as starting material. LC-MS (Method 1) : t _R = 3.18 min, m/z (M+H) ⁺ = 474.0. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.77 (s, 1H) , 10.47 (s, 1H) , 9.74 (s, 1H) , 9.07 (d, J = 4.8 Hz, 1H) , 8.57 (s, 1H) , 8.22 (s, 1H) , 7.68 (t, J = 7.6 Hz, 1H) , 7.48 (s, 1H) , 7.11 (d, J = 8.4 Hz, 1H) , 6.98 (d, J = 7.2 Hz, 1H) , 4.67 (s, 2H) , 4.39 (s, 2H) , 3.96 (s, 3H) , 3.81 (s, 3H) , 2.87 (d, J = 4.8 Hz, 3H) .

Example 36

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 by utilizing similar preparative procedure of the second step of compound 33 with 22c (400 mg, 1.22 mmol) and (5-bromo-2-fluorophenyl) methanol (376 mg, 1.83 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.60 min, m/z (M+H) ⁺ = 451.

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, 50%purity, 37%yield) was synthesized by utilizing similar preparative procedure of the second step of compound 34 with 36a (100 mg, 0.22 mmol) as starting material. LC-MS (Method 3) : t _R = 1.59 min, m/z (M+H) ⁺ = 488.3.

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 by utilizing similar preparative procedure of the second step of compound 6 with 36b (80 mg, 0.16 mmol) as starting material. LC-MS (Method 3) : t _R = 1.53 min, m/z (M-H) ^-= 456.7.

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 by utilizing similar preparative procedure of the seventh step of compound 1 with 36c (38 mg, 0.08 mmol) and 1i (26 mg, 0.12 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.59 min, m/z (M+H) ⁺ = 625.7.

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)

Compound 36e (87 mg, 92%yield) was synthesized by utilizing similar preparative procedure of the third step of compound 31 with 36d (103 mg, 0.16 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.40 min, m/z (M+H) ⁺ = 525.5.

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 by utilizing similar preparative procedure of the sixth step of compound 33 with 36e (70 mg, 0.13 mmol) as starting material. LC-MS (Method 1) : t _R = 3.07 min, m/z (M+H) ⁺ = 491.3. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.76 (s, 1H) , 9.81 (s, 1H) , 8.74 (d, J = 2.0 Hz, 1H) , 8.69 (s, 1H) , 8.55 (s, 1H) , 8.49 -8.45 (m, 2H) , 7.47 (d, J = 2.0 Hz, 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 = 4.4 Hz, 3H) .

Example 37

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 by utilizing similar preparative procedure of the second step of compound 33 with 22c (100 mg, 0.31 mmol) and (3-bromo-5- (trifluoromethyl) phenyl) methanol (117 mg, 0.46 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.67 min, m/z (M+H) ⁺ = 503.1.

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 by utilizing similar preparative procedure of the second step of compound 34 with 37a (120 mg, 0.24 mmol) as starting material. LC-MS (Method 3) : t _R = 1.68 min, m/z (M+H) ⁺ = 538.3.

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 by utilizing similar preparative procedure of the second step of compound 6 with 37b (85 mg, 0.16 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.62 min, m/z (M+H) ⁺ = 508.6.

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 by utilizing similar preparative procedure of compound 1 with 37c (36 mg, 0.07 mmol) and 1i (22 mg, 0.11 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.64 min, m/z (M+H) ⁺ = 677.3.

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 by utilizing similar preparative procedure of the third step of compound 31 with 37d (51 mg, 0.08 mmol) as starting materials. LC-MS (Method 3) : t _R = 1.19 min, m/z (M+H) ⁺ = 577.1.

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 by utilizing similar preparative procedure of the final step of compound 33 with 37e (30 mg, 0.05 mmol) as starting materials. LC-MS (Method 2) : t _R = 3.04 min, m/z (M+H) ⁺ = 541.2. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.77 (s, 1H) , 10.07 (s, 1H) , 8.86 (s, 1H) , 8.72 (s, 1H) , 8.66 (d, J = 2.0 Hz, 1H) , 8.56 -8.54 (m, 2H) , 7.49 (d, J = 2.0 Hz, 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 = 4.4 Hz, 3H) .

Example 38

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 by utilizing similar preparative procedure of the fourth step of compound 1 with 38a (800 mg, 3.51 mmol) and tert-butyl carbamate (822 mg, 7.02 mmol) as starting materials. ¹H NMR (400 MHz, DMSO-d ₆) : δ 7.99 (s, 1H) , 7.90 (s, 1H) , 7.67 (d, J = 7.5 Hz, 1H) , 6.71 (d, J = 7.5 Hz, 1H) , 3.52 (s, 3H) , 1.51 (s, 9H) .

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 above solution was stirred at RT for 2 hrs. The reaction mixture was concentrated to dryness to give 38c (105 mg, yield given) as brown oil. LCMS (Method 3) : t _R =0.29 min, m/z (M+H) ⁺ = 165.1.

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)

Compound 38d (38 mg, 30%yield) was synthesized by utilizing similar preparative procedure of the seventh step of compound 1 with 38c (105 mg, 0.37 mmol) and 11c (78 mg, 0.38 mmol) as starting materials. LCMS (Method 3) : t _R = 1.03 min, m/z (M+H) ⁺ = 334.3.

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 (38)

Compound 38 (9 mg, 19%yield) was synthesized by utilizing similar preparative procedure of the final step of compound 1 with 38d (38 mg, 0.11 mmol) and 4-fluoroaniline (63 mg, 0.60 mmol) as starting materials. LCMS (Method 1) : t _R = 3.13 min, m/z (M+H) ⁺ = 408.9. ¹H NMR (400 MHz, DMSO-d ₆) : δ 11.74 (s, 1H) , 9.69 (s, 1H) , 8.63 (s, 1H) , 8.38 (d, J = 4.4 Hz, 1H) , 7.70 (s, 1H) , 7.64 (d, J = 7.2 Hz, 2H) , 7.19 (t, J = 8.8 Hz, 2H) , 6.67 (d, J = 7.6 Hz, 1H) , 3.49 (s, 3H) , 2.79 (d, J = 4.4 Hz, 3H) .

Example 39

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 stirred at 0 ℃, followed by the addition of NaOH (10N, 2.6 mL, 27.4mmol) dropwise at the same condition. After stirring for 2 h at RT, the mixture was quenched with HCl (50 mL) and water (50 mL) . The solid formed was collected and dried under reduced pressure to afford the product (2.3 g, 37%) as a light-yellow solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.04 (dt, J = 13.4, 0.7 Hz, 1H) , 7.49 –7.43 (m, 2H) , 7.35 (dd, J = 1.3, 0.7 Hz, 1H) .

Step 2. 2- (4-Bromothiophen-2-yl) ethan-1-amine (39b)

A solution of LiBH ₄ (8.2 mol, 4.1 mL, 2N) in THF (3.0 mL) was treated with trimethylchlorosilane (1.78 g, 16.4 mmol) dropwise at RT under nitrogen atmosphere, followed by the addition of 39a (480 mg, 2.05 mmol) dropwise in THF (6mL) . The resulting mixture stirred overnight at RT. The mixture was quenched with MeOH and basified by 4N NaOH to pH = 8～9 and extracted with EA. The organic phases were combined, dried over Na ₂SO ₄, concentrated under reduced pressure to afford the product (280 mg, 68%) as a light-yellow oil.

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 triphosgene (120 mg, 0.4 mmol) in DCM (0.5 mL) dropwise at 0 ℃, followed by the addition of saturated sodium bicarbonate (2.5 mL) solution dropwise at 0 ℃. The resulting mixture stirred for 1 h at 0 ℃, dried over Na ₂SO ₄ and concentrated to afford the crude product (150 mg) use for next step without purification.

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 FeCl ₃ (192.18 mg, 1.18 mmol) at RT. The mixture was stirred for 3 h at 50 ℃. The residue was purified by Prep-TLC (eluent: PE: EtOAc = 1: 1) to afford the product (80 mg, 32%yield) as a light yellow oil.

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) were added dipotassium carbonate (89 mg, 0.646 mmol) and iodoethane (76 mg, 0.485 mmol) dropwise at rt. The mixture was stirred overnight at 65 ℃. The residue was purified by Prep-TLC (eluent: PE: EtOAc = 1: 3) to afford the product (50 mg, 59%yield) as a light yellow oil.

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) , K ₃PO ₄ (81 mg, 0.38 mmol) in dioxane (1.4 mL) was stirred at 90 ℃ under N ₂. The reaction mixture was cooled down to RT, concentrated and the residue was purified by Prep-TLC (eluent: PE: EtOAc = 1: 2) to afford the product (21 mg, 37%yield) as a light yellow oil.

Step 7. 3-Amino-5-ethyl-6, 7-dihydrothieno [3, 2-c] pyridin-4 (5H) -one (39g)

To a stirred solution of 39e (20 mg, 67.48 umol) in DCM (0.5 mL) was added TFA (148.00 mg, 1.30 mmol, 0.1 mL) dropwise at 0 ℃. The mixture was stirred for 2 h at rt. The mixture was dilute with DCM and concentrated under reduced pressure to get the crude product (25 mg) use for next step without purification.

Step 8. Methyl 4-chloro-6- (cyclopropanecarboxamido) nicotinate (39h)

A solution of methyl 4, 6-dichloropyridine-3-carboxylate (42 mg, 0.2 mmol) , Pd (OAc) ₂ (4.58 mg, 0.02 mmol) , dppf (33 mg, 0, 06 mmol) , K ₃PO ₄ (85 mg, 0.4 mmol) and cyclopropanecarboxamide (85 mg, 0.2 mmol) in dioxane (1 mL) was stirred overnight at 75 ℃. The reaction mixture was cooled down to RT, concentrated and the residue was purified by Prep-TLC (eluent: PE: EtOAc = 1: 2) to afford the product (40 mg, 78%yield) as an off-white solid.

Step 9. Methyl 6- (cyclopropanecarboxamido) -4- ( (5-ethyl-4-oxo-4, 5, 6, 7-tetrahydro thieno [3, 2-c] pyridin-3-yl) amino) nicotinate (39i)

A mixture of 39g (239 mg, 0.068 mmol) , 39h (23 mg, 0.088mmol) , K ₂CO ₃ (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 at 85 ℃ under N ₂ overnight. The mixture was cooled down to RT, then filtered through a celite pad and concentrated. The residue was concentrated and purified by Prep-TLC (eluent: PE: EtOAc = 1: 1) give the product (12 mg, 43%yield) as a brown-yellow oil.

Step 10. Lithium 6- (cyclopropanecarboxamido) -4- ( (5-ethyl-4-oxo-4, 5, 6, 7-tetra hydrothieno [3, 2-c] pyridin-3-yl) amino) nicotinate (39j)

To a stirred mixture of 39i (12 mg, 0.029 mmol) in THF (0.9 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (8 mg, 0.21mmol) for 12 h at RT. The mixture was concentrated under reduced pressure to give the crude product (19 mg) as a brown-yellow solid.

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) were addedmethyl-d3-amine hydrochloride (10 mg, 0.14 mmol) , O- (7-Azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluroniumxafluorophosphate (54 mg, 0.14 mmol) and N, N-diisopropylethyl amine (37 mg, 0.28 mmol) . The mixture was stirred overnight at RT. The mixture was purified by Prep- HPLC over RP-18 (eluent: CH ₃CN in H ₂O (0.05%TFA) from 20%to 60%, v/v) to afford the title product (1.6 mg) . LC-MS: m/z (M+H) ⁺ = 414.1. ¹H NMR (400 MHz, DMSO-d ₆) δ 11.20 (s, 1H) , 10.79 (s, 1H) , 8.41 (d, J = 4.0 Hz, 2H) , 8.32 (s, 1H) , 6.92 (s, 1H) , 3.62 (t, J = 6.8 Hz, 2H) , 3.47 (q, J = 7.1 Hz, 2H) , 3.04 (t, J = 6.8 Hz, 2H) , 2.76 (d, J = 4.4 Hz, 3H) , 2.04 –1.95 (m, 1H) , 1.10 (t, J = 7.1 Hz, 3H) .

Example 40

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 6-chloro-4- ( (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N-methylpyridazine-3-carboxamide 40a (35 mg, 0.09 mmol) , cyclopropanecarboxamide (16 mg, 0.19 mmol) , Pd ₂ (dba) ₃ (9 mg, 0.009 mmol) , XantPhos (7 mg, 0.014 mmol) and Cs ₂CO ₃ (61 mg, 0.19 mmol) were dissolved in 1, 4-dioxane (1 mL) . The above reaction was stirred at 100 ℃ for 4 hrs. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (10 mL*3) . The combined organic layers were concentrated to dryness. The residue was purified by prep-HPLC (Method A) to give the title compound 40 (9 mg, 16%yield) as a white solid. LC-MS (Method 1) : t _R = 3.16 min, m/z (M+H) ⁺ = 423.1. ¹H NMR (400 MHz, CDCl ₃) : δ 11.10 (s, 1H) , 9.12 (br s, 1H) , 8.18 (s, 1H) , 8.10 -8.04 (m, 2H) , 7.82 (d, J = 6.8 Hz, 1H) , 7.50 (d, J = 7.6 Hz, 1H) , 7.30 -7.23 (m, 1H) , 4.00 (s, 3H) , 3.81 (s, 3H) , 3.04 (d, J = 5.2 Hz, 3H) , 1.27 -1.23 (m, 1H) , 1.12 -1.08 (m, 2H) , 0.95 -0.88 (m, 2H) .

Example 41

Step 1. 6- (Cyclopropanecarboxamido) -4- ( (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d ₃) pyridazine-3-carboxamide (41)

To a mixture of 6-amino-4- ( (2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) amino) -N- (methyl-d ₃) pyridazine-3-carboxamide 41a (100 mg, 0.28 mmol, WO2020/86616, Paragraph 00510; 00514) and DIPEA (108 mg, 0.84 mmol) in THF (2 mL) was added cyclopropanecarbonyl chloride (59 mg, 0.56 mmol) at RT. The mixture was stirred at RT for 2 hours and then concentrated to dryness. The residue was dissolved in MeOH (4 mL) , then K ₂CO ₃ (116 mg, 0.84 mmol) was added to the mixture. The mixture was stirred at RT for 40 minutes. The mixture was diluted with H ₂O (8 mL) and extracted with DCM (15 mL*2) . The combined organic layers were concentrated to dryness. The residue was purified by prep-HPLC (Method A) to give the title compound 41 (40 mg, 33%yield) as a white solid. LC-MS (Method 2) : t _R = 3.21 min, m/z (M+H) ⁺ = 426.3. ¹H NMR (400 MHz, CDCl ₃) : δ 11.05 (s, 1H) , 9.25 (br s, 1H) , 8.19 (s, 1H) , 8.11 (s, 1H) , 8.06 (br s, 1H) , 7.81 (dd, J = 8.0, 1.6 Hz, 1H) , 7.50 (dd, J = 8.0, 1.6 Hz, 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) .

Example 42

Step 1. 2-Bromo-3- (dimethoxymethyl) phenol (42b)

To a solution of 42a (2 g, 9.95 mmol) and trimethoxymethane (5.28 g, 49.75 mmol, 5.45 mL) in MeOH (30 mL) was added p-TSA (172 mg, 1.00 mmol) . The mixture was stirred at 100 ℃ for 16 hrs. The solvent was removed under vacuum to give crude 42b (2.5 g, 101%crude yield) as a yellow oil. LC-MS (Method 4) : t _R = 3.54 min, m/z (M+H) ⁺= 215.0.

Step 2. 2, 4-Dibromo-3-hydroxybenzaldehyde (42c)

To a solution of 42b (500 mg, 2.02 mmol) in CHCl ₃ (5 mL) was added a solution of molecular bromine (323.39 mg, 2.02 mmol) in CHCl ₃ (5 mL) at 0 ℃. The reaction was stirred at 25 ℃ for 16 hrs. The reaction was quenched by aq. Na ₂S ₂O ₃ (40 ml) and extracted with EtOAc (25 ml*3) . The combined organic layers were washed with brine (25 ml) , dried over Na ₂SO ₄, filtered and concentrated. The residue was purified by flash silica gel chromatography (eluent: PE:EtOAc from 10 : 1 to 3 : 1) to give the title compound 42c (300 mg, 52.96%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.44 (s, 1H) , 10.17 (d, J = 0.8 Hz, 1H) , 7.83-7.65 (m, 1H) , 7.27 (d, J = 8.4 Hz, 1 H) . LC-MS (Method 4) : t _R = 2.915 min, m/z (M+H) ⁺= 280.9.

Step 3. 2, 4-Dibromo-3-methoxybenzaldehyde (42d)

To a solution of 42c (300 mg, 1.07 mmol) and K ₂CO ₃ (296 mg, 2.14 mmol) in DMF (3 mL) was added iodomethane (228 mg, 1.61 mmol) . The mixture was stirred at 25 ℃ for 2 hrs, then poured into water (20 ml) and extracted with EtOAc (20 ml*3) . The combined organic layers were washed with brine (30 mL) , dried over Na ₂SO ₄, filtered and concentrated under vacuum to give crude compound 42d (300 mg, 95.23%yield) as a yellow solid. LC-MS (Method 4) : t _R = 4.00 min, m/z (M+H) ⁺= 294.9.

Step 4. (E) -1- (2, 4-Dibromo-3-methoxybenzylidene) -2-ethylhydrazine hydrochloride (42e)

Compound 42d (300 mg, 1.02 mmol) and ethylhydrazine hydrochloride (128 mg, 1.33 mmol) were dissolved in EtOH (5 mL) . The resulting mixture was stirred at 25 ℃ for 1 hour and then cold to 0 ℃. The cloudy mixture was filtered and the solid washed with EtOH (1 mL) to afford the title compound 42e (270 mg, 71.02%yield) as off-white solid. LC-MS (Method 4) : t _R = 4.62 min, m/z (M+H) ⁺= 337.0.

Step 5. 6-Bromo-1-ethyl-7-methoxy-1H-indazole (42f)

To a solution of 42e (270 mg, 0.72 mmol) in DMF (2.5 mL) was added K ₂CO ₃ (300.09 mg, 2.17 mmol) and CuI (14 mg, 72.49 μmol) . The mixture was stirred at 100 ℃ for 16 hrs. Water (40 ml) was added to the above mixture. The solution was extracted with EtOAc (20 ml *3) . The combined organic layers were washed with brine (20 ml) , dried over Na ₂SO ₄, filtered and concentrated under vacuum to give crude compound 42f (150 mg, 81.12%yield) as a pale yellow solid. LC-MS (Method 4) : t _R = 3.99 min, m/z (M+H) ⁺= 255.0.

Step 6. tert-Butyl (1-ethyl-7-methoxy-1H-indazol-6-yl) carbamate (42g)

Compound 42f (45 mg, 0.18 mmol) , tert-butyl carbamate (41 mg, 0.35 mmol) , Pd ₂ (dba) ₃ (16 mg, 17.64 μmol) , XantPhos (21 mg, 35.28 μmol) and Cs ₂CO ₃ (144 mg, 0.44 mmol) were dissolved in dioxane (1 mL) . The resulting mixture was stirred at 100 ℃ for 16 hrs under N ₂. The mixture was diluted with H ₂O, extracted with EtOAc, washed with brine, dried over Na ₂SO ₄ and filtered. The filtration was concentrated to dryness. The residue was purified by flash chromatography (PE: EA= 10/1 to 1/1) to give the title compound 42g (35 mg, 68.10%yield) as a pale yellow solid. LC-MS (Method 4) : t _R = 3.99 min, m/z (M+H) ⁺=292.3.

Step 7. 1-Ethyl-7-methoxy-1H-indazol-6-amine (42h)

To a solution of 42g (31 mg, 0.1 mmol) in dioxane (0.5 mL) was added a solution of HCl (g) in dioxane (4M, 0.5 mL) . The mixture was stirred at RT for 30 min. The mixture was concentrated to dryness. The residue was diluted with H ₂O (10 mL) and extracted with EtOAc (10 mL*3) . The organic layers were washed with aq. Na ₂CO ₃ (15 mL) and brine (15 mL) and separated. The solution was dried over Na ₂SO ₄ and filtered. The filtrate was concentrated to give the title compound 42h (20 mg, 98.29%yield) as a yellow solid. LC-MS (Method 4) : t _R = 1.73 min, m/z (M+H) ⁺=192.3.

Step 8. 4, 6-Dichloronicotinoyl chloride (42j)

To a solution of 42i (1 g, 5.21 mmol) in DCM (10 mL) was added oxalyl dichloride (793 mg, 6.25 mmol) and DMF (19 mg, 0.26 mmol) sequentially at 0 ℃. Then the mixture was stirred at r. t. overnight. The mixture was concentrated to dryness to afford crude product 42j (1.1 g, 100 %yield) as a yellow oil.

Step 9. 4, 6-Dichloro-N- (methyl-d ₃) nicotinamide (42k)

To a solution of 42j (1.1 g, 5.23 mmol) in DCM (20 mL) were added methan-d3-amine hydrochloride (406 mg, 5.75 mmol) and TEA (2.64 g, 26.14 mmol) at 0 ℃. Then the mixture was stirred at RT for 1 hour. The mixture was diluted with H ₂O (20 ml) and extracted with DCM (20 ml) . The organic layer was separated and washed with brine (20 ml) , dried over Na ₂SO ₄ and filtered. The filtration was concentrated to dryness to give the title compound 42k (800 mg, 73.56%yield) as off-white solid. LC-MS (Method4) : t _R = 2.18 min, m/z (M+H) ⁺=208.0.

Step 10. 6-Chloro-4- ( (1-ethyl-7-methoxy-1H-indazol-6-yl) amino) -N- (methyl-d3) nicotinamide (42l)

To a solution of 42h (20 mg, 0.10 mmol) and 42k (26 mg, 0.13 mmol) in THF (1 mL) was added NaHMDS (134.25 mg, 732.11 umol, 0.15 mL) at 0 ℃, then the mixture was stirred at RT for 30 min. The mixture was diluted with H ₂O (20 ml) and extracted with EtOAc (20 ml) . The organic layer was washed with brine (20 ml) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated to dryness to give the title compound 42l (30 mg, 79.06%yield) as a yellow solid. LC-MS (Method 4) : t _R = 3.52 min, m/z (M+H) ⁺=363.2.

Step 11. 4- ( (1-Ethyl-7-methoxy-1H-indazol-6-yl) amino) -6- ( (5-fluoropyridin-2-yl) amino) -N- (methyl-d ₃) nicotinamide (42)

Compound 42l (30 mg, 82.68 μmol) , 5-fluoropyridin-2-amine (19 mg, 0.17 mmol) , XantPhos (9.71 mg, 16.54 μmol) , Cs ₂CO ₃ (67.35 mg, 0.20 mmol) and Pd ₂ (dba) ₃ (7.57 mg, 8.27 μmol) were dissolved in DMA (1 mL) . The resulting mixture was stirred at 145 ℃ for 2 hrs. The mixture was concentrated to dryness and purified by prep-HPLC (Method D) to give the title compound 42 (2.2 mg, 5.79%yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.54 (s, 1H) , 9.71 (s, 1H) , 8.47 (s, 1H) , 8.44 (s, 1H) , 8.03 (d, J = 1.6 Hz, 1 H) , 8.01 (s, 1H) , 7.68-7.65 (m, 1H) , 7.60-7.56 (m, 1H) , 7.54 (d, J = 8.8 Hz, 1H) , 7.46 (m, 1H) , 7.21 (d, J = 8.8 Hz, 1H) , 4.52 (q, J = 7.2 Hz, 2H) , 3.78 (s, 3H) , 1.37 (t, J = 7.2 Hz, 3H) . LC-MS (Method 4) : t _R = 2.66 min, m/z (M+H) ⁺=439.2.

Example 43

4- ( (1-Ethyl-7-methoxy-1H-indazol-6-yl) amino) -N- (methyl-d ₃) -6- ( (1-methyl-1H-pyrazol-3-yl) amino) nicotinamide (43)

Compound 42l (20 mg, 55.12 μmol) , 1-methyl-1H-pyrazol-3-amine (11 mg, 0.11 mmol) , XantPhos (6 mg, 11.02 μmol) , Cs ₂CO ₃ (44.90 mg, 0.14 mmol) and Pd ₂ (dba) ₃ (5 mg, 5.51 μmol) were dissolved in DMA (1 mL) . The resulting mixture was stirred at 160℃ for 1 hour under N ₂ atmosphere. The mixture was concentrated to dryness and purified by prep-HPLC (Method D) to give the compound 43 (2.0 mg, 8.57%yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ 10.57 (s, 1H) , 9.20 (s, 1H) , 8.40 (s, 1H) , 8.03 (s, 1H) , 7.53 (d, J = 8.4 Hz, 1 H) , 7.45 (d, J = 1.6 Hz, 1H) , 7.24 (d, J = 8.4 Hz, 1H) , 7.20 (s, 1H) , 6.06 (d, J = 1.6 Hz, 1H) , 4.55 (q, J = 7.2 Hz, 2H) , 3.81 (s, 3H) , 3.62 (s, 3H) , 1.40 (t, J = 7.2 Hz, 3H) . LC-MS (Method 4) : t _R =2.42 min, m/z (M+H) ⁺=424.3.

Example 44

Step 1. Methyl 4-chloro-6- (cyclopropanecarboxamido) nicotinate (44b)

A mixture of 44a (2.0 g, 9.71 mmol) , cyclopropanecarboxamide (826 mg, 9.71 mmol) , Pd (OAc) ₂ (109 mg, 0.49 mmol) , dppf (538.17 mg, 0.97 mmol) , K ₃PO ₄ (4.12 g, 19.42 mmol) in dioxane (30 mL) was stirred at 90 ℃ for 4 hours under N ₂. The mixture was diluted with H ₂O (100 mL) and extracted with EtOAc (60 mL*3) . The organic layers were washed with brine (100 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated to dryness. The residue was purified by flash chromatography (PE : EA from 10: 1 to 1: 1) to give the compound 44b (1.8 g, 72.81%yield) as a white solid. LC-MS (Method 4) : t _R = 3.33 min, m/z (M+H) ⁺=255.0.

Step 2. Lithium 4-chloro-6- (cyclopropanecarboxamido) nicotinate (44c)

To a solution of 44b (500 mg, 1.96 mmol) in a solvent containing of MeOH (2 ml) , THF (2 ml) and water (1 ml) was added LiOH. H ₂O (165 mg, 3.93 mmol) . Then the mixture was stirred at RT overnight. The mixture was concentrated to dryness to give compound 44c (480 mg, 99.15%yield) as a white solid. LC-MS (Method 4) : t _R = 3.81 min, m/z (M+H) ⁺=241.1.

Step 3. 4-Chloro-6- (cyclopropanecarboxamido) -N- (methyl-d ₃) nicotinamide (44d)

To a solution of 44c (480 mg, 1.95 mmol) in DCM (15 mL) was sequentially added methan-d ₃-amine hydrochloride (275 mg, 3.89 mmol) , DIEA (1.51 g, 11.68 mmol) and T ₃P (1.86 g, 2.92 mmol, 50%in EtOAc) at 0 ℃. The resulting mixture was stirred at RT overnight. The mixture was diluted with H ₂O (30 mL) and extracted with DCM (30 mL*3) . The organic layers were washed with brine (50 mL) , dried over Na ₂SO ₄ and filtered. The filtrate was concentrated to dryness to give 44d (300 mg, 60.03%yield) as a white solid. LC-MS (Method 4) : t _R = 2.25 min, m/z (M+H) ⁺=257.1.

Step 4. 6- (Cyclopropanecarboxamido) -4- ( (1-ethyl-7-methoxy-1H-indazol-6-yl) amino) -N- (methyl-d ₃) nicotinamide (44)

A mixture of 42h (20 mg, 0.10 mmol) , 44d (27 mg, 0.10 mmol) and p-TSA (18 mg, 0.1 mmol) in dioxane (1 mL) was stirred at 100 ℃ for 15 hours. The mixture was concentrated to dryness. The residue was purified by prep-HPLC (1%NH ₄HCO ₃, ACN, 25-65%) to give compound 44 (8.5 mg, 19.75%yield) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d ₆) : δ10.67 (s, 1H) , 10.49 (s, 1H) , 8.57 (s, 1H) , 8.47 (s, 1H) , . 8.00 (s, 1H) , 7.78 (s, 1 H) , 7.47 (d, J =8.4 Hz, 1H) , 7.05 (d, J = 8.4 Hz, 1H) , 4.50 (q, J = 7.2 Hz, 2H) , 3.74 (s, 3H) , 1.91-1.88 (s, 1H) , 1.35 (t, J = 7.2 Hz, 3H) , 0.71-0.66 (m, 4H) . LC-MS (Method 4) : t _R = 2.16 min, m/z (M+H) ⁺=412.2.

Biochemical assay

JAK1, JAK2 and TYK2 inhibition assay

JAK activity was determined in the reaction buffer 50 mM HEPES, 0.01%Brij35, 10 mM MgCl ₂, 2 mM DTT by a microfluidic assay. The phosphorylation of a FAM labeled peptide substrate was monitored in the Caliper EZ Reader II (Perkin Elmer) . The assay condition for each batch of enzyme (Carna Biosciences) was optimized to obtain 10%conversion rate of peptide substrate.

The test compounds were dissolved in DMSO to a stock concentration of 10 mM. Three-fold serially diluted compounds with top concentration of 5 μM were pre-incubated with JAK1, JAK2 or TYK2 for 10 min at ambient temperature. The final DMSO concentration of assay mixture was 1%. FAM labeled peptide substrate (final concentration 3 μM) and ATP (Km concentration or 1mM) were sequentially added to initiate the kinase reaction at 28℃ for 90 min (JAK) , 15 min (JAK2) and 30 min (TYK2) , respectively. The reaction was stopped by adding 50 mM EDTA.

The well in the test plate without enzyme was defined as 100%inhibition. And the well without compound but with equivalent DMSO was defined as no inhibition. The percent inhibition was calculated by the following formula:

wherein

Conversion%_ _max = the conversion rate in the positive well without addition of compound

Conversion%_ _sample = the conversion rate of test compounds

Conversion%_ _min = the conversion rate in the well without addition of enzyme

The dose-response (percent inhibition) curve was plotted and IC50 values were determined by GraphPad software. The IC50 values of tested compounds were list in Table 1.

Table 1. Exemplary Compounds

Table 2. JAK1, JAK2 and TYK2 IC50 Values of Illustrative Compounds

Anti-proliferative assay

Dimerization domain of Tel protein fused with JAK kinase domain was permanently transduced into Ba/F3 cells, whose proliferation is dependent on JAK activity in the absence of IL-3 induction. These engineered Ba/F3 cells (Ba/F3-FL-TYK2-P760L, Ba/F3-TEL-TYK2 and Ba/F3-TEL-JAK2) were used to monitor JAK inhibitory activities of the compounds in the cellular. Ba/F3 cells were cultured in RPMI-1640 (Corning) containing 10%fetal bovine serum. Cells were seeded at 2000/well of white flat bottom 96-well plates. The well containing medium only was used as background control. After 24h growth, cells were treated with compounds. The test compounds were dissolved in DMSO to a stock concentration of 20 mM. 3-fold serially diluted compounds for 9 concentrations with top concentration of 20 μM was added into the each well. The final DMSO concentration was 0.1%. The cells continued to grow at 37℃ in 5%CO ₂ for 72 h after compound treatment. The viability was measured by cellular ATP determination using the Cell-Titer Glo luciferase reagent (Promega) . The Luminescence value was recorded by a multi-label reader Envision (PerkinElmer) . Inhibition Rate was calculated relative to vehicle (DMSO) treated control wells using following formula:

wherein

RLU_compound = the relative light unit of cells treated with test compounds

RLU_blank = the relative light unit of medium with DMSO only

RLU_control = the relative light unit of cells treated with DMSO only

The dose-response (percent inhibition) curve was plotted and IC50 values (the concentration that causes 50%growth inhibition) were determined by GraphPad software. The IC50 of tested compounds are shown in Table 3.

Table 3. Ba/F3 Cells IC50 Values of Exemplary Compounds

Applicant’s disclosure is described herein in preferred embodiments with reference to the Figures, in which like numbers represent the same or similar elements. Reference throughout this specification to “one embodiment, ” “an embodiment, ” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment, ” “in an embodiment, ” and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and/or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures, materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.

Incorporation by Reference

References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.

Equivalents

The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

A compound having the structural formula (I) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of X ¹ and X ² is independently selected from CH and N;

each of X ⁴ and X ⁵ is independently selected from CH, CF and N;

X ³ is NR, O, CH ₂ or CF ₂;

R ¹¹ is a H, F, C ₁-C ₃ alkyl or CD ₃;

R ¹² is C (=O) R ^12’ or R ^12’, wherein R ^12’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^12a, wherein R ^12a is selected from the group consisting of halogen, CF ₃, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ¹³ is a C ₁-C ₃ alkyl, CD ₃ or CF ₃;

R ¹⁴ is H, C ₁-C ₆ alkyl or heteroalkyl or a C ₃-C ₆ cycloalkyl or heterocycloalkyl, or a 5-or 6-membered heteroaryl group comprising 1, 2 or 3 hetero atoms selected from N, O and S, or R ¹⁴ is OR ^14’, wherein R ^14’ is C ₁-C ₆ alkyl or heteroalkyl or a C ₃-C ₆ cycloalkyl or heterocycloalkyl, each substituted with 0-2 R ^14a, wherein R ^14a is selected from the group consisting of halogen, R, OR, amino, CF ₃ and CN;

R ¹⁵ at each occurrence is independently selected from F, Cl, CN, OR, and a C ₁-C ₃ alkyl;

R at each occurrence is independently H or a C ₁-C ₆ alkyl; and

k is 0, 1, 2 or 3.
The compound of claim 1, wherein R ¹² is C (=O) R ^12’.
The compound of claim 1, wherein R ¹² is R ^12’.
The compound of claim 1, wherein R ¹² is an aryl or heteroaryl.
The compound of claim 1, wherein R ¹² is unsubstituted or substituted phenyl or pyridinyl group.
The compound of any one of claims 1-5, wherein each of X ¹ and X ² is CH.
The compound of any one of claims 1-6, wherein each of X ⁴ and X ⁵ is CH.
The compound of any one of claims 1-6, wherein one or both of X ⁴ and X ⁵ is CF.
The compound of any one of claims 1-6, wherein X ⁴ is CH and X ⁵ is N.
The compound of any one of claims 1-6, wherein X ⁴ is N and X ⁵ is CH, having the structural formula:
The compound of any one of claims 1-9, wherein X ³ is NR.
The compound of claim 11, wherein X ³ is NH.
The compound of claim 11, wherein X ³ is O.
The compound of any one of claim 5-13, wherein R ^12’ is an unsubstituted or substituted phenyl.
The compound of any one of claim 5-13, wherein R ^12’ is an unsubstituted or substituted pyrazole.
The compound of any one of claim 5-13, wherein R ^12’ is a C ₁-C ₆ alkyl substituted with an amino or morpholino group.
The compound of any one of claims 1-16, wherein R ¹³ is CH ₃.
The compound of any one of claims 1-16, wherein R ¹³ is CD ₃.
The compound of any one of claims 1-16, wherein R ¹³ is CF ₃.
The compound of any one of claims 11-19, having the structural formula:

wherein

each R ¹⁶ is independently selected from CN, Cl, F, a C ₁-C ₃ alkyl and OR, and

j is 0, 1, 2, 3, 4 or 5.
The compound of claim 20, wherein j is 1 and R ¹⁶ is at the meta position:
The compound of any one of claims 1-21, wherein R ¹¹ is CH ₃.
The compound of any one of claims 1-21, wherein R ¹¹ is CD ₃.
The compound of any one of claims 1-23, wherein R ¹⁵ is F.
The compound of any one of claims 20-24, wherein R ¹⁶ is CN.
A compound having the structural formula (II) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ²¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ²² is

R ^22’, wherein R ^22’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^22a, wherein R ^22a is selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

an aryl or heteroaryl group, each substituted with 0-2 R ^24a; or

(C=O) R ²⁷;

R ²³ is

wherein

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 is substituted with 0-4 R ^24b;

R ^24a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^24b at 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, OR, C ₁-C ₃ alkyl, C ₃-C ₅ cycloalkyl, CD ₃, CH ₂CF ₃ or CF ₃;

R ²⁶ is H, a C ₁-C ₆ alkyl, CD ₃, or C ₃-C ₆ cycloalkyl, substituted with 0-3 R ^24a;

R ²⁷ is a C _1-6 alkyl or C _3-6 cycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^24b;

each of R and R’ is independently H or a C ₁-C ₆ alkyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 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; and

p is 1 or 2.
The compound of claim 26, wherein p is 1 and R ²³ is:
The compound of claim 26, wherein p is 2.
The compound of any one of claims 26-28, wherein Y ¹ is CH and Y ² is CH:
The compound of any one of claims 26-28, wherein Y ¹ is CH and Y ² is N:
The compound of any one of claims 26-28, wherein Y ¹ is N and Y ² is CH:
The compound of any one of claims 26-28, wherein Y ¹ is N and Y ² is N:
The compound of any one of claims 26-28, wherein one or both of Y ¹ and Y ² is CF.
The compound of any one of claims 26-33, wherein Y ³ is NR.
The compound of claim 32, wherein Y ³ is NH.
The compound of any one of claims 26-35, wherein R ²³ is selected from:
The compound of claim 36, wherein R ²³ is:
The compound of claim 36, wherein R ²³ is:
The compound of claim 36, wherein R ²³ is:
The compound of claim 36, wherein R ²³ is:
The compound of any one of claims 26-40, wherein R ²¹ is CH ₃.
The compound of any one of claims 26-40, wherein R ²¹ is CD ₃.
The compound of any one of claims 26-42, wherein R ²² is (C=O) R ²⁷, wherein R ²⁷ is selected from C ₁-C ₆ alkyl, cyclopropyl or cyclobutyl, substituted with 0-2 R ^24b.
The compound of any one of claims 26-42, wherein R ²² is pyridine substituted with 0-2 R ^24b.
The compound of claim 43, having the structural formula:
The compound of claim 43, having the structural formula:
The compound of claim 43, having the structural formula:
The compound of claim 43, having the structural formula:
The compound of claim 43, having the structural formula:
The compound of claim 43, having the structural formula:
The compound of claim 43, having the structural formula:
The compound of claim 43, having the structural formula:
The compound of any one of claims 43-52, wherein R ²⁷ is cyclopropyl.
The compound of any one of claims 26-53, wherein R ²⁴ is a C ₁-C ₁₂ alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, optionally substituted with one or more of F, Cl, CN, OR, CH ₃, CF ₃ and OCF ₃.
The compound of any one of claims 26-53, wherein R ²⁴ is an aryl or heteroaryl, optionally substituted with one or more of F, Cl, CN, OR, NRR’, CH ₃, CF ₃ and OCF ₃.
The compound of any one of claims 26-55, wherein R ²⁵ is H.
The compound of any one of claims 26-55, wherein R ²⁵ is F, Cl, CN, OR, CH ₃, CHF ₂ or CF ₃.
A compound having the structural formula (III) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring A is a 5-or 6-membered aryl or heteroaryl;

X ¹ is selected from NR, O, CH ₂ and CF ₂;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁶ is NR ³⁶, CH ₂, O, S, SO or SO ₂;

R ³² is R ^32’ or OR ^32’, wherein R ^32’ is a C _1-12 alkyl, 3-to 6-membered cycloalkyl or heterocycloalkyl comprising 1, 2 or 3 heteroatoms selected from N, O and S, or a 5-or 6-membered aryl or heteroaryl group, each substituted with 0-3 R ^32a;

R ^32a is independently at each occurrence, H, OCF ₃, CN, NO ₂, - (CH ₂) _rOR ^b, - (CH ₂) _rSR ^b, - (CH ₂) _rC (O) R ^b, - (CH ₂) _rC (O) OR ^b, - (CH ₂) _rOC (O) R ^b, (CH ₂) _rNR ^gR ^g, - (CH ₂) _rC (O) NR ^gR ^g, - (CH ₂) _rNR ^bC (O) R ^c, - (CH ₂) _rNR ^bC (O) OR ^c, -NR ^bC (O) NR ^gR ^g, -S (O) _vNR ^gR ^g, -NR ^bS (O) _vR ^c, -S (O) _vR ^c, C _1-6 alkyl substituted with 0-3 R ^a, C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a, 3-to 6-membered cycloalkyl substituted with 0-3 R ^a, or 3-to 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^a;

each of R ³³ and R ³⁴ is independently selected from H, F, Cl, CN, OR ^g, CH ₃, CD ₃, CF ₃, OCD ₃, OCF ₃ and - (CH ₂) _p-Q;

R ³⁵ is H, F, a C ₁-C ₃ alkyl and CD ₃;

R ³⁶ is R substituted with 0-3 R ^d;

R ^a at each occurrence is independently H, F, Cl, Br, OCF ₃, CF ₃, CHF ₂, CN, NO ₂, - (CH ₂) _rOR ^b, - (CH ₂) _rSR ^b, - (CH ₂) _rC (O) R ^b, - (CH ₂) _rC (O) OR ^b, - (CH ₂) _rOC (O) R ^b, - (CH ₂) _rNR ^gR ^g, - (CH ₂) _rC (O) NR ^gR ^g, - (CH ₂) _rNR ^bC (O) R ^c, - (CH ₂) _rNR ^bC (O) OR ^c, -NR ^bC (O) NR ^gR ^g, -S (O) _vNR ^gR ^g, -NR ^bS (O) _vR ^c, -S (O) R ^c, -S (O) ₂R ^c, C _1-6 alkyl substituted with 0-3 R ^f, C _1-6 haloalkyl, 3-to 6-membered cycloalkyl substituted with 0-3 R ^f, or 3-to 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^f;

R ^b is H, C _1-6 alkyl substituted with 0-3 R ^d, C _1-6 haloalkyl, C _3-6 cycloalkyl substituted with 0-2 R ^d, or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^d;

R ^c is C _1-6 alkyl substituted with 0-3 R ^f, (CH ₂) _r-C _3-6 cycloalkyl substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^d is independently at each occurrence, hydrogen, F, Cl, Br, OCF ₃, CF ₃, CN, NO ₂, -OR ^e, - (CH ₂) _rC (O) R ^c, -NR ^eR ^e, -NR ^eC (O) OR ^c, C _1-6 alkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^e is independently at each occurrence, hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^f is independently at each occurrence, hydrogen, halo, CN, NH ₂, OH, C _3-6 cycloalkyl, CF ₃, O (C _1-6 alkyl) or a 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S;

R ^g at each occurrence is independently H, C _1-4 alkyl substituted with 0-3 R ^f, CF ₃, C _3-10 cycloalkyl substituted with 0-1 R ^f, (CH) _r-phenyl substituted with 0-3 R ^d or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^d;

Q is a water solubilizing group, optionally selected from OH, OR, NRR’, heterocyclic and heteroaryl groups, wherein R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO ₂;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

r is 0, 1, 2, 3, 4 or 5.
The compound of claim 58, wherein X ¹ is NH, having the structural formula (III ₁) :
The compound of claim 58 or 59, wherein Ring A is a 6-membered aryl or heteroaryl.
The compound of claim 60, having the structural formula (III ₂) :

wherein each of Z ⁵ and Z ⁸ is CH or N.
The compound of claim 61, wherein Z ⁸ is CH, having the structural formula (III ₃) :

wherein Z ⁵ is CH or N, provided that Z ² and Z ⁵ are not both CH.
The compound of claim 62, wherein each of Z ³ and Z ⁴ is NH.
The compound of claim 62 or 63, wherein Z ¹ is CH, Z ² is CH, and Z ⁵ is N.
The compound of claim 62 or 63, wherein (CRR’) _m is (CH ₂) _m and (CRR’) _n is (CH ₂) _n.
The compound of any one of claims 62-65, having the structural formula:
The compound of any one of claims 62, 63 and 65, wherein Z ¹ is N, Z ² is CH, and Z ⁵ is N.
The compound of any one of claims 62, 63, 65 and 67, having the structural formula:
The compound of any one of claims 62, 63 and 65, wherein Z ¹ is CH, Z ² is N, and Z ⁵ is N.
The compound of any one of claims 62, 63, 65 and 69, having the structural formula:
The compound of any one of claims 62, 63 and 65, wherein Z ¹ is CH, Z ² is N, and Z ⁵ is CH.
The compound of any one of claims 62, 63, 65 and 71, having the structural formula:
The compound of any one of claims 62, 63 and 65, wherein Z ¹ is N, Z ² is N, and Z ⁵ is N.
The compound of any one of claims 62, 63, 65 and 73, having the structural formula:
The compound of any one or claims 62-74, wherein R ³² is a 6-membered aryl or heteroaryl group comprising 0, 1 or 2 nitrogen atoms and 0 or 1 oxygen atom.
The compound of any one or claims 62-75, wherein R ³² is selected from:
The compound of any one or claims 62-74, wherein R ³² is a 3-to 6-membered cycloalkyl or heterocycloalkyl comprising 1, 2 or 3 heteroatoms wherein the heteroatoms are selected from N, O and S, substituted with 0-3 R ^32a.
The compound of claim 77, wherein R ³² is a 3-membered cycloalkyl substituted with 0-3 R ^32a.
The compound of claim 78, wherein R ³² is cyclopropyl substituted with 0-3 R ^32a.
The compound of any one or claims 62-74, wherein R ³² is a 5-membered heteroaryl group comprising 1, 2 or 3 nitrogen atoms and 0 or 1 oxygen atom.
The compound of any one or claims 62-74, wherein R ³² is a triazole, oxadiazole, thiazole, oxazole or pyrazole substituted with 0-3 R ^32a.
The compound of any one or claims 62-74, wherein R ³² is selected from:
The compound of claim 81, wherein R ³² is a N-methyl-1, 2, 4-triazole.
The compound of claim 83, having the structural formula:
The compound of claim 83, having the structural formula:
The compound of claim 83, having the structural formula:
The compound of claim 83, having the structural formula:
The compound of any one of claims 62-87, wherein Z ⁶ is NCH ₃.
The compound of any one of claims 62-87, wherein Z ⁶ is O.
The compound of any one of claims 62-87, wherein Z ⁶ is S.
The compound of any one of claims 62-87, wherein Z ⁶ is CH ₂.
The compound of any one of claims 62-91, wherein m = n = 1.
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of any one of claims 62-87, having the structural formula:
The compound of claim 61, wherein Z ⁵ is N and Z ⁸ is N.
The compound of claim 61 or 109, having the structural formula (III ₄) :
The compound of claim 110, having the structural formula (III ₃ ^a) :
The compound of claim 110 or 111, having the structural formula (III ₃ ^b) :
The compound of claim 110 or 111, having the structural formula (III ₃ ^c) :
The compound of claim 110 or 111, having the structural formula (III ₃ ^d) :
The compound of claim 110 or 111, having the structural formula (III ₃ ^e) :
The compound of any one of claims 58-115, wherein R ³³ is OR.
The compound of any one of claims 58-115, wherein R ³³ is OCH ₃.
The compound of any one of claims 58-117, wherein R ³⁴ is H.
The compound of any one of claims 58-117, wherein R ³⁴ is selected from F, Cl, CN, CH ₃, CF ₃ and OCF ₃.
The compound of any one of claims 58-117, wherein R ³⁴ is - (CH ₂) _p-Q and Q is an amino or morpholino group.
The compound of any one of claims 58-120, wherein R ³⁵ is CH ₃.
The compound of any one of claims 58-120, wherein R ³⁵ is CD ₃.
The compound of claim 58 or 59, wherein Ring A is a 5-membered aryl or heteroaryl.
The compound of claim 123, having the structural formula (III ₅) :
The compound of claim 124, wherein (CRR’) _m is (CH ₂) _m and (CRR’) _n is (CH ₂) _n.
The compound of claim 124 or 125, having the structural formula:
The compound of claim 124 or 125, having the structural formula:
The compound of claim 127, wherein R ³⁵ is CH ₃ or CD ₃.
The compound of claim 127 or 128, wherein R ³³ is OCH ₃.
The compound of claim 129, wherein m is 1 and n is 2.
A compound having the structural formula (IV) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ⁴¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁴² is

R ^42’, wherein R ^42’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each 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;

R ⁴³ is

wherein

each of X ⁴, X ⁵, X ⁶, X ⁷, X ⁸, X ⁹ and X ¹⁰ is independently selected from C, CH, N and NH;

R ^42a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^42b is a C _1-6 alkyl or C _3-6 cycloalkyl, aryl or heteroaryl, each 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 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 is substituted with 0-4 R ^42c;

R ⁴⁶ each occurrence is independently F, Cl, CN, OR, C ₁-C ₃ alkyl, C ₃-C ₅ cycloalkyl, CD ₃, CH ₂CF 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 a C ₁-C ₆ alkyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 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; and

j is 0, 1 or 2.
The compound of claim 131, wherein R ⁴³ is selected from:

wherein

R ⁴⁴ or R ⁴⁵, when bond to N, is H, a 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; and

R ⁴⁴ or R ⁴⁵, when bond to C, is H, 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.
The compound of claim 131 or 132, wherein R ⁴⁷ is C ₁-C ₃ alkoxy.
The compound of claim 131 or 132, wherein R ⁴⁷ is OCH ₃ or OCD ₃.
The compound of any one of claims 131-134, wherein j is 0.
The compound of any one of claims 131-134, wherein j is 1, and R ⁴⁶ is F or Cl.
The compound of any one of claims 131-136, wherein Y ¹ is CH and Y ² is CH:
The compound of any one of claims 131-136, wherein Y ¹ is CH and Y ² is N:
The compound of any one of claims 131-136, wherein Y ¹ is N and Y ² is CH:
The compound of any one of claims 131-136, wherein Y ¹ is N and Y ² is N:
The compound of any one of claims 131-136, wherein one or both of Y ¹ and Y ² is CF.
The compound of any one of claims 131-141, wherein Y ³ is NR.
The compound of claim 142, wherein Y ³ is NH.
The compound of claim 131, having the structural formula:
The compound of claim 131, having the structural formula:
The compound of claim 131, having the structural formula:
The compound of claim 131, having the structural formula:
The compound of claim 131, having the structural formula:
The compound of claim 131, having the structural formula:
The compound of claim 131, having the structural formula:
The compound of any one of claims 131-150, wherein R ⁴¹ is CH ₃.
The compound of any one of claims 131-150, wherein R ⁴¹ is CD ₃.
The compound of any one of claims 131-152, wherein R ⁴² is (C=O) R ^42b, wherein R ^42b is selected from C ₁-C ₆ alkyl, cyclopropyl or cyclobutyl, substituted with 0-2 R ^42c.
The compound of claim 153, wherein R ⁴² is (C=O) R ^42b, wherein R ^42b is cyclopropyl.
The compound of claim 153, wherein R ⁴² is (C=O) R ^42b, wherein R ^42b is cyclobutyl, optionally substituted with CN.
The compound of claim 153, wherein R ⁴² is (C=O) R ^42b, wherein R ^42b is C ₁-C ₆ alkyl, optionally substituted with NRR’ or OR.
The compound of any one of claims 131-152, wherein R ⁴² is pyridine substituted with 0-2 R ^42c.
A compound having the structural formula (V) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring B is a 5-or 6-membered aryl or heteroaryl;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁵ is selected from NR, O, CH ₂ and CF ₂;

Z ⁶ is NR ⁵⁶, CH ₂, O, S, SO or SO ₂;

each of X ⁴, X ⁷, X ⁸ and X ⁹ is independently selected from CH, N and NH;

R ⁵¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁵² is independently selected from H, F, Cl, CN, OR ^g, CH ₃, CF ₃, OCF ₃ and - (CH ₂) _p-Q;

R ^52a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^52c at each occurrence is independently H, halo, CN, OR, NRR’, OCF ₃, CF ₃, C _1-6 alkyl substituted with 0-3 R ^52a, C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^52a, C _2-6 alkynyl substituted with 0-3 R ^52a;

R ⁵⁵ each occurrence is independently H, C _1-6 alkyl, substituted with 0-3 R ^52a, 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 is substituted with 0-4 R ^52c;

R ⁵⁶ is R substituted with 0-3 R ^d;

R ⁵⁷ is H, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, OCD ₃ or OCF ₃;

R ^c is C _1-6 alkyl substituted with 0-3 R ^f, (CH ₂) _r-C _3-6 cycloalkyl substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^d is independently at each occurrence, hydrogen, F, Cl, Br, OCF ₃, CF ₃, CN, NO ₂, -OR ^e, - (CH ₂) _rC (O) R ^c, -NR ^eR ^e, -NR ^eC (O) OR ^c, C _1-6 alkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^e is independently at each occurrence, hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^f is independently at each occurrence, hydrogen, halo, CN, NH ₂, OH, C _3-6 cycloalkyl, CF ₃, O (C _1-6 alkyl) or a 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S;

R ^g at each occurrence is independently H, C _1-4 alkyl substituted with 0-3 R ^f, CF ₃, C _3-10 cycloalkyl substituted with 0-1 R ^f, (CH) _r-phenyl substituted with 0-3 R ^d or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^d;

Q is a water solubilizing group, optionally selected from OH, OR, NRR’, heterocyclic and heteroaryl groups, wherein R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO ₂;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

q is 0, 1, 2, 3 or 4.
The compound of claim 158, wherein each of Z ³, Z ⁴ and Z ⁵ is NH, having the structural formula (V ₁) :
The compound of claim 158 or 159, wherein Ring B is a 6-membered aryl or heteroaryl.
The compound of claim 160, having the structural formula (V ₂) :

wherein each of Z ⁷ and Z ⁸ is independently CH or N.
The compound of claim 161, having the structural formula (V ₃) :

wherein

R ⁵⁴ is H, a C ₁-C ₆ alkyl or C _1-6 alkoxy, CD ₃, or C ₃-C ₅ cycloalkyl, substituted with 0-3 R ^52a; and

R ⁵⁵ is H or C _1-6 alkyl or C _1-6 alkoxy, substituted with 0-3 R ^52a.
The compound of claim 161, having the structural formula (V ₄) :

wherein

R ⁵⁴ is H, a C ₁-C ₆ alkyl, CD ₃, or C ₃-C ₅ cycloalkyl, substituted with 0-3 R ^52a; and

R ⁵⁵ is H or C _1-6 alkyl or C _1-6 alkoxy, substituted with 0-3 R ^52a.
The compound of any one of claims 158-163, wherein Z ⁶ is O or S.
The compound of any one of claims 158-163, wherein Z ⁶ is NR.
The compound of any one of claims 158-165, wherein each of m and n is 1.
The compound of any one of claims 158-166, wherein R ⁵¹ is CH ₃.
The compound of any one of claims 158-166, wherein R ⁵¹ is CD ₃.
The compound of any one of claims 158-168, wherein R ⁵⁷ is C ₁-C ₃ alkoxy.
The compound of any one of claims 158-168, wherein R ⁵⁷ is OCH ₃, OCD ₃ or OCF ₃.
The compound of any one of claims 158-170, wherein q is 1 and R ⁵² is F, Cl, CN, CH ₃, CF ₃ or OCF ₃.
A compound selected from the group consisting of:
A pharmaceutical composition comprising a compound according to any of claims 1-172, effective to treat or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
A pharmaceutical composition comprising an amount of a compound having the structural formula of (I) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of X ¹ and X ² is independently selected from CH and N;

each of X ⁴ and X ⁵ is independently selected from CH, CF and N;

X ³ is NR, O, CH ₂ or CF ₂;

R ¹¹ is a H, F, C ₁-C ₃ alkyl or CD ₃;

R ¹² is C (=O) R ^12’ or R ^12’, wherein R ^12’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^12a, wherein R ^12a is selected from the group consisting of halogen, CF ₃, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ¹³ is a C ₁-C ₃ alkyl, CD ₃ or CF ₃;

R ¹⁴ is H, C ₁-C ₆ alkyl or heteroalkyl or a C ₃-C ₆ cycloalkyl or heterocycloalkyl, or a 5-or 6-membered heteroaryl group comprising 1, 2 or 3 hetero atoms selected from N, O and S, or R ¹⁴ is OR ^14’, wherein R ^14’ is C ₁-C ₆ alkyl or heteroalkyl or a C ₃-C ₆ cycloalkyl or heterocycloalkyl, each substituted with 0-2 R ^14a, wherein R ^14a is selected from the group consisting of halogen, R, OR, amino, CF ₃ and CN;

R ¹⁵ at each occurrence is independently selected from F, Cl, CN, OR, and a C ₁-C ₃ alkyl;

R at each occurrence is independently H or a C ₁-C ₆ alkyl; and

k is 0, 1, 2 or 3,

effective to treat, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
A pharmaceutical composition comprising an amount of a compound having the structural formula of (II) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ²¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ²² is

R ^22’, wherein R ^22’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^22a, wherein R ^22a is selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

an aryl or heteroaryl group, each substituted with 0-2 R ^24a; or

(C=O) R ²⁷;

R ²³ is

wherein

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 is substituted with 0-4 R ^24b;

R ^24a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^24b at 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, OR, C ₁-C ₃ alkyl, C ₃-C ₅ cycloalkyl, CD ₃, CH ₂CF ₃ or CF ₃;

R ²⁶ is H, a C ₁-C ₆ alkyl, CD ₃, or C ₃-C ₆ cycloalkyl, substituted with 0-3 R ^24a;

R ²⁷ is a C _1-6 alkyl or C _3-6 cycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^24b;

each of R and R’ is independently H or a C ₁-C ₆ alkyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 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; and

p is 1 or 2,

effective to treat, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
A pharmaceutical composition comprising an amount of a compound having the structural formula of (III) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring A is a 5-or 6-membered aryl or heteroaryl;

X ¹ is selected from NR, O, CH ₂ and CF ₂;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁶ is NR ³⁶, CH ₂, O, S, SO or SO ₂;

R ³² is R ^32’ or OR ^32’, wherein R ^32’ is a C _1-12 alkyl, 3-to 6-membered cycloalkyl or heterocycloalkyl comprising 1, 2 or 3 heteroatoms selected from N, O and S, or a 5-or 6-membered aryl or heteroaryl group, each substituted with 0-3 R ^32a;

R ^32a is independently at each occurrence, H, OCF ₃, CN, NO ₂, - (CH ₂) _rOR ^b, - (CH ₂) _rSR ^b, - (CH ₂) _rC (O) R ^b, - (CH ₂) _rC (O) OR ^b, - (CH ₂) _rOC (O) R ^b, (CH ₂) _rNR ^gR ^g, - (CH ₂) _rC (O) NR ^gR ^g, - (CH ₂) _rNR ^bC (O) R ^c, - (CH ₂) _rNR ^bC (O) OR ^c, -NR ^bC (O) NR ^gR ^g, -S (O) _vNR ^gR ^g, -NR ^bS (O) _vR ^c, -S (O) _vR ^c, C _1-6 alkyl substituted with 0-3 R ^a, C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a, 3-to 6-membered cycloalkyl substituted with 0-3 R ^a, or 3-to 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^a;

each of R ³³ and R ³⁴ is independently selected from H, F, Cl, CN, OR ^g, CH ₃, CD ₃, CF ₃, OCD ₃, OCF ₃ and - (CH ₂) _p-Q;

R ³⁵ is H, F, a C ₁-C ₃ alkyl and CD ₃;

R ³⁶ is R substituted with 0-3 R ^d;

R ^a at each occurrence is independently H, F, Cl, Br, OCF ₃, CF ₃, CHF ₂, CN, NO ₂, - (CH ₂) _rOR ^b, - (CH ₂) _rSR ^b, - (CH ₂) _rC (O) R ^b, - (CH ₂) _rC (O) OR ^b, - (CH ₂) _rOC (O) R ^b, - (CH ₂) _rNR ^gR ^g, - (CH ₂) _rC (O) NR ^gR ^g, - (CH ₂) _rNR ^bC (O) R ^c, - (CH ₂) _rNR ^bC (O) OR ^c, -NR ^bC (O) NR ^gR ^g, -S (O) _vNR ^gR ^g, -NR ^bS (O) _vR ^c, -S (O) R ^c, -S (O) ₂R ^c, C _1-6 alkyl substituted with 0-3 R ^f, C _1-6 haloalkyl, 3-to 6-membered cycloalkyl substituted with 0-3 R ^f, or 3-to 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^f;

R ^b is H, C _1-6 alkyl substituted with 0-3 R ^d, C _1-6 haloalkyl, C _3-6 cycloalkyl substituted with 0-2 R ^d, or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^d;

R ^c is C _1-6 alkyl substituted with 0-3 R ^f, (CH ₂) _r-C _3-6 cycloalkyl substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^d is independently at each occurrence, hydrogen, F, Cl, Br, OCF ₃, CF ₃, CN, NO ₂, -OR ^e, - (CH ₂) _rC (O) R ^c, -NR ^eR ^e, -NR ^eC (O) OR ^c, C _1-6 alkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^e is independently at each occurrence, hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^f is independently at each occurrence, hydrogen, halo, CN, NH ₂, OH, C _3-6 cycloalkyl, CF ₃, O (C _1-6 alkyl) or a 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S;

R ^g at each occurrence is independently H, C _1-4 alkyl substituted with 0-3 R ^f, CF ₃, C _3-10 cycloalkyl substituted with 0-1 R ^f, (CH) _r-phenyl substituted with 0-3 R ^d or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^d;

Q is a water solubilizing group, optionally selected from OH, OR, NRR’, heterocyclic and heteroaryl groups, wherein R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO ₂;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

r is 0, 1, 2, 3, 4 or 5,

effective to treat, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
A pharmaceutical composition comprising an amount of a compound having the structural formula of (IV) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ⁴¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁴² is

R ^42’, wherein R ^42’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each 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;

R ⁴³ is

wherein

each of X ⁴, X ⁵, X ⁶, X ⁷, X ⁸, X ⁹ and X ¹⁰ is independently selected from C, CH, N and NH;

R ^42a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^42b is a C _1-6 alkyl or C _3-6 cycloalkyl, aryl or heteroaryl, each 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 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 is substituted with 0-4 R ^42c;

R ⁴⁶ each occurrence is independently F, Cl, CN, OR, C ₁-C ₃ alkyl, C ₃-C ₅ cycloalkyl, CD ₃, CH ₂CF 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 a C ₁-C ₆ alkyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 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; and

j is 0, 1 or 2,

effective to treat, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
A pharmaceutical composition comprising an amount of a compound having the structural formula of (V) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring B is a 5-or 6-membered aryl or heteroaryl;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁵ is selected from NR, O, CH ₂ and CF ₂;

Z ⁶ is NR ⁵⁶, CH ₂, O, S, SO or SO ₂;

each of X ⁴, X ⁷, X ⁸ and X ⁹ is independently selected from CH, N and NH;

R ⁵¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁵² is independently selected from H, F, Cl, CN, OR ^g, CH ₃, CF ₃, OCF ₃ and - (CH ₂) _p-Q;

R ^52a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^52c at each occurrence is independently H, halo, CN, OR, NRR’, OCF ₃, CF ₃, C _1-6 alkyl substituted with 0-3 R ^52a, C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^52a, C _2-6 alkynyl substituted with 0-3 R ^52a;

R ⁵⁵ each occurrence is independently H, C _1-6 alkyl, substituted with 0-3 R ^52a, 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 is substituted with 0-4 R ^52c;

R ⁵⁶ is R substituted with 0-3 R ^d;

R ⁵⁷ is H, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, OCD ₃ or OCF ₃;

R ^c is C _1-6 alkyl substituted with 0-3 R ^f, (CH ₂) _r-C _3-6 cycloalkyl substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^d is independently at each occurrence, hydrogen, F, Cl, Br, OCF ₃, CF ₃, CN, NO ₂, -OR ^e, - (CH ₂) _rC (O) R ^c, -NR ^eR ^e, -NR ^eC (O) OR ^c, C _1-6 alkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^e is independently at each occurrence, hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^f is independently at each occurrence, hydrogen, halo, CN, NH ₂, OH, C _3-6 cycloalkyl, CF ₃, O (C _1-6 alkyl) or a 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S;

R ^g at each occurrence is independently H, C _1-4 alkyl substituted with 0-3 R ^f, CF ₃, C _3-10 cycloalkyl substituted with 0-1 R ^f, (CH) _r-phenyl substituted with 0-3 R ^d or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^d;

Q is a water solubilizing group, optionally selected from OH, OR, NRR’, heterocyclic and heteroaryl groups, wherein R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO ₂;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

q is 0, 1, 2, 3 or 4,

effective to treat, or reduce one or more diseases or disorders, in a mammal, including a human, and a pharmaceutically acceptable excipient, carrier, or diluent.
The pharmaceutical composition of any one of claims 173-178, being suitable for oral administration.
The pharmaceutical composition of any one of claims 173-178, being suitable for topical administration.
The pharmaceutical composition of any one of claims 173-176, being suitable for GI-restricted administration.
The pharmaceutical composition of any one of claims 173-181, being useful to treat or reduce one or more of inflammatory diseases, immune-mediated diseases and cancers, or a related disease or disorder.
The pharmaceutical composition of claim 182, wherein the disease or disorder is an inflammatory disease.
The pharmaceutical composition of claim 182, wherein the disease or disorder is an immune-mediated disease.
The pharmaceutical composition of claim 182, wherein the disease or disorder is cancer.
The pharmaceutical composition of any one of claims 175-185, wherein the disease or disorder is selected from: inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myelogenous leukemia (CML) , essential thrombocythemia (ET) , polycythemia vera (PV) , myelofibrosis (MF) , breast cancer and ovarian cancer.
A unit dosage form comprising a pharmaceutical composition according to any of claims 173-186.
The unit dosage form of claim 187, being a tablet.
The unit dosage form of claim 187, being a capsule.
The unit dosage form of claim 187, being a topical formulation.
A method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (I) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of X ¹ and X ² is independently selected from CH and N;

each of X ⁴ and X ⁵ is independently selected from CH, CF and N;

X ³ is NR, O, CH ₂ or CF ₂;

R ¹¹ is a H, F, C ₁-C ₃ alkyl or CD ₃;

R ¹² is C (=O) R ^12’ or R ^12’, wherein R ^12’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^12a, wherein R ^12a is selected from the group consisting of halogen, CF ₃, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ¹³ is a C ₁-C ₃ alkyl, CD ₃ or CF ₃;

R ¹⁴ is H, C ₁-C ₆ alkyl or heteroalkyl or a C ₃-C ₆ cycloalkyl or heterocycloalkyl, or a 5-or 6-membered heteroaryl group comprising 1, 2 or 3 hetero atoms selected from N, O and S, or R ¹⁴ is OR ^14’, wherein R ^14’ is C ₁-C ₆ alkyl or heteroalkyl or a C ₃-C ₆ cycloalkyl or heterocycloalkyl, each substituted with 0-2 R ^14a, wherein R ^14a is selected from the group consisting of halogen, R, OR, amino, CF ₃ and CN;

R ¹⁵ at each occurrence is independently selected from F, Cl, CN, OR, and a C ₁-C ₃ alkyl;

R at each occurrence is independently H or a C ₁-C ₆ alkyl; and

k is 0, 1, 2 or 3,

wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.
A method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (II) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ²¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ²² is

R ^22’, wherein R ^22’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^22a, wherein R ^22a is selected from the group consisting of halogen, CN, OR, amino, alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

an aryl or heteroaryl group, each substituted with 0-2 R ^24a; or

(C=O) R ²⁷;

R ²³ is

wherein

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 is substituted with 0-4 R ^24b;

R ^24a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^24b at 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, OR, C ₁-C ₃ alkyl, C ₃-C ₅ cycloalkyl, CD ₃, CH ₂CF ₃ or CF ₃;

R ²⁶ is H, a C ₁-C ₆ alkyl, CD ₃, or C ₃-C ₆ cycloalkyl, substituted with 0-3 R ^24a;

R ²⁷ is a C _1-6 alkyl or C _3-6 cycloalkyl, aryl or heteroaryl, each substituted with 0-2 R ^24b;

each of R and R’ is independently H or a C ₁-C ₆ alkyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 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; and

p is 1 or 2,

wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.
A method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (III) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring A is a 5-or 6-membered aryl or heteroaryl;

X ¹ is selected from NR, O, CH ₂ and CF ₂;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁶ is NR ³⁶, CH ₂, O, S, SO or SO ₂;

R ³² is R ^32’ or OR ^32’, wherein R ^32’ is a C _1-12 alkyl, 3-to 6-membered cycloalkyl or heterocycloalkyl comprising 1, 2 or 3 heteroatoms selected from N, O and S, or a 5-or 6-membered aryl or heteroaryl group, each substituted with 0-3 R ^32a;

R ^32a is independently at each occurrence, H, OCF ₃, CN, NO ₂, - (CH ₂) _rOR ^b, - (CH ₂) _rSR ^b, - (CH ₂) _rC (O) R ^b, - (CH ₂) _rC (O) OR ^b, - (CH ₂) _rOC (O) R ^b, (CH ₂) _rNR ^gR ^g, - (CH ₂) _rC (O) NR ^gR ^g, - (CH ₂) _rNR ^bC (O) R ^c, - (CH ₂) _rNR ^bC (O) OR ^c, -NR ^bC (O) NR ^gR ^g, -S (O) _vNR ^gR ^g, -NR ^bS (O) _vR ^c, -S (O) _vR ^c, C _1-6 alkyl substituted with 0-3 R ^a, C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^a, 3-to 6-membered cycloalkyl substituted with 0-3 R ^a, or 3-to 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^a;

each of R ³³ and R ³⁴ is independently selected from H, F, Cl, CN, OR ^g, CH ₃, CD ₃, CF ₃, OCD ₃, OCF ₃ and - (CH ₂) _p-Q;

R ³⁵ is H, F, a C ₁-C ₃ alkyl and CD ₃;

R ³⁶ is R substituted with 0-3 R ^d;

R ^a at each occurrence is independently H, F, Cl, Br, OCF ₃, CF ₃, CHF ₂, CN, NO ₂, - (CH ₂) _rOR ^b, - (CH ₂) _rSR ^b, - (CH ₂) _rC (O) R ^b, - (CH ₂) _rC (O) OR ^b, - (CH ₂) _rOC (O) R ^b, - (CH ₂) _rNR ^gR ^g, - (CH ₂) _rC (O) NR ^gR ^g, - (CH ₂) _rNR ^bC (O) R ^c, - (CH ₂) _rNR ^bC (O) OR ^c, -NR ^bC (O) NR ^gR ^g, -S (O) _vNR ^gR ^g, -NR ^bS (O) _vR ^c, -S (O) R ^c, -S (O) ₂R ^c, C _1-6 alkyl substituted with 0-3 R ^f, C _1-6 haloalkyl, 3-to 6-membered cycloalkyl substituted with 0-3 R ^f, or 3-to 6-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^f;

R ^b is H, C _1-6 alkyl substituted with 0-3 R ^d, C _1-6 haloalkyl, C _3-6 cycloalkyl substituted with 0-2 R ^d, or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^d;

R ^c is C _1-6 alkyl substituted with 0-3 R ^f, (CH ₂) _r-C _3-6 cycloalkyl substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^d is independently at each occurrence, hydrogen, F, Cl, Br, OCF ₃, CF ₃, CN, NO ₂, -OR ^e, - (CH ₂) _rC (O) R ^c, -NR ^eR ^e, -NR ^eC (O) OR ^c, C _1-6 alkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^e is independently at each occurrence, hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^f is independently at each occurrence, hydrogen, halo, CN, NH ₂, OH, C _3-6 cycloalkyl, CF ₃, O (C _1-6 alkyl) or a 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S;

R ^g at each occurrence is independently H, C _1-4 alkyl substituted with 0-3 R ^f, CF ₃, C _3-10 cycloalkyl substituted with 0-1 R ^f, (CH) _r-phenyl substituted with 0-3 R ^d or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^d;

Q is a water solubilizing group, optionally selected from OH, OR, NRR’, heterocyclic and heteroaryl groups, wherein R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO ₂;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

r is 0, 1, 2, 3, 4 or 5,

wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.
A method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (IV) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

each of Y ¹ and Y ² is independently selected from CH, CF and N;

Y ³ is NR, O, CH ₂ or CF ₂;

R ⁴¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁴² is

R ^42’, wherein R ^42’ is a C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl or heterocycloalkyl, aryl or heteroaryl, each 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;

R ⁴³ is

wherein

each of X ⁴, X ⁵, X ⁶, X ⁷, X ⁸, X ⁹ and X ¹⁰ is independently selected from C, CH, N and NH;

R ^42a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^42b is a C _1-6 alkyl or C _3-6 cycloalkyl, aryl or heteroaryl, each 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 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 is substituted with 0-4 R ^42c;

R ⁴⁶ each occurrence is independently F, Cl, CN, OR, C ₁-C ₃ alkyl, C ₃-C ₅ cycloalkyl, CD ₃, CH ₂CF 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 a C ₁-C ₆ alkyl, or R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 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; and

j is 0, 1 or 2,

wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.
A method for treating, reducing or preventing a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the structural formula of (V) :

or a pharmaceutically acceptable form or an isotope derivative thereof,

wherein

Ring B is a 5-or 6-membered aryl or heteroaryl;

each of Z ¹ and Z ² is independently selected from CH, CF and N;

each of Z ³ and Z ⁴ is independently selected from NR, CH ₂ and CF ₂;

Z ⁵ is selected from NR, O, CH ₂ and CF ₂;

Z ⁶ is NR ⁵⁶, CH ₂, O, S, SO or SO ₂;

each of X ⁴, X ⁷, X ⁸ and X ⁹ is independently selected from CH, N and NH;

R ⁵¹ is a H, F, C ₁-C ₃ alkyl and CD ₃;

R ⁵² is independently selected from H, F, Cl, CN, OR ^g, CH ₃, CF ₃, OCF ₃ and - (CH ₂) _p-Q;

R ^52a at each occurrence is independently H, D, halo, OH, OR, CH ₃, CF ₃, CH ₂CF ₃ or CN, NRR’, (CH ₂) _nNRR’ or a 4-to 6-membered heterocycle having 1-4 heteroatoms selected from N, O and S;

R ^52c at each occurrence is independently H, halo, CN, OR, NRR’, OCF ₃, CF ₃, C _1-6 alkyl substituted with 0-3 R ^52a, C _1-6 haloalkyl, C _2-6 alkenyl substituted with 0-3 R ^52a , C _2-6 alkynyl substituted with 0-3 R ^52a;

R ⁵⁵ each occurrence is independently H, C _1-6 alkyl, substituted with 0-3 R ^52a, 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 is substituted with 0-4 R ^52c;

R ⁵⁶ is R substituted with 0-3 R ^d;

R ⁵⁷ is H, C ₁-C ₃ alkyl, C ₁-C ₃ alkoxy, OCD ₃ or OCF ₃;

R ^c is C _1-6 alkyl substituted with 0-3 R ^f, (CH ₂) _r-C _3-6 cycloalkyl substituted with 0-3 R ^f or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^d is independently at each occurrence, hydrogen, F, Cl, Br, OCF ₃, CF ₃, CN, NO ₂, -OR ^e, - (CH ₂) _rC (O) R ^c, -NR ^eR ^e, -NR ^eC (O) OR ^c, C _1-6 alkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^e is independently at each occurrence, hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or (CH ₂) _r-phenyl substituted with 0-3 R ^f;

R ^f is independently at each occurrence, hydrogen, halo, CN, NH ₂, OH, C _3-6 cycloalkyl, CF ₃, O (C _1-6 alkyl) or a 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S;

R ^g at each occurrence is independently H, C _1-4 alkyl substituted with 0-3 R ^f, CF ₃, C _3-10 cycloalkyl substituted with 0-1 R ^f, (CH) _r-phenyl substituted with 0-3 R ^d or 5-to 7-membered heterocycloalkyl comprising 1-3 heteroatoms selected from N, O and S substituted with 0-3 R ^d;

Q is a water solubilizing group, optionally selected from OH, OR, NRR’, heterocyclic and heteroaryl groups, wherein R and R’, together with the nitrogen atom to which they are bound, form a 4-to 7-membered ring comprising 0-2 heteroatoms selected from O, NR, S and SO ₂;

R is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

R’ is H or a C ₁-C ₆ alkyl substituted with 0-3 R ^d;

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; and

q is 0, 1, 2, 3 or 4,

wherein the disease or disorder is selected from inflammatory diseases, immune-mediated diseases, cancer, or a related disease or disorder thereof, in a mammal, including a human.
The method of any one of claims 191-195, wherein the disease or disorder is an inflammatory disease.
The method of any one of claims 191-195, wherein the disease or disorder is an immune-mediated disease.
The method of any one of claims 191-195, wherein the disease or disorder is cancer.
The method of any one of claims 191-195, wherein the disease or disorder is selected from: inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myelogenous leukemia (CML) , essential thrombocythemia (ET) , polycythemia vera (PV) , myelofibrosis (MF) , breast cancer and ovarian cancer.
The method of any of claims 191-199, wherein administration is via oral administration.
The method of any of claims 191-199, wherein administration is via topical administration.
The method of any of claims 191-199, wherein administration is via GI-restricted administration.
Use of a compound of any of claims 1-172, and a pharmaceutically acceptable excipient, carrier, or diluent, in preparation of a medicament for treating a disease or disorder.
The use of claim 203, wherein the disease or disorder is one or more of inflammatory diseases, immune-mediated diseases and cancer.
The use of claim 204, wherein the disease or disorder is an inflammatory disease.
The use of claim 204, wherein the disease or disorder is an immune-mediated disease.
The use of claim 204, wherein the disease or disorder is cancer.
The use of any one of claims 203-207, wherein the medicament is for oral administration.
The use of any one of claims 203-207, wherein the medicament is for topical administration.
The use of any one of claims 203-207, wherein the medicament is for GI restriction administration.