RU2564419C1 - Heterocyclic analogues of pyrimidines as jak inhibitors - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of structural formula

which possesses JAK kinase inhibitory activity. In formula (I), R represents H; F; Cl; CH₃ or CF₃; cycle A represents a 5-merous aromatic heterocycle, wherein Z¹, Z² and Z³ are independently specified in a group consisting of C(R¹); N and N(R¹), provided at least one of Z¹, Z², Z³ represents N or N(R¹); each of R¹ independently represents H, C(O)R²; T¹; C_1-6alkyl; wherein C_1-6alkyl is independently substituted by one or more R³, which are identical or different; R² is specified in T¹; R⁴, R^4a are independently specified in a group consisting of H; T¹; C_1-6alkyl; wherein C_1-6alkyl is optionally substituted by one or more R⁵, which are identical or different; Y⁰ represents (CR^Y3R^Y4)_n; n means 0 or 1; one of the groups R^Y1; R^Y2; R^Y3; R^Y4 represents R^Y0, and others are specified in a group consisting of H and CH₃; X¹ represents C(R^6a) or N; X² means C(R^6b) or N; X³ means CH; X⁴ means C(R^6c); X⁵ means C(R^6d). The T¹, R³, R⁵, R^Y5, R^Y5a, R^6a, R^6b, R^6c, R^6d, R^Y0, T^Y1 radical values are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compounds, to the compound applicable in the method of treating or preventing an immunological, inflammatory, autoimmune or allergic disorder or disease related to graft rejection, and to the method of treating, controlling, delaying the onset or preventing JAK-related diseases or disorders.

37 cl, 9 tbl

Description

The present invention relates to a new class of kinase inhibitors, including pharmaceutically acceptable salts, prodrugs and metabolites of the inhibitors mentioned, which are useful for modulating the activity of protein kinases to regulate various cell functions, for example, signal transduction, proliferation and secretion of cytokines. More specifically, the invention provides compounds that inhibit, regulate and / or modulate kinase activity, in particular JAK3 activity, and signal transmission pathways related to the above types of cellular activity. In addition, the present invention relates to pharmaceutical compositions comprising these compounds, intended, for example, for the treatment or prophylaxis of immunological, inflammatory, autoimmune or allergic disorders or diseases, or transplant rejection, or graft versus host disease, as well as methods for producing these compounds.

Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides and other cellular metabolites, and play a key role in all aspects of the physiology of eukaryotic cells. Specifically, protein kinases and lipid kinases are involved in signaling acts that regulate cell activation, growth, differentiation and survival in response to extracellular mediators or stimuli, for example, growth factors, cytokines or chemokines. Typically, protein kinases are divided into two groups, namely, protein kinases, which predominantly phosphorylate tyrosine residues, and protein kinases, which predominantly phosphorylate serine and / or threonine residues. Tyrosine kinases include transmembrane growth factor receptors, for example, epidermal growth factor receptor (EGFR), and cytosolic non-receptor kinases, for example, Janus kinases (JAK).

Excessively high activity of protein kinases is involved in many diseases, including cancer, metabolic diseases, autoimmune or inflammatory disorders. This effect can be directly or indirectly caused by a violation of the control mechanisms due to mutation, overexpression, or inadequate activation of the enzyme. In all of these cases, selective inhibition of kinases is expected to have a positive effect.

One of the kinase groups that has recently focused on the search for new drugs is the family of non-receptor tyrosine kinases called Janus kinases (JAK). In mammals, this family includes four proteins, namely JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Each of these proteins contains a kinase domain and a catalytically inactive pseudokinase domain. JAK proteins bind to cytokine receptors through their amino-terminal FERM domains (domains of the protein group 4.1, ezrin, radixin, moesin). After binding of cytokines to the corresponding receptors, JAKs are activated and phosphorylate receptors, resulting in the formation of sites to which signal molecules (docking sites) are attached, especially for members of the signal protein and transcription activator (Stat) families (Yamaoka et al., 2004. The Janus kinases (Jaks. Genome Biology 5 (12): 253).

In mammals, JAK1, JAK2, and TYK2 proteins are expressed in all body tissues. In contrast, JAK3 expression occurs predominantly in hematopoietic cells and is tightly regulated by cell development and activation (Musso et al., 1995. 181 (4): 1425-31).

A study of JAK-deficient cell lines and mice with targeted genetic changes revealed the main, non-duplicated functions of JAKs in cytokine signaling. JAK1-knocked out mice exhibit a perinatal lethal phenotype, probably associated with neurological effects that prevent them from sucking (Rodig et al., 1998. Cell 93 (3): 373-83). Removal of the JAK2 gene leads to death of the embryo at the age of 12.5 days as a result of a violation of erythropoiesis (Neubauer et al., 1998. Cell 93 (3): 397-409). It is interesting to note that JAK3 deficiency was first detected in humans in the form of an autosomal recessive severe combined immunodeficiency (SCID) (Macchi et al., 1995. Nature 377 (6544): 65-68). JAK3-knocked out mice also exhibit SCID, but they show no other disorders besides immune, and this suggests that the JAK3 inhibitor as an immunosuppressant could have a limited in vivo effect and, therefore, it is an interesting potential immune suppressant (Papageorgiou and Wikman 2004, Trends in Pharmacological Sciences 25 (11): 558-62).

Activating JAK3 mutations have been observed in patients with acute megakaryoblastic leukemia (AMKL) (Walters et al., 2006. Cancer Cell 10 (1): 65-75). These mutated forms of JAK3 can transform Ba / F3 cells, leading to factor-independent growth, and cause signs of megakaryoblastic leukemia in the mouse model.

Diseases and disorders associated with JAK3 inhibition are described in more detail, for example, in WO 01/42246 and WO 2008/060301.

Several JAK3 inhibitors that can be used in medicine have been described in the literature (O'Shea et al., Nat. Rev.Drug Discov. 3 (7): 555-64). A potent JAK3 inhibitor (CP-690 550) has been reported to be effective in an animal model of organ transplantation (Changelian et al., 2003, Science 302 (5646): 875-888) and clinical trials (see review in: Pesu et al. 2008. Immunol. Rev. 223, 132-142). The CP-690 550 inhibitor does not show selectivity for JAK3 kinase and inhibits JAK2 kinase with almost the same efficiency (Jiang et al., 2008, J. Med. Chem. 51 (24): 8012-8018). A selective JAK3 inhibitor that inhibits JAK3 more strongly than JAK2 is expected to have more beneficial therapeutic properties since inhibition of JAK2 can cause anemia (Ghoreschi et al., 2009, Nature Immunol. 4, 356-360).

Pyrimidine derivatives exhibiting the ability to inhibit JAK3 and JAK2 kinases are described in WO-A 2008/009458. WO-A 2008/118822 and WO-A 2008/118823 describe the use of pyrimidine compounds in the treatment of conditions in which modulation of the JAK signaling pathway or inhibition of JAK kinases, including JAK3.

Fluorinated pyrimidine compounds as JAK3 inhibitors are described in WO-A 2010/118986. Heterocyclyl analogues of pyrazolopyrimidine as JAK inhibitors are described in WO-A 2011/048082.

Application WO-A 2008/129380 relates to sulfonylamide derivatives for the treatment of abnormal cell growth. WO-A 2006/117560 and J. of Molecular Graphics and Modeling (29) 2010, 309-320 describe pyrazolylamino-substituted pyrimidines and their use in the treatment of cancer. EP 1054004 A1 describes pyrimidine derivatives and their use in inflammation.

Although JAK inhibitors are known in the art, there is a need to develop new JAK inhibitors having at least somewhat more effective pharmaceutical properties, such as, for example, properties related to activity, selectivity, especially with respect to JAK2 kinase, and ADME (absorption , distribution, metabolism and excretion).

Thus, it is an object of the present invention to provide a new class of JAK inhibitor compounds which preferably exhibit selectivity for JAK2 and can be effective in the treatment or prevention of JAK related disorders.

Accordingly, the present invention relates to compounds of formula (I)

or their pharmaceutically acceptable salts or isotopic derivatives, where

R represents H; F; Cl; Br; CN; CH ₃ ; CF ₃ or C (O) NH ₂ ;

cycle A is a 5-membered aromatic heterocycle in which Z ¹ , Z ² and Z ^{3 are} independently selected from the group consisting of C (R ¹ ); N and N (R ¹ ), provided that at least one of Z ¹ , Z ² , Z ³ represents N or N (R ¹ );

each of R ¹ independently represents H, halogen; CN; C (O) OR ² ; OR ² ; C (O) R ² ; C (O) N (R ² R ^2a ); S (O) ₂ N (R ² R ^2a ); S (O) N (R ² R ^2a ); S (O) ₂ R ² ; S (O) R ² ; N (R ² ) S (O) ₂ N (R ^2a R ^2b ); N (R ² ) S (O) N (R ^2a R ^2b ); SR ² ; N (R ² R ^2a ); NO ₂ ; OC (O) R ² ; N (R ² ) C (O) R ^2a ; N (R ² ) S (O) ₂ R ^2a ; N (R ² ) S (O) R ^2a ; N (R ² ) C (O) N (R ^2a R ^2b ); N (R ² ) C (O) OR ^2a ; OC (O) N (R ² R ^2a ); T ¹ ; C _1-6 alkyl; C _2-6 alkenyl; or C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ³ that are the same or different;

R ² , R ^2a , R ^{2b are} independently selected from the group consisting of H; T ¹ ; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ³ that are the same or different;

R ³ represents halogen; CN; C (O) OR ⁴ ; OR ⁴ ; C (O) R ⁴ ; C (O) N (R ⁴ R ^4a ); S (O) ₂ N (R ⁴ R ^4a ); S (O) N (R ⁴ R ^4a ); S (O) ₂ R ⁴ ; S (O) R ⁴ ; N (R ⁴ ) S (O) ₂ N (R ^4a R ^4b ); N (R ⁴ ) S (O) N (R ^4a R ^4b ); SR ⁴ ; N (R ⁴ R ^4a ); NO ₂ ; OC (O) R ⁴ ; N (R ⁴ ) C (O) R ^4a ; N (R ⁴ ) S (O) ₂ R ^4a ; N (R ⁴ ) S (O) R ^4a ; N (R ⁴ ) C (O) N (R ^4a R ^4b ); N (R ⁴ ) C (O) OR ^4a ; OC (O) N (R ⁴ R ^4a ); or T ¹ ;

R ⁴ , R ^4a , R ^{4b are} independently selected from the group consisting of H; T ¹ ; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ⁵ that are the same or different;

R ⁵ represents halogen; CN; C (O) OR ^5a ; OR ^5a ; C (O) R ^5a ; C (O) N (R ^5a R ^5b ); S (O) ₂ N (R ^5a R ^5b ); S (O) N (R ^5a R ^5b ); S (O) ₂ R ^5a ; S (O) R ^5a ; N (R ^5a ) S (O) ₂ N (R ^5b R ^5c ); N (R ^5a ) S (O) N (R ^5b R ^5c ); SR ^5a ; N (R ^5a R ^5b ); NO ₂ ; OC (O) R ^5a ; N (R ^5a ) C (O) R ^5a ; N (R ^5a ) S (O) ₂ R ^5b ; N (R ^5a ) S (O) R ^5b ; N (R ^5a ) C (O) N (R ^5b R ^5c ); N (R ^5a ) C (O) OR ^5b ; or OC (O) N (R ^5a R ^5b );

R ^5a , R ^5b , R ^{5c are} independently selected from the group consisting of H; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more halogen atoms that are the same or different;

T ¹ represents C _3-7 cycloalkyl; saturated 4-7 membered heterocyclyl; or 7-11 membered heterobicyclyl; where T ^{1 is} optionally substituted with one or more R ¹⁰ that are the same or different;

Y ⁰ represents (CR ^Y3 R ^Y4 ) _n ;

n is 0; or 1;

one of R ^Y1 ; R ^Y2 ; R ^Y3 ; R ^Y4 ; represents R ^Y0 , and others are selected from the group consisting of H; CH ₃ ; and CF ₃ ;

R ^Y0 is unsubstituted C _1-4 alkyl; CH ₂ CH ₂ OR ^Y5 ; CH ₂ CH ₂ C (O) T ^Y1 ; CH ₂ CH ₂ C (O) OR ^Y5 ; CH ₂ CH ₂ OC (O) R ^Y5 ; CH ₂ CH ₂ N (R ^Y5 R ^Y5a ); CH ₂ CH ₂ N (R ^Y5 ) C (O) R ^Y5a ; CH ₂ CH ₂ C (O) N (R ^Y5 R ^Y5a ); CH ₂ OR ^Y5 ; CH ₂ C (O) T ^Y1 ; CH ₂ C (O) OR ^Y5 ; CH ₂ OC (O) R ^Y5 ; CH ₂ N (R ^Y5 R ^Y5a ); CH ₂ N (R ^Y5 ) C (O) R ^Y5a ; CH ₂ C (O) N (R ^Y5 R ^Y5a ); C (O) T ^Y1 ; C (O) OR ^Y5 ; or C (O) N (R ^Y5 R ^Y5a );

R ^Y5 , R ^{Y5a are} independently selected from the group consisting of H; T ^Y1 ; and C _1-4 alkyl, wherein C _1-4 alkyl is optionally substituted with one or more R ^Y6 that are the same or different;

R ^Y6 is halogen; OR ^Y7 ; C (O) T ^Y1 ; C (O) OR ^Y7 ; OC (O) R ^Y7 ; N (R ^Y7 R ^Y7a ); or N (R ^Y7 ) C (O) R ^Y7a ;

R ^Y7 ; RY ^{7a are} independently selected from the group consisting of H, C _1-4 alkyl; or T ^Y1 , where C _1-4 alkyl is optionally substituted with one or more halogen atoms that are the same or different;

T ^Y1 represents unsubstituted C _3-7 cycloalkyl; unsubstituted saturated 4-7 membered heterocyclyl; or saturated 7-11 membered heterobicyclyl;

X ¹ represents C (R ^6a ) or N; X ² is C (R ^6b ) or N; X ³ is CH, CF, COH or N; X ⁴ is C (R ^6c ) or N; X ⁵ is C (R ^6d ) or N; provided that no more than two of the numbers X ¹ , X ² , X ⁴ , X ⁵ are N atoms;

R ^6a , R ^6b , R ^6c , R ^{6d are} independently selected from the group consisting of H, halogen; CN; C (O) OR ⁷ ; OR ⁷ ; C (O) R ⁷ ; C (O) N (R ⁷ R ^7a ); S (O) ₂ N (R ⁷ R ^7a ); S (O) N (R ⁷ R ^7a ); S (O) ₂ R ⁷ ; S (O) R ⁷ ; N (R ⁷ ) S (O) ₂ N (R ^7a R ^7b ); N (R ⁷ ) S (O) N (R ^7a R ^7b ); SR ⁷ ; N (R ⁷ R ^7a ); NO ₂ ; OC (O) R ⁷ ; N (R ⁷ ) C (O) R ^7a ; N (R ⁷ ) S (O) ₂ R ^7a ; N (R ⁷ ) S (O) R ^7a ; N (R ⁷ ) C (O) N (R ^7a R ^7b ); N (R ⁷ ) C (O) OR ^7a ; OC (O) N (R ⁷ R ^7a ); T ² ; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ¹¹ that are the same or different;

a pair of R ^6a / R ^{6b is} optionally combined to form a cyclic fragment of T ³ ;

R ⁷ , R ^7a , R ^{7b are} independently selected from the group consisting of H; CN; T ² ; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ⁸ that are the same or different;

R ⁸ represents halogen; CN; C (O) OR ⁹ ; OR ⁹ ; C (O) R ⁹ ; C (O) N (R ⁹ R ^9a ); S (O) ₂ N (R ⁹ R ^9a ); S (O) N (R ⁹ R ^9a ); S (O) ₂ R ⁹ ; S (O) R ⁹ ; N (R ⁹ ) S (O) ₂ N (R ^9a R ^9b ); N (R ⁹ ) S (O) N (R ^9a R ^9b ); SR ⁹ ; N (R ⁹ R ^9a ); NO ₂ ; OC (O) R ⁹ ; N (R ⁹ ) C (O) R ^9a ; N (R ⁹ ) S (O) ₂ R ^9a ; N (R ⁹ ) S (O) R ^9a ; N (R ⁹ ) C (O) N (R ^9a R ^9b ); N (R ⁹ ) C (O) OR ^9a ; OC (O) N (R ⁹ R ^9a ); or T ² ;

R ⁹ , R ^9a , R ^{9b are} independently selected from the group consisting of H; T ² ; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ¹² that are the same or different;

R ¹⁰ represents halogen; CN; C (O) OR ¹³ ; OR ¹³ ; oxo (= O), where the cycle is at least partially saturated; C (O) R ¹³ ; C (O) N (R ¹³ R ^13a ); S (O) ₂ N (R ¹³ R ^13a ); S (O) N (R ¹³ R ^13a ); S (O) ₂ R ¹³ ; S (O) R ¹³ ; N (R ¹³ ) S (O) ₂ N (R ^13a R ^13b ); N (R ¹³ ) S (O) N (R ^13a R ^13b ); SR ¹³ ; N (R ¹³ R ^13a ); NO ₂ ; OC (O) R ¹³ ; N (R ¹³ ) C (O) R ^13a ; N (R ¹³ ) S (O) ₂ R ^13a ; N (R ¹³ ) S (O) R ^13a ; N (R ¹³ ) C (O) N (R ^13a R ^13b ); N (R ¹³ ) C (O) OR ^13a ; OC (O) N (R ¹³ R ^13a ); C _1-6 alkyl; C _2-6 alkenyl; or C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ¹⁴ that are the same or different;

R ¹³ , R ^13a , R ^{13b are} independently selected from the group consisting of H; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ¹⁴ that are the same or different;

R ¹¹ , R ^{12 are} independently selected from the group consisting of halogen; CN; C (O) OR ¹⁵ ; OR ¹⁵ ; C (O) R ¹⁵ ; C (O) N (R ¹⁵ R ^15a ); S (O) ₂ N (R ¹⁵ R ^15a ); S (O) N (R ¹⁵ R ^15a ); S (O) ₂ R ¹⁵ ; S (O) R ¹⁵ ; N (R ¹⁵ ) S (O) ₂ N (R ^15a R ^15b ); N (R ¹⁵ ) S (O) N (R ^15a R ^15b ); SR ¹⁵ ; N (R ¹⁵ R ^15a ); NO ₂ ; OC (O) R ¹⁵ ; N (R ¹⁵ ) C (O) R ^15a ; N (R ¹⁵ ) S (O) ₂ R ^15a ; N (R ¹⁵ ) S (O) R ^15a ; N (R ¹⁵ ) C (O) N (R ^15a R ^15b ); N (R ¹⁵ ) C (O) OR ^15a ; OC (O) N (R ¹⁵ R ^15a ); or T ² ;

R ¹⁵ , R ^15a , R ^{15b are} independently selected from the group consisting of H; T ² ; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more halogens that are the same or different;

R ¹⁴ represents halogen; CN; C (O) OR ¹⁶ ; OR ¹⁶ ; C (O) R ¹⁶ ; C (O) N (R ¹⁶ R ^16a ); S (O) ₂ N (R ¹⁶ R ^16a ); S (O) N (R ¹⁶ R ^16a ); S (O) ₂ R ¹⁶ ; S (O) R ¹⁶ ; N (R ¹⁶ ) S (O) ₂ N (R ^16a R ^16b ); N (R ¹⁶ ) S (O) N (R ^16a R ^16b ); SR ¹⁶ ; N (R ¹⁶ R ^16a ); NO ₂ ; OC (O) R ¹⁶ ; N (R ¹⁶ ) C (O) R ^16a ; N (R ¹⁶ ) S (O) ₂ R ^16a ; N (R ¹⁶ ) S (O) R ^16a ; N (R ¹⁶ ) C (O) N (R ^16a R ^16b ); N (R ¹⁶ ) C (O) OR ^16a ; or OC (O) N (R ¹⁶ R ^16a );

R ¹⁶ , R ^16a , R ^{16b are} independently selected from the group consisting of H; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more halogens that are the same or different;

T ² represents phenyl; naphthyl; indenyl; indanyl; C _3-7 cycloalkyl; 4-7 membered heterocyclyl; or a 7-11 membered heterobicyclyl, wherein T ^{2 is} optionally substituted with one or more R ¹⁷ that are the same or different;

T ³ represents phenyl; C _3-7 cycloalkyl; 4-7 membered heterocyclyl; or 7-11 membered heterobicyclyl, wherein T ^{3 is} optionally substituted with one or more R ¹⁸ that are the same or different;

R ¹⁷ , R ^{18 are} independently selected from the group consisting of halogen; CN; C (O) OR ¹⁹ ; OR ¹⁹ ; oxo (= O), where the cycle is at least partially saturated; C (O) R ¹⁹ ; C (O) N (R ¹⁹ R ^19a ); S (O) ₂ N (R ¹⁹ R ^19a ); S (O) N (R ¹⁹ R ^19a ); S (O) ₂ R ¹⁹ ; S (O) R ¹⁹ ; N (R ¹⁹ ) S (O) ₂ N (R ^19a R ^19b ); N (R ¹⁹ ) S (O) N (R ^19a R ^19b ); SR ¹⁹ ; N (R ¹⁹ R ^19a ); NO ₂ ; OC (O) R ¹⁹ ; N (R ¹⁹ ) C (O) R ^19a ; N (R ¹⁹ ) S (O) ₂ R ^19a ; N (R ¹⁹ ) S (O) R ^19a ; N (R ¹⁹ ) C (O) N (R ^19a R ^19b ); N (R ¹⁹ ) C (O) OR ^19a ; OC (O) N (R ¹⁹ R ^19a ); C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ²⁰ that are the same or different;

R ¹⁹ , R ^19a , R ^{19b are} independently selected from the group consisting of H; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ²⁰ that are the same or different;

R ²⁰ represents halogen; CN; C (O) OR ²¹ ; OR ²¹ ; C (O) R ²¹ ; C (O) N (R ²¹ R ^21a ); S (O) ₂ N (R ²¹ R ^21a ); S (O) N (R ²¹ R ^21a ); S (O) ₂ R ²¹ ; S (O) R ²¹ ; N (R ²¹ ) S (O) ₂ N (R ^21a R ^21b ); N (R ²¹ ) S (O) N (R ^21a R ^21b ); SR ²¹ ; N (R ²¹ R ^21a ); NO ₂ ; OC (O) R ²¹ ; N (R ²¹ ) C (O) R ^21a ; N (R ²¹ ) S (O) ₂ R ^21a ; N (R ²¹ ) S (O) R ^21a ; N (R ²¹ ) C (O) N (R ^21a R ^21b ); N (R ²¹ ) C (O) OR ^21a ; or OC (O) N (R ²¹ R ^21a );

R ²¹ , R ^21a , R ^{21b are} independently selected from the group consisting of H; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more halogens that are the same or different;

provided that the following compounds are excluded from this definition:

.

.

Compounds excluded from the scope of formula (I) are disclosed in WO 2006 / 117560A in the examples on pages 27-29.

In the event that a variable fragment or substituent can be selected from a group of different variants, and this variable fragment or substituent occurs more than once in a compound, variants of this variable fragment or substituent may be the same or different.

In the framework of the present invention, the following terms have the following meanings:

The term “optionally substituted” means unsubstituted or substituted. Typically, but not limited to, the term “one or more substituents” means one, two, or three, preferably one or two, and more preferably one. Typically, these substituents may be the same or different.

The term “alkyl” means a straight or branched hydrocarbon chain. Each hydrogen at the carbon atom of alkyl can be replaced by substituents, which are described in more detail in the text of the application.

The term “alkenyl” means a straight or branched hydrocarbon chain that includes at least one carbon-carbon double bond. Each hydrogen at the carbon atom of alkenyl can be replaced by substituents, which are described in more detail in the text of the application.

The term “alkynyl” means a straight or branched hydrocarbon chain that includes at least one carbon-carbon triple bond. Each hydrogen at the carbon atom of alkenyl can be replaced by substituents, which are described in more detail in the text of the application.

The term “C _1-4 alkyl” means an alkyl chain containing 1-4 carbon atoms, for example, if an alkyl radical is present at the end of the molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or if the alkyl group binds two parts of the molecule, for example, -CH ₂ -, -CH ₂ -CH ₂ -, -CH (CH ₃ ) -, -CH ₂ -CH ₂ -CH ₂ -, -CH (C ₂ H ₅ ) -, -C (CH ₃ ) ₂ -. Each hydrogen at the carbon atom of C _1-4 alkyl can be replaced by substituents, which are described in more detail in the text of the application. Accordingly, the term “C _2-4 alkyl” is also defined.

The term “C _1-6 alkyl” means an alkyl chain containing 1-6 carbon atoms, for example, if an alkyl radical is present at the end of the molecule: C _1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or, if the alkyl group binds two parts of the molecule, for example, -CH ₂ -, -CH ₂ -CH ₂ -, -CH (CH ₃ ) -, -CH ₂ -CH ₂ -CH ₂ -, -CH (C ₂ H ₅ ) -, -C (CH ₃ ) ₂ -. Each hydrogen at the carbon atom of C _1-6 alkyl can be replaced by substituents, which are described in more detail in the text of the application.

The term “C _2-6 alkenyl” means an alkenyl chain containing 2-6 carbon atoms, for example, if an alkenyl radical is present at the end of the molecule: —CH = CH ₂ , —CH = CH — CH ₃ , —CH ₂ —CH = CH ₂ , -CH = CH-CH ₂ -CH ₃ , -CH = CH-CH = CH ₂ or, if the alkenyl group binds two parts of the molecule, for example, -CH = CH-. Each hydrogen at the carbon atom of C _2-6 alkenyl can be replaced by substituents, which are described in more detail in the text of the application.

The term “C _2-6 alkynyl” means an alkynyl chain having 2-6 carbon atoms, for example, if the alkynyl radical is present at the end of the molecule: —C≡CH, —CH ₂ —C≡CH, —CH ₂ —CH ₂ - C≡CH, -CH ₂ -C≡C-CH ₃ or, if the alkynyl group binds two parts of the molecule, for example, -C≡C-. Each hydrogen at the carbon atom of C _2-6 alkynyl can be replaced by substituents, which are described in more detail in the text of the application.

The term “C _3-7 cycloalkyl” means a cyclic alkyl residue containing 3-7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Preferably, the term “cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Each hydrogen at the carbon atom of C _2-6 alkynyl can be replaced by substituents, which are described in more detail in the text of the application. Accordingly, the term “C _3-5 cycloalkyl” is also defined.

The term “halogen” means fluoro, chloro, bromo or iodo. In general, it is preferred that the halogen be fluorine or chlorine.

The term "4-7 membered heterocyclyl" or "4-7 membered heterocycle" means a cycle comprising 4, 5, 6 or 7 cyclic atoms, which may contain double bonds in an amount up to the maximum (aromatic or non-aromatic cycle, which is completely or partially unsaturated or saturated), where at least one and up to four atoms of the cycle are replaced by heteroatoms selected from the group consisting of sulfur (including —S (O) -, —S (O) ₂ -), oxygen and nitrogen fragments (including fragment = N (O) -), and where the indicated cycle is associated with the rest of the mole Kula through carbon or nitrogen atoms. Examples of 4-7 membered heterocycles are azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiaziazole, isothiaziol, thiaziazole, thiaziazole, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxiazolidine, thiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine pyridine azole, triazolidine, tetrazolidine, diazepan, azepine or homopiperazine. Accordingly, the term “5-6 membered heterocycle” or “5-6 membered heterocycle” is also defined.

The term “saturated 4-7 membered heterocycle” or “saturated 4-7 membered heterocycle” means a fully saturated “4-7 membered heterocyclyl” or “4-7 membered heterocycle”.

The term “5-membered aromatic heterocyclyl” or “5-membered aromatic heterocycle” means a heterocycle derived from cyclopentadienyl in which at least one carbon atom is replaced by a hetero atom selected from the group consisting of sulfur (including —S (O) -, -S (O) ₂ -), oxygen and nitrogen (including the moiety = N (O) -). Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole.

The term “7-11 membered heterobicyclic” or “7-11 membered heterobicycle” means a two-ring heterocyclic system comprising from 7 to 11 cyclic atoms, where at least one cyclic atom is included in both cycles, which may contain double bonds in the amount up to the maximum (aromatic or non-aromatic cycle, which is completely or partially unsaturated or saturated), where at least one and up to six cyclic atoms are replaced by heteroatoms selected from the group consisting of sulfur (including fragments -S (O) -, -S (O) ₂ -), oxygen and nitrogen (including the fragment = N (O) -), and where the indicated cyclic system is connected to the rest of the molecule via a carbon or nitrogen atom. Examples 7-11 membered heterobicycle are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazolinyl, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term “7-11 membered heterobicycle” also encompasses spiro structures from two cycles, such as 1,4-dioxa-8-azaspiro [4.5] decane or 2-oxa-6-azaspiro [3.3] heptan-6-yl, or bridging heterocycles, such as 8-azabicyclo [3.2.1] octane or 2,5-diazabicyclo [2.2.2] octan-2-yl.

The term “saturated 7-11 membered heterobicyclic” or “saturated 7-11 membered heterobicyclic” means a fully saturated “7-11 membered heterobicyclic” or “7-11 membered heterobicyclic”.

Preferred compounds of formula (I) are those in which one or more of the fragments included therein has the meanings indicated below, all combinations of preferred substituent values being included within the scope of the present invention. As for all preferred compounds of formula (I), the present invention also includes all tautomeric and stereoisomeric forms, as well as mixtures thereof in all ratios, and, in addition, pharmaceutically acceptable salts.

In preferred embodiments of the present invention, the substituents mentioned below independently take on the following meanings. Therefore, one or more of these substituents may have the following preferred or more preferred meanings.

Preferably, n is 0.

Preferably, in the formula (I), the fragments R ^Y1 , R ^Y2 and Y ^{0 are} determined in such a way that the formula (I) takes the form of the formulas (Ia), (Ib), (Ic) or (Id):

.

.

Preferably, Z ² in formulas (Ia) to (Id) is N (R ¹ ), where R ^{1 is} not H. Formula (Ia) is even more preferred.

Preferably, R ^Y0 is unsubstituted C _2-4 alkyl; CH ₂ CH ₂ OR ^Y5 ; CH ₂ CH ₂ C (O) T ^Y1 ; CH ₂ CH ₂ C (O) OR ^Y5 ; CH ₂ CH ₂ OC (O) OR ^Y5 ; CH ₂ CH ₂ N (R ^Y5 R ^Y5a ); CH ₂ CH ₂ N (R ^Y5 ) C (O) R ^Y5a ; CH ₂ CH ₂ C (O) N (R ^Y5 R ^Y5a ); CH ₂ OR ^Y5 ; CH ₂ C (O) T ^Y1 ; CH ₂ C (O) OR ^Y5 ; CH ₂ OC (O) R ^Y5 ; CH ₂ N (R ^Y5 R ^Y5a ); CH ₂ N (R ^Y5 ) C (O) R ^Y5a ; CH ₂ C (O) N (R ^Y5 R ^Y5a ); C (O) T ^Y1 ; C (O) OR ^Y5 ; or C (O) N (R ^Y5 R ^Y5a ). More preferably, R ^Y0 is CH ₂ CH ₃ ; CH ₂ OR ^Y5 ; C (O) OR ^Y5 ; C (O) N (R ^Y5 R ^Y5a ); or C (O) T ^Y1 . Even more preferably, R ^Y0 is CH ₂ OR ^Y5 , in particular CH ₂ OH. Even more preferably, R ^Y0 is CH ₂ OH; CH ₂ CH ₃ ; C (O) OH; C (O) CH ₃ ; C (O) NHCH ₃ ; C (O) N (CH ₃ ) ₂ ; C (O) NHCH ₂ CH ₃ ; C (O) NHCH ₂ CH ₂ CH ₂ OCH ₃ ; pyrrolidin-1-ylcarbonyl; or piperidin-1-ylcarbonyl. Even more preferably, R ^Y0 is CH ₂ OCH ₃ ; cyclopentylaminocarbonyl; CH ₂ CH ₂ OH; or 2,2,2-trifluoroethylaminocarbonyl.

Preferably, cycle A is a pyrrolyl or pyrazolyl ring; more preferably a pyrazolyl ring. Even more preferably, the cycle is selected from the group consisting of:

Even more preferably, the cycle is

Preferably, cycle A is unsubstituted. More preferably, cycle A is substituted with one or two (preferably one) R ¹ fragments that are different from H and are the same or different.

Preferably, one of the fragments Z ¹ , Z ² , Z ³ represents N (R ¹ ), and R ^{1 is} not H.

Preferably, R ¹ represents C (O) OR ² ; C (O) R ² ; or C (O) N (R ² R ^2a ) (preferably C (O) NHR ² ). Preferably, R ¹ is morpholin-4-ylcarbonyl. Preferably, R ¹ is N-methylpyrrolidin-2-one-3-yl.

Preferably, R ¹ is unsubstituted C _1-4 alkyl (preferably methyl); or C _1-4 alkyl substituted with one or two (preferably one) R ³ fragments that are the same or different.

Preferably, R ³ means halogen; OR ⁴ ; C (O) OR ⁴ ; C (O) T ¹ ; or C (O) N (R ⁴ R ^4a ). Also preferably, R ³ is OR ⁴ ; C (O) OR ⁴ ; or C (O) N (R ⁴ R ^4a ). More preferably, R ³ is NH ₂ or halogen. More preferably, R ³ is C (O) N (R ⁴ R ^4a ). Even more preferably, R ³ is OH; C (O) OC _1-4 alkyl (preferably ethyl or 2-propyl); C (O) NHC _1-4 alkyl (preferably methyl); or C (O) N (C _1-4 alkyl) ₂ (preferably dimethyl). Even more preferably, R ³ is C (O) NH ₂ .

More preferably, R ^{1 is} selected from the group consisting of CH ₂ CH ₂ OH; CH ₂ CH (OH) CH ₃ ; CH ₂ C (O) OH; CH ₂ C (O) OC _1-4 alkyl (preferably ethyl or 2-propyl); CH ₂ C (O) NHC _1-4 alkyl (preferably methyl); or CH ₂ C (O) N (C _1-4 alkyl) ₂ (preferably dimethyl). Even more preferably, R ¹ is CH ₂ C (CH ₃ ) ₂ OH; (CH ₂ ) ₃ OH; cyclopropylaminocarbonylmethyl; CH ₂ C (O) N (CH ₃ ) CH ₂ CN; C (CH ₃ ) ₂ C (O) NH ₂ ; CH ₂ C (O) NH (CH ₂ ) ₂ N (CH ₃ ) ₂ ; CH ₂ C (O) NH (CH ₂ ) ₃ N (CH ₃ ) ₂ ; morpholin-4-ylcarbonylmethyl; 3-aminopropyl; isopropyloxyethyl; CH ₂ C (O) NHCH (CH ₃ ) ₂ ; CH ₂ C (O) NHCH (CH ₃ ) CH ₂ OH; or 2,2-difluoroethyl. Even more preferably, R ¹ is CH ₃ or CH ₂ CH ₂ OH. Even more preferably, R ¹ is CH ₂ C (O) NH ₂ or CH ₂ C (O) NHCH ₃ .

Preferably, R is F; Cl; CF ₃ ; or CH ₃ . More preferably, R is Cl.

Preferably, none of the fragments X ¹ , X ² , X ⁴ , X ⁵ is N. Preferably, X ³ means CH. More preferably, X ¹ , X ² , X ⁴ , X ⁵ are CH moieties.

Preferably, no more than three (preferably no more than two, even more preferably no more than one) fragments of R ^6a , R ^6b , R ^6c , R ^6d are different from H. Accordingly, in a preferred embodiment, none of the fragments R ^6a , R ^6b , R ^6c , R ^{6d is} not different from H, and in another preferred embodiment, one of the fragments R ^6a , R ^6b , R ^6c , R ^{6d is} not H.

Preferably, the fragments R ^6a , R ^6b , R ^6c , R ^{6d are} independently selected from the group consisting of H, halogen; CN; C (O) OR ⁷ ; OR ⁷ ; C (O) R ⁷ ; C (O) N (R ⁷ R ^7a ); S (O) ₂ N (R ⁷ R ^7a ); S (O) N (R ⁷ R ^7a ); S (O) ₂ R ⁷ ; S (O) R ⁷ ; SR ⁷ ; N (R ⁷ R ^7a ); NO ₂ ; OC (O) R ⁷ ; N (R ⁷ ) C (O) R ^7a ; N (R ⁷ ) C (O) N (R ^7a R ^7b ); N (R ⁷ ) C (O) OR ^7a ; OC (O) N (R ⁷ R ^7a ); T ² ; C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl, where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl is optionally substituted with one or more R ¹¹ groups that are the same or different.

Preferably, the fragments R ^6a , R ^6b , R ^6c , R ^{6d are} independently selected from the group consisting of H, halogen (preferably F); or T ² , for example, 2-oxa-6-azaspiro [3.3] heptan-6-yl, N-methylpyrazol-4-yl. Preferably, the fragments R ^6a , R ^6b , R ^6c , R ^{6d are} independently selected from the group consisting of H; halogen; CF ₃ ; OR ⁷ , for example, OCH ₃ ; or T ² , for example, N-methylpyrazol-4-yl or morpholin-3-one-4-yl. More preferably, fragments R ^6a , R ^6b , R ^6c , R ^{6d are} independently selected from the group consisting of H; and halogen (preferably F).

Compounds of formula (I) in which some or all of the above groups have preferred meanings are also the subject of the present invention.

Even more preferred compounds of the present invention are selected from the group consisting of:

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;

2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;

(S) -2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;

(R) -5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) -N4- (1-phenylpropyl) pyrimidin-2,4-diamine;

(S) -2 - ((2 - ((1-methyl-1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) -2-phenylethanol;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylpropan-1-ol;

2 - ((2 - ((1-methyl-1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) -2-phenylpropan-1-ol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;

(S) -2 - ((5-fluoro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;

2 - ((2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) -5-methylpyrimidin-4-yl) amino) -2-phenylethanol;

(S) - (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrrol-2-yl) (morpholino) methanone;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -3-phenylpropan-1-ol;

methyl 2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylacetate;

methyl 2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylacetate;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylacetic acid;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylacetic acid;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -3-phenylpropan-1-ol;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-methyl-2-phenylacetamide;

(S) -isopropyl 2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetate;

(S) -ethyl 2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetate;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetic acid;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethyl-2-phenylacetamide;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethyl-2 phenylacetamide;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-ethyl-2-phenylacetamide ;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-ethyl-2-phenylacetamide;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N- (2-methoxyethyl) -2-phenylacetamide ;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N, N dimethylacetamide;

2- (4 - ((5-chloro-4 - ((1- (2,6-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N methylacetamide;

2- (4 - ((5-chloro-4 - ((1- (3-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;

2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyramidin-4-yl) amino) -2-phenyl-1- (pyrrolidin-1- sludge) ethanone;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenyl-1- ( pyrrolidin-1-yl) ethanone;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;

1- (4 - ((5-chloro-4 - ((1- (3-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propan-2- ol;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;

1- (4 - ((5-chloro-4 - ((1- (2,6-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propan- 2-ol;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2,6-difluorophenyl) ethanol;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2,6-difluorophenyl) ethanol;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) -2- (2,6-difluorophenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N- (2-hydroxyethyl) -2-phenylacetamide ;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N- (2-hydroxyethyl) -2-phenylacetamide;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N- (2-methoxyethyl) -2-phenylacetamide;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenyl-1- (piperidin-1- sludge) ethanone;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenyl-1- ( piperidin-1-yl) ethanone; and

2- (3- (2-oxa-6-azaspiro [3.3] heptan-6-yl) phenyl) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino ) pyrimidin-4-yl) amino) ethanol.

Other preferred compounds of the present invention are selected from the group consisting of:

(S) -5-chloro-N4- (2-methoxy-1-phenylethyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;

1- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropane -2-ol;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-cyclopentyl-2-phenylacetamide;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-cyclopentyl-2-phenylacetamide ;

1- (4 - ((5-chloro-4 - ((1- (3-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropane -2-ol;

1- (4 - ((5-chloro-4 - ((1- (2,6-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2 methylpropan-2-ol;

3- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propan-1- ol;

(R) -3 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino-3-phenylpropan-1-ol;

(R) -2- (4 - ((5-chloro-4 - ((3-hydroxy-1-phenylpropyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-isopropylacetamide ;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-cyclopropylacetamide ;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3- (1-methyl-1H-pyrazol-4 -yl) phenyl) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N- ( cyanomethyl) -N-methylacetamide;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (4-fluorophenyl) ethanol;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (4-fluorophenyl) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropanamide;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-methoxyphenyl) ethanol;

(S) -2 - ((2 - ((1H-pyrazol-4-yl) amino) -5-chloropyrimidin-4-yl) amino) -2-phenylethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-methoxyphenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;

(S) -2 - ((2 - ((1H-pyrazol-4-yl) amino) -5-chloropyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (pyridin-2- sludge) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (pyridin-2-yl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1 -yl) acetamide;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-methoxyphenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-methoxyphenyl) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (3-methoxyphenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) acetamide;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((1- (3-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;

(S) -2 - ((2 - ((1H-pyrazol-4-yl-amino) -5-chloropyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N- ( 2- (dimethylamino) ethyl) acetamide;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N- ( 3- (dimethylamino) propyl) acetamide;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (pyridin-3-yl) ethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (pyridin-3- sludge) ethanol;

2- (3-bromophenyl) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3- (1-methyl-1H -pyrazol-4-yl) phenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-methoxyphenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-methoxyphenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (pyridin-3-yl) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (2-methoxyphenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -N-methylacetamide;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (3-methoxyphenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -N-methylacetamide;

(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (2-methoxyphenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -1-morpholinoethanone;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (3-methoxyphenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -1-morpholinoethanone;

(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -1-morpholinoethanone;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (pyridin-3-yl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1 -yl) -1-morpholinoethanone;

(S) -2 - ((5-chloro-2 - ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-methoxyphenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-methoxyphenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (pyridin-3-yl) ethanol;

(S) -2- (4 - ((5-fluoro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;

(S) -2 - ((5-chloro-2 - ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;

(S) -2- (4 - ((5-fluoro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;

(S) -2- (4 - ((5-fluoro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -1-morpholinoethanone ;

(S) -2 - ((2 - ((1- (3-aminopropyl) -1H-pyrazol-4-yl) amino) -5-chloropyrimidin-4-yl) amino) -2-phenylethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-isopropyoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;

(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-isopropylacetamide;

2- (4 - ((5-chloro-4 - (((S) -1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino-1H-pyrazol-1-yl) - N - ((S) -1-hydroxypropan-2-yl) acetamide;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-chlorophenyl) ethanol;

2- (4 - ((5-chloro-4 - ((1- (2-chlorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;

2- (4 - ((5-chloro-4 - ((1- (2-chlorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-chlorophenyl) ethanol;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3,5-difluorophenyl) ethanol;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3,5-difluorophenyl) ethanol;

2- (4 - ((5-chloro-4 - ((1- (3,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N methylacetamide;

4- (3- (1 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-hydroxyethyl) phenyl) morpholin-3 -she;

5-chloro-N4- (1- (2-fluorophenyl) propyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine;

2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) propyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) -N, N dimethylacetamide;

2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) -N- ( 2,2,2-trifluoroethyl) acetamide;

2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2,5-difluorophenyl) ethanol;

2- (4 - ((5-chloro-4 - ((1- (2,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N methylacetamide;

2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (2- (trifluoromethyl) phenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;

2- (4 - ((5-chloro-4 - ((1- (2,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;

(S) -2- (4 - ((4 - ((2-hydroxy-1-phenylethyl) amino) -5-methylpyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;

(S) -2- (4 - ((4 - ((2-hydroxy-1-phenylethyl) amino) -5-methylpyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N, N- dimethylacetamide;

3- (4 - ((5-chloro-4 - (((S) -2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -1-methylpyrrolidine -2-she;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3- (1-methyl-1H -pyrazol-4-yl) phenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluoro-5- (1 methyl-1H-pyrazol-4-yl) phenyl) ethanol;

(S) -4- (3- (1 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-hydroxyethyl) phenyl ) morpholin-3-one;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2,5-difluorophenyl) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((1- (2,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1- il) acetamide;

(S) -2- (4 - ((5-chloro-4 - ((1- (2,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1- silt) -N-methylacetamide;

(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3,5-difluorophenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3,5- difluorophenyl) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((1- (3,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1- il) acetamide;

(S) -2- (4 - ((5-chloro-4 - ((1- (3,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1- silt) -N-methylacetamide;

(S) -2- (2,5-difluorophenyl) -2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2- (2,5-difluorophenyl) -2 - ((5-fluoro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2- (4 - ((4 - ((1- (2,5-difluorophenyl) -2-hydroxyethyl) amino) -5-fluoropyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -N-methylacetamide;

(S) -2- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) -2 - ((5-methyl-2 - ((1-methyl-1H-pyrazol-4-yl) amino ) pyrimidin-4-yl) amino) ethanol;

(S) -2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluoro-5- (1 methyl-1H-pyrazol-4-yl) phenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3- (1 methyl-1H-pyrazol-4-yl) phenyl) ethanol;

(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluoro- 5- (1-methyl-1H-pyrazol-4-yl) phenyl) ethanol;

(S) -2 - ((5-fluoro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluoro- 5- (1-methyl-1H-pyrazol-4-yl) phenyl) ethanol;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) ethyl) amino) pyrimidin-2 -yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;

(S) -2- (4 - ((5-fluoro-4 - ((2-hydroxy-1- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) ethyl) amino) pyrimidin-2 -yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;

(S) -2- (4 - ((5-chloro-4 - ((1- (3-fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;

(S) -2- (4 - ((5-fluoro-4 - ((1- (3-fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;

(S) -2- (3,5-difluorophenyl) -2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2- (3,5-difluorophenyl) -2 - ((5-fluoro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2- (4 - ((4 - ((1- (3,5-difluorophenyl) -2-hydroxyethyl) amino) -5-fluoropyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) acetamide;

(S) -2- (4 - ((4 - ((1- (3,5-difluorophenyl) -2-hydroxyethyl) amino) -5-fluoropyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -N-methylacetamide;

(S) -4- (3- (1 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-hydroxyethyl) - 2-fluorophenyl) morpholin-3-one;

(S) -2- (2,5-difluorophenyl) -2 - ((5-methyl-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2- (3,5-difluorophenyl) -2 - ((5-methyl-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2 - ((5-chloro-2 - ((1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2- fluorophenyl) ethanol;

(S) -2 - ((2 - ((1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) amino) -5-methylpyrimidin-4-yl) amino) -2- (2,5 difluorophenyl) ethanol;

(S) -2 - ((2 - ((1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) amino) -5-methylpyrimidin-4-yl) amino) -2- (3,5 difluorophenyl) ethanol;

2 - ((2 - ((1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) amino) -5-methylpyrimidin-4-yl) amino) -2- (2,6-difluorophenyl) ethanol ;

2- (4 - ((4 - ((1- (2,6-difluorophenyl) -2-hydroxyethyl) amino) -5-methylpyrimidin-2-yl) amino-1H-pyrazol-1-yl) -1-morpholinoethanone ;

(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (pyridin-3-yl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1 -yl) -N-methylacetamide;

(S) -2- (3-bromophenyl) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2- (3-bromo-5-fluorophenyl) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2- (3-bromophenyl) -2 - ((5-methyl-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2- (3-bromo-5-fluorophenyl) -2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2- (3-bromophenyl) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;

(S) -2- (3-bromo-5-fluorophenyl) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4- sludge) amino) ethanol;

(S) -2- (3-bromo-5-fluorophenyl) -2 - ((5-fluoro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4- sludge) amino) ethanol;

(S) -2- (4 - ((4 - ((1- (3-bromophenyl) -2-hydroxyethyl) amino) -5-chloropyrimidin-2-yl) amino) -1H-pyrazol-1-yl) - N-methylacetamide;

(S) -2- (4 - ((4 - ((1- (3-bromophenyl) -2-hydroxyethyl) amino) -5-fluoropyrimidin-2-yl) amino) -1H-pyrazol-1-yl) - N-methylacetamide;

(S) -2- (4 - ((4 - ((1- (3-bromo-5-fluorophenyl) -2-hydroxyethyl) amino) -5-chloropyrimidin-2-yl) amino) -1H-pyrazol-1 -yl) -N-methylacetamide;

(S) -2- (4 - ((4 - ((1- (3-bromo-5-fluorophenyl) -2-hydroxyethyl) amino) -5-fluoropyrimidin-2-yl) amino) -1H-pyrazol-1 -yl) -N-methylacetamide; and

2- (3-bromophenyl) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol.

If tautomerism, for example, keto-enol tautomerism, compounds of general formula (I), individual forms, for example, ketone and enol forms, are included in the invention individually and as a mixture in any ratio. The same applies to stereoisomers, for example, enantiomers, cis / trans isomers, conformers, and the like.

Isotope-labeled compounds ("isotopic derivatives") of formula (I) are also included in the scope of the present invention. Methods for introducing isotopic labels are known in the art. Preferred isotopes are isotopes of elements such as H, C, N, O and S.

If desired, the isomers can be separated by methods well known in the art, for example, liquid chromatography. Enantiomers can be similarly separated using, for example, chiral stationary phases. In addition, enantiomers can be resolved by converting them into diastereomers, i.e. linking them to an enantiomerically pure auxiliary compound, followed by separation of the resulting diastereomers and cleavage of the residue of the auxiliary compound. Alternatively, any enantiomer of a compound of formula (I) can be obtained by stereoselective synthesis using optically pure starting materials.

The compounds of formula (I) may exist in crystalline or amorphous form. In addition, some crystalline forms of the compounds of formula (I) may exist as polymorphs that are within the scope of the present invention. The polymorphic forms of the compounds of formula (I) can be characterized and differentiated using a variety of traditional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD), infrared (IR, IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (ssNMR).

If the compounds of formula (I) contain one or more acidic or basic groups, the invention also encompasses the corresponding pharmaceutically or toxicologically acceptable salts, in particular salts applicable in pharmaceuticals. Thus, for example, compounds of formula (I) that contain acidic groups can be used according to the present invention, for example, in the form of alkali metal salts, alkaline earth metal salts or ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or ammonium salts or organic amines, for example ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of formula (I) that contain one or more basic groups, i.e. groups that can be protonated may be included in the scope of the present invention and used in the form of addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid, benzoic acid , propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid a slot, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to a person skilled in the art. If the molecule of the compound of formula (I) simultaneously contains acidic and basic groups, the invention also includes, in addition to the salt forms already mentioned, internal salts or betaines (zwitterions). The corresponding salts of the compounds of formula (I) can be obtained by standard methods known to those skilled in the art, such as, for example, by reacting compounds of formula (I) with organic or inorganic acids or bases, in a solvent or dispersion medium, or by anionic or cationic exchange with other salts. The present invention also includes all salts of the compounds of formula (I) which, due to their low physiological compatibility, are not directly suitable for use in pharmaceuticals, but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

In the present invention, the term “pharmaceutically acceptable” means that the corresponding compound, carrier or molecule is suitable for administration to humans. Preferably, this term means regulatory approval, for example, EMEA (Europe) and / or FDA (United States) and / or any other national regulatory authority for use in animals, preferably humans.

In addition, the present invention includes all solvates of the compounds of the present invention.

According to the present invention, the JAK kinase includes all members of the JAK family (for example, JAK1, JAK2, JAK3 and TYK2).

According to the present invention, the expression “JAK1” or “JAK1 kinase” means “Janus kinase 1”. The human gene encoding JAK1 is located on chromosome 1p31.3.

According to the present invention, the expression “JAK2” or “JAK2 kinase” means “Janus kinase 2”. The human gene encoding JAK2 is located on chromosome 9p24.

According to the present invention, the expression “JAK3” or “JAK3 kinase” means “Janus kinase 3”. The gene encoding JAK3 is located on the 19p13.1 human chromosome and is predominantly located in hematopoietic cells. JAK3 is a cytoplasmic protein tyrosine kinase that binds to the gamma chain of the interleukin 2 receptor (IL-2). This chain is also a component of the receptors of a number of lymphotropic cytokines, including interleukins IL-4, IL-7, IL-9, IL-15 and IL-21 (Schindler et al., 2007, J. Biol. Chem. 282 (28): 29959-63). JAK3 plays a key role in the response of immune cells to cytokines, particularly in mast cells, lymphocytes and macrophages. Inhibition of JAK3 has been shown to be beneficial in the prevention of transplant rejection (Changelian et al., 2003, Science 302 (5646): 875-888).

In addition, according to the present invention, the expression “JAK3” or “JAK3 kinase” includes mutant forms of JAK3, preferably mutant forms of JAK3, which are found in patients with acute megakaryoblastic leukemia (AMKL). More preferably, these mutant forms include mutations at one amino acid residue. JAK3 activating mutations have been observed in patients with acute megakaryoblastic leukemia (AMKL) (Walters et al., 2006. Cancer Cell 10 (1): 65-75). Thus, in a preferred embodiment, the expression “JAK” also includes a JAK3 protein having V7221 or P132T mutations.

According to the present invention, the expression "TYK2" or "TYK2 kinase" means "protein tyrosine kinase 2". The JAK3 and TYK2 genes are grouped on chromosome 19p13.1 and 19p13.2, respectively.

As shown in the examples, the compounds of the present invention were investigated in terms of their selectivity for JAK3 kinase compared to JAK2 kinase. It was shown that all tested compounds bind JAK3 more selectively than JAK2 (see table 8 below).

Therefore, it is believed that the compounds of the present invention are useful for the prophylaxis or treatment of diseases and disorders associated with JAK, for example, immunological, inflammatory, autoimmune or allergic disorders, transplant rejection, graft versus host disease, or proliferative diseases, for example, cancer.

In preferred embodiments, the compounds of the present invention are selective JAK3 inhibitors.

Double JAK1 / JAK3 inhibitors are equally preferred.

The compounds of the present invention can be further characterized by determining whether they affect JAK3, for example, its kinase activity (Changelian et al., 2003, Science 320 (5646): 875-888 and online supplement; Yang et al. 2007. Bioorg. Med. Chem. Letters 17 (2): 326-331).

Briefly, the kinase activity of JAK3 can be measured using a recombinant GST-JAK3 fusion protein comprising a catalytic domain (JH1 catalytic domain). JAK3 kinase activity was measured by ELISA as follows: the plates were coated overnight with a random copolymer of L-glutamic acid and tyrosine (4: 1; 100 μg / ml) as a substrate. The plates are washed, incubated with the recombinant JAK3 JH1 protein: GST (100 ng / well) in the presence or absence of an inhibitor for 30 minutes at room temperature. An HPR-conjugated anti-phosphoryl tyrosine (ICN) PY20 antibody was added and TMB (3.3 ', 5,' -tetramethylbenzidine) was developed (Changelian et al., 2003, Science 320 (5646): 875-888 and online supplement).

A cell analysis technique (TF-1 cell proliferation) has been described to evaluate the inhibitory effect of low molecular weight drugs on JAK2 or JAK3-dependent signaling (Chen et al., 2006, Bioorg.Med.Chem. Letters 16 (21): 5633-5638 )

The present invention relates to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt or isotopic derivative thereof, as an active ingredient, along with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.

The term "pharmaceutical composition" means a composition comprising one or more active ingredients, one or more inert ingredients that form a carrier, as well as any products that are directly or indirectly formed by mixing, complexing or aggregating any two or more ingredients, or as a result of the dissociation of one or more ingredients, or as a result of other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition obtained by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The term “carrier” refers to a diluent, adjuvant, excipient or carrier with which the therapeutically active substance is administered. Such pharmaceutical carriers may be sterile liquids, for example, water and oils, including oils derived from petroleum, vegetable animal or synthetic origin, including, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, etc. . If the pharmaceutical composition is administered orally, the preferred carrier is water. If the pharmaceutical composition is administered intravenously, the preferred carriers are saline and aqueous dextrose. Saline solution as well as aqueous solutions of dextrose and glycerol are preferably used as liquid carriers in the case of solutions for administration by injection. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. . The composition, if desired, may also contain small amounts of wetting, emulsifying agents or pH buffering agents. These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, and the like. The compositions can be shaped into a suppository, including traditional binders and carriers, for example, triglycerides. Oral formulations may include standard carriers, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, pharmaceutical grade magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described by E.W. Martin at “Remington's Pharmaceutical Sciences”. The compositions of the present invention will contain a therapeutically effective amount of an active agent, preferably in purified form, in combination with the necessary amount of carrier in order to obtain a dosage form that is conveniently administered to a patient. The composition should correspond to the chosen route of administration.

The pharmaceutical composition of the present invention may include one or more additional compounds as active ingredients, for example, one or more compounds of formula (I), which are not the first compound in the composition, or other JAK inhibitors. Additional biologically active compounds may be steroids, leukotriene antagonists, cyclosporine or rapamycin.

The compounds of the present invention or their pharmaceutically acceptable salts or isotopic derivatives and other pharmaceutically active agents can be administered together or separately and, if administered separately, this administration can be carried out separately or sequentially in any order. In the case of combining in the same composition, it should be borne in mind that the two active compounds must be stable and compatible with each other and other components of the composition. If compounds are included in separate formulations, these formulations may take any convenient form, usually such as is known in the art for these compounds.

In addition, the present invention encompasses cases where a compound of formula (I) or a pharmaceutically acceptable salt or isotope derivative thereof, or a pharmaceutical composition comprising a compound of formula (I) is administered in combination with another drug or pharmaceutically active agent and / or when a pharmaceutical the composition of the present invention further includes such a drug or pharmaceutically active agent.

In this context, the term “drug or pharmaceutically active agent” includes a drug or pharmaceutical agent that will elicit a biological or medical response from a tissue, system, animal or human, as implied, for example, by a researcher or clinician.

The terms “combined” or “in combination” or “combination” should be understood as functional combined administration, where some or all of the compounds can be administered individually in different formulations, in different ways (for example, subcutaneous, intravenous or oral) and at different times. Individual compounds of such combinations can be administered either sequentially as part of separate pharmaceutical compositions, as well as simultaneously as part of combined pharmaceutical compositions.

For example, in the treatment of rheumatoid arthritis, a combination with other agents based on chemotherapeutic agents or antibodies is provided. Suitable examples of pharmaceutically active agents that can be used in combination with the compounds of the present invention and their salts for the treatment of rheumatoid arthritis include: immunosuppressants such as amtolmethine guacyl, misoribine and romexolone; anti-TNFα agents such as etanercept, infliximab, adalimumab, anakinra, abatacept, rituximab; tyrosine kinase inhibitors such as leflunomide; clicrein antagonists such as subreum; interleukin 11 agonists such as oprelvekin; interferon beta 1 agonists; hyaluronic acid agonists such as NRD-101 (Aventis); interleukin 1 receptor antagonists such as anakinra; CD8 antagonists such as amiprilose hydrochloride; beta-amyloid protein precursor antagonists such as reumacon; matrix metalloproteinase inhibitors such as cypemastat, as well as other anti-rheumatic disease modifying agents (DMARDs), such as methotrexate, sulfasalazine, cyclosporin A, hydroxychloroquine, auranofin, aurothioglucose, sodium aurothiomalate and penicillamine.

In particular, the treatment of the present invention can be used as monotherapy or, in addition to the administration of the compounds of the present invention, the treatment can include conventional treatment with surgery, radiation therapy or chemotherapy. Accordingly, the compounds of the present invention can also be used in combination with existing therapeutic agents for the treatment of proliferative diseases such as cancer. Suitable agents to be used in such combinations include:

(i) antiproliferative / antineoplastic drugs and their combinations used in the treatment of cancer, such as alkylating agents (e.g. cis-platinum, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosourea); antimetabolites (for example, antifolates such as fluoropyrimidines including 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mitramycin); antimitotic agents (for example, vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine, and taxoids such as paclitaxel and taxotere); as well as topoisomerase inhibitors (for example, epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecins);

(ii) cytostatic agents such as antiestrogens (e.g. tamoxifen, toremifene, raloxifene, droloxifene and iodoxifen), lowering estrogen receptor regulators (e.g. fulvestrant), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyperton or acetone) LHRH agonists (e.g., goserelin, leuprorelin and buserelin), progestogens (e.g. megesterol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, worazole and exemestane), as well as 5α-reductase inhibitors such as finasteride;

(iii) anti-invasive agents (e.g. c-Src kinase inhibitors, such as 4- (6-chloro-2,3-methylenedioxyanilino) -7- [2- (methylpiperazin-1-yl) ethoxy] -5-tetrahydropyran - 4-yloxyquinazoline (AZD0530) and N- (2-chloro-6-methylphenyl) -2- {6- [4- (2-hydroxyethyl) piperazin-1-yl] -2-methylpyrimidin-4-ylamino} thiazol-5 β-carboxamide (dasatinib, BMS-354825), as well as metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor activity);

(iv) growth factor activity inhibitors: for example, such inhibitors include antibodies against growth factors and antibodies against growth factor receptors (for example, an anti-erbB2 antibody trastuzumab [Herceptin ^TM ] and an anti-erbB1 antibody cetuximab [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, e.g., epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD 1839), Λ / - (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido Λ / - (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033), and erbB2 tyrosine kinase inhibitors such as lapatinib), hepatocyte growth factor family inhibitors, seme inhibitors platelet-derived growth factors, such as imatinib, serine / threonine kinase inhibitors (e.g., Ras / Raf signaling pathways, e.g., farnesyl transferase inhibitors, such as sorafenib (BAY 43-9006)) and cellular signal transduction inhibitors via MEK and / or Akt kinases;

(v) anti-angiogenic agents, for example, inhibiting the action of vascular endothelial growth factor, for example, an antibody against vascular endothelial growth factor bevacizumab (Avastin ^TM ) and VEGF tyrosine kinase receptor inhibitors such as 4- (4-bromo-2-fluoroanilino) -6 -methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline (ZD6474; Example 2 in WO 01/32651), 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD2171; example 240 in WO 00/47212), vatalanib (RTK787; WO 98/35985) and SUI 1248 (sunitinib; WO 01/60814), as well as compounds that act by d ugim mechanisms (for example linomide, inhibitors of integrin αvβ3 activity and angiostatin);

(vi) agents affecting the vessels of the tumor tissue, such as combrestatin A4 and the compounds disclosed in international patent application WO 99/02166;

(vii) antisense drugs, for example, targeting the above targets, such as ISIS 2503 and anti-ras antisense agent;

(viii) gene therapy-based approaches, including approaches based on the replacement of abnormal genes, for example, abnormal p53, BRCA1 or BRCA2 genes, GDEPT (gene-directed enzymatic prodrug therapy) methods, for example, that use cytosine deaminase, thymidine kinase or the bacterial enzyme nitroreductase, and approaches aimed at increasing the tolerance of chemotherapy or radiation therapy to the patient, for example, therapy aimed at the multidrug resistance gene; and

(ix) immunotherapeutic approaches, including ex-vivo and in-vivo methods for increasing the immunogenicity of tumor cells of a patient, such as transfection with cytokines, for example, interleukin 2, interleukin 4 or colony-stimulating factor granulocytes and macrophages, approaches aimed at decreasing T-cell tolerance, approaches using transfected immune cells, for example, dendritic cells transfected with cytokines, approaches using tumor lines of cells transfected with cytokines, as well as approaches using ant and idiotypic antibodies.

Additional combination treatment methods are described in WO-A 2009/0088992 and WO-A 2007/107318, which are incorporated herein by reference.

Accordingly, the individual compounds forming such combinations can be administered either sequentially, as separate pharmaceutical compositions, or simultaneously in the combined pharmaceutical compositions.

The pharmaceutical compositions of the present invention include compositions suitable for oral, rectal, local, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (via nasal or buccal inhalation) or nasal administration, although the most convenient route of administration is each case will depend on the nature and severity of the condition being treated and on the nature of the active ingredient. From the compositions of the present invention, it makes sense to obtain dosage forms, which is achieved by any of the methods well known in pharmaceutical technology.

In practical use, the compounds of formula (I) as an active ingredient can be mixed to obtain a homogeneous mixture with a pharmaceutical carrier, in accordance with traditional methods for the preparation of pharmaceutical mixtures. The carrier may take a wide range of forms, depending on the form of the preparation desired for administration, for example, oral or parenteral (including intravenous). In preparing the compositions for oral dosage forms, any of the traditional pharmaceutical media can be used, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, and the like. in the case of liquid oral preparations, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. in the case of solid oral preparations, for example, powders, hard or soft capsules and tablets, moreover, solid oral preparations are preferred over liquid preparations.

Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage forms, upon receipt of which, solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated using standard aqueous and non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The percentage of active compound in these compositions, of course, can vary and, as a rule, is in the range from about 2 percent to about 60 mass. percent by weight of a unit dosage form. The amount of active compound in such therapeutically applicable compositions is such that a therapeutically effective dose can be obtained. The active compounds can also be administered intranasally, for example, in the form of liquid drops or a spray.

Tablets, pills, capsules and the like may also contain a binder, for example, tragacanth gum, gum arabic, corn starch or gelatin; excipients, for example, dicalcium phosphate; a disintegrating agent, for example, corn starch, potato starch, alginic acid; a lubricant, for example magnesium stearate; and a sweetener, for example, sucrose, lactose or saccharin. If the dosage form is a capsule, it, in addition to the materials of the above types, may contain a liquid carrier, for example, a fatty oil.

The dosage form may contain a number of other materials, for example, as a coating or intended to modify the physical form. For example, tablets may be coated with shellac, sugar, or both of these materials. A syrup or elixir, in addition to the active ingredient, may contain sucrose as a sweetener, methyl and propyl parabens as preservatives, a coloring agent and a flavoring agent, for example, cherry or orange flavoring.

The compounds of formula (I) can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water mixed with the required amount of a surfactant, for example, hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof with oils. Under normal conditions of storage and use, these preparations contain preservatives to prevent the development of microorganisms.

Pharmaceutical forms which are suitable for injection use include sterile aqueous solutions or dispersions and sterile powders for the preparation of sterile aqueous solutions or dispersions immediately prior to use. In any case, the dosage form must be sterile and have such a degree of fluidity that it can be entered using a syringe. It must be stable under the conditions of production and storage and must be protected from the contaminating action of microorganisms, such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g. glycerin, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof and vegetable oils.

For administration to a mammal, in particular humans, an effective dose of a compound of the present invention, any suitable route of administration may be used. For example, oral, rectal, topical, parenteral, ophthalmic, pulmonary, nasal, etc., may be administered. introduction. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably, the compounds of formula (I) are administered orally.

The effective dosage of the active ingredient used may vary depending on the particular compound, the route of administration, the condition being treated, and the severity of the condition. Such a dosage can easily be established by a person skilled in the art.

A therapeutically effective amount of a compound of the present invention will usually depend on a number of factors, including, for example, the age and weight of the animal, the particular condition requiring treatment, and its severity, the nature of the composition, and its route of administration. However, an effective amount of a compound of formula (I) for the treatment of inflammatory diseases, for example, rheumatoid arthritis (RA), will typically be in the range from 0.1 to 100 mg / kg body weight of the recipient (mammal) per day and, more often, in the range of 1 to 10 mg / kg body weight per day. Thus, for an adult mammal weighing 70 kg, the required amount of the compound could be from 70 to 700 mg per day, and this amount can be given in a single dose per day or, more often, in the form of several (for example, two, three, four, five, or six) smaller doses throughout the day, so that the total daily dosage remains the same. An effective amount of a pharmaceutically acceptable salt, prodrug or metabolite of a compound can be determined on the basis of an appropriate proportion from an effective amount of the compound of formula (I) itself. It is anticipated that similar dosages will be suitable for the treatment of other conditions listed above.

As used herein, the term “effective amount” means that amount of a drug or pharmaceutical agent that elicits a biological or medical response to a tissue, system, animal or human that is intended, for example, by a researcher or clinician.

In addition, the term “therapeutically effective amount” means any amount that, when compared with a corresponding subject that has not received such an amount, results in an improvement, cure, prevention or alleviation of a disease, disorder or side effect, or a decrease in the rate of progression of the disease or disorder . Quantities effective to improve normal physiological functions are also within the scope of the term described.

Another aspect of the present invention relates to a compound of the present invention, a pharmaceutically acceptable salt or isotopic derivative thereof for use as a medicine.

Another aspect of the present invention relates to a compound of the present invention, a pharmaceutically acceptable salt or isotope derivative thereof for use in a method for treating or preventing a disease or disorder associated with JAK.

In the context of the present invention, a JAK-related disease or disorder is defined as a disease or disorder in which JAK is involved.

In a preferred embodiment, the disease or disorder associated with JAK is an immunological, inflammatory, autoimmune or allergic disorder or disease associated with transplant rejection or a graft versus host reaction.

Thus, another aspect of the present invention relates to a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method for treating or preventing an immunological, inflammatory, autoimmune or allergic disorder or disease associated with transplant rejection or a graft versus host reaction.

Inflammation of a tissue or organ occurs in a number of disorders and diseases and, in some cases, is due to activation of the receptors of the cytokine family. Typical examples of inflammatory disorders associated with JAK activation include, but are not limited to, skin inflammation due to radiation, asthma, allergic inflammation, and chronic inflammation.

In accordance with the present invention, an autoimmune disease is a disease that is at least partially caused by an immune response of an organism against its own components, for example, proteins, lipids or DNA. Examples of organ-specific autoimmune disorders are insulin-dependent diabetes (type I), which affects the pancreas, Hashimoto's thyroiditis and Graves' disease, which affects the thyroid gland, malignant anemia, which affects the stomach, Cushing's disease and Addison's disease, which affect the adrenal gland active hepatitis that affects the liver; polycystic ovary syndrome (PCOS), celiac disease, psoriasis, inflammatory bowel disease (IBD), and ankylosing spondylitis. Examples of non-organ-specific autoimmune disorders are rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus and myasthenia gravis.

Type I diabetes occurs due to the selective autoimmune aggression of autoreactive T cells against beta cells of insulin secreting Langerhans islets. Targeting the drug to JAK3 in this disease is based on evidence that many cytokines that transmit a signal through the JAK pathway are involved in autoimmune T cell-mediated beta cell destruction. Indeed, it has been shown that JANEX-1, which is a JAK2 inhibitor, prevents the development of spontaneous autoimmune diabetes in the NOD mouse model of type I diabetes.

In a preferred embodiment, the autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), psoriasis, systemic lupus erythematosus (SLE) and multiple sclerosis (MS).

Rheumatoid arthritis (RA) is a chronic, progressive, severe inflammatory disease that affects approximately 1% of the world's population. RA is a symmetric polyarticular arthritis that primarily affects the small joints of the hands and feet. In addition to inflammation of the synovial layer and lining of the joints (cartilage), the aggressive front of the tissue called the pannus penetrates the local structures of the joints and destroys them (Firestein 2003, Nature 423: 356-361).

Inflammatory bowel disease (IBD) is characterized by chronic recurrent bowel inflammation. IBD is divided into phenotypes of Crohn's disease and ulcerative colitis. Crohn's disease most often affects the terminal region of the ileum and colon and is discrete and transmural (penetrating the intestinal wall). In contrast, with ulcerative colitis, inflammation is continuous and is limited to a layer of the mucous membrane of the rectum and colon. In approximately 10% of cases of inflammatory diseases localized in the rectum and colon, a clear distinction cannot be made between Crohn's disease and ulcerative colitis, and these cases are referred to as "colitis of an indeterminate nature." Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Neutrophil-induced lesions can be prevented with neutrophil migration inhibitors (Asakura et al., 2007, World J Gastroenterol. 13 (15): 2145-9).

Psoriasis is a chronic inflammatory dermatosis that affects about 2% of the population. It is characterized by red scaly spots on the skin that usually appear on the scalp, elbows and knees, and may be associated with severe arthritis. These lesions are caused by abnormal proliferation of keratinocytes and the infiltration of inflammatory cells into the dermis and epidermis (Schön et al., 2005, New Engl.J. Med. 352: 1899-1912).

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease caused by T-cell mediated B-cell activation, which leads to glomerulonephritis and renal failure. In the early stages of SLE in humans, it is characterized by the development of long-lived autoreactive CD4 + memory cells (D'Cruz et al., 2007, Lancet 369 (9561): 587-596).

Multiple sclerosis (MS) is an inflammatory and demyelinating neurological disease. It was considered an autoimmune disorder mediated by type 1 CD4 + T helper cells, but modern research has revealed a role for other immune cells (Hemmer et al., 2002, Nat. Rev. Neuroscience 3, 291-301).

Mast cells express JAK3, and JAK3 is a key regulator of IgE-mediated mast cell responses, including release of inflammatory mediators. JAK3 has been shown to be a suitable target in the treatment of allergic reactions mediated by mast cells. Allergic reactions associated with mast cell activation include immediate allergic reactions of type I, for example, allergic rhinitis (hay fever), allergic rash (urticaria), angioedema (Quincke's edema), allergic asthma and anaphylaxis, for example, anaphylactic shock. These disorders can be treated or prevented by inhibiting JAK3 activity, for example, by administering the JAK3 inhibitor of the present invention.

Graft rejection (allograft rejection) includes, but is not limited to, acute and chronic allograft rejection after, for example, transplantation of a kidney, heart, liver, lung, bone marrow, skin, and cornea. T cells are known to play a major role in a specific immune response that causes allograft rejection. It is possible to treat over-acute, acute and chronic organ transplant rejection. Super acute rejection occurs within a few minutes after transplantation. Acute rejection usually occurs within six to twelve months of the transplant being in the body. Overexposure and acute rejection can usually be reversed with immunosuppressive treatment. Chronic rejection, characterized by a gradual loss of organ function, is a constant cause for concern for the transplant recipient, as it can occur at any time after transplantation.

The graft versus host (GVHD) reaction is a major complication in allogeneic bone marrow transplantation (BMT). GVHD is caused by donor T cells that recognize and respond to differences in the histocompatibility complex of the recipient, which leads to significant complications and mortality. JAK3 plays a key role in the induction of GVHD, and treatment with a JAK3 inhibitor, namely JANEX-1, has been shown to reduce the severity of GVHD (see review in Cetkovic-Cvrlje and Ucken, 2004).

In a preferred embodiment of the present invention, the inflammatory disease is an eye disease.

Dry eye syndrome (DES, also known as dry keratoconjunctivitis) is one of the most common problems that eye doctors face. DES is sometimes referred to as tearing disorder syndrome (Jackson, 2009. Canadian Journal of Ophthalmology 44 (4), 385-394). DES affects up to 10% of the population aged 20 to 45 years, and the prevalence of the disease increases with age. Although there is a wide range of artificial tears, these products provide only temporary relief of symptoms. Therefore, there is a need for agents, compositions and therapeutic methods for treating dry eyes.

This application is intended to mean that the term “dry eye disorder” encompasses painful conditions summarized in the latest official report of the International Dry Eye Workshop (DEWS), which defines a dry eye as a “multifactorial disease of lacrimation and the surface of the eye that leads to discomfort, visual impairment and instability of the lacrimal film with potential damage to the surface of the eye. It is accompanied by an increase in the osmolality of the tear film and inflammation of the surface of the eye. " (Lemp, 2007. “The Definition and Classification oa Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop”, The Ocular Surface, 5 (2), 75-92). Dry eye is sometimes also called dry keratoconjunctivitis. In some embodiments, the treatment of disorders associated with dry eyes includes the alleviation of specific symptoms of the disorder, such as discomfort, visual impairment, instability of the tear film, hyperosmolarity of the tears, and inflammation of the surface of the eye.

Uveitis is the most common form of intraocular inflammation, and it remains a significant cause of vision loss. Modern methods of treating uveitis include the systemic administration of drugs that cause severe side effects and generally have an immunosuppressive effect. In clinical practice, chronic progressive or recurrent forms of non-infectious uveitis are treated with topical and / or systemic administration of corticosteroids. Macrolides, such as cyclosporine and rapamycin, and, in some cases, cytotoxic agents, such as cyclophosphamide and chlorambucil, as well as antimetabolites, such as azathioprine, methotrexate and leflunomide (Srivastava et al., 2010. Uveitis: Mechanisms and recent advances in therapy, Clinica Chimica Acta, doi: 10.1016 / j.cca.2010.04.017).

Other eye diseases, combination treatment methods and routes of administration are described, for example, in WO-A 2010/039939, which is incorporated herein by reference.

In another preferred embodiment, the disease or disorder associated with JAK is a proliferative disease, in particular cancer.

Diseases and disorders associated with, inter alia, JAK are proliferative disorders or diseases, in particular cancer.

Therefore, another aspect of the present invention relates to a compound, a pharmaceutically acceptable salt or isotopic derivative of the present invention, for use in a method for treating or preventing a proliferative disease, in particular cancer.

The term "cancer" covers a group of diseases characterized by uncontrolled growth and spread of abnormal cells. All types of cancers typically include certain abnormalities in the regulation of cell growth, division and survival, leading to malignant growth of these cells. Key factors contributing to this malignant cell growth are signal independence, insensitivity to growth cessation signals, apoptosis deactivation, unlimited replicative potential, constant angiogenesis, tumor ingrowth and metastasis, and genome instability (Hanahan and Weinberg, 2000. The Hallmarks of Cancer. Cell 100, 57-70).

Cancers are generally classified as hematologic cancers (e.g., leukemia and lymphomas) and solid cancers, e.g., sarcomas and carcinomas (e.g., cancers of the brain, breast, lung, colon, stomach, liver, pancreas, prostate, ovary )

The JAK inhibitors of the present invention may also find use in the treatment of certain malignant diseases, including skin cancer and hematologic malignancies, such as lymphomas and leukemias.

In particular, it is expected that cancers with a JAK-STAT signaling pathway activated, for example, by activating JAK3, will respond to treatment with JAK3 inhibitors. Examples of cancers involving JAK3 mutations are acute megakaryoblastic leukemia (AMKL) (Walters et al., 2006. Cancer Cell 10 (1): 65-75) and breast cancer (Jeong et al., 2008, Clin. Cancer Res. 14 , 3716-3721).

Proliferative diseases or disorders include a group of diseases characterized by enhanced cell reproduction, which is observed with myeloproliferative disorders (MPD), for example, with true polycythemia (PV).

Another aspect of the present invention relates to the use of a compound of the present invention, a pharmaceutically acceptable salt or isotopic derivative thereof, for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with JAK.

A further aspect of the present invention relates to the use of a compound of the present invention, a pharmaceutically acceptable salt or isotope derivative thereof, for the manufacture of a medicament for the treatment or prophylaxis of immunological, inflammatory, autoimmune or allergic disorders or diseases, or transplant rejection or graft versus host reaction ".

Another aspect of the present invention relates to the use of a compound of the present invention, a pharmaceutically acceptable salt or isotopic derivative thereof, for the manufacture of a medicament for the treatment or prophylaxis of a proliferative disease, in particular cancer.

In the context of these uses of the present invention, JAK related diseases and disorders include the above diseases and disorders.

A further aspect of the present invention relates to a method for treating, regulating, delaying the onset or prophylaxis of a mammalian patient in need of one or more conditions selected from the group consisting of JAK-related diseases and disorders, where the method comprises administering to said patient a therapeutically effective amount of a compound of the present invention, a pharmaceutically acceptable salt or isotopic derivative thereof.

Another aspect of the present invention relates to a method for treating, regulating, delaying the onset or prophylaxis in a mammalian patient in need of one or more conditions selected from the group consisting of immunological, inflammatory, autoimmune or allergic disorders or diseases, or rejection of a graft or graft versus host reaction, wherein the method comprises administering to a specified patient a therapeutically effective amount of a compound of the present invention or its pharmaceutically acceptable salt or isotopic derivative.

Another aspect of the present invention relates to a method for treating, regulating, delaying the onset or prophylaxis of a mammalian patient in need of a proliferative disease, in particular cancer, wherein the method comprises administering to said patient a therapeutically effective amount of a compound of the present invention, its pharmaceutically acceptable salt or isotopic derivative.

In the context of these methods of the present invention, JAK related diseases and disorders include the diseases and disorders listed above.

It is understood that in the present invention, the term "treatment" refers to all methods that are able to slow down, interrupt, stop or stop the progression of the disease, but not necessarily completely eliminate all its symptoms.

All the embodiments discussed above relating to the pharmaceutical composition of the present invention also relate to the first or second medical use or methods of the present invention.

General methods for preparing the compounds of the present invention are known in the art (for example, from WO 2006/117560 A1). The experimental section below describes production methods that can also be used in similar methods using techniques known to a person skilled in the art, in particular, methods for protecting reactive functional groups or activating functional groups.

Analytical techniques

LCMS was performed on an Agilent 1100 instrument; UPLCMS (ultra-efficient LCMS) was performed on a Waters UPBINARY instrument using water and ACN (0.1% formic acid for low pH, 0.1% ammonia for high pH) with an injection volume of 3 μl. Detection was carried out at a wavelength of 254 and 210 nm.

Method A: UPLC low pH

Method B: UPLC high pH

Column: Waters Acquity UPLC BEH C18, 30 × 2.1 mm, 1.7 mm, flow rate 0.5 ml / min

Table 1 Time (min) Water (%) ACN (%) 0.00 95.0 5,0 0.20 95.0 5,0 1.00 5,0 95.0 1,50 5,0 95.0 1.70 95.0 5,0 2.70 95.0 5,0

Method C: LCMS low pH

Method D: LCMS high pH

Column: Phenomenex Gemini-C18, 3 × 30 mm, 3 microns, flow rate 1.2 ml / min

table 2 Time (min) Water (%) ACN (%) 0.00 95.0 5,0 3.00 5,0 95.0 4,50 5,0 95.0 4.60 95.0 5,0 5.00 stop

Method E: LCMS low pH 16 minutes

Column: Phenomenex Gemini-C18, 4.6 × 150 mm, 5 microns, flow rate 1.0 ml / min, low pH

Table 3 Time (min) Water (%) ACN (%) 0.00 95.0 5,0 11.00 5,0 95.0 13.50 5,0 95.0 13.01 95.0 5,0 16.00 95.0 5,0

Method F: UPLC, high pH, 6 minutes

Column: Waters Acquity UPLC BEH C18, 2.1 × 50 mm, 1.7 microns, flow rate 0.5 ml / min, low pH

Table 4 Time (min) Water (%) ACN (%) 0.00 95.0 5,0 0.20 95.0 5,0 4.20 5,0 95.0 4.70 5,0 95.0 4.75 95.0 5,0 6.00 95.0 5,0

ACN Acetonitrile Ar Aryl Aq (aq) Water Boc Tert-butoxycarbonyl brs (r.s.) Extended singlet d (d) Doublet

dd (dd) Doublet of doublets DCM Dichloromethane Dipa Diisopropylethylamine DMF (DMF) N, N'-Dimethylformamide DMSO (DMSO) Dimethyl sulfoxide DP Pulldown drug analysis (Drug pulldown) Dtt Dithiothreitol EDTA Ethylenediaminetetraacetic acid EtOAc Ethyl acetate eq (equiv.) Equivalents g (g) Grams h (h) Clock Hatu N, N, N ', N'-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate Hcl Hydrochloric acid H ₂ O Water HPLC (HPLC) High Performance Liquid Chromatography Hz (Hz) Hertz IC ₅₀ The concentration at which inhibition is 50% of the maximum IPA Propan-2-ol iPr Isopropyl J Spin-spin interaction constant L (L) Liters LC-MS (LCMS) Liquid chromatography mass spectroscopy

m (m) Multiplet M Molar Meoh Methanol mg (mg) Milligrams MgSO ₄ Magnesium sulfate Min (min) Minutes mL (ml) Milliliters mm (mm) Millimeters Mmol (mmol) Millimoli mol% Molar percent μL Microliters NaHCO ₃ Sodium bicarbonate nm (nm) Nanometers Pbs Phosphate buffered saline Rpm (rpm) Rpm RT Retention time sat. (sat.) Saturated s (s) Singlet td (td) Triplet of Doublets t (t) Triplet

experimental part

A brief description of typical examples of synthetic routes for the compounds of the present invention is given below in Schemes A1-A4.

Conditions: stage i) K ₂ CO ₃ , ACN 60 ° C; stage ii) 10% Pd / C, H ₂ , MeOH.

Conditions: step i) R ^Y5 NH ₂ , HATU, DIPEA, DMF; stage ii) TFA, DCM.

Conditions: step i) IPA, DIPEA, retention time 24 hours; stage ii) IPA, HCl, 80 ° C, 24 hours;

Compounds for which in the formula (I) n = 1 can be obtained in a similar manner.

Conditions: step i) Pd ₂ (dba) ₃ , Xantphos, Cs ₂ CO ₃ , Spiomorpholine, 1,4-dioxane;

General procedure for the synthesis of 4-amino-1-N-alkylated pyrazoles

Scheme A1, stage 1

A solution of 4-nitropyrazole (1.0 eq.), Potassium carbonate (2.0 eq.) And an alkylating reagent (1.1 eq.) In acetonitrile (10 volumes) was heated at 60 ° C for 18 hours. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSO ₄ ) and concentrated in vacuo.

Stage 2

The crude nitro compound residue was dissolved in methanol (50 volumes), palladium-carbon (10 wt%) was added, and the reaction mixture was stirred in an H ₂ atmosphere for 18 hours. The resulting mixture was filtered through celite and the filtrate was concentrated in vacuo to give the desired product.

General Procedure for the Preparation of Amide-Substituted Benzylamines

Scheme A2, stage 1

With stirring, the corresponding amine (1.1 eq.), HATU (1.3 eq.) And DIPEA ( 2 equiv.). Then the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with DCM, washed with water, dried using a hydrophobic frit and concentrated in vacuo. Reverse phase flash chromatography (30 g C18 column, 5% -95% ACN with formic acid in water with formic acid) afforded the desired amide.

Scheme A2 Stage 2

BOC-aminomethylamide was stirred for 1 h at room temperature in TFA / DCM (1: 4). The reaction mixture was transferred onto an SPE toluenesulfonic acid cartridge, and after washing, the product was eluted with 2N ammonia in methanol. Organic solvents were removed in vacuo to give the desired product.

Scheme A3, stage 1

General procedure for the synthesis of intermediate N- (2-chloro-5-fluoropyrimidin-4-yl) benzylamines

To a solution of 2,4-dichloro-5-fluoropyrimidine (1.0 equiv.) And DIPEA (2.0 equiv.) In propan-2-ol (10 volumes), substituted benzylamine (1.0) was added dropwise at 0 ° C. equiv.), and the resulting mixture was stirred overnight at room temperature. Then the reaction mixture was diluted with EtOAc (20 volumes), water (20 volumes) and brine (10 volumes). The organic layer was collected, dried (MgSO ₄ ) and concentrated under reduced pressure.

General procedure for the synthesis of intermediate N- (2-chloro-5-chloropyrimidin-4-yl) benzylamines

To a solution of 2,4,5-trichloropyrimidine (1.0 equiv.) And DIPEA (2.0 equiv.) In propan-2-ol (10 volumes), substituted benzylamine (1.0 equiv. ), and the resulting mixture was stirred overnight at room temperature. Then the reaction mixture was diluted with EtOAc (20 volumes), water (20 volumes) and brine (10 volumes). The organic layer was separated, dried (MgSO ₄ ), concentrated under reduced pressure to obtain the desired product.

General procedure for the synthesis of intermediate N- (2-chloro-5-methylpyrimidin-4-yl) benzylamines

To a solution of 2,4-dichloro-5-methylpyrimidine (1.0 equiv.) And DIPEA (2.0 equiv.) In propan-2-ol (10 volumes), substituted benzylamine (1.0) was added dropwise at 0 ° C. equiv.), and the resulting mixture was stirred overnight at room temperature. Then the reaction mixture was diluted with EtOAc (20 volumes), water (20 volumes) and brine (10 volumes). The organic layer was separated, dried (MgSO ₄ ), concentrated under reduced pressure to obtain the desired product.

General methods for the synthesis of test compounds

Scheme A3, stage 2

A mixture of N- (2-chloro-5-chloropyrimidin-4-yl) benzylamine, substituted with 1H-pyrazol-4-amine (1.0 eq.) And 4 M HCl in dioxane (0.1 eq.) Was stirred at 80 ° C for 18 hours in propan-2-ol (5 volumes). Then the reaction mixture was diluted with EtOAc (20 volumes) and NaHCO ₃ (10 volumes), the organic phase was separated, dried (MgSO ₄ ) and evaporated to give the desired product. Then, the resulting products were, if necessary, purified by flash chromatography (EtOAc / petroleum ether) or HPLC.

General Procedure for the Preparation of Amino-Substituted Test Compounds

A4 layout

A suspension of aryl bromide (1.0 eq.), Spiomorpholine (1.5 eq.), Pd ₂ (dba) ₃ (0.01 eq.), XANTPHOS (0.05 eq.) And cesium carbonate (3.0 eq. ) were refluxed in degassed 1,4-dioxane (10 volumes) overnight. The mixture was cooled and filtered, the filtrate was passed through a PS-SH cartridge and the solvent was removed in vacuo. Purification can be carried out by reverse phase chromatography.

The following is a more detailed description of typical routes for the synthesis of compounds of the present invention.

General procedure for the synthesis of 4-amino-1-N-alkylated pyrazoles 1.3.

Conditions: stage i) K ₂ CO ₃ , ACN, 60 ° C, 18 h; stage ii) 10% Pd / C, H ₂ , MeOH, retention time 18 hours

Stage 1

A solution of 4-nitropyrazole (1.0 eq.), Potassium carbonate (2.0 eq.) And an alkylating reagent (1.1 eq.) In ACN (10 volumes) was heated at 60 ° C for 18 hours. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water. The organic phase was separated, dried (MgSO ₄ ) and concentrated in vacuo.

Stage 2

Alkylated nitropyrazole 1.2 was dissolved in MeOH (50 volumes), palladium-carbon (10 wt%) was added, and the reaction mixture was stirred in an H ₂ atmosphere for 18 hours. The resulting mixture was filtered through celite and the filtrate was concentrated in vacuo to give the desired product.

General procedure for the preparation of amide substituted benzylamines 2.3.

Conditions: step i) R ^Y5 NH ₂ , HATU, DIPEA, DMF, retention time 1 h; stage ii) TFA, DCM, 1 h.

Stage 1

To a solution of compound 2.1 (1.0 equiv.) In DMF (2 ml), the corresponding amine R ^Y5 NH ₂ (1.1 equiv.), HATU (1.3 equiv.) And DIPEA (2.0 equiv.) Were added with stirring. ) Then the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with DCM and washed with water, dried using a hydrophobic frit, and concentrated in vacuo. Flash chromatography on reverse phase (30 g, column C18, 5-95% ACN with formic acid in water with formic acid) yielded the desired amide 2.2.

Stage 2

Amide 2.2 was stirred for 1 h at room temperature in a mixture of TFA / DCM (1: 4). The reaction mixture was applied to an SPE cartridge with toluenesulfonic acid and, after washing with MeOH, the product was eluted with 2N. ammonia in MeOH. Organic solvents were removed in vacuo to give the desired product 2.3.

General procedure for the preparation of morpholine-substituted benzylamines 3.2

Conditions: step i) CuI, morpholin-3-one, N, N'-dimethylethylene diamine, K ₂ CO ₃ , 1,4-dioxane.

Aryl bromide 3.1 (1.0 equiv.), Morpholin-3-one (1.25 equiv.), CuI (0.2 equiv.), N, N'-dimethylethylenediamine (0.4 equiv.) And K ₂ CO ₃ (2.0 equiv.) Was heated to 110 ° C. in dioxane for 18 hours. The reaction mixture was cooled, diluted with water and EtOAc. The organic layer was washed (water, brine), dried (MgSO ₄ ) and concentrated to give compound 3.2.

General procedure for the synthesis of intermediates 4.3.

Conditions: stages i) IPA, DIPEA, retention time 18 hours

Alpha substituted benzylamine 4.1 was added dropwise to a solution of 2,4-dichloro-5-substituted pyrimidine 4.2 (1.0 equiv.) And DIPEA (2.0 equiv.) In IPA (10 volumes) at 0 ° C (1, 0 equiv.) And the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted either with water, collecting the resulting precipitate of compound 4.3 by filtration, or EtOAc (20 volumes), water (20 volumes) and saturated brine (10 volumes). The organic layer was separated, dried (MgSO ₄ ) and concentrated under reduced pressure to give compound 4.3. If necessary, purification was carried out by flash chromatography on silica gel (gradient EtOAc-petroleum ether).

Alternative Procedure for the Preparation of Amide-Substituted Intermediates 5.4

Conditions: step i) AcCl, MeOH, 80 ° C; stage ii) DIPEA, IPA, CT, 24 hours; stage iii) 1 M LiOH, MeOH, retention time 24 hours; stage iv) R ^Y5 NH ₂ , HATU, DIPEA, DMF

Stage 1

To a solution of amino acid 5.1 (1.0 equiv.) In MeOH (2 ml), acetyl chloride (2.0 equiv.) Was added with stirring. The reaction mixture was stirred for 15 minutes at room temperature and then at 80 ° C. overnight. The reaction mixture was concentrated in vacuo, the residue was neutralized with saturated NaHCO ₃ solution and extracted with EtOAc to give amino ether 5.2.

Stage 2

Aminoester 5.2 (1.2 equiv.) With stirring was added to a chilled (0 ° C) solution of 2,4-dichloro-5-substituted pyrimidine (1.0 equiv.) And DIPEA (2.5 equiv.) In IPA. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was diluted with water and EtOAc. The organic layer was washed (brine), dried (MgSO ₄ ) and concentrated in vacuo to give a residue that was used without further purification.

Stage 3

The remainder of step 2 was dissolved in MeOH and treated at room temperature with 1 M LiOH (3.0 eq.). The reaction mixture was stirred overnight at room temperature, then neutralized with 2 M HCl, concentrated and triturated with ether to give acid 5.3 as an off-white solid.

Stage 4

To a solution of acid 5.3 (1.0 equiv.) In DMF (2 ml), the corresponding amine R ^Y5 NH ₂ (1.1 equiv.), HATU (1.3 equiv.) And DIPEA (2.0 equiv.) Were added with stirring. ) Then the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo. Flash chromatography on reverse phase (30 g, column C18, 5% -95% ACN with ammonia in water with ammonia) yielded the desired amide 5.4.

General method for the synthesis of test compounds 6.1

Conditions: stage i) IPA, HCl, 80 ° C, 18 h

A mixture of 2-chloropyrimidine intermediate 4.3 (1.0 eq.), Substituted with 1H-pyrazol-4-amine 1.3 (1.0 eq.) And 4 M HCl in dioxane (0.1 eq.) Was stirred at 80 ° C for 18 hours at IPA (5 volumes). Then the reaction mixture was diluted with EtOAc (20 volumes) and NaHCO ₃ (10 volumes), the organic phase was separated, dried (MgSO ₄ ) and concentrated, obtaining the desired test compound 6.1. which, if necessary, was further purified by flash chromatography (EtOAc / petroleum ether) or HPLC.

General method for the synthesis of test compounds 7.2

Conditions: step i) methylpyrazole boron ether, Pd (dppf) Cl ₂ , DCM, Na ₂ CO ₃ , ACN / H ₂ O, 120 ° C, 30 min

Aryl bromide 7.1 (1.0 equiv.), Pinacol ester of 1-methylpyrazole-4-boronic acid (1.2 equiv.), 2M Na ₂ CO ₃ (2.0 equiv.) And Pd (dppf) Cl ₂ DCM (0 , 05 equiv.) In the ACN was subjected to microwave irradiation at 130 ° C for 30 minutes. The reaction mixture was diluted with MeOH and filtered. The filtrates were concentrated and purified by preparative HPLC to give compound 7.2.

General method for the synthesis of test compounds 8.1

Conditions: stage i) Pd ₂ (dba) ₃ , Xantphos, Cs ₂ CO ₃ , spiomorpholine, 1,4-dioxane, 110 ° C, 18 h

Suspension of aryl bromide 7.1 (1.0 equivalent), spiomorpholine (1.5 equivalent), Pd ₂ (dba) ₃ (0.01 equivalent), XANTPHOS (0.05 equivalent) and cesium carbonate (3.0 equivalent .) was refluxed in degassed 1,4-dioxane (10 volumes) overnight. The resulting mixture was cooled and filtered. The filtrate was passed through a PS-SH cartridge, after which the solvent was quenched in vacuo. Product purification can be carried out using reverse phase chromatography to give test compound 8.1.

General method for the synthesis of test compound 9.2

Conditions: stage i) NaH, MeI, DMF, ct, 2 h

To a solution of compound 9.1 (20 mg) in DMF (2 ml) was added NaH (1.0 eq.) And then MeI (1.5 eq.). The reaction mixture was stirred at room temperature for 2 hours, then quenched with MeOH, concentrated and purified by preparative HPLC to give test compound 9.2.

General Procedure for the Synthesis of Compound 10.2 and its Conversion into Amide 10.3

Conditions: step i) NaOH, MeOH, retention time 18 hours; stage ii) R ^Y5 NH ₂ , HATU, DIPEA, DMF

Stage 1

To a solution of compound 10.1 in MeOH was added 1 M NaOH (2 equiv.). The reaction mixture was stirred overnight at room temperature, then neutralized with 2 M HCl, concentrated and triturated with ether to give acid 10.2.

Stage 2

To a solution of 10.2 (1.0 equiv.) In DMF (2 ml), the corresponding amine R ^Y5 NH ₂ (1.1 equiv.), HATU (1.3 equiv.) And DIPEA (2.0 equiv.) ^Were added with stirring. . Then the reaction mixture was stirred for 1 h at room temperature. The reaction mixture was diluted with DCM, washed (brine), dried (MgSO ₄ ) and concentrated in vacuo. Reverse phase chromatography (30 g, C18 column, 5% -95% ACN with formic acid in water with formic acid) afforded the desired amide 10.3.

General method for the synthesis of test compounds 11.1

The conditions of step i) CuI, morpholin-3-one, N, N'-dimethylenediamine, K ₂ CO ₃ , 1,4-dioxane.

Aryl bromide 7.1 (1.0 eq.), Morpholin-3-one (1.25 eq.), CuI (0.2 eq.), N, N'-dimethylenediamine (0.4 eq.) And K ₂ CO ₃ (2.0 equiv.) Was heated at 110 ° C. in dioxane for 18 hours. The reaction mixture was cooled, diluted with water and EtOAc. The organic layer was washed (water, brine), dried (MgSO ₄ ) and concentrated to give compound 11.1. Purification was performed by reverse phase chromatography.

The practitioner in this field it is clear how to combine or modify the above methods, in particular in combination with the implementation of the activation or the introduction of protective chemical groups.

Preparation of (S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N- methylacetamide (23)

Stage 1

To a solution of 4-nitro-1H-pyrazole (100 g, 0.88 mol) in ACN (2 L) was added K ₂ CO ₃ (183.2 g, 1.33 mol) and methyl 2-chloroacetate (95.6 g , 0.88 mol). The resulting mixture was heated to 60 ° C and stirred for 5 hours. The mixture was then filtered and the solvent removed to give methyl 2- (4-nitro-1H-pyrazol-1-yl) acetate as a white solid (150 g, 92 %). 1 H NMR (400 MHz, CDCl 3): δ 8.28 (s, 1H), 8.11 (s, 1H), 4.98 (s, 2H), 3.84 (s, 3H).

Stage 2

A solution of methyl 2- (4-nitro-1H-pyrazol-1-yl) acetate (150 g, 0.81 mol) and methylamine in ethanol (2 L) was heated to reflux and stirred overnight. Then the reaction mixture was allowed to cool and was filtered. The precipitate was washed with EtOAc (800 ml) and dried in vacuo to give N-methyl-2- (4-nitro-1H-pyrazol-1-yl) acetamide as a pale yellow solid (148 g, 99%). ¹ H NMR (400 MHz, d ₆ -DMSO): δ 8.82 (s, 1H), 8.24 (s, 1H), 8.15 (d, J = 4.4 Hz, 1H), 4, 85 (s, 2H); 2.61 (d, J = 4.4 Hz, 3H).

Stage 3

To a solution of N-methyl-2- (4-nitro-1H-pyrazol-1-yl) acetamide (80 g, 0.43 mol) in MeOH (1.5 L) under N _{2 was} added Pd-C (10% , 16 g). The resulting suspension was degassed in vacuo and the H ₂ vessel was filled several times. The mixture was stirred in an H ₂ atmosphere (50 psi) at 30 ° C. overnight and then filtered through a pad of celite, which was washed with MeOH (3 × 300 ml). The combined filtrate was concentrated to dryness to give 2- (4-amino-1H-pyrazol-1-yl) -N-methylacetamide (441.7 g, 89% yield, 6 portions) as a red solid, which was used without further purification .

Stage 4

To IPA (150 ml) at -78 ° C were added 2,4,5-trichloropyrimidine (1.34 g, 7.31 mmol), (S) -2-phenylglycinol (1 g, 7.29 mmol) and DIPEA ( 2.6 ml, 14.89 mmol). The resulting solution was allowed to warm to room temperature and was stirred overnight. Then the reaction mixture was poured into water (500 ml) with stirring, the resulting white precipitate was collected by filtration and dried in vacuum, obtaining (S) -2 - ((2,5-dichloropyrimidin-4-yl) amino) -2-phenylethanol as solid white.

¹ H NMR (400 MHz, d ₆ -DMSO): δ 8.21 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8 Hz, 2H), 7.33 (t, J = 8 Hz, 2H), 7.25 (t, J = 8 Hz, 1H), 5.21 (td, J = 8.2, 5.2 Hz, 1H) 5.04 (t, J = 6 Hz, 1H); 3.87-3.81 (m, 1H); 3.73-3.68 (m, 1H). LC-MS (procedure B): retention time = 0.98 min, (ES ⁺ ) 284.

Stage 4 (alternative technique)

To a solution of 2,4,5-trichloropyrimidine (150 g, 0.818 mol) and (S) -2-phenylglycinol (112.2 g, 0.818 mol) in IPA (1.05 L), DIPEA was slowly added with stirring at 0 ° C. (317.2 g, 2.45 mol). The reaction mixture was stirred at 0 ° C for 1 h and allowed to warm to room temperature. The reaction mixture was stirred overnight at room temperature. TLC R _f 0.6 (CH ₂ Cl ₂ / CH ₃ OH = 10/1) showed completion of the reaction. The resulting precipitate was filtered off, washed with cold IPA and then dried, yielding (S) -2 - ((2,5-dichloropyrimidin-4-yl) amino) -2-phenylethanol (550 g, yield: 78.8%, 3 portions ) as a white solid.

Stage 5

K (S) -2 - ((2,5-dichloropyrimidin-4-yl) amino) -2-phenylethanol (0.37 g, 1.30 mmol) and 2- (4-amino-1H-pyrazol-1- il) -N-methylacetamide (0.2 g, 1.30 mol) in IPA (15 ml) was added one drop of concentrated hydrochloric acid. The resulting solution was heated in the microwave at 140 ° C for 1 h and left to stand at room temperature overnight. The resulting white precipitate was collected by filtration and dried in vacuo to give (S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H -pyrazol-1-yl) -N-methylacetamide as an off-white solid

¹ H NMR (400 MHz, d _6- DMSO): δ 10.28 (br s, 1H), 8.62 (br s, 1H), 8.19 (br s, 1H), 8.04 (br.s, 1H), 7.74 (br.s, 1H), 7.48 (s, 1H), 7.40 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 5.33-5.28 (m, 1H), 4.81-4.71 (m, 3H ), 3.89 (dd, J = 11.2, 8.6 Hz, 1H), 3.74 (dd, J = 11.2, 4.8 Hz, 1H), 2.51 (d, J = 2 Hz, 3H). LC-MS (procedure B): retention time = 0.86 min, (ES ⁺ ) 402.

Stage 5 (alternative technique)

A mixture of (S) -2 - ((2,5-dichloropyrimidin-4-yl) amino) -2-phenylethanol (100 g, 0.352 mol) and 2- (4-amino-1H-pyrazol-1-yl) -N -methylacetamide (0.352 mol) in IPA (1.5 L) was stirred overnight at 75 ° C. TLC R _f (CH ₂ Cl ₂ / CH ₃ OH = 10/1) indicated that the reaction was complete. The resulting precipitate was filtered off, washed with cold IPA and then dried, yielding a white solid. This white solid was then dissolved in water and then adjusted to pH 7 with a saturated aqueous NaHCO ₃ solution. The resulting residue was separated by filtration, washed with cold water and then dried, obtaining a free base. Several portions of the free base were combined (380 g) and dissolved in boiling acetone (20 L). The mixture was filtered to remove insoluble impurities. Then, with rapid stirring, HCl (4 M in dioxane, 250 ml, 1 mol) was added dropwise to the resulting hot solution. After this, the reaction mixture was allowed to cool to room temperature and filtered. The filtered precipitate was washed with cold acetone and dried in vacuo to give (S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) - 1H-pyrazol-1-yl) -N-methylacetamide as hydrochloride (yield 324 g, 41.3%, 5 portions) as a white solid.

¹ H NMR (400 MHz, D ₂ O): δ 2,600 (s, 3H), 3,817-3,833 (d, J = 2.4 Hz, 2H), 4,670-4,673 (m, 2H), 5,097 (5, 1H ), 7.175-7.223 (m, 6H), 7.329 (s, 1H), 7.723 (s, 1H). LC-MS: (M + H) ⁺ 402.

Preparation of (S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino-1H-pyrazol-1-yl) acetamide (78)

Stage 1

To a solution of 4-nitro-1H-pyrazole (2 g, 17.68 mmol) in ACN (200 ml) was added K ₂ CO ₃ (4.9 g, 35.43 mmol) and chloroacetamide (1.66 g, 17, 75 mmol). The mixture was heated to 60 ° C and stirred overnight. The mixture was allowed to cool, filtered and the solvent removed to give 2- (4-nitro-1H-pyrazol-1-yl) acetamide as a white solid (3 g, 100%).

¹ H NMR (400 MHz, d ₆ -DMSO): δ 8.82 (s, 1H), 8.26 (s, 1H), 7.67 (br.s, 1H), 7.41 (br.s , 1H); 4.88 (s, 2H).

Stage 2

To a solution of 2- (4-nitro-1H-pyrazol-1-yl) acetamide (3 g, 17.64 mmol) in MeOH (150 ml) in an atmosphere of N _{2 was} added Pd-C (10%, 0.3 g) . The suspension was degassed in vacuo and the reaction vessel H ₂ was filled several times. The mixture was stirred in an atmosphere of H ₂ at atmospheric pressure and room temperature overnight and then filtered through a pad of celite. The resulting filtrate was concentrated to dryness to give 2- (4-amino-1H-pyrazol-1-yl) acetamide as a burgundy solid that was used without further purification.

¹ H NMR (400 MHz, d ₆ -DMSO): δ 7.17 (br s, 2H), 7.02 (s, 1H), 6.93 (s, 1H), 4.55 (s, 2H ), 3.85 (br s, 2H).

Stage 3

DIPEA (1.5 ml, 8.59 mmol) and (S) -2-amino-2- (2-fluorophenyl) ethan-1-ol hydrochloride (0.5 g) were added to IPA (15 ml) at 0 ° C. 2.61 mmol) and then 2,4,5-trichloropyrimidine (0.45 g, 2.46 mmol). The resulting solution was allowed to warm to room temperature and was stirred overnight. Then the reaction mixture was poured into water (50 ml) with stirring, and the resulting white precipitate was collected by filtration and dried in vacuo to give (S) -2 - ((2,5-dichloropyrimidin-4-yl) amino) -2- (2 -fluorophenyl) ethanol as an off-white / yellow solid (0.64 g, 86%), which was used without further purification.

¹ H NMR (400 MHz, d ₆ -DMSO): δ 8.23 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.48 (td, J = 7.6 1.5 Hz, 1H), 7.41-7.26 (m, 1H), 7.26-7.08 (m, 2H), 5.51 (td, J = 8.1, 5.0 Hz, 1H), 5.16 (t, J = 5.9 Hz, 1H), 3.92-3.75 (m, 1H), 3.75-3.63 (m, 1H). LC-MS (procedure B): retention time = 1.04 min, (ES ⁺ ) 302.

Stage 4

(S) -2 - ((2,5-dichloropyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol (0.096 g, 0.32 mmol) and 2- (4) were added to IPA (15 ml). amino-1H-pyrazol-1-yl) acetamide (0.07 g, 0.50 mmol). The resulting solution was heated at 80 ° C. overnight, allowed to cool and a solid precipitated by the addition of a saturated solution of NaHCO ₃ . The collected solid was purified by reverse phase chromatography to give (S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino -1H-pyrazol-1-yl) acetamide as an off-white solid.

¹ H NMR (400 MHz, d ₆ -DMSO): δ 9.11 (s, 1H), 7.94 (s, 1H), 7.60 (s, 1H), 7.40 (dd, J = 15 , 1, 7.3 Hz, 2H), 7.35-7.25 (m, 2H), 7.23 (s, 1H), 7.21-7.13 (m, 2H), 7.03 ( s, 1H), 5.53 (dd, J = 13.2, 6.0 Hz, 1H), 5.17 (s, 1H), 4.64 (s, 2H), 3.75 (t, J = 5.8 Hz, 2H). LC-MS (procedure E): retention time = 4.86 min, (ES ⁺ ) 406.

Preparation of (S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino-1H-pyrazol-1-yl) acetamide (78) (alternative method)

Synthesis path

Stage i) DIPEA, IPA 0 ° C 18 h; stage ii) 4.0 M HCl dioxane, IPA, 60 ° C, 24-48 hours; stage iii) 7n. NH ₃ MeOH, EtOH 18 h.

(S) -2 - ((2,5-dichloropyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol

A solution of (S) -2-amino-2- (2-fluorophenyl) ethanol hydrochloride (500 mg, 2.62 mmol) and DIPEA (1.1 ml, 3.0 equiv.) In IPA (10 ml) was stirred for 10 minutes. The solution was cooled in an ice water bath and then 2,4,5-trichloropyrimidine (450 mg, 2.46 mmol) was added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. Water (30 ml) was added and the precipitate formed was collected by filtration as an off-white / yellow solid (0.64 g, 87% yield). UPLC (high pH) retention time 1.04 min, m / z 302 (ES +);

¹ H NMR (400 MHz, d ₆ -DMSO): δ 8.23 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.48 (td, J = 7.6 1.5 Hz, 1H), 7.41-7.26 (m, 1H), 7.26-7.08 (m, 2H), 5.51 (td, J = 8.1, 5.0 Hz, 1H), 5.16 (t, J = 5.9 Hz, 1H), 3.92-3.75 (m, 1H), 3.75-3.63 (m, 1H).

(S) -ethyl 2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -H-pyrazol-1-yl )acetate

(S) -2 - ((2,5-dichloropyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol (1.90 g, 6.3 mmol) and ethyl 2- (4-amino-1H -pyrazol-1-yl) acetate (1.60 g, 1.5 eq.) was stirred in EtOH (40 ml) with HCl in dioxane (4 M, 1.60 ml, 1.0 eq.) and heated to 50 ° C for 40 hours. The reaction mixture was evaporated, removing half the volume of the solvent, and then partitioned between EtOAc and NaHCO ₃ (aq.). The aqueous layer was extracted with EtOAc, the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to give 3.0 g of a dark red solid. 169 mg of this red solid was further purified by flash chromatography (10 g silica, 50-100% EtOAc / pet. Ether) to give 124 mg (73% yield) of a colorless solid.

(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino-1H-pyrazol-1-yl) acetamide

(S) -ethyl 2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -H-pyrazol-1-yl ) acetate (2.84 g, 6.53 mmol) was dissolved in 7N. a solution of NH ₃ in MeOH (14 ml) and was stirred at room temperature for 64 hours. The resulting precipitate was collected by filtration, then triturated with IPA, again collected by filtration, washed with IPA and dried overnight in a vacuum oven. LCMS (5) retention time 4.81 minutes m / z 406 (ES +).

¹ H NMR (400 MHz, d ₆ -DMSO): δ 9.11 (s, 1H), 7.94 (s, 1H), 7.60 (s, 1H), 7.40 (dd, 15.1 , 7.3 Hz, 2H), 7.35-7.25 (m, 2H), 7.23 (s, 1H), 7.21-7.13 (m, 2H), 7.03 (s, 1H), 5.53 (dd, J = 13.2, 6.0 Hz, 1H), 5.17 (s, 1H), 4.64 (s, 2H), 3.75 (t, J = 5 8 Hz, 2H). It was determined that the percentage of ee enantiomeric excess was> 98%.

(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino-1H-pyrazol-1-yl) acetamide (alternative reaction conditions)

(S) -ethyl 2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -H-pyrazol-1-yl ) acetate (822 mg, 1.89 mmol) was dissolved in 7n. solution of NH ₃ in MeOH (15 ml) and heated in a microwave at 120 ° C for 30 minutes. The reaction mixture was evaporated, yielding 718 mg of a red solid (yield 94%). This solid was dissolved in EtOAc with a small amount of MeOH to increase solubility and then washed with NaHCO ₃ (aq). The aqueous layer was extracted with 2 × EtOAc. The organic phases were combined and washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to give 647 mg (84% yield) of a peach-colored solid.

HCl salt formation

Compound 78 in the form of a free base (1.02 g, 2.51 mmol) was suspended in IPA (20 ml) at 60 ° C. To this suspension was added 2 M HCl (1.38 ml, 2.76 mmol) to obtain a colorless solution. This solution was allowed to cool to room temperature, then the solvents were carefully removed, first by flash evaporation in a stream of nitrogen and then in vacuo to give 916 mg (83% yield) of UPLC at high pH. Retention time 1.77 minutes, m / z 406 (ES +), melting point (with decomposition) 89 ° C, melting 180 ° C.

Biological research

Determining the effect of the compounds of the present invention on JAK

The compounds of the present invention described in the previous examples were investigated in the Kinobeads ^™ assay as described for ZAP-70 (WO-A 2007/137867). Briefly, test compounds (at various concentrations) and an affinity matrix with immobilized aminopyridopyrimidine ligand 24 were added to aliquots of the cell lysate and allowed to bind to proteins in the lysate sample. After incubation, granules with bound proteins were separated from the lysate. Then the bound proteins were washed away, the presence of JAK1, JAK2, JAK3 and TYK2 was determined and quantified using specific antibodies in the dot blotting technique and the Odyssey infrared detection system. The dose-response relationships were constructed for individual kinases and IC ₅₀ values were calculated. Kinobeads ^™ analysis for ZAP-70 (WO-A 2007/137867) and for determining the kinase selectivity profile (WO-A 2006/134056) have been described previously.

Protocols

Washing affinity matrix

The affinity matrix was washed twice with 15 ml of 1 × DP buffer containing 0.2% NP40 (IGEPAL® CA-630, Sigma, No. 13021) and then resuspended in 1 × DP buffer containing 0.2% NP40 (3% suspension of granules )

5 × DP buffer: 250 mM Tris-HCl, pH 7.4, 25% glycerol, 7.5 mM MgCl ₂ , 750 mM NaCl, 5 mM Na ₃ VO ₄ ; A 5 × DP buffer was filtered through a 0.22 μm filter and stored in aliquots at -80 ° C. 5x DP buffer was diluted with H ₂ O to 1x DP buffer containing 1 mM DTT and 25 mM NaF.

Getting test compounds

Concentrated solutions of test compounds were prepared in DMSO. In a 96-well plate, 30 μl of solutions of diluted test compounds at a concentration of 5 mM in DMSO were prepared. Based on these solutions, a series of successive dilutions of 1: 3 (9 steps) was prepared. For control experiments (without test compounds), a buffer containing 2% DMSO was used.

Cell Culture and Cell Lysate Production

Molt4 cells (ATCC catalog number CRL-1582) and Ramos cells (ATCC catalog number CRL-1596) were grown in 1 L Spinner flasks (Integra Biosciences, No. 182101) as a suspension in RPMI 1640 medium (Invitrogen, No. 21875-034 ) supplemented with 10% calf serum (Invitrogen) at a cell density of 0.15 × 10 ⁶ to 1.2 × 10 ⁶ cells / ml. Cells were collected by centrifugation, washed once with 1 × PBS buffer (Invitrogen, No. 14190-094), precipitated cells were frozen in liquid nitrogen, and then stored at -80 ° C. Cells were homogenized using a Potter S homogenizer in lysis buffer: 50 mM Tris-HCl, 0.8% NP40, 5% glycerol, 150 mM NaCl, 1.5 mM MgCl ₂ , 25 mM NaF, 1 mM sodium vanadate, 1 mM DTT, pH 7.5. One complete EDTA-free tablet was added to 25 ml of buffer (Protease Inhibitor Shake, Roche Diagnostics, 1873580). Cellular material was homogenized 10 times using a Potter S motorized homogenizer, transferred to 50 ml falcon tubes, incubated for 30 minutes on ice and centrifuged for 10 minutes at 20,000 g at 4 ° C (10,000 rpm in a pre-cooled Sorvall SLA600 centrifuge) . The supernatant was transferred to an (UZ) polycarbonate ultracentrifuge tube (Beckmann, 355654) and centrifuged for 1 h at 100,000 g at 4 ° C (33,500 rpm in a pre-cooled Ti50.2 centrifuge). The supernatant was transferred to new 50 ml falcon tubes, the protein concentration was determined using a Bradford assay (BioRad), and samples containing 50 mg of protein per aliquot were prepared. Samples were immediately used for experiments or frozen in liquid nitrogen and stored frozen at -80 ° C.

Cell Lysate Dilution

Cell lysates (approximately 50 mg protein per plate) were thawed in a water bath at room temperature and then stored on ice. To the thawed cell lysate was added 1 × DP 0.8% NP40 buffer containing protease inhibitors (1 tablet per 25 ml buffer, EDTA-free protease inhibitor cocktail; Roche Diagnostics 1873580) to achieve a final protein concentration of 10 mg / ml total protein . Diluted cell lysates were stored on ice. A mixed Molt4 / Ramos lysate was prepared by mixing one volume of Molt4 lysate and two volumes of Ramos lysate (1: 2 ratio).

Incubation of the lysate with test compound and affinity matrix

In 96-well filter plates (Multiscreen HTS, BV Filter Plates, Millipore # MSBVN1250), 100 μl of affinity matrix (3% suspension of granules), 3 μl of compound solution and 50 μl of diluted lysate were added per well. The plates were tightly closed and incubated for 3 hours in a cold room on a plate shaker (Heidolph tiramax 1000) at 750 rpm. After this, the plates were washed 3 times with 230 μl wash buffer (1 × DP 0.4% NP40). Filter plates were placed on top of a sample collection plate (Greiner bio-one, PP-microplate 96-well, V-shaped 65120) and the granules were washed with 20 μl of sample buffer (100 mM Tris, pH 7.4, 4% SDS, 0, 00025% Bromophenol Blue, 20% Glycerin, 50 mM DTT). The eluate was rapidly frozen at -80 ° C and stored at -20 ° C.

Detection and quantification of eluted kinases

The kinases in the eluates were detected and quantified by spotting the sample on a nitrocellulose membrane using the first antibody against the kinase of interest and the fluorescently labeled second antibody (anti-rabbit IRDye ^™ antibody 800 (Licor, # 926-32211)). The Odyssey infrared imaging system from LI-COR Biosciences (Lincoln, Nebraska, USA) was used according to the manufacturer's instructions (Schutz-Geschwendener et al., 2004. Quantitative, two-color Western blot detection with infrared fluorescence. Published in May 2004 LI-COR Biosciences, http://www.licor.com).

After applying the eluate stain, nitrocellulose membranes (BioTrace NT; PALL, # BTNT30R) were first blocked by incubation with Odyssey blocking buffer (LICOR, 927-40000) for 1 hour at room temperature. The blocked membranes were then incubated for 16 hours at the temperature indicated in Table 4 with the first antibody diluted with Odyssey blocking buffer (LICOR # 927-40000). After this, the membranes were washed twice within 10 minutes with PBS buffer containing 0.2% Tween 20 at room temperature. The membranes were then incubated for 60 minutes at room temperature with a detection antibody (anti-rabbit IRDye ^™ antibody 800, Licor, # 926-32211) diluted with Odyssey blocking buffer (LICOR # 927-40000). The membranes were then washed twice for 10 minutes with 1 × PBS buffer containing 0.2% Tween 20 at room temperature. The membrane was then washed once with PBS buffer to remove Tween 20 residues. The membranes were stored in PBS buffer at 4 ° C and then scanned with an Odyssey instrument. Fluorescent signals were recorded and analyzed according to the manufacturer's instructions.

Table 7
Sources and dilutions of antibodies Target kinase The first antibody (dilution) Pace. primary incubation The second antibody (dilution) Jak1 Cell signaling # 3332
1: 100 4 ° C Licor anti-rabbit 800 (1: 15000) Jak2 Cell signaling # 3230
1: 100 room temp. Licor anti-rabbit 800 (1: 15000) Jak3 Cell signaling # 3775
1: 100 4 ° C Licor anti-rabbit 800 (1: 5000) TYK2 Cell signaling # 06-638
1: 1000 room temp. Licor anti-rabbit 800 (1: 5000)

Cell analysis

pSTAT5 analysis

Principle of analysis

Phosphorylation of STAT5 is one of the closest events in cascaded signaling following JAK3 activation. Therefore, STAT5 phosphorylation is a suitable indicator for assessing the effect of JAK3 inhibition on signal transmission. Stimulation of human YT cells, which are an NK-like cell line, with interleukin-2 (IL-2) leads to phosphorylation of STAT5 at tyrosine residue 694 (Tyr694), which can be quantified by immunodetection using specific antibodies and a suitable detection technique, in this case analysis techniques AlphaScreen.

Analysis protocol

Cell cultivation and seeding

Human YT cells were grown in RPMI medium (Lonza, BE12-167) supplemented with 2 mM L-glutamine (Invitrogen, 25030-024) and 10% thermally inactivated FBS (Invitrogen, 10106-169) and stored in a wet incubator (37 ° C , 5% CO ₂ ). Cells were harvested by centrifugation, washed once with HBSS (Invitrogen, 14180-046), resuspended in HBSS at a concentration of 1.5 × 10 ⁶ cells / ml and sown with 0.9 × 10 ⁴ cells in a volume of 6 μl per well in 96-well white tablet (PerkinElmer, 6005569).

Test compound treatment and stimulation of IL-2

Test compounds were dissolved in DMSO and a series of samples were prepared with sequential dilutions of 1: 3 (9 steps). To obtain a dose-response curve, 3 μl of a compound with a concentration of 4x in 4% DMSO / HBSS was added to each cell image in a 96 well plate, resulting in a final concentration of DMSO of 1%. Cells were incubated for one hour in a wet incubator (37 ° C, 5% CO ₂ ). To each well was added 3 μl of a 4x IL-2 solution (recombinant human IL-2, Peprotech 200-02; 120 nM solution in HBSS) and incubated for 30 minutes at room temperature. Cells were lysed by adding 3 μl of 5x lysis buffer (SureFire lysis buffer; Perkin Elmer, TGRS5S10K) and incubated at room temperature for 10 minutes with gentle shaking.

Signal detection

For signal detection in the AlphaScreen® methodology, the SureFire Phospho-STAT5 kit (Tyr694 / Tyr699) was used in accordance with the manufacturer's instructions (Perkin Elmer, TGRS5S10K). Acceptor granules were added according to the manufacturer's recommendations (reactivation buffer / activation buffer / acceptor granules in a ratio of 40: 10: 1) and incubated at room temperature for 1.5 hours with gentle shaking. Then, donor granules were added following the recommendations (dilution buffer / donor granules in a 20: 1 ratio) and incubated at room temperature for 1.5 hours with gentle shaking. The plates were read on an Envision instrument (Perkin Elmer) according to the AlphaScreen protocol. Data were analyzed in the BioAssay program using non-linear regression for a sigmoidal dose-response relationship with a variable slope.

Table 9 shows the data for selected compounds of the present invention in pSTAT5 cell analysis.

Claims (37)

1. The compound of formula (I)

or its pharmaceutically acceptable salt, where:
R represents H; F; Cl; CH ₃ or CF ₃ ;
cycle A is a 5-membered aromatic heterocycle in which Z ¹ , Z ² and Z ^{3 are} independently selected from the group consisting of C (R ¹ ); N and N (R ¹ ), provided that at least one of Z ¹ , Z ² , Z ³ represents N or N (R ¹ );
each of R ¹ independently represents H, C (O) R ² ; T ¹ ; C _1-6 alkyl; where C _1-6 alkyl is optionally substituted with one or more R ³ that are the same or different;
R ² selected from T ¹ ;
R ³ represents halogen; C (O) OR ⁴ ; OR ⁴ ; C (O) R ⁴ ; C (O) N (R ⁴ R ^4a ) or N (R ⁴ R ^4a );
R ⁴ , R ^{4a are} independently selected from the group consisting of H; T ¹ ; C _1-6 alkyl; where C _1-6 alkyl is optionally substituted with one or more R ⁵ that are the same or different;
R ⁵ represents CN; OR ^5a or N (R ^5a R ^5b );
R ^5a , R ^{5b are} independently selected from the group consisting of H; C _1-6 alkyl;
T ¹ represents C ₃ cycloalkyl; saturated 5-6 membered heterocyclyl containing 1-2 heteroatoms selected from N and O;
wherein the T ¹ group is optionally substituted with one or more R ¹⁰ that are the same or different;
Y ⁰ represents (CR ^Y3 R ^Y4 ) _n ;
n is 0 or 1;
one of the groups R ^Y1 ; R ^Y2 ; R ^Y3 ; R ^Y4 is R ^Y0 , and others are selected from the group consisting of H and CH ₃ ;
R ^Y0 is unsubstituted C _1-4 alkyl; CH ₂ CH ₂ OR ^Y5 ; CH ₂ OR ^Y5 ; C (O) T ^Y1 ; C (O) OR ^Y5 ; or C (O) N (R ^Y5 R ^Y5a );
R ^Y5 , R ^{Y5a are} independently selected from the group consisting of H; T ^Y1 ; and C _1-4 alkyl, wherein C _1-4 alkyl is optionally substituted with one or more R ^Y6 that are the same or different;
R ^Y6 is halogen or OR ^Y7 ;
R ^{Y7 is} selected from C _1-4 alkyl;
T ^Y1 represents unsubstituted C ₅ cycloalkyl; or unsubstituted saturated 5-6 membered heterocyclyl containing one heteroatom selected from N;
X ¹ represents C (R ^6a ) or N; X ² is C (R ^6b ) or N; X ³ is CH; X ⁴ is C (R ^6c ); X ⁵ means C (R ^6d );
R ^6a , R ^6b , R ^6c , R ^{6d are} independently selected from the group consisting of H, halogen; OR ⁷ ; T ² ; C _1-6 alkyl; where C _1-6 alkyl is optionally substituted with one or more R ¹¹ that are the same or different;
R ^{7 is} selected from C _1-6 alkyl;
R ¹⁰ represents oxo (= O) or C _1-6 alkyl; R ¹¹ selected from halogen;
T ² is a 5-6 membered heterocyclyl containing 2 heteroatoms selected from N or O; or a 7-membered heterobicyclyl containing 2 heteroatoms selected from N or O, wherein the T ² moiety is optionally substituted with one or more R ¹⁷ that are the same or different;
R ^{17 is} selected from the group consisting of oxo (= O), or C _1-6 alkyl; provided that the following compounds are excluded from this definition:

2. The compound of claim 1, wherein n is 0. 3. The compound according to claim 1 or 2, where in the formula (I) R ^Y1 , R ^Y2 and Y ^{0 are} defined so that the formula (I) takes the form of the formulas (Ia), (Ib), (Ic) or (Id ):

4. The compound according to claim 3, where Z ² represents N (R ¹ ), and R ¹ is different from N. 5. The compound according to claim 3, where in the formula (I) R ^Y1 , R ^Y2 and Y ^{0 are} determined in such a way that formula (I) takes the form of formula (Ia). 6. The compound according to claim 1, where R ^Y0 means unsubstituted C _2-4 alkyl; CH ₂ CH ₂ OR ^Y5 ; CH ₂ OR ^Y5 ; C (O) T ^Y1 ; C (O) OR ^Y5 ; or C (O) N (R ^Y5 R ^Y5a ). 7. The compound of claim 1, wherein R ^Y0 is CH ₂ CH ₃ ; CH ₂ OR ^Y5 ; C (O) OR ^YS ; C (O) N (R ^Y5 R ^Y5a ); or C (O) T ^Y1 . 8. The compound of claim 1, wherein R ^Y0 is CH ₂ OR ^Y5 . 9. The compound of claim 8, wherein R ^Y0 is CH ₂ OH. 10. The compound of claim 1, wherein cycle A is a pyrrolyl or pyrazolyl ring. 11. The compound of claim 1, wherein cycle A is

. 12. The compound according to claim 1, where cycle A is unsubstituted or substituted by one or two substituents R ¹ that are different from H and are the same or different. 13. The compound according to claim 1, where one of the fragments Z ¹ , Z ² , Z ³ represent N (R ¹ ), and R ¹ differs from N. 14. The compound of claim 1, wherein R ¹ is unsubstituted C _1-4 alkyl; or C _1-4 alkyl substituted with one or two R ³ fragments that are the same or different. 15. The compound according to claim 1, where R ³ means halogen; OR ⁴ ; C (O) OR ⁴ ; C (O) T ¹ ; or C (O) N (R ⁴ R ^4a ). 16. The compound according to claim 1, where R ³ means OR ⁴ ; C (O) OR ⁴ ; or C (O) N (R ⁴ R ^4a ). 17. The compound of claim 15 or 16, wherein R ³ is C (O) N (R ⁴ R ^4a ). 18. The compound of claim 1, wherein R is F; Cl; CF ₃ or CH ₃ . 19. The compound of claim 18, wherein R is Cl. 20. The compound according to claim 1, where none of the fragments X ¹ , X ² , X ⁴ , X ⁵ is N. 21. The compound according to claim 1, where no more than three fragments from among R ^6a , R ^6b , R ^6c , R ^6d differ from N. 22. The compound according to p. 21, where none of the fragments R ^6a , R ^6b , R ^6c , R ^6d does not differ from N. 23. The compound of claim 22, wherein one of the moieties R ^6a , R ^6b , R ^6c , R ^6d is other than H. 24. The compound of claim 1, wherein the fragments R ^6a , R ^6b , R ^6c , R ^{6d are} independently selected from the group consisting of H; halogen; CF ₃ ; OR ⁷ ; or T ² . 25. The compound according to claim 1, where the fragments of R ^6a , R ^6b , R ^6c , R ^{6d are} independently selected from the group consisting of H; halogen; or T ² . 26. The compound of claim 1, wherein the fragments R ^6a , R ^6b , R ^6c , R ^{6d are} independently selected from the group consisting of H; and halogen. 27. The compound of claim 26, wherein the fragments R ^6a , R ^6b , R ^6c , R ^{6d are} independently selected from the group consisting of H; and F. 28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;
2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;
(S) -2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;
(R) -5-chloro-N2- (1-methyl-1H-pyrazol-4-yl) -N4- (1-phenylpropyl) pyrimidin-2,4-diamine;
(S) -2 - ((2 - ((1-methyl-1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) -2-phenylethanol;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylpropan-1-ol;
2 - ((2 - ((1-methyl-1H-pyrazol-4-yl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) -2-phenylpropan-1-ol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;
(S) -2 - ((5-fluoro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;
2 - ((2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) -5-methylpyrimidin-4-yl) amino) -2-phenylethanol;
(S) - (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrrol-2-yl) (morpholino) methanone;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -3-phenylpropan-1-ol;
methyl 2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylacetate;
methyl 2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylacetate;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylacetic acid;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylacetic acid;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -3-phenylpropan-1-ol;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-methyl-2-phenylacetamide;
(S) -isopropyl 2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetate;
(S) -ethyl 2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetate;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetic acid;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethyl-2-phenylacetamide;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N, N-dimethyl-2 phenylacetamide;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-ethyl-2-phenylacetamide ;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-ethyl-2-phenylacetamide;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N- (2-methoxyethyl) -2-phenylacetamide ;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N, N dimethylacetamide;
2- (4 - ((5-chloro-4 - ((1- (2, b-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N methylacetamide;
2- (4 - ((5-chloro-4 - ((1- (3-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;
2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenyl-1- (pyrrolidin-1- sludge) ethanone;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenyl-1- ( pyrrolidin-1-yl) ethanone;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;
1- (4 - ((5-chloro-4 - ((1- (3-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propan-2- ol;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;
1- (4 - ((5-chloro-4 - ((1- (2,6-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propan- 2-ol;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2, b-difluorophenyl) ethanol;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2,6-difluorophenyl) ethanol;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) -2- (2,6-difluorophenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N- (2-hydroxyethyl) -2-phenylacetamide ;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N- (2-hydroxyethyl) -2-phenylacetamide;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N- (2-methoxyethyl) -2-phenylacetamide;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenyl-1- (piperidin-1- sludge) ethanone;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenyl-1- ( piperidin-1-yl) ethanone;
2- (3- (2-oxa-6-azaspiro [3.3] heptan-6-yl) phenyl) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino ) pyrimidin-4-yl) amino) ethanol;
(S) -5-chloro-N4- (2-methoxy-1-phenylethyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;
1- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropane -2-ol;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-cyclopentyl-2-phenylacetamide;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -N-cyclopentyl-2-phenylacetamide ;
1- (4 - ((5-chloro-4 - ((1- (3-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropane -2-ol;
1- (4 - ((5-chloro-4 - ((1- (2,6-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2 methylpropan-2-ol;
3- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) 2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) propan-1-ol ;
(R) -3 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino-3-phenylpropan-1-ol;
(R) -2- (4 - ((5-chloro-4 - ((3-hydroxy-1-phenylpropyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-isopropylacetamide ;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-cyclopropylacetamide ;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3- (1-methyl-1H-pyrazol-4 -yl) phenyl) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N- ( cyanomethyl) -N-methylacetamide;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (4-fluorophenyl) ethanol;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (4-fluorophenyl) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -2-methylpropanamide;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-methoxyphenyl) ethanol;
(S) -2 - ((2 - ((1H-pyrazol-4-yl) amino) -5-chloropyrimidin-4-yl) amino) -2-phenylethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-methoxyphenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;
(S) -2 - ((2 - ((1H-pyrazol-4-yl) amino) -5-chloropyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (pyridin-2- sludge) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (pyridin-2-yl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1 -yl) acetamide;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-methoxyphenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-methoxyphenyl) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (3-methoxyphenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) acetamide;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((1- (3-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;
(S) -2 - ((2 - ((1H-pyrazol-4-yl) amino) -5-chloropyrimidin-4-yl) amino) -2- (3-fluorophenyl) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N- ( 2- (dimethylamino) ethyl) acetamide;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N- ( 3- (dimethylamino) propyl) acetamide;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (pyridin-3-yl) ethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (pyridin-3- sludge) ethanol;
2- (3-bromophenyl) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-
pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3- (1-methyl-1Н -pyrazol-4-yl) phenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-methoxyphenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-methoxyphenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (pyridin-3-yl) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (2-methoxyphenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -N-methylacetamide;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (3-methoxyphenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -N-methylacetamide;
(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (2-methoxyphenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -1-morpholinoethanone;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (3-methoxyphenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -1-morpholinoethanone;
(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -1-morpholinoethanone;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (pyridin-3-yl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1 -yl) -1-morpholinoethanone;
(S) -2 - ((5-chloro-2 - ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-methoxyphenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-methoxyphenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (pyridin-3-yl) ethanol;
(S) -2- (4 - ((5-fluoro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;
(S) -2 - ((5-chloro-2 - ((1-ethyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1-isopropyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) ethanol;
(S) -2- (4 - ((5-fluoro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;
(S) -2- (4 - ((5-fluoro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -1-morpholinoethanone ;
(S) -2 - ((2 - ((1- (3-aminopropyl) -1H-pyrazol-4-yl) amino) -5-chloropyrimidin-4-yl) amino) -2-phenylethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-isopropoxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-phenylethanol;
(S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-isopropylacetamide;
2- (4 - ((5-chloro-4 - (((S) -1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino-1H-pyrazol-1-yl) - N - ((S) -1-hydroxypropan-2-yl) acetamide;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-chlorophenyl) ethanol;
2- (4 - ((5-chloro-4 - ((1- (2-chlorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;
2- (4 - ((5-chloro-4 - ((1- (2-chlorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide ;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-chlorophenyl) ethanol;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3,5-difluorophenyl) ethanol;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3,5-difluorophenyl) ethanol;
2- (4 - ((5-chloro-4 - ((1- (3,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N methylacetamide;
4- (3- (1 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-hydroxyethyl) phenyl) morpholin-3 -she;
5-chloro-N4- (1- (2-fluorophenyl) propyl) -N2- (1-methyl-1H-pyrazol-4-yl) pyrimidine-2,4-diamine;
2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) propyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) -N, N dimethylacetamide;
2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2-fluorophenyl) -N- ( 2,2,2-trifluoroethyl) acetamide;
2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2,5-difluorophenyl) ethanol;
2- (4 - ((5-chloro-4 - ((1- (2,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N methylacetamide;
2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (2- (trifluoromethyl) phenyl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;
2- (4 - ((5-chloro-4 - ((1- (2,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) acetamide;
(S) -2- (4 - ((4 - ((2-hydroxy-1-phenylethyl) amino) -5-methylpyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;
(S) -2- (4 - ((4 - ((2-hydroxy-1-phenylethyl) amino) -5-methylpyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N, N- dimethylacetamide;
3- (4 - ((5-chloro-4 - (((S) -2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -1-methylpyrrolidine -2-she;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3- (1-methyl-1H -pyrazol-4-yl) phenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluoro-5- (1 methyl-1H-pyrazol-4-yl) phenyl) ethanol;
(S) -4- (3- (1 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-hydroxyethyl) phenyl ) morpholin-3-one;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2,5-difluorophenyl) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((1- (2,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1- il) acetamide;
(S) -2- (4 - ((5-chloro-4 - ((1- (2,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1- silt) -N-methylacetamide;
(S) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3,5-difluorophenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3,5- difluorophenyl) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((1- (3,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1- il) acetamide;
(S) -2- (4 - ((5-chloro-4 - ((1- (3,5-difluorophenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1- silt) -N-methylacetamide;
(S) -2- (2,5-difluorophenyl) -2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2- (2,5-difluorophenyl) -2 - ((5-fluoro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2- (4 - ((4 - ((1- (2,5-difluorophenyl) -2-hydroxyethyl) amino) -5-fluoropyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -N-methylacetamide;
(S) -2- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) -2 - ((5-methyl-2 - ((1-methyl-1H-pyrazol-4-yl) amino ) pyrimidin-4-yl) amino) ethanol;
(S) -2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluoro-5- (1 methyl-1H-pyrazol-4-yl) phenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3- (1 methyl-1H-pyrazol-4-yl) phenyl) ethanol;
(S) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluoro- 5- (1-methyl-1H-pyrazol-4-yl) phenyl) ethanol;
(S) -2 - ((5-fluoro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (3-fluoro- 5- (1-methyl-1H-pyrazol-4-yl) phenyl) ethanol;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) ethyl) amino) pyrimidin-2 -yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;
(S) -2- (4 - ((5-fluoro-4 - ((2-hydroxy-1- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) ethyl) amino) pyrimidin-2 -yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;
(S) -2- (4 - ((5-chloro-4 - ((1- (3-fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;
(S) -2- (4 - ((5-fluoro-4 - ((1- (3-fluoro-5- (1-methyl-1H-pyrazol-4-yl) phenyl) -2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1-yl) -N-methylacetamide;
(S) -2- (3,5-difluorophenyl) -2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2- (3,5-difluorophenyl) -2 - ((5-fluoro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2- (4 - ((4 - ((1- (3,5-difluorophenyl) -2-hydroxyethyl) amino) -5-fluoropyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) acetamide;
(S) -2- (4 - ((4 - ((1- (3,5-difluorophenyl) -2-hydroxyethyl) amino) -5-fluoropyrimidin-2-yl) amino) -1H-pyrazol-1-yl ) -N-methylacetamide;
(S) -4- (3- (1 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2-hydroxyethyl) - 2-fluorophenyl) morpholin-3-one;
(S) -2- (2,5-difluorophenyl) -2 - ((5-methyl-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2- (3,5-difluorophenyl) -2 - ((5-methyl-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2 - ((5-chloro-2 - ((1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) -2- (2- fluorophenyl) ethanol;
(S) -2 - ((2 - ((1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) amino) -5-methylpyrimidin-4-yl) amino) -2- (2,5 difluorophenyl) ethanol;
(S) -2 - ((2 - ((1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) amino) -5-methylpyrimidin-4-yl) amino) -2- (3,5 difluorophenyl) ethanol;
2 - ((2 - ((1- (2,2-difluoroethyl) -1H-pyrazol-4-yl) amino) -5-methylpyrimidin-4-yl) amino) -2- (2,6-difluorophenyl) ethanol ;
2- (4 - ((4 - ((1- (2,6-difluorophenyl) -2-hydroxyethyl) amino) -5-methylpyrimidin-2-yl) amino-1H-pyrazol-1-yl) -1-morpholinoethanone ;
(S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1- (pyridin-3-yl) ethyl) amino) pyrimidin-2-yl) amino) -1H-pyrazol-1 -yl) -N-methylacetamide;
(S) -2- (3-bromophenyl) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2- (3-bromo-5-fluorophenyl) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2- (3-bromophenyl) -2 - ((5-methyl-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2- (3-bromo-5-fluorophenyl) -2 - ((5-fluoro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2- (3-bromophenyl) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol;
(S) -2- (3-bromo-5-fluorophenyl) -2 - ((5-chloro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4- sludge) amino) ethanol;
(S) -2- (3-bromo-5-fluorophenyl) -2 - ((5-fluoro-2 - ((1- (2-hydroxyethyl) -1H-pyrazol-4-yl) amino) pyrimidin-4- sludge) amino) ethanol;
(S) -2- (4 - ((4 - ((1- (3-bromophenyl) -2-hydroxyethyl) amino) -5-chloropyrimidin-2-yl) amino) -1H-pyrazol-1-yl) - N-methylacetamide;
(S) -2- (4 - ((4 - ((1- (3-bromophenyl) -2-hydroxyethyl) amino) -5-fluoropyrimidin-2-yl) amino) -1H-pyrazol-1-yl) - N-methylacetamide;
(S) -2- (4 - ((4 - ((1- (3-bromo-5-fluorophenyl) -2-hydroxyethyl) amino) -5-chloropyrimidin-2-yl) amino) -1H-pyrazol-1 -yl) -N-methylacetamide;
(S) -2- (4 - ((4 - ((1- (3-bromo-5-fluorophenyl) -2-hydroxyethyl) amino) -5-fluoropyrimidin-2-yl) amino) -1H-pyrazol-1 -yl) -N-methylacetamide; and
2- (3-bromophenyl) -2 - ((5-chloro-2 - ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) amino) ethanol. 29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is (S) -2- (4 - ((5-chloro-4 - ((2-hydroxy-1-phenylethyl) amino) pyrimidin-2-yl ) amino) -1H-pyrazol-1-yl) -N-methylacetamide:

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is (S) -2- (4 - ((5-chloro-4 - ((1- (2-fluorophenyl) -2-hydroxyethyl) amino) pyrimidine -2-yl) amino-1H-pyrazol-1-yl) acetamide:

31. A pharmaceutical composition having JAK kinase inhibitory activity, comprising a compound, a pharmaceutically acceptable salt thereof according to any one of claims. 1-30, along with a pharmaceutically acceptable carrier. 32. The compound or a pharmaceutically acceptable salt thereof according to claim 1 for use as a medicament having inhibitory activity against JAK kinases. 33. The compound or its pharmaceutically acceptable salt according to claim 1 for use in a method for treating or preventing a disease or disorder associated with JAK. 34. The compound or its pharmaceutically acceptable salt according to claim 1 for use in a method of treating or preventing an immunological, inflammatory, autoimmune or allergic disorder, or a disease associated with transplant rejection, or a graft versus host reaction mediated by JAK kinase activity. 35. The compound or its pharmaceutically acceptable salt according to claim 1 for use in a method for treating or preventing a proliferative disease mediated by JAK kinase activity. 36. The use of compounds according to any one of paragraphs. 1-30, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with JAK. 37. A method of treating, regulating, slowing the onset or prophylaxis of a mammalian patient, if necessary, one or more conditions selected from the group consisting of diseases and disorders associated with JAK, comprising administering to the patient a therapeutically effective amount of a compound of any of paragraphs. 1-30 or a pharmaceutically acceptable salt thereof.