阅读说明：本技术 方法和医疗用途 (Method and medical use ) 是由 莱斯利-安·马丁 乔安娜·尼基托罗维奇-布尼亚克 于 2018-06-19 设计创作，主要内容包括：本文描述的发明提供了一种用于治疗有相应需要的受试者中的雌激素受体阳性乳腺癌的方法,该方法包括向所述受试者施用治疗有效量的MPS1抑制剂,其中：(i)所述受试者先前已经用内分泌疗法治疗；和/或(ii)所述乳腺癌对内分泌疗法耐受。(The invention described herein provides a method for treating estrogen receptor positive breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an MPS1 inhibitor, wherein: (i) the subject has been previously treated with endocrine therapy; and/or (ii) the breast cancer is resistant to endocrine therapy.)

1. A method for treating estrogen receptor positive breast cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an MPS1 inhibitor, wherein:

(i) the subject has been previously treated with endocrine therapy; and/or

(ii) The breast cancer is resistant to endocrine therapy.

2. The method of claim 1, wherein the subject has previously failed treatment with the endocrine therapy.

3. The method of any one of claims 1 and 2, wherein the subject has relapsed during or after treatment with the endocrine therapy.

4. The method of any one of the preceding claims, wherein the subject has experienced disease progression during or after treatment with the endocrine therapy.

5. The method of any one of the preceding claims, wherein the subject has developed an endocrine therapy-resistant breast cancer during or after treatment with the endocrine therapy.

6. The method of any one of claims 1-5, wherein the breast cancer is resistant to endocrine therapy de novo.

7. The method according to any of the preceding claims, wherein the endocrine therapy comprises/consists essentially of/consists of: administration of endocrine agents.

8. The method according to claim 7, wherein the endocrine agent is selected from one or more of aromatase inhibitors, Selective Estrogen Receptor Modulators (SERMs) and selective estrogen receptor degraders/downregulators (SERDs).

9. The method according to any of the preceding claims, wherein the endocrine therapy comprises/consists essentially of/consists of: treatment with aromatase inhibitors and SERDs alone, sequentially or in combination.

10. The method according to any one of claims 7 and 8, wherein the endocrine therapy comprises/consists essentially of/consists of: treatment with SERMs and SERDs alone, sequentially or in combination.

11. The method of any one of claims 8 and 9, wherein the aromatase inhibitor is selected from the group consisting of: anastrozole, exemestane and letrozole, or a pharmaceutically acceptable salt or solvate thereof.

12. The method according to any one of claims 8 and 10 wherein the SERM is tamoxifen or a pharmaceutically acceptable salt or solvate thereof.

13. The method according to any one of claims 8 to 10, wherein the SERD is fulvestrant or a pharmaceutically acceptable salt or solvate thereof.

14. The method of any one of the preceding claims, wherein the subject is pre-menopausal.

15. A method according to one of claims 1-13, wherein the subject is postmenopausal.

16. The method of any one of the preceding claims, wherein (i) the subject has been previously additionally treated with a CDK4/6 inhibitor; and/or (ii) said breast cancer is additionally resistant to treatment with a CDK4/6 inhibitor.

17. The method of claim 16, wherein the subject has failed treatment with the CDK4/6 inhibitor.

18. The method of any one of claims 16 and 17, wherein the subject has relapsed during or after treatment with the CDK4/6 inhibitor.

19. The method of any one of claims 16 to 18, wherein the subject has undergone disease progression during or after treatment with the CDK4/6 inhibitor.

20. The method of any one of the preceding claims, wherein the subject has developed CDK4/6 inhibitor-resistant breast cancer during or after treatment with the CDK4/6 inhibitor.

21. The method of any one of claims 1 to 20, wherein the breast cancer is resistant de novo to treatment with a CDK4/6 inhibitor.

22. The method of any one of claims 16 to 21, wherein the CDK4/6 inhibitor is selected from the group consisting of: pipabride, abemaciclib and ribactide, or a pharmaceutically acceptable salt or solvate thereof.

23. The method according to any one of the preceding claims, wherein the method further comprises administering to the subject an endocrine agent and the MPS1 inhibitor, separately, sequentially and/or in combination.

24. The method of claim 19, wherein the endocrine agent is selected from the group consisting of: tamoxifen and fulvestrant, or a pharmaceutically acceptable salt or solvate thereof.

25. The method according to any preceding claim, wherein the compound capable of inhibiting MPS1 is an MPS1 inhibitor, suitably selected from the group consisting of: NMS-P715, S81694 (NMS-P153), AZ3146, BAY 1217389, BAY1161909, MPS1-IN-3, MPS1-IN-2, CFI-402257, CCT289346, a compound of formula I, a compound of formula II, a compound of formula III and a compound of formula IV, or a pharmaceutically acceptable salt or solvate thereof;

wherein formula I is:

wherein:

w is N or C-R₃；

X is CH or N;

z is N or C-H;

R₁selected from the group consisting of chloro, (1-6C) alkyl, (1-8C) heteroalkyl, aryl (1-2C) alkyl, heteroaryl (1-2C) alkyl, heterocyclyl (1-2C) alkyl, (3-8C) cycloalkyl (1-2C) alkyl, NR₇R₈、OR₉、C(O)R₉、C(O)OR₉、OC(O)R₉、N(R₁₀)OR₉、N(R₁₀)C(O)OR₉、C(O)N(R₁₀)R₉、N(R₁₀)C(O)R₉、S(O)_pR₉(wherein p is 0, 1 or 2), SO₂N(R₁₀)R₉、N(R₁₀)SO₂R₉、N(R₁₀)SOR₉Or SON (R)₁₀)R₉；

And wherein R₁Optionally substituted with one or more substituent groups selected from: fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, (1-4C) alkyl, (1-4C) alkoxy, S (O)_qCH₃(wherein q is 0, 1 or 2), methylamino or dimethylamino, aryl (1-2C) alkyl, heteroaryl (1-2C) alkyl, heterocyclyl (1-2C) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-2C) alkyl,

and wherein is present in R₁Any (1-4C) alkyl, (1-4C) alkoxy, aryl, heteroaryl, heterocyclyl, or (3-8C) cycloalkyl moiety within the substituent groups above is optionally further substituted with: fluorine, chlorine, trifluoromethyl, trifluoromethoxyRadical, cyano radical, nitro radical, hydroxy radical, amino radical, carboxy radical, carbamoyl radical, sulfamoyl radical, (1-4C) alkyl radical, NR_aR_b、OR_a、C(O)R_a、C(O)OR_a、OC(O)R_a、N(R_b)OR_a、C(O)N(R_b)R_a、N(R_b)C(O)R_a、S(O)_pR_a(wherein p is 0, 1 or 2), SO₂N(R_b)R_aOr N (R)_b)SO₂R_aWherein R is_aAnd R_bEach independently selected from H or (1-4C) alkyl;

R₃is hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, halogen, CF₃CN and (1-4C) alkoxy;

R₄is hydrogen, (1-3C) alkyl, (1-3C) alkoxy, fluorine, chlorine or CF₃；

Ar has the formula:

wherein:

(iv)A₁、A₂and A₃All are CH;

(v)A₁、A₂and A₃One of N and the others are CH; or

(vi)A₁、A₂And A₃Two of which are N and the other is CH;

R₅selected from hydrogen, cyano, (1-3C) alkyl, (1-3C) fluoroalkyl, (1-3C) alkoxy, (1-3C) fluoroalkoxy, halogen, (1-3C) alkanoyl, C (O) NR₁₅R₁₆Or S (O)₂NR₁₅R₁₆And wherein R is₁₅And R₁₆Each independently selected from H or (1-3C) alkyl,

and wherein R is present in₅Any alkyl or alkoxy moiety within a substituent group is optionally further substituted with hydroxy or methoxy;

R₆selected from halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxyl,Carbamoyl, sulfamoyl, ureido, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl,

or R₆Is a group of the formula:

-L¹-L²-R₁₇

wherein

L¹Is absent or of the formula- [ CR₁₈R₁₉]_nA linking group of (a), wherein n is an integer selected from 1,2,3 or 4, and R₁₈And R₁₉Each independently selected from hydrogen or (1-2C) alkyl;

L²absent or selected from O, S, SO₂、N(R₂₀)、C(O)、C(O)O、OC(O)、CH(OR₂₀)、C(O)N(R₂₀)、N(R₂₀)C(O)、N(R₂₀)C(O)N(R₂₁)、S(O)₂N(R₂₀) Or N (R)₂₁)SO₂Wherein R is₂₀And R₂₁Each independently selected from hydrogen or (1-2C) alkyl; and is

R₁₇Is (1-6C) alkyl, aryl- (1-6C) alkyl, (3-6C) cycloalkyl- (1-4C) alkyl, heteroaryl- (1-4C) alkyl, heterocyclyl- (1-4C) alkyl,

and wherein R₁₇Optionally further substituted with one or more substituent groups independently selected from: oxo, halogen, cyano, nitro, hydroxy, NR₂₂R₂₃(1-4C) alkoxy, (1-4C) alkyl, (3-8C) cycloalkyl- (1-3C) alkyl, (1-5C) alkanoyl, (1-5C) alkylsulfonyl, heterocyclyl- (1-2C) alkyl, heteroaryl- (1-2C) alkyl, CONR₂₂R₂₃And SO₂NR₂₂R₂₃(ii) a Wherein R is₂₂And R₂₃Each independently selected from hydrogen, (1-4C) alkyl or (3-6C) cycloalkyl (1-2C) alkyl;

and wherein when said substituent group comprises an alkyl, cycloalkyl, heterocyclyl or heteroaryl moiety, then said moiety is optionally further substituted by: hydroxy, fluoro, chloro, cyano, CF₃、OCF₃Alkyl (1-2C), (1-2C)) Alkoxy, SO₂(1-2C) alkyl or NR_eR_f(wherein R is_eAnd R_fEach independently selected from hydrogen, (1-3C) alkyl, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl);

or R₁₇Is a group having the formula:

-L³-L⁴-R₂₄

L³is absent or of the formula- [ CR₂₅R₂₆]_nA linking group of (a), wherein n is an integer selected from 1,2,3 or 4, and R₂₅And R₂₆Each independently selected from hydrogen or (1-2C) alkyl;

L⁴absent or selected from O, S, SO₂、N(R₂₇)、C(O)、C(O)O、OC(O)、CH(OR₂₇)、C(O)N(R₂₇)、N(R₂₇)C(O)、N(R₂₇)C(O)N(R₂₈)、S(O)₂N(R₂₇) Or N (R)₂₈)SO₂Wherein R is₂₇And R₂₈Each independently selected from hydrogen or (1-2C) alkyl; and is

R₂₄Is (1-6C) alkyl, aryl- (1-6C) alkyl, (3-6C) cycloalkyl- (1-4C) alkyl, heteroaryl- (1-4C) alkyl, heterocyclyl- (1-4C) alkyl;

R₈and R₉Each independently selected from hydrogen, (1-6C) alkyl, (1-6C) alkoxy, (3-9C) cycloalkyl- (1-2C) alkyl, aryl- (1-2C) alkyl, heterocyclyl- (1-2C) alkyl, heteroaryl- (1-2C) alkyl, and wherein R is₈And R₉Optionally further substituted by one or more groups selected from hydroxy, fluoro, chloro, cyano, CF₃、OCF₃A (1-2C) alkyl or (1-2C) alkoxy;

R₇and R₁₀Independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl- (1-2C) alkyl, and wherein R₇And R₁₀Optionally further substituted by one or more groups selected from hydroxy, fluoro, chloro, cyano, CF₃、OCF₃A (1-2C) alkyl or (1-2C) alkoxy;

the following conditions were followed:

when Z is N, X is only N;

when both X and Z are N, W is only N; and is

When R is₁Is S (O)₂R₉And R is₉When it is a heterocyclic group, R₆Is not methoxy;

wherein formula II is:

wherein:

R₁selected from:

(iii) a 5-or 6-membered heteroaryl, said 5-or 6-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro, (1-4C) alkyl, NR_aR_b、OR_a、C(O)R_a、C(O)OR_a、OC(O)R_a、N(R_b)OR_a、C(O)N(R_b)R_a、N(R_b)C(O)R_a、S(O)_pR_a(wherein p is 0, 1 or 2), SO₂N(R_b)R_aOr N (R)_b)SO₂R_a，

Wherein R is_aAnd R_bEach independently selected from H or (1-4C) alkyl, and wherein any alkyl moiety present in the substituent group is optionally further substituted by one or more substituents selected from: halogen, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro, (1-4C) alkyl, 4-7 membered heterocyclyl, NR_cR_d、OR_c、C(O)R_c、C(O)OR_c、OC(O)R_c、N(R_d)OR_c、C(O)N(R_d)R_c、N(R_d)C(O)R_c、S(O)_qR_c(wherein q is 0, 1 or 2), SO₂N(R_d)R_cOr N (R)_d)SO₂R_cWherein R is_cAnd R_dEach independently selected from H or (1-4C) alkyl; or

Wherein the 5-or 6-membered heteroaryl is optionally fused to a 4-, 5-, 6-or 7-membered heterocyclic ring, wherein the fused ring system is optionally substituted with one or more substituents independently selected from: halogen, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro, (1-4C) alkyl, NR_kR_l、OR_k、C(O)R_k、C(O)OR_k、OC(O)R_k、N(R_l)OR_k、C(O)N(R_l)R_k、N(R_l)C(O)R_k、S(O)_pR_k(wherein p is 0, 1 or 2), SO₂N(R_k)R_lOr N (R)_k)SO₂R_lWherein R is_kAnd R_lEach independently selected from H or (1-4C) alkyl,

and wherein any alkyl moiety present in said substituent group is optionally further substituted by one or more substituents selected from the group consisting of: halogen, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro, (1-4C) alkyl, 4-7 membered heterocyclyl, NR_mR_n、OR_m、C(O)R_m、C(O)OR_m、OC(O)R_m、N(R_n)OR_m、C(O)N(R_n)R_m、N(R_n)C(O)R_m、S(O)_qR_m(wherein q is 0, 1 or 2), SO₂N(R_n)R_mOr N (R)_n)SO₂R_mWherein R is_mAnd R_nEach independently selected from H or (1-4C) alkyl; or

(iv) The group-C (O) N (R)_f)R_e-or-S (O)₂N(R_f)R_e-；

Wherein R is_eAnd R_fEach independently selected from H or (1-4C) alkyl optionally substituted with halogen or (1-2C) alkoxy;

or R_eAnd R_fAre linked such that together with the nitrogen atom to which they are attached, they form a 4-, 5-or 6-membered heterocyclic ring, wherein the ring is optionallyIs substituted with one or more substituents independently selected from the group consisting of: halogen, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro, (1-4C) alkyl, NR_gR_h、OR_g、C(O)R_g、C(O)OR_g、OC(O)R_g、N(R_h)OR_g、C(O)N(R_h)R_g、N(R_h)C(O)R_g、S(O)_pR_h(wherein p is 0, 1 or 2), SO₂N(R_h)R_gOr N (R)_h)SO₂R_gWherein R is_gAnd R_hEach independently selected from H or (1-4C) alkyl;

R₂selected from hydrogen, fluorine, chlorine, (1-3C) alkoxy or (1-3C) fluoroalkoxy;

and:

(iii)R₃selected from hydrogen or (1-3C) alkyl, and R₄Selected from (1-6C) alkyl, (3-9C) cycloalkyl- (1-4C) alkyl, aryl- (1-4C) alkyl, heterocyclyl- (1-4C) alkyl, heteroaryl- (1-4C) alkyl, and wherein R is₄Optionally further substituted with one or more substituents selected from: hydroxy, fluoro, chloro, cyano, CF₃、CHF₂、OCF₃、OCHF₂(1-4C) alkyl, NR_oR_p、OR_o、C(O)R_o、C(O)OR_p、OC(O)R_o、N(R_p)OR_o、C(O)N(R_p)R_o、N(R_p)C(O)R_o、S(O)_pR_o(wherein p is 0, 1 or 2), SO₂N(R_p)R_oOr N (R)_p)SO₂R_oOr (3-6C) cycloalkyl, (3-6C) cycloalkyl- (1-2C) alkyl, 4-membered heterocyclyl, 5-membered heterocyclyl or 6-membered heterocyclyl, 4-membered heterocyclyl- (1-2C) alkyl, 5-membered heterocyclyl- (1-2C) alkyl or 6-membered heterocyclyl- (1-2C) alkyl, wherein R is_oAnd R_pEach independently selected from H or (1-4C) alkyl, (3-6C) cycloalkyl or (3-6C) cycloalkyl- (1-4C) alkyl; or

(iv)R₃And R₄Are connected so that they and to which they are attachedTogether, the nitrogen atoms form a nitrogen-linked 4-membered, 5-membered, 6-membered or 7-membered heterocyclic ring,

wherein the ring is optionally fused to a further 3-, 4-, 5-or 6-membered carbocyclic or heterocyclic ring, a 5-or 6-membered heteroaromatic ring or a benzene ring to form a bicyclic heterocyclic ring system, or

To a further 4-, 5-or 6-membered carbocyclic or heterocyclic ring via a spiro carbon atom to form a spirobicyclic ring system;

and wherein the heterocycle, bicyclic ring system, or spirobicyclic ring system is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyano, nitro, (1-4C) alkyl, NR_iR_j、OR_i、C(O)R_i、C(O)OR_i、OC(O)R_i、N(R_j)OR_i、C(O)N(R_j)R_i、N(R_j)C(O)R_i、S(O)_qR_i(wherein q is 0, 1 or 2), SO₂N(R_j)R_iOr N (R)_j)SO₂R_iWherein R is_iAnd R_jEach independently selected from H or (1-4C) alkyl;

with the proviso that the compound is not one of the following:

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -N8- (2-methoxy-2-methylpropyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1- (2-methoxyethyl) -2-methyl-1H-imidazol-5-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methylsulfonyl) piperazin-1-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1, 3-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N8- (2-methoxy-2-methylpropyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (6-oxa-2-azaspiro [3.4] oct-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-5-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2- (difluoromethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (2-methoxy-2-methylpropyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

(4- (3-methoxy-4- ((8- ((2-methoxy-2-methylpropyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-2-yl) amino) phenyl) -1-methyl-1H-pyrazol-5-yl) methanol;

wherein formula III is

Wherein:

x is CH or N;

y is N or C-H;

R₂selected from (1-6C) alkyl, (1-8C) heteroalkyl, aryl (1-2C) alkyl, 5-or 6-membered heteroaryl (1-2C) alkyl, 3-to 6-membered heterocyclyl (1-2C) alkyl, (3-8C) cycloalkyl (1-2C) alkyl, NR₁₁R₁₂、OR₁₃、C(O)R₁₃、C(O)OR₁₃、OC(O)R₁₃、N(R₁₄)OR₁₃、N(R₁₄)C(O)OR₁₃、C(O)N(R₁₄)R₁₃、N(R₁₄)C(O)R₁₃、S(O)_xR₁₃(wherein x is 0, 1 or 2), SO₂N(R₁₄)R₁₃Or N (R)₁₄)SO₂R₁₃；

And wherein R₂Optionally substituted with one or more substituent groups selected from: fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, (1-4C) alkyl, (1-4C) alkoxy, S (O)_xCH₃(wherein x is 0, 1 or 2), methylamino or dimethylamino, aryl (1-2C) alkyl, heteroaryl (1-2C) alkyl, heterocyclyl (1-2C) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-2C) alkyl,

And wherein is present in R₂Any (1-4C) alkyl, (1-4C) alkoxy, aryl, heteroaryl, heterocyclyl, or (3-8C) cycloalkyl moiety within the substituent groups above is optionally further substituted with: fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, (1-4C) alkyl, NR_cR_d、OR_c、C(O)R_c、C(O)OR_c、OC(O)R_c、N(R_d)OR_c、C(O)N(R_d)R_c、N(R_d)C(O)R_c、S(O)_yR_c(wherein y is 0, 1 or 2), SO₂N(R_d)R_cOr N (R)_d)SO₂R_cWherein R is_cAnd R_dEach independently selected from H or (1-4C) alkyl;

R₃is hydrogen, (1-4C) alkyl, (3-6C) cycloalkyl, halogen, CF₃CN and (1-4C) alkoxy;

R₄is hydrogen, (1-3C) alkyl, fluorine, chlorine or CF₃；

Ar has the formula:

wherein:

(iii)A₁、A₂and A₃All are CH; or

(iv)A₃Is CH, and A₁Or A₂Is selected from N or CH;

R₅is hydrogen, cyano, (1-3C) alkyl, (1-3C) fluoroalkyl, (1-3C) alkoxy, (1-3C) fluoroalkoxy, halogen, (1-3C) alkanoyl, C (O) NR₁₅R₁₆Or S (O)₂NR₁₅R₁₆And wherein R is₁₅And R₁₆Each independently selected from H or (1-3C) alkyl, and wherein R is present₅Any alkyl or alkoxy moiety within a substituent group is optionally further substituted with hydroxy or methoxy;

R₆is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, ureido, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl,

or R₆Is a group of the formula:

-L¹-L²-R₁₇

wherein

L¹Is absent or of the formula- [ CR₁₈R₁₉]_nA linking group of (a), wherein n is an integer selected from 1,2,3 or 4, and R₁₈And R₁₉Each independently selected from hydrogen or (1-2C) alkyl;

L²absent or selected from O, S, SO₂、N(R₂₀)、C(O)、C(O)O、OC(O)、CH(OR₂₀)、C(O)N(R₂₀)、N(R₂₀)C(O)、N(R₂₀)C(O)N(R₂₁)、S(O)₂N(R₂₀) Or N (R)₂₁)SO₂Wherein R is₂₀And R₂₁Each independently selected from hydrogen or (1-2C) alkyl; and is

R₁₇Is (1-6C) alkyl, aryl- (1-6C) alkyl, (3-6C) cycloalkyl- (1-4C) alkyl, heteroaryl- (1-4C) alkyl, heterocyclyl- (1-4C) alkyl,

and wherein R₁₇Optionally further substituted with one or more substituent groups independently selected from: oxo, halogen, cyano, nitro, hydroxy, NR₂₂R₂₃(1-4C) alkoxy, (1-4C) alkyl, (3-8C) cycloalkyl- (1-3C) alkyl, (1-5C) alkanoyl, (1-5C) alkylsulfonyl, heterocyclyl- (1-2C) alkyl, heteroaryl- (1-2C) alkyl, CONR₂₂R₂₃And SO₂NR₂₂R₂₃(ii) a Wherein R is₂₂And R₂₃Each independently selected from hydrogen, (1-4C) alkyl or (3-6C) cycloalkyl (1-2C) alkyl; or R₂₂And R₂₃Can be linked such that they form, together with the nitrogen atom to which they are attached, a 4-6 membered heterocyclic ring;

and wherein when said substituent group comprises an alkyl, cycloalkyl, heterocyclyl or heteroaryl moiety, then said moiety is optionally further substituted by: hydroxy, fluoro, chloro, cyano, CF₃、OCF₃Alkyl (1-2C), alkoxy (1-2C), SO₂(1-2C) alkyl or NR_eR_f(wherein R is_eAnd R_fEach independently selected from hydrogen, (1-3C) alkyl, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl);

or R₁₇Is a group having the formula:

-L³-L⁴-R₂₄

wherein

L³Is absent or of the formula- [ CR₂₅R₂₆]_nA linking group of (a), wherein n is an integer selected from 1,2,3 or 4, and R₂₅And R₂₆Each independently selected from hydrogen or (1-2C) alkyl;

L⁴absent or selected from O, S, SO₂、N(R₂₇)、C(O)、C(O)O、OC(O)、CH(OR₂₇)、C(O)N(R₂₇)、N(R₂₇)C(O)、N(R₂₇)C(O)N(R₂₈)、S(O)₂N(R₂₇) Or N (R)₂₈)SO₂Wherein R is₂₇And R₂₈Each independently selected from hydrogen or (1-2C) alkyl; and is

R₂₄Is (1-6C) alkyl, aryl- (1-6C) alkyl, (3-6C) cycloalkyl- (1-4C) alkyl, heteroaryl- (1-4C) alkyl, heterocyclyl- (1-4C) alkyl;

R₁₂selected from hydrogen, (1-6C) alkyl, (1-6C) alkoxy, (3-6C) cycloalkyl- (1-2C) alkyl, aryl- (1-2C) alkyl, heterocyclyl- (1-2C) alkyl, heteroaryl- (1-2C) alkyl, and wherein R is₁₂Optionally further substituted by one or more groups selected from hydroxy, fluoro, chloro, cyano, CF₃、OCF₃A (1-2C) alkyl or (1-2C) alkoxy;

R₁₃selected from hydrogen, (1-6C) alkyl, (1-6C) alkoxy, (3-6C) cycloalkyl- (1-2C) alkyl, aryl- (1-2C) alkyl, heteroaryl- (1-2C) alkyl, and wherein R₁₃Optionally further substituted by one or more groups selected from hydroxy, fluoro, chloro, cyano, CF₃、OCF₃A (1-2C) alkyl or (1-2C) alkoxy;

R₁₁and R₁₄Independently selected from hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl- (1-2C) alkyl, and wherein R₁₁And R₁₄Optionally further substituted by one or more groups selected from hydroxy, fluoro, chloro, cyano, CF₃、OCF₃A (1-2C) alkyl or (1-2C) alkoxy; the following conditions were followed:

when Y is N, X may be only N; and is

When both X and Y are N, R₃Selected from H or fluorine, and R₂Is not NR₁₁R₁₂A group;

wherein formula IV is:

wherein:

R₁is hydrogen, (1-5C) alkyl, (1-5C) fluoroalkyl, (3-8C) cycloalkyl- (1-4C) alkyl, arylYl- (1-4C) alkyl, heteroaryl- (1-4C) alkyl, -S (O)₂-R^a、-C(O)-R^aor-C (O) -O-R^aWherein R is^aIs (1-5C) alkyl, (3-8C) cycloalkyl- (1-4C) alkyl, aryl- (1-4C) alkyl, heteroaryl or heteroaryl- (1-4C) alkyl, and wherein R is present₁Any of the (1-5C) alkyl, (3-8C) cycloalkyl- (1-4C) alkyl, aryl- (1-4C) alkyl, heteroaryl- (1-4C) alkyl groups of the substituent groups is optionally substituted with methyl, trifluoromethyl, methoxy, trifluoromethoxy, halogen, cyano, nitro, hydroxy, mercapto, amino, carboxyl, carbamoyl or sulfamoyl;

R₂is aryl, aryl (1-2C) alkyl, 5-or 6-membered heteroaryl or 5-or 6-membered heteroaryl (1-2C) alkyl,

wherein R is₂Optionally substituted with one or more substituents selected from:

halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, mercapto, amino, carboxyl, carbamoyl, sulfamoyl,

or a group of the formula:

L-L⁰-R^b

wherein

L is absent or of the formula- [ CR_gR_h]_nA linking group of (a), wherein n is an integer selected from 1,2,3 or 4, and R_gAnd R_hEach independently selected from hydrogen or (1-2C) alkyl;

L⁰absent or selected from O, S, SO₂、N(R^c)、C(O)、C(O)O、OC(O)、CH(OR^c)、C(O)N(R^c)、N(R^c)C(O)、N(R^c)C(O)N(R^d)、S(O)₂N(R^c) Or N (R)^c)SO₂Wherein R is^cAnd R^dEach independently selected from hydrogen or (1-2C) alkyl; and is

R^bIs (1-4C) alkyl, aryl- (1-4C) alkyl, (3-6C) cycloalkyl- (1-4C) alkyl, heteroaryl- (1-4C) alkyl,Heterocyclyl, or heterocyclyl- (1-4C) alkyl;

and wherein R^bOptionally further substituted with one or more substituents independently selected from: oxo, halogen, cyano, nitro, hydroxy, NR^eR^f(1-5C) alkyl, (1-5C) alkoxy, (1-5C) alkanoyl, (1-5C) sulfonyl or aryl; and wherein R^eAnd R^fEach independently selected from hydrogen or (1-4C) alkyl or (3-6C) cycloalkyl- (1-4C) alkyl; or R^eAnd R^fCan be linked such that they, together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic, heteroaryl ring or carbocyclic ring;

R₃is H, (1-3C) alkyl, halogen or CF₃；

R₄Is cyano, (1-3C) alkyl, (1-3C) fluoroalkyl, (1-3C) alkoxy, (1-3C) perfluoroalkoxy, halogen, (1-3C) alkanoyl, C (O) NRⁱR^jOr S (O)₂NRⁱR^j(ii) a Wherein R isⁱAnd R^jEach independently selected from H or (1-3C) alkyl;

x is CH or CR₅；

W, Y and Z are each independently selected from N, CH or CR₅；

R₅Is halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, mercapto, amino, carboxy, carbamoyl, sulfamoyl, ureido, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl,

or R₅Is a group of the formula:

-L¹-L²-R₇

wherein

L¹Is absent or of the formula- [ CR₈R₉]_nA linking group of (a), wherein n is an integer selected from 1,2,3 or 4, and R₈And R₉Each independently selected from hydrogen or (1-2C) alkyl;

L²absent or selected from O, S, SO₂、N(R₁₀)、C(O)、C(O)O、OC(O)、CH(OR₁₀)、C(O)N(R₁₀)、N(R₁₀)C(O)、N(R₁₀)C(O)N(R₁₁)、S(O)₂N(R₁₀) Or N (R)₁₃)SO₂Wherein R is₁₀And R₁₁Each independently selected from hydrogen or (1-2C) alkyl; and is

R₇Is (1-6C) alkyl, aryl- (1-6C) alkyl, (3-6C) cycloalkyl- (1-6C) alkyl, heteroaryl- (1-6C) alkyl, heterocyclyl- (1-6C) alkyl,

and wherein R₇Optionally further substituted with one or more substituents independently selected from: hydrogen, oxo, halogen, cyano, nitro, hydroxy, NR₁₂R₁₃(1-4C) alkoxy, (1-5C) alkyl, (3-8C) cycloalkyl- (1-5C) alkyl, aryl- (1-5C) alkyl, (1-5C) alkanoyl, (1-5C) alkylsulfonyl, heterocyclyl- (1-5C) alkyl, heteroaryl- (1-5C) alkyl, CONR₁₂R₁₃And SO₂NR₁₂R₁₃；

R₁₂And R₁₃Each independently selected from hydrogen or (1-2C) alkyl; or R₁₂And R₁₃Can be linked such that they, together with the nitrogen atom to which they are attached, form a 4-7 membered heterocyclic or heteroaryl ring;

or both W and Z, both W and Y, or both Z and X are CR₅And R on adjacent carbon atoms₅Groups are linked such that together with the carbon atom to which they are attached, they form a fused 4-7 membered heterocyclic, heteroaryl or carbocyclic ring.

26. The method according to claim 25, wherein the MPS1 inhibitor is selected from the group consisting of: NMS-P715, BAY 1217389, BAY 1161909, CCT289346, a compound of formula I, a compound of formula II, a compound of formula III and a compound of formula IV, or a pharmaceutically acceptable salt or solvate thereof.

27. The method according to claim 25, wherein the MPS1 inhibitor is selected from the group consisting of: a compound of formula I, a compound of formula II, a compound of formula III, and a compound of formula IV, or a pharmaceutically acceptable salt or solvate thereof.

28. The method according to claim 25, wherein the MPS1 inhibitor is selected from the group consisting of: a compound of formula I or a compound of formula II, or a pharmaceutically acceptable salt or solvate thereof.

29. The method according to any one of the preceding claims, wherein the MPS1 inhibitor is selected from the following:

5- (furan-2-yl) -N- (4-methoxyphenyl) isoquinolin-3-amine;

n- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-amine;

n- (2-methoxy-4- ((1-methylpiperidin-4-yl) oxy) phenyl) -5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-amine;

n- (2, 4-dimethoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-amine;

3-chloro-N, N-dimethyl-4- ((5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl) amino) benzamide;

3-methoxy-N, N-dimethyl-4- ((5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl) amino) benzamide;

(3-methoxy-4- ((5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

n- (2-chloro-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-amine;

(3-chloro-4- ((5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

(3-methoxy-4- ((5- (pyridin-3-yl) isoquinolin-3-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

n- (4- (3, 5-dimethylisoxazol-4-yl) -2-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-amine;

(3-methoxy-4- ((8- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-2-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-chloro-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-chloro-4- (1-methyl-1H-imidazol-5-yl) phenyl) -5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-amine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-amine;

(3-methoxy-4- ((5- (pyrimidin-5-yl) isoquinolin-3-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

n- (2-methoxy-4- (1-methyl-1H-imidazol-5-yl) phenyl) -5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-amine;

(4- ((5- (1, 5-dimethyl-1H-pyrazol-4-yl) isoquinolin-3-yl) amino) -3-methoxyphenyl) (3-methoxyazetidin-1-yl) methanone;

(3-methoxy-4- ((5- (1-methyl-1H-pyrazol-3-yl) isoquinolin-3-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

n- (2-chloro-4- (1, 2-dimethyl-1H-imidazol-5-yl) phenyl) -5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-amine;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-amine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8-phenylpyrido [3,4-d ] pyrimidin-2-amine;

8-cyclopropyl-N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-5-methyl-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-2-amine;

(3-methoxy-4- ((5- (1-methyl-1H-pyrazol-5-yl) isoquinolin-3-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

(4- ((5- (1, 3-dimethyl-1H-pyrazol-4-yl) isoquinolin-3-yl) amino) -3-methoxyphenyl) (3-methoxyazetidin-1-yl) methanone;

(4- ((5- (1-isopropyl-1H-pyrazol-4-yl) isoquinolin-3-yl) amino) -3-methoxyphenyl) (3-methoxyazetidin-1-yl) methanone;

4- ((5- (1-methyl-1H-pyrazol-4-yl) isoquinolin-3-yl) amino) -N- (1-methylpiperidin-4-yl) -3- (trifluoromethoxy) benzamide;

(4- ((5- (3, 5-dimethylisoxazol-4-yl) isoquinolin-3-yl) amino) -3-methoxyphenyl) (3-methoxyazetidin-1-yl) methanone;

(3-methoxy-4- ((5- (1-methyl-1H-imidazol-5-yl) isoquinolin-3-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (pyrrolidin-1-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-2-amine;

4- (4- (3- ((2-methoxy-4- (3-methoxyazetidine-1-carbonyl) phenyl) amino) isoquinolin-5-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester;

(3-methoxy-4- ((5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) isoquinolin-3-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

(3-methoxy-4- ((5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) isoquinolin-3-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

(3-methoxy-4- ((5- (1- (2-methoxyethyl) -1H-pyrazol-4-yl) isoquinolin-3-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

n8, N8-diethyl-N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

N8-cyclopentyl-N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

(4- ((5- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) isoquinolin-3-yl) amino) -3-methoxyphenyl) (3-methoxyazetidin-1-yl) methanone;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -5- (1-methyl-1H-pyrazol-4-yl) -2, 6-naphthyridin-3-amine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (piperidin-1-yl) pyrido [3,4-d ] pyrimidin-2-amine;

N8-cyclohexyl-N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (3-methylpyrrolidin-1-yl) pyrido [3,4-d ] pyrimidin-2-amine;

8- (3, 3-difluoropyrrolidin-1-yl) -N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -2, 6-naphthyridin-3-amine;

n8- (cyclopropylmethyl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (1-methyl-1H-pyrazol-4-yl) -N- (2-methyl-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

N8-cyclopentyl-N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-ethoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-isopropoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2- (2-methoxyethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (1-methyl-1H-pyrazol-4-yl) pyrido [3,4-d ] pyrimidin-2-amine;

N8-isopentyl-N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8-morpholinopyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (4-methylpiperazin-1-yl) pyrido [3,4-d ] pyrimidin-2-amine;

8- (3, 3-difluoroazetidin-1-yl) -N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (2-methylpyrrolidin-1-yl) pyrido [3,4-d ] pyrimidin-2-amine;

N8-isobutyl-N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (cyclohexylthio) -N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

N8-cyclohexyl-N2- (2-methoxy-4- (1- (2- (4-methylpiperazin-1-yl) ethyl) -1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (1-ethyl-1H-pyrazol-4-yl) -N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

8- (1-isopropyl-1H-pyrazol-4-yl) -N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (3-methoxyazetidin-1-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n1- (cyclopropylmethyl) -N7- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -2, 6-naphthyridine-1, 7-diamine;

N1-cyclohexyl-N7- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -2, 6-naphthyridine-1, 7-diamine;

N8-cyclohexyl-N2- (4- (1- (2- (dimethylamino) ethyl) -1H-pyrazol-4-yl) -2-methoxyphenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (cyclopropylmethyl) -N2- (2-methyl-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

N8-cyclohexyl-N2- (2-methyl-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (cyclopropylmethyl) -N2- (2-ethoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (cyclohexylmethyl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

2- (4- (4- ((8- (cyclohexylamino) pyrido [3,4-d ] pyrimidin-2-yl) amino) -3-methoxyphenyl) -1H-pyrazol-1-yl) ethanol;

8- (cyclopropylmethoxy) -N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

1- ((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) -2-methylpropan-2-ol;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (oxetan-3-ylmethyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (3, 3-dimethylbut-2-yl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

3- ((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) -2, 2-dimethylpropan-1-ol;

n2- (2-ethoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-6-morpholinylpyridin-3-yl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-6- (methylsulfonyl) pyridin-3-yl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-imidazol-5-yl) phenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1, 3-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (1-cyclopropylethyl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

2- (4- (3-methoxy-4- ((8- ((tetrahydro-2H-pyran-4-yl) amino) pyrido [3,4-d ] pyrimidin-2-yl) amino) phenyl) -1H-pyrazol-1-yl) ethanol;

n2- (4- (1, 5-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

(R) -N8- (3, 3-dimethylbut-2-yl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

(S) -N8- (3, 3-dimethylbut-2-yl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (tetrahydrofuran-3-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- ((tetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

1- (2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) pyrrolidin-3-ol;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (tert-butyl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (1-methylcyclohexyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (1- (2, 2-difluoroethyl) -1H-pyrazol-4-yl) -N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4-morpholinylphenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (2, 2-difluoropropyl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (3-methoxy-2, 2-dimethylpropyl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (2,2, 2-trifluoroethyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) methyl) cyclobutanol;

8-chloro-N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-ethyl-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1-methyl-1H-pyrazol-4-yl) -2- (trifluoromethoxy) phenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8, N8-dimethylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) -2-methylpropane-2-sulfinamide;

n2- (2-methoxy-4- (4-morpholinylpiperidin-1-yl) phenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- ((3-methyloxetan-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (piperidin-1-yl) phenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) -2-methylpropane-2-sulfonamide;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (oxetan-3-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

(1- (3-methoxy-4- ((8- (neopentylamino) pyrido [3,4-d ] pyrimidin-2-yl) amino) phenyl) piperidin-4-yl) (morpholinyl) methanone;

n2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

1- (((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) methyl) cyclopropanol;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (1-methylpiperidin-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

2- ((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) -2-methylpropan-1-ol;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (2-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (oxetan-2-ylmethyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-chloro-4-morpholinylphenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4- (methylsulfonyl) piperazin-1-yl) phenyl) -N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (1, 5-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (1, 5-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N8- ((3-methyloxetan-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1, 5-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N8- (2-methoxy-2-methylpropyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -N8- (2-methoxy-2-methylpropyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-ethoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

2- ((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) ethanol;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (2-methoxyethyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

1- ((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) propan-2-ol;

2- ((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) propan-1-ol;

n2- (4- (1, 5-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

4- (2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) thiomorpholine 1, 1-dioxide;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -5-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (6-oxa-2-azaspiro [3.4] oct-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) azetidine-3-carbonitrile;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (2-oxa-6-azaspiro [3.5] non-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n8- ((3-fluorooxetan-3-yl) methyl) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4-chloro-2-methoxyphenyl) -8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2, 4-dichlorophenyl) -8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

4- ((8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-yl) amino) -3-methoxybenzonitrile;

n- (2-chloro-4- (methylsulfonyl) phenyl) -8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-chloro-4- (pyrimidin-5-yl) phenyl) -8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-chloro-4- (5-methyl-1, 3, 4-oxadiazol-2-yl) phenyl) -8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

6-cyclopropyl-N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

2- ((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) propane-1, 3-diol;

3-methoxy-2- ((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) propan-1-ol;

(3- (((2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) amino) methyl) oxetan-3-yl) methanol;

(S) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

(R) -N2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4-chloro-2-fluorophenyl) -8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

4- ((8- (2-oxa-6-azaspiro [3.4] oct-6-yl) pyrido [3,4-d ] pyrimidin-2-yl) amino) -3-chlorobenzonitrile;

n2- (2-methoxy-4- (1- (2-methoxyethyl) -2-methyl-1H-imidazol-5-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4- (methylsulfonyl) piperazin-1-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (pyridin-4-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -5-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -5-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (2-methylmorpholinyl) pyrido [3,4-d ] pyrimidin-2-amine;

(4- (3-methoxy-4- ((8- ((2-methoxy-2-methylpropyl) amino) pyrido [3,4-d ] pyrimidin-2-yl) amino) phenyl) -1-methyl-1H-pyrazol-5-yl) methanol;

(4- (3-methoxy-4- ((8- (((3-methyltetrahydrofuran-3-yl) methyl) amino) pyrido [3,4-d ] pyrimidin-2-yl) amino) phenyl) -1-methyl-1H-pyrazol-5-yl) methanol;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-4- (1- (2-methoxyethyl) -2-methyl-1H-imidazol-5-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1- (2-methoxyethyl) -2-methyl-1H-imidazol-5-yl) phenyl) -N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -N8- (2-methoxy-2-methylpropyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 6-dihydro-2H-pyran-4-yl) -N- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) pyrido [3,4-d ] pyrimidin-2-amine;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-6- (1-methyl-1H-tetrazol-5-yl) pyridin-3-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (6- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxypyridin-3-yl) -N8- (2-methoxy-2-methylpropyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (pyrimidin-5-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (1- (tetrahydrofuran-3-yl) ethyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1, 3-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N8- (2-methoxy-2-methylpropyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1, 3-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (4-methoxypiperidin-1-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) piperidine-4-carbonitrile;

n- (2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) -8- (4- (methylsulfonyl) piperazin-1-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (1, 3-dimethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N8- (2-methoxy-2-methylpropyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (6-oxa-2-azaspiro [3.4] oct-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (6- (1, 3-dimethyl-1H-pyrazol-4-yl) -2-methoxypyridin-3-yl) -N8- (2-methoxy-2-methylpropyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (6- (1, 5-dimethyl-1H-pyrazol-4-yl) -2-methoxypyridin-3-yl) -N8- (2-methoxy-2-methylpropyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-6- (1-methyl-1H-1, 2, 3-triazol-5-yl) pyridin-3-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-6- (2-methyl-2H-1, 2, 3-triazol-4-yl) pyridin-3-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

(3-methoxy-4- ((8- ((2-methoxy-2-methylpropyl) amino) pyrido [3,4-d ] pyrimidin-2-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

3-methoxy-4- ((8- ((2-methoxy-2-methylpropyl) amino) pyrido [3,4-d ] pyrimidin-2-yl) amino) -N, N-dimethylbenzamide;

(3-methoxy-4- ((8- ((2-methoxy-2-methylpropyl) amino) pyrido [3,4-d ] pyrimidin-2-yl) amino) phenyl) (4-methylpiperazin-1-yl) methanone;

(1- (2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) pyrrolidin-3-yl) methanol;

(1- (2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) piperidin-3-yl) methanol;

(4- (2- ((2-methoxy-4- (1-methyl-1H-pyrazol-4-yl) phenyl) amino) pyrido [3,4-d ] pyrimidin-8-yl) morpholin-2-yl) methanol;

n2- (2- (difluoromethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (2-methoxy-2-methylpropyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2- (difluoromethoxy) -4-fluorophenyl) -N8- (2-methoxy-2-methylpropyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4- (1-ethyl-1H-pyrazol-4-yl) -2-methoxyphenyl) -N8- (2-methoxy-2-methylpropyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

(3-methoxy-4- ((8- (neopentylamino) pyrido [3,4-d ] pyrimidin-2-yl) amino) phenyl) (3-methoxyazetidin-1-yl) methanone;

n2- (2-methoxy-4- (tetrahydro-2H-pyran-4-yl) phenyl) -N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (4-chloro-2- (difluoromethoxy) phenyl) -N8- (2-methoxy-2-methylpropyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -5-methyl-N8- ((3-methyloxetan-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -5-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -5-methyl-8- (6-oxa-2-azaspiro [3.4] oct-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n8- (2-methoxy-2-methylpropyl) -N2- (2-methoxy-4- (1-methyl-1H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2- (difluoromethoxy) -4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N8- (2-methoxy-2-methylpropyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

(4- (3-methoxy-4- ((8- ((2-methoxy-2-methylpropyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-2-yl) amino) phenyl) -1-methyl-1H-pyrazol-5-yl) methanol;

n2- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

1- (((2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) amino) methyl) cyclobutanol;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) piperidine-4-carbonitrile;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidin-3-ol;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- ((3-methyloxetan-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (((2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) amino) methyl) cyclopropanol;

n2- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) piperidine-4-carbonitrile;

1- (2- ((4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-difluoroazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (2-methylmorpholinyl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

8- (3-azabicyclo [3.1.0] hex-3-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

8- (3- (dimethylamino) azetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) piperidin-4-ol;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylpyrrolidin-3-ol;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) pyrrolidine-3-carbonitrile;

n2- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (1-methyl-1H-pyrazol-5-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (oxazol-2-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxypyrrolidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylpyrrolidine-3-carbonitrile;

8- (2, 2-dimethylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (3- (trifluoromethyl) azetidin-1-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (2-azaspiro [3.3] hept-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

(R) -N8- (3, 3-dimethylbut-2-yl) -N2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

(S) -N8- (3, 3-dimethylbut-2-yl) -N2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -N8- ((1-methoxycyclobutyl) methyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (1-methylazetidin-3-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (oxetan-3-ylmethyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (pyrrolidin-1-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (2-azaspiro [3.4] oct-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-ethylazetidin-3-ol;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (1-methylpiperidin-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (4- (dimethylamino) piperidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- ((tetrahydro-2H-pyran-4-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- ((4-methyltetrahydro-2H-pyran-4-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-ethylpiperidine-4-carbonitrile;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (2- (3-methyltetrahydrofuran-3-yl) ethyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (1- (tetrahydro-2H-pyran-4-yl) ethyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (pent-3-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (tetrahydrofuran-3-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3-ethoxy-3-methylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-ethyl-3-methoxyazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

8- (3-ethoxy-3-ethylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-isopropyl-3-methoxyazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

8- (3-ethoxy-3-isopropylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-ethylazetidine-3-carbonitrile;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-isopropylazetidine-3-carbonitrile;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -2,2, 3-trimethylazetidine-3-carbonitrile;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-2, 2-dimethylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-2, 2, 3-trimethylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -2, 2-dimethylazetidine-3-carbonitrile;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (1-methylpiperidin-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (4- (dimethylamino) piperidin-1-yl) -N- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- ((tetrahydro-2H-pyran-4-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- ((4-methyltetrahydro-2H-pyran-4-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

4-ethyl-1- (2- ((2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) piperidine-4-carbonitrile;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (2- (3-methyltetrahydrofuran-3-yl) ethyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (1- (tetrahydro-2H-pyran-4-yl) ethyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (pent-3-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n2- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (tetrahydrofuran-3-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3-ethoxy-3-methylazetidin-1-yl) -N- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

8- (3-ethyl-3-methoxyazetidin-1-yl) -N- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

8- (3-ethoxy-3-ethylazetidin-1-yl) -N- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

8- (3-isopropyl-3-methoxyazetidin-1-yl) -N- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

8- (3-ethoxy-3-isopropylazetidin-1-yl) -N- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

3-ethyl-1- (2- ((2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) azetidine-3-carbonitrile;

3-isopropyl-1- (2- ((2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) azetidine-3-carbonitrile;

1- (2- ((2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -2,2, 3-trimethylazetidine-3-carbonitrile;

8- (3-methoxy-2, 2-dimethylazetidin-1-yl) -N- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

8- (3-methoxy-2, 2, 3-trimethylazetidin-1-yl) -N- (2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-methoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -2, 2-dimethylazetidine-3-carbonitrile;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

8- (3-methoxy-3-methylazetidin-1-yl) -N- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-methoxy-4- (1-methyl-1H-tetrazol-5-yl) phenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3, 3-dimethylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2- (difluoromethoxy) -4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-ethoxy-4- (4-ethyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -8- (3, 3-dimethylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-methoxyphenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -8- (3, 3-dimethylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

8- (3-methoxy-3-methylazetidin-1-yl) -N- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-1, 2, 3-triazol-5-yl) phenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -8- (3, 3-dimethylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (1, 2-dimethyl-1H-imidazol-5-yl) -2-methoxyphenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) -8- (3, 3-dimethylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (1, 5-dimethyl-1H-imidazol-2-yl) -2-methoxyphenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

8- (3-methoxy-3-methylazetidin-1-yl) -N- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (2-methoxy-4- (1-methyl-1H-imidazol-2-yl) phenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

8- (3, 3-dimethylazetidin-1-yl) -N- (4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (2, 4-dimethyloxazol-5-yl) -2-methoxyphenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethyl azetidin-1-yl) -N- (4- (2, 4-dimethyl oxazol-5-yl) -2-ethoxyphenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (2, 4-dimethyloxazol-5-yl) -2-ethoxyphenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (2, 5-dimethyloxazol-4-yl) -2-methoxyphenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethyl azetidin-1-yl) -N- (4- (2, 5-dimethyl oxazol-4-yl) -2-ethoxyphenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -4-methylpiperidine-4-carbonitrile;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) -8- (4-methoxypiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) -8- (4-methoxy-4-methylpiperidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) -6-methyl-8- (1-oxa-6-azaspiro [3.3] hept-6-yl) pyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) -6-methyl-N8- ((3-methyltetrahydrofuran-3-yl) methyl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) -6-methyl-8- (2-oxa-7-azaspiro [4.4] non-7-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) -6-methyl-N8- (tetrahydro-2H-pyran-4-yl) pyrido [3,4-d ] pyrimidine-2, 8-diamine;

n- (4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) -6-methyl-8- (7-oxa-2-azaspiro [3.5] non-2-yl) pyrido [3,4-d ] pyrimidin-2-amine;

n2- (4- (2, 5-dimethyloxazol-4-yl) -2-ethoxyphenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine.

30. The method according to any preceding claim, wherein the MPS1 inhibitor is selected from the following:

n-cyclopropyl-4- (6- (2, 3-difluoro-4-methoxyphenoxy) -8- ((3,3, 3-trifluoropropyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -2-methylbenzamide;

(R) -2- (4-fluorophenyl) -N- (4- (2- ((2-methoxy-4- (methylsulfonyl) phenyl) amino) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) phenyl) propanamide;

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

(S) -N8- (3, 3-dimethylbut-2-yl) -N2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

or a pharmaceutically acceptable salt or solvate thereof.

31. The method according to any one of the preceding claims, wherein the MPS1 inhibitor is selected from the following:

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

(S) -N8- (3, 3-dimethylbut-2-yl) -N2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

or a pharmaceutically acceptable salt or solvate thereof.

32. An MPS1 inhibitor for use in treating an estrogen receptor positive breast cancer in a subject in need thereof, wherein:

(i) the subject has been previously treated with endocrine therapy; and/or

(ii) The breast cancer is resistant to endocrine therapy.

33. The compound for use according to claim 32, wherein the subject has failed treatment with the endocrine therapy.

34. The compound for use according to any one of claims 32 and 33, wherein the subject has relapsed during or after treatment with the endocrine therapy.

35. The compound for use according to any one of claims 32 to 34, wherein the subject has experienced disease progression during or after treatment with the endocrine therapy.

36. The compound for use according to any one of claims 32 to 35, wherein the subject has developed an endocrine therapy-resistant breast cancer during or after treatment with the endocrine therapy.

37. The compound for use according to any one of claims 32 to 36, wherein the breast cancer is resistant to endocrine therapy de novo.

38. The compound for use according to any one of claims 32 to 37, wherein the endocrine therapy comprises/consists essentially of/consists of: administration of endocrine agents.

39. The compound for use according to claim 38, wherein the endocrine agent is selected from one or more of aromatase inhibitors, Selective Estrogen Receptor Modulators (SERMs) and selective estrogen receptor degraders/downregulators (SERDs).

40. The compound for use according to any one of claims 38 and 39, wherein the endocrine therapy comprises/consists essentially of/consists of: treatment with aromatase inhibitors and SERDs alone, sequentially or in combination.

41. The compound for use according to any one of claims 38 and 39, wherein the endocrine therapy comprises/consists essentially of/consists of: treatment with SERMs and SERDs alone, sequentially or in combination.

42. The compound for use according to any one of claims 39 and 40, wherein said aromatase inhibitor is selected from the group consisting of: anastrozole, exemestane and letrozole, or a pharmaceutically acceptable salt or solvate thereof.

43. The compound for use according to any one of claims 39 and 41, wherein the SERM is tamoxifen or a pharmaceutically acceptable salt or solvate thereof.

44. The compound for use according to any one of claims 39 to 41, wherein the SERD is fulvestrant or a pharmaceutically acceptable salt or solvate thereof.

45. A compound for use according to any one of claims 32 to 44, wherein the subject is pre-menopausal.

46. A compound for use according to any one of claims 32 to 44, wherein the subject is post-menopausal.

47. The compound for use according to any one of claims 32 to 46, wherein (i) the subject has been previously additionally treated with a CDK4/6 inhibitor; and/or (ii) said breast cancer is additionally resistant to treatment with a CDK4/6 inhibitor.

48. The compound for use according to claim 47, wherein said subject has failed treatment with said CDK4/6 inhibitor.

49. The compound for use according to any one of claims 47 and 48, wherein the subject has relapsed during or after treatment with the CDK4/6 inhibitor.

50. The compound for use according to any one of claims 47 to 49, wherein said subject has experienced disease progression during or after treatment with said CDK4/6 inhibitor.

51. The compound for use according to any one of claims 47 to 50, wherein the subject has developed CDK4/6 inhibitor-resistant breast cancer during or after treatment with the CDK4/6 inhibitor.

52. The compound for use according to any one of claims 47 to 51, wherein said breast cancer is resistant de novo to treatment with a CDK4/6 inhibitor.

53. The compound for use according to any one of claims 47 to 52, wherein said CDK4/6 inhibitor is selected from the group consisting of: pipabride, abemaciclib and ribactide, or a pharmaceutically acceptable salt or solvate thereof.

54. The compound for use according to any one of claims 32 to 53, wherein the compound capable of inhibiting MPS1 is for use alone, sequentially and/or in combination with an endocrine agent.

55. The compound for use according to claim 54, wherein the endocrine agent is selected from the group consisting of: tamoxifen and fulvestrant, or a pharmaceutically acceptable salt or solvate thereof.

56. The compound for use according to any one of claims 32 to 55, wherein said compound capable of inhibiting MPS1 is an MPS1 inhibitor, suitably selected from the group consisting of: NMS-P715, S81694 (NMS-P153), AZ3146, BAY 1217389, BAY 1161909, MPS1-IN-3, MPS1-IN-2, CFI-402257, CCT289346, a compound of formula I, a compound of formula II, a compound of formula III and a compound of formula IV, or a pharmaceutically acceptable salt or solvate thereof, wherein formula I, formula II, formula III and formula IV are as defined IN claim 21.

57. The compound for use according to claim 56, wherein the MPS1 inhibitor is selected from the group consisting of: NMS-P715, BAY 1217389, BAY 1161909, CCT289346, a compound of formula I, a compound of formula II, a compound of formula III and a compound of formula IV, or a pharmaceutically acceptable salt or solvate thereof.

58. The compound for use according to claim 56, wherein the MPS1 inhibitor is selected from the group consisting of: a compound of formula I, a compound of formula II, a compound of formula III, and a compound of formula IV, or a pharmaceutically acceptable salt or solvate thereof.

59. The compound for use according to claim 56, wherein the MPS1 inhibitor is selected from the group consisting of: a compound of formula I or a compound of formula II, or a pharmaceutically acceptable salt or solvate thereof.

60. The compound for use according to any one of claims 32 to 59, wherein the MPS1 inhibitor is selected from the compounds defined in claim 29.

61. The compound for use according to claim 56, wherein the MPS1 inhibitor is selected from the following:

n-cyclopropyl-4- (6- (2, 3-difluoro-4-methoxyphenoxy) -8- ((3,3, 3-trifluoropropyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -2-methylbenzamide;

(R) -2- (4-fluorophenyl) -N- (4- (2- ((2-methoxy-4- (methylsulfonyl) phenyl) amino) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) phenyl) propanamide;

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

(S) -N8- (3, 3-dimethylbut-2-yl) -N2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

or a pharmaceutically acceptable salt or solvate thereof.

62. The compound for use according to claim 61, wherein the MPS1 inhibitor is selected from the following:

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

(S) -N8- (3, 3-dimethylbut-2-yl) -N2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

or a pharmaceutically acceptable salt or solvate thereof.

63. use of an MPS1 inhibitor for the manufacture of a medicament for treating estrogen receptor positive breast cancer in a subject in need thereof, wherein:

(i) the subject has been previously treated with endocrine therapy; and/or

(ii) The breast cancer is resistant to endocrine therapy.

64. The use of claim 63, wherein the subject has failed treatment with the endocrine therapy.

65. The use of any one of claims 63 and 64, wherein the subject has relapsed during or after treatment with the endocrine therapy.

66. The use of any one of claims 63-65, wherein the subject has experienced disease progression during or after treatment with the endocrine therapy.

67. The use of any one of claims 63-66, wherein the subject has developed an endocrine therapy-resistant breast cancer during or after treatment with the endocrine therapy.

68. The use of any one of claims 63-67, wherein the breast cancer is resistant to endocrine therapy de novo.

69. The use according to any one of claims 63 to 68, wherein the endocrine therapy comprises/consists essentially of/consists of: administration of endocrine agents.

70. The use according to claim 69, wherein the endocrine agent is selected from one or more of an aromatase inhibitor, a Selective Estrogen Receptor Modulator (SERM) and a selective estrogen receptor degrader/down regulator (SERD).

71. The use according to any one of claims 63 to 70, wherein the endocrine therapy comprises/consists essentially of/consists of: treatment with aromatase inhibitors and SERDs alone, sequentially or in combination.

72. The use according to any one of claims 63 to 70, wherein the endocrine therapy comprises/consists essentially of/consists of: treatment with SERMs and SERDs alone, sequentially or in combination.

73. The use according to any one of claims 70 and 71, wherein the aromatase inhibitor is selected from the group consisting of: anastrozole, exemestane and letrozole, or a pharmaceutically acceptable salt or solvate thereof.

74. The use according to any one of claims 70 and 72 wherein the SERM is tamoxifen or a pharmaceutically acceptable salt or solvate thereof.

75. The use according to any one of claims 70 to 72, wherein the SERD is fulvestrant or a pharmaceutically acceptable salt or solvate thereof.

76. Use according to any one of claims 63-75, wherein the subject is pre-menopausal.

77. Use according to any one of claims 63-75, wherein the subject is post-menopausal.

78. The use of any one of claims 63 to 77, wherein (i) the subject has been previously additionally treated with a CDK4/6 inhibitor; and/or (ii) said breast cancer is additionally resistant to treatment with a CDK4/6 inhibitor.

79. The use of claim 78, wherein said subject has failed treatment with said CDK4/6 inhibitor.

80. The use of any one of claims 78 and 79, wherein the subject has relapsed during or after treatment with the CDK4/6 inhibitor.

81. The use according to any one of claims 78 to 80, wherein said subject has undergone disease progression during or after treatment with said CDK4/6 inhibitor.

82. The use of any one of claims 78 to 81, wherein the subject has developed CDK4/6 inhibitor-resistant breast cancer during or after treatment with the CDK4/6 inhibitor.

83. The use according to any one of claims 78 to 82, wherein the breast cancer is resistant de novo to treatment with a CDK4/6 inhibitor.

84. The use according to any one of claims 78 to 83, wherein the CDK4/6 inhibitor is selected from the group consisting of: pipabride, abemaciclib and ribactide, or a pharmaceutically acceptable salt or solvate thereof.

85. The use according to any one of claims 63 to 84, wherein the compound capable of inhibiting MPS1 is for use alone, sequentially and/or in combination with an endocrine agent.

86. The use of claim 85, wherein the endocrine agent is selected from the group consisting of: tamoxifen and fulvestrant, or a pharmaceutically acceptable salt or solvate thereof.

87. The use according to any one of claims 63 to 86, wherein the compound capable of inhibiting MPS1 is an MPS1 inhibitor, said MPS1 inhibitor being suitably selected from the group consisting of: NMS-P715, S81694 (NMS-P153), AZ3146, BAY 1217389, BAY 1161909, MPS1-IN-3, MPS1-IN-2, CFI-402257, CCT289346, a compound of formula I, a compound of formula II, a compound of formula III and a compound of formula IV, or a pharmaceutically acceptable salt or solvate thereof; wherein formula I, formula II, formula III and formula IV are as defined in claim 21.

88. The use according to claim 87, wherein the MPS1 inhibitor is selected from the group consisting of: NMS-P715, BAY 1217389, BAY 1161909, CCT289346, a compound of formula I, a compound of formula II, a compound of formula III and a compound of formula IV, or a pharmaceutically acceptable salt or solvate thereof.

89. The use according to claim 87, wherein the MPS1 inhibitor is selected from the group consisting of: a compound of formula I, a compound of formula II, a compound of formula III, and a compound of formula IV, or a pharmaceutically acceptable salt or solvate thereof.

90. The use according to claim 89, wherein the MPS1 inhibitor is selected from the group consisting of: a compound of formula I or a compound of formula II, or a pharmaceutically acceptable salt or solvate thereof.

91. The use according to any one of claims 63 to 90, wherein the MPS1 inhibitor is selected from a compound as defined in claim 29.

92. The use according to claim 87, wherein the MPS1 inhibitor is selected from the following:

n-cyclopropyl-4- (6- (2, 3-difluoro-4-methoxyphenoxy) -8- ((3,3, 3-trifluoropropyl) amino) imidazo [1,2-b ] pyridazin-3-yl) -2-methylbenzamide;

(R) -2- (4-fluorophenyl) -N- (4- (2- ((2-methoxy-4- (methylsulfonyl) phenyl) amino) - [1,2,4] triazolo [1,5-a ] pyridin-6-yl) phenyl) propanamide;

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

(S) -N8- (3, 3-dimethylbut-2-yl) -N2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

or a pharmaceutically acceptable salt or solvate thereof.

93. The use according to claim 92, wherein the MPS1 inhibitor is selected from the following:

n2- (4- (4, 5-dimethyl-4H-1, 2, 4-triazol-3-yl) -2-ethoxyphenyl) -6-methyl-N8-neopentylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

(S) -N8- (3, 3-dimethylbut-2-yl) -N2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidine-2, 8-diamine;

8- (3, 3-dimethylazetidin-1-yl) -N- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

n- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -8- (3-methoxy-3-methylazetidin-1-yl) -6-methylpyrido [3,4-d ] pyrimidin-2-amine;

1- (2- ((2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) amino) -6-methylpyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidine-3-carbonitrile;

n2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine;

or a pharmaceutically acceptable salt or solvate thereof.

Background

It has long been recognized that many breast cancers are hormone dependent. Estrogen (Oestrogen), which may be interchangeably referred to as estrogen (estrogen), acts as an endocrine growth factor, particularly in most breast cancers. The loss of estrogen from these tumors is therefore the primary therapeutic modality for breast cancer.

The most common Breast Cancer (BC) diagnosed in the clinic is Estrogen Receptor (ER) positive, and ER positive BC account for over 80% of cases.

Estrogens mediate their effects by binding to the ER. Estrogen-bound ER is classically associated with an Estrogen Responsive Element (ERE) on target genes that control proliferation and cell survival. ER has two distinct activation domains, AF-1 and AF-2. AF-2 is integral with the ligand binding domain and is regulated by estrogen binding. AF-1 activity is regulated by phosphorylation, while AF-2 associates with a coactivator of the p160 family, controlling the ER transcriptional complex.

Classically, patients with ER-positive BC are treated with endocrine agents such as tamoxifen (tamoxifen) or Aromatase Inhibitors (AI), which block estrogen signaling.

Although more than 50% of patients show a response to endocrine therapy, most relapses, with either head (denovo) or acquired tolerance disease, make it one of the biggest challenges for breast cancer research (reviewed by Ma et al 2015). One striking feature of endocrine tolerant BC is the fact that most patients continue to express ER. To date, a variety of molecular mechanisms have been associated with the tolerogenic phenotype, all of which converge to the level of cyclin D, forcing cell cycle progression. This high heterogeneity in the adaptive mechanism highlights the importance of finding common nodes that contribute to treatment failure during the course of ER-positive BC progression.

Since uncontrolled proliferation is a hallmark of cancer (reviewed by Hanahan & Weinberg 2011), direct targeting of the cell cycle with CDK inhibitors has provided attractive suggestions, but until recently little specificity has been shown, and the associated clinical toxicity has been unacceptable (Asghar et al 2015). The CDK4/6-RB axis (axis) is critical for cell cycle entry and not surprisingly, most cancers disrupt this axis to promote proliferation, e.g., 19% of breast cancers show amplification of CDK4, while CCND1 amplification is associated with endocrine tolerance (reviewed by Musgrove et al 2011).

Recently, CDK4/6 inhibitors in combination with endocrine therapy have been shown to improve clinical outcomes in ER + breast cancer patients. However, not all patients will benefit from such combination therapy and many will eventually relapse due to acquired tolerance.

There is a need in the art for new treatment options for ER + breast cancer. In particular, there is a need in the art for new, effective therapies for the treatment of endocrine-tolerant ER + breast cancer.

Summary of The Invention

Herein, it was first shown that MPS1 surprisingly correlates with resistance to endocrine therapy, and furthermore, MPS1 provides a reasonable target for the treatment of breast cancer that is resistant to endocrine therapy.

In one aspect, the present invention relates to a method for treating estrogen receptor positive breast cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an MPS1 inhibitor, wherein:

(i) the subject has been previously treated with endocrine therapy; and/or

(ii) The breast cancer is resistant to endocrine therapy.

In one aspect, the present invention relates to an MPS1 inhibitor for use in treating an estrogen receptor positive breast cancer in a subject in need thereof, wherein:

(i) the subject has been previously treated with endocrine therapy; and/or

(ii) The breast cancer is resistant to endocrine therapy.

In one aspect, the present invention relates to the use of an MPS1 inhibitor for the manufacture of a medicament for the treatment of an estrogen receptor positive breast cancer in a subject in need thereof, wherein:

(i) the subject has been previously treated with endocrine therapy; and/or

(ii) The breast cancer is resistant to endocrine therapy.

In one aspect, the invention relates to a combination comprising an MPS1 inhibitor and an endocrine agent.

In one aspect, the invention relates to a pharmaceutical product comprising an MPS1 inhibitor and an endocrine agent.

In one aspect, the invention relates to a method for treating estrogen receptor positive breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an MPS1 inhibitor and a therapeutically effective amount of an endocrine agent, individually, sequentially or in combination.

In one aspect, the invention relates to a pharmaceutical product for use in treating estrogen receptor positive breast cancer comprising an MPS1 inhibitor and an endocrine agent, wherein a compound capable of inhibiting MPS1 and the endocrine agent are for separate administration, for sequential administration, or for combined administration.

In one aspect, the invention relates to the use of a pharmaceutical product comprising an MPS1 inhibitor and an endocrine agent in the manufacture of a medicament for the treatment of estrogen receptor positive breast cancer, wherein the compound capable of inhibiting MPS1 and the endocrine agent are for separate administration, for sequential administration, or for combined administration.

In one aspect, the invention relates to MPS1 inhibitors and endocrine agents for use in the treatment of estrogen receptor positive breast cancer.

In one aspect, the present invention relates to an MPS1 inhibitor for use in the treatment of estrogen receptor positive breast cancer, wherein the MPS1 inhibitor is for administration alone, sequentially or in combination with an endocrine agent.

In one aspect, the invention relates to an endocrine agent for use in the treatment of estrogen receptor positive breast cancer, wherein the endocrine agent is for administration alone, sequentially or in combination with an MPS1 inhibitor.

In one aspect, the invention relates to the use of an MPS1 inhibitor and an endocrine agent in the preparation of a medicament for the treatment of estrogen receptor positive breast cancer.

In one aspect, the present invention relates to the use of an MPS1 inhibitor in the manufacture of a medicament for the treatment of estrogen receptor positive breast cancer, wherein the MPS1 inhibitor is for administration alone, sequentially or in combination with an endocrine agent.

In one aspect, the invention relates to the use of an endocrine agent for the manufacture of a medicament for the treatment of estrogen receptor positive breast cancer, wherein the endocrine agent is for administration alone, sequentially or in combination with an MPS1 inhibitor.

Preferred, suitable and optional features of any one particular aspect of the invention are also preferred, suitable and optional features of any other aspect.

Brief Description of Drawings

Fig. 1A shows a schematic representation of the a methodology.

FIG. 1B shows B the identification of the G2/M checkpoint protein as a co-determinant of tolerance by the intersection (intervention) of kinase panel screens from several LTED cell lines ER + or ER-; validation of the role of mps1 in the LTED-tolerant phenotype was assessed by targeted knock-down (knockdown) with siRNA against MPS 1. PLK1 was used as a positive control.

Figure 1C shows analysis of RNA-seq data from MCF7 versus MCF7-LTED shows increased expression in an endocrine tolerance model; a comprehensive analysis of protein abundance showed that MPS1 was increased in MCF7-LTED cells.

Figure 1D shows an immunoblot analysis of F showing increased expression of MPS1 in the MCF7-LTED and SUM44-LTED cell lines.

Fig. 2A shows the in-treatment (ontransent) gene expression of MPS1 in patients treated with anastrozole (anastrozole), and B shows the correlation of the in-treatment gene expression of MPS1 with 2-week Ki67 values. The spearman rank correlation coefficient (P) and P value are depicted.

Figure 3C shows baseline expression of MPS1, and D shows gene expression in treatment of MPS1 in patients treated with letrozole (letrozole).

Figure 4 shows a Kaplan-Meier plot that reveals the correlation of high or low pre-treatment gene expression of MPS1 in ER + BC patients treated with tamoxifen, from publicly available data collected over 10.

Fig. 5 shows the results of treating various breast cancer cells with increasing concentrations of CCT289346 in the presence or absence of E2.

Figure 6 shows treatment of spherical cultures of wt-MCF7 and MCF7-LTED cells (spheroid cultures) containing wt or mutant ESR1 with MPS1 inhibitor CCT 289346. The histogram presents cell viability determined using TitreGlo.

Figure 7 shows the response of breast cancer cell lines to increasing concentrations of MPS1 inhibitor NMS-P175.

Figure 8 shows the response of breast cancer cell lines to increasing concentrations of the MPS1 inhibitor BAY 1161909.

Fig. 9A and 9B show the response of breast cancer cell lines in 2D (fig. 9A) and spherical cultures (fig. 9B) to increasing concentrations of the MPS1 inhibitor BAY 1217389. Histograms present measurements of bulb viability using TiterGlo.

Figure 10 shows four cell lines: results of Wt-SUM44, SUM44 LTED, HCC1428 and HCC1428 LTED, these four cell lines were cultured with increasing concentrations of MPS1 inhibitor CCT289346 in the presence or absence of estradiol (E2) for 6 days with medium change on day 3. Cell viability was assessed using TitreGlo. Data were normalized to vehicle control for each condition.

Figure 11 shows the results of treating wt-MCF7 cells with increasing concentrations of CCT289346 in the presence or absence of E2 or E2.

Figure 12 shows the results of treating cells with increasing concentrations of: A. fulvestrant (fulvestrant) alone or in combination with 50nM CCT 289346; B. 4-OHT alone or in combination with 50nM CCT289346, with medium changed on day 3. Cell viability was measured using TitreGlo.

Fig. 13A and 13B show the results of proliferation assays in piparib-resistant and sensitive cell lines.

Figure 14 shows the results of kinase group siRNA library screening in the piparix tolerization model. A. Venn diagram (Venn diagram), which identifies MPS1 as one of the common targets in all tolerance models. B. Histogram showing the variation in cell viability (mean ± standard error of mean) normalized to non-targeted si controls generated from library screening.

FIG. 15 shows treatment of wt-MCF7 and wt-T47D piparide-tolerant cell lines with increasing concentrations of CCT289346 or NMS-P715 for 6 days with or without piparide, where the medium was changed on day 3. Cell viability was determined using TiterGlo and data were expressed as fold cell viability.

FIG. 16 shows MCF7-LTED and T47D-LTED piparide-tolerant cell lines treated with increasing concentrations of CCT289346 or NMS-P715 for 6 days in the presence or absence of piparide, with medium changed on day 3. Cell viability was determined using TiterGlo and data were expressed as fold cell viability.

FIG. 17 shows the role of CCT289346 (also known as BOS172722) in MCF7-LTED tumor growth.

FIG. 18 shows the effect of CCT289346 alone or CCT289346 in combination with fulvestrant in the PDX model HBCx-34.

FIG. 19 shows the effect of CCT289346 alone or CCT289346 in combination with fulvestrant in the PDX model HBCx-34.

Detailed Description

Definition of

As used herein, Estrogen receptor Positive (ER +) breast cancer ginger refers to a breast cancer that naturally expresses an Estrogen receptor (suitably a Nuclear Estrogen receptor; suitably ER- α.) any suitable technique known in the art can be used to identify whether a breast cancer expresses an Estrogen receptor, including ligand binding assays and immunohistochemistry techniques.

As used herein, the term endocrine therapy refers to any treatment capable of removing estrogen, blocking estrogen production, reducing estrogen levels, blocking estrogenic effects, reducing estrogenic effects, and/or capable of causing instability, degradation, and/or down-regulation of estrogen receptors. Suitably, the endocrine therapy comprises/consists essentially of/consists of: administration of endocrine agents.

As used herein, the term endocrine agent ginger refers to any chemical compound or biological agent that is capable of removing estrogen, blocking estrogen production, and/or reducing the level of estrogen. Suitably, the endocrine agent is a chemical compound, such as a drug or drug-like molecule.

As used herein, ginger having previously failed therapy may mean that the subject has been determined by the relevant skilled artisan to have failed therapy with endocrine therapy. The skilled artisan will be able to readily determine when a subject has failed endocrine therapy treatment. For example, failure of treatment with endocrine therapy may manifest as one or more of the following during or after therapy: disease progression (e.g., growth, recurrence of cancer, spread of cancer, increased tumor division, increased proliferation), deficient response (i.e., no pathological change in cancer, no change in tumor size), and inadequate response (inadequate tumor size reduction, inadequate pathological response).

As used herein, administration of ginger in combination refers to a therapy in which two agents (e.g., an MPS1 inhibitor and an endocrine agent) are administered simultaneously.

As used herein, sequential administration of ginger means that one agent is administered after the other agent, however, the time period between administration of each agent enables both agents to act therapeutically simultaneously. Thus, sequential ginger administration may allow one agent to be administered within 5 minutes, 10 minutes, or a few hours after the other, so long as the circulatory half-life of the first administered agent is such that both are present in therapeutically effective amounts at the same time. The time delay between administration of the agents may vary depending on the precise nature of the agents, their interaction, and their respective half-lives.

As used herein, administering ginger alone means that one agent is administered after another agent, however, the time period between administrations is such that when the second agent is administered, the first administered agent is no longer present in a therapeutically effective amount. Thus, the two agents alone exert their therapeutic effects. Nevertheless, the overall therapeutic effect observed when both agents act therapeutically individually may be greater than either agent used alone.

As used herein, one or more subject ginger and/or one or more patient ginger, suitably refer to mammals (e.g. human and non-human mammals, such as domestic animals (cattle, sheep, goats) or companion animals (cats, dogs, horses, rabbits).

As used herein, a cancer that is resistant to endocrine therapy ginger or endocrine resistant ginger can mean that the cancer has been determined by the relevant skilled artisan to be resistant to endocrine therapy. The skilled artisan will be readily able to determine when a cancer is resistant to endocrine therapy. For example, clinically, tolerance can manifest as recurrence or recurrence of cancer during or after endocrine therapy. Alternatively, tolerance may be observed as clinical progression of the primary disease, which typically involves an increase in the size of the primary tumor or spread of the disease to regional nodes or beyond distant metastatic sites. Pathological changes such as increased tumor size or increased proliferation are markers of potential resistance to therapy. In neoadjuvant treatment regimens (neoadjivant setting), tolerance appears as a major lack of response (no change or increase in tumor size and no evidence of a pathological response) at the early stage of treatment, suggesting either innate tolerance or de novo tolerance; or as a major lack of response later after a period of response, indicating acquired tolerance. Alternatively, tolerance to endocrine therapy can be measured in a patient not receiving endocrine therapy (endocrine therapy) by reference to a genotypic and/or phenotypic marker of tolerance

patient) was determined.

As used herein, the term CDK4/6 inhibitor refers to a chemical or biological agent capable of inhibiting CDK4 and CDK 6. Suitably, the CDK4/6 inhibitor is selective for CDK4/6 relative to other kinases, in particular relative to other CDKs. Suitably, the CDK4/6 inhibitor herein has nanomolar IC to CDK4 and CDK6₅₀. Suitably, the inhibitor of CDK4/6 is a chemical compound, such as a drug or drug-like molecule.

As used herein, the term MPS1 inhibitor refers to a chemical or biological agent capable of inhibiting MPS1 (monopolar spindle) kinase. Suitably, the MPS1 inhibitor is selective for MPS1 over other kinases. Suitably, the MPS1 inhibitors herein have nanomolar IC to MPS1₅₀. Suitably, the MPS1 inhibitor is a chemical compound, such as a drug or drug-like molecule.

As used herein, the term "BAY 1161909" refers to the following compounds:

as used herein, the term "BAY 1217389" refers to the following compounds:

as used herein, the term "NMS-P715" refers to the following compounds:

as used herein, the term "AZ 3146" refers to the following compounds:

as used herein, the term "MPS 1-IN-3" refers to the following compounds:

as used herein, the term "MPS 1-IN-2" refers to the following compounds:

as used herein, the term "CFI-402257" refers to the following compounds:

as used herein, the term "CCT 289346" refers to N2- (2-ethoxy-4- (4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) -6-methyl-N8-neopentyl pyrido [3,4-d ] pyrimidine-2, 8-diamine.

treatment ginger and therapeutically effective amount ginger, as used herein by itself or in combination with another term or terms, refers to an amount of a compound, composition or medicament that (a) inhibits or results in the amelioration of a particular disease, condition or disorder; (b) attenuating, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder; (c) or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein. It is to be understood that the terms treatment ginger and treatment effective ginger encompass any of the above-mentioned effects (a) - (c) alone or in combination with any other effect (a) - (c). It will be appreciated that in, for example, a human or other mammal, a therapeutically effective amount may be determined experimentally in a laboratory or clinical treatment protocol, or may be that amount required by the united states Food and Drug Administration (FDA) or equivalent foreign regulatory body (forign regulatory body) in accordance with the guidelines for the particular disease and subject being treated. It is understood that determination of the appropriate dosage form, dosage and route of administration is within the level of ordinary skill in the pharmaceutical and medical arts.

As used herein, whether by itself or in conjunction with another term or terms, -treated (treating) ginger, -treated (treated) ginger, and -treated (treating) ginger may refer to medical acts and outcomes and include acts and outcomes of prevention, amelioration, palliation, and cure. In some embodiments, the terms treatment (healing) ginger, treatment (treated) ginger, and treatment (treatment) ginger refer to the act and outcome of healing and reducing or decreasing the severity of a particular condition, characteristic, symptom, disorder, or disease described herein. For example, treatment may include reduction of several symptoms of the condition or disorder or complete eradication of the condition or disorder. It should be understood that the term as used herein to prevent ginger is not absolute, but refers to the behavior and results where administration of a compound or composition reduces the likelihood or severity of a condition, symptom, or disease state, and/or delays the onset of a condition, symptom, or disease state for a period of time.

The compounds and intermediates described herein may be named according to the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) naming system, it being understood that the term Compound ginger of formula I and the more commonly used term Compound ginger refer to and include any and all compounds described by and/or with reference to formula I, unless expressly stated to the contrary, apply mutatis mutandis also to the terms Compound ginger of formula II, Compound ginger of formula III, Compound ginger of formula IV and Compound ginger of formula V And the optical isomers, i.e., the R and S enantiomers. This understanding extends to pharmaceutical compositions and methods of treatment employing or comprising one or more compounds of formula I, formula II, formula III, formula IV, and formula V, by themselves or in combination with additional agents.

The various hydrocarbon-containing portions provided herein can be described using a prefix that specifies the minimum and maximum number of carbon atoms in the portion, e.g., "(C)_a-b) "or" C_a-C_b"or" (a-b) C ". For example, (C)_a-b) Alkyl indicates an alkyl moiety having an integer "a" to an integer "b" (including the integer "a" and the integer "b") number of carbon atoms. Certain moieties may also be described in terms of minimum and maximum numbers of members with or without specific reference to a particular atom or overall structure.For example, the term a-to b-membered ring ginger or having the member ginger between a and b refers to a moiety having the number of atoms from the integer "a" to the integer "b" (including the integer "a" and the integer "b").

about ginger when used herein in conjunction with a measurable value such as, for example, an amount or time period, is meant to encompass reasonable variations in that value, for example, to allow for experimental error in the measurement of that value.

alkyl ginger and alkyl group ginger, as used herein by itself or in combination with another term or terms, refer to branched or unbranched saturated hydrocarbon chains. Unless otherwise specified, an alkyl group typically contains 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms or 1-3 carbon atoms, and may be substituted or unsubstituted. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, and the like.

alkylene ginger and alkylene radical ginger, as used herein by itself or in combination with another term or terms, refer to branched or unbranched saturated hydrocarbon chains. Unless otherwise specified, alkylene groups typically contain 1 to 10 carbon atoms, such as 1 to 6 carbon atoms or 1 to 3 carbon atoms, and may be substituted or unsubstituted. Representative examples include, but are not limited to, methylene (-CH)₂-) ethylene isomer (-CH (CH)₃) -and-CH₂CH₂-) and the propylene isomer (-CH (CH)₃)CH₂–、–CH(CH₂CH₃)–、–C(CH₃)₃-and-CH₂CH₂CH₂-) and the like.

As used herein by itself or in combination with another term or terms, alkenyl zingiber and alkenyl group zingiber refer to branched or unbranched hydrocarbon chains comprising at least one double bond. Unless otherwise specified, an alkenyl group typically contains 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and may be substituted or unsubstituted. Representative examples include, but are not limited to, vinyl, 3-buten-1-yl, 2-vinylbutyl, and 3-hexen-1-yl.

As used herein by itself or in combination with another term or terms, alkynyl ginger and alkynyl group ginger refer to branched or unbranched hydrocarbon chains comprising at least one triple bond. Unless otherwise specified, alkynyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and may be substituted or unsubstituted. Representative examples include, but are not limited to, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.

As used herein by itself or in combination with another term or terms, aromatic ginger refers to monocyclic and polycyclic ring systems containing 4n +2 pi electrons, where n is an integer. Aromatic is to be understood as meaning and including ring systems comprising only carbon atoms (i.e. arylzingiber) as well as ring systems comprising at least one heteroatom selected from N, O or S (i.e. heteroaromatic zingiber or heteroarylzingiber). The aromatic ring system may be substituted or unsubstituted.

non-aromatic ginger, as used herein by itself or in combination with another term or terms, refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system. As used herein, non-aromatic refers to and includes ring systems containing only carbon atoms as well as ring systems containing at least one heteroatom selected from N, O or S. The non-aromatic ring system may be substituted or unsubstituted.

As used herein by itself or in combination with another term or terms, the aryl ginger and aryl radical ginger refer to phenyl and 7-15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro and/or fused ring systems, wherein at least one of the rings is aromatic. The aryl group may be substituted or unsubstituted. Unless otherwise specified, an aryl group may contain 6 ring atoms (i.e., phenyl), or be a ring system containing 9 to 15 atoms, such as 9 to 11 ring atoms, or 9 or 10 ring atoms. Representative examples include, but are not limited to, naphthyl, indanyl, 1,2,3, 4-tetrahydronaphthyl, 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl, and 6,7,8, 9-tetrahydro-5H-benzocycloheptenyl. Suitably, the aryl groups are phenyl and naphthyl, suitably phenyl.

As used herein, by itself or in combination with one or more additional terms, an arylene ginger and an arylene group ginger means a phenylene (-C)₆H₄-) or a 7-to 15-membered bicyclic or tricyclic hydrocarbon ring system, including bridged, spiro and/or fused ring systems, wherein at least one of the rings is aromatic. The arylene group may be substituted or unsubstituted. In some embodiments, the arylene group can comprise 6 ring atoms (i.e., phenylene), or a ring system comprising 9 to 15 atoms, such as 9 to 11 ring atoms or 9 or 10 ring atoms. The arylene group may be substituted or unsubstituted.

As used herein by itself or in combination with another term or terms, alkylaryl ginger and alkylaryl group ginger refer to alkyl groups in which a hydrogen atom is replaced by an aryl group, wherein alkyl and aryl groups are as previously defined, such as, for example, benzyl (C)₆H₅CH₂-). The alkylaryl group can be substituted or unsubstituted.

As used herein, the carbocyclic groups ginger and carbocyclic ginger, by themselves or in combination with another term or terms, refer to monocyclic and polycyclic ring systems, i.e., hydrocarbon ring systems, containing only carbon atoms in one or more of the rings, regardless of or with reference to aromaticity or unsaturation. Thus, carbocyclic groups should be understood to mean and include ring systems that are fully saturated (such as, for example, cyclohexyl groups), ring systems that are aromatic (such as, for example, phenyl groups), and ring systems having fully saturated, aromatic, and/or unsaturated moieties (such as, for example, cyclohexenyl, 2, 3-dihydro-indenyl, and 1,2,3, 4-tetrahydro-naphthyl). The terms carbocycle (carbocycle) and carbocycle (carbocycle) also include bridged, fused and spiro ring systems.

As used herein by itself or in combination with another term or terms, the cycloalkyl gingers and cycloalkyl group gingers refer to ring systems of non-aromatic carbocyclic rings that may be saturated or unsaturated monocyclic, bicyclic or tricyclic, and may be bridged, spirocyclic and/or fused. Cycloalkyl groups may be substituted or unsubstituted. Unless otherwise specified, cycloalkyl groups typically contain from 3 to 12 ring atoms. In some cases, a cycloalkyl group can contain 4 to 10 ring atoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, etc.). Representative examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl (norbonyl), norbornenyl, bicyclo [2.2.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.1] heptene, bicyclo [3.1.1] heptane, bicyclo [3.2.1] octane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane, and bicyclo [3.2.2] decane. Suitably, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

As used herein by itself or in combination with another term or terms, alkylcycloalkyl ginger and alkylcycloalkyl radical ginger refer to alkyl radicals wherein the hydrogen atom is replaced by a cycloalkyl radical, wherein alkyl radical and cycloalkyl radical are as previously defined, such as, for example, cyclohexylmethyl (C₆H₁₁CH₂-). The alkylcycloalkyl group may be substituted or unsubstituted.

As used herein by itself or in combination with another term or terms, haloalkyl ginger and haloalkyl group ginger refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes saturated alkyl groups as well as both unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, -CF₃、–CHF₂、–CH₂F、–CF₂CF₃、–CHFCF₃、–CH₂CF₃、–CF₂CH₃、–CHFCH₃、–CF₂CF₂CF₃、–CF₂CH₂CH₃、–CF＝CF₂、–CCl＝CH₂、–CBr＝CH₂、–Cl＝CH₂、–C≡C-CF₃、–CHFCH₂CH₃and-CHFCH₂CF₃. Haloalkyl groups may be substituted or unsubstituted. Suitably, the haloalkyl group is selected from CHF₂And CF₃Suitably CF₃。

As used herein by itself or in combination with another term or terms, haloalkoxy ginger and haloalkoxy group ginger refer to alkoxy groups (i.e., O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkoxy includes saturated alkoxy groups as well as both unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, -OCF₃、–OCHF₂、–OCH₂F、–OCF₂CF₃、–OCHFCF₃、–OCH₂CF₃、–OCF₂CH₃、–OCHFCH₃、–OCF₂CF₂CF₃、–OCF₂CH₂CH₃、–OCF＝CF₂、–OCCl＝CH₂、–OCBr＝CH₂、–OCHFCH₂CH₃and-OCHFCH₂CF₃. The haloalkoxy group may be substituted or unsubstituted. Suitably, the haloalkoxy group is selected from-OCHF₂and-OCF₃suitably-OCF₃。

halogen (halo) ginger and halogen (halogen) ginger include fluorine, chlorine, bromine and iodine atoms and fluorine, chlorine, bromine and iodine substituents as used herein by itself or in combination with another term or terms.

As used herein by itself or in combination with another term or terms, the heteroaryl ginger and heteroaryl group ginger refer to (a) 5-and 6-membered monocyclic aromatic rings containing at least one other than one or more carbon atomsA heteroatom such as nitrogen, oxygen or sulfur, and (b) 7-to 15-membered bicyclic and tricyclic rings containing at least one heteroatom such as nitrogen, oxygen or sulfur in addition to one or more carbon atoms, and wherein at least one of the rings is aromatic. In some cases, a heteroaryl group can contain two or more heteroatoms, which can be the same or different. Heteroaryl groups may be substituted or unsubstituted, and may be bridged, spiro, and/or fused. In some cases, a heteroaryl group can contain 5,6, or 8 to 15 ring atoms. In other instances, a heteroaryl group can contain 5 to 10 ring atoms, such as 5,6, 9, or 10 ring atoms. Representative examples include, but are not limited to, 2, 3-dihydrobenzofuranyl, 1, 2-dihydroquinolinyl, 3, 4-dihydroisoquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydroquinolinyl, benzoxazinyl, benzothiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, pyrimidinyl, 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3-pyridazinyl or 4-pyridazinyl, 2-pyrazinyl, thienyl, pyridazinyl, and the like, 2-thienyl, 3-thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl, pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, pyrrolyl, benzimidazolyl, benzofuranyl, benzofurazanyl (benzofurazanyl), 2H-1-benzopyranyl, benzothiadiazinyl, benzothiazolyl, benzothienyl, benzoxazolyl, cinnolinyl, furopyridinyl (furylpyridinyl), indolinyl, indolizinyl, indolyl or 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl or 7-indolyl, 3H-indolyl, Quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl, 10-aza-tricyclo [6.3.1.0^2,7]Dodecyl-2 (7),3, 5-trienyl, 12-oxa-10-aza-tricyclo [6.3.1.0^2,7]Dodeca-2- (7),3, 5-trienyl, 12-aza-tricyclo [7.2.1.0 ]^2,7]Dodeca-2- (7),3, 5-trienyl, 10-aza-tricyclo [6.3.2.0 ]^2,7]Tridec-2 (7),3, 5-trienyl, 2,3,4,5-tetrahydro-1H-benzo [ d ]]Aza derivatives

Radical (2,3,4, 5-tetrahydroo-1H-benzol [ d ]]azepinyl), 1,3,4,5-tetrahydro-benzo [ d]Aza derivatives

-2-keto (1,3,4, 5-tetrahydrogen-benzol [ d ]]azepin-2-onyl), 1,3,4,5-tetrahydro-benzo [ b]Aza derivatives

-2-keto, 2,3,4, 5-tetrahydro-benzo [ c]Aza derivatives

-1-keto, 1,2,3, 4-tetrahydro-benzo [ e ]][1,4]Diaza derivatives-5-keto, 2,3,4,5-tetrahydro-1H-benzo [ e ]][1,4]Diaza derivatives

A group, 5,6,8, 9-tetrahydro-7-oxa-benzocycloheptenyl group, 2,3,4,5-tetrahydro-1H-benzo [ b]Aza derivatives

1,2,4, 5-tetrahydro-benzo [ e ]][1,3]Diaza derivatives

-3-keto, 3,4-dihydro-2H-benzo [ b ]][1,4]Dioxa medicine

Radical (3, 4-dihydro-2H-benzol [ b ]][1,4]dioxinyl), 3,4-dihydro-2H-benzo [ f)][1,4]Oxazazem

-5-keto (3, 4-dihydro-2H-benzol [ f)][1,4]oxazepin-5-onyl)、6,7,8, 9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, 5-dioxo-6, 7,8, 9-tetrahydro-5-thia-8-aza-benzocycloheptenyl and 2,3,4, 5-tetrahydro-benzo [ f][1,4]Oxazazem

And (4) a base. Suitably, heteroaryl is a 5-or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

As used herein by itself or in combination with another term or terms, alkylheteroaryl ginger and alkylheteroaryl radical ginger refer to alkyl radicals wherein the hydrogen atom is replaced by a heteroaryl radical, wherein the alkyl radical and heteroaryl radical are as previously defined. The alkylheteroaryl group may be substituted or unsubstituted. When the number of carbons is provided, e.g. (C)_n-m) Alkyl heteroaryl, range refers to the entire group. Suitably, the alkyl groups formed have from 1 to 6 carbons, suitably from 1 to 3 carbons.

As used herein by itself or in conjunction with another term or terms, the heterocyclic groups ginger and heterocyclic groups ginger refer to monocyclic and polycyclic ring systems containing carbon atoms and at least one heteroatom selected from nitrogen, oxygen, sulfur or phosphorus in one or more rings, regardless of or with reference to aromaticity or unsaturation. Thus, heterocyclic groups should be understood to mean and include fully saturated ring systems (such as, for example, piperidinyl groups), ring systems that are aromatic (such as, for example, pyridinyl groups), and ring systems having fully saturated, aromatic and/or unsaturated moieties (such as, for example, 1,2,3, 6-tetrahydropyridinyl and 6, 8-dihydro-5H- [1,2,4] triazolo [4,3-a ] pyrazinyl). The terms heterocycle (heterocyclic) and heterocycle (heterocyclic) also include bridged ring systems, fused ring systems and spiro ring systems.

As used herein by itself or in conjunction with another term or terms, the heterocycloalkyl ginger and heterocycloalkyl group ginger refer to 3-to 15-membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems that contain at least one heteroatom, such as nitrogen, oxygen, sulfur, or phosphorus, in addition to one or more carbon atoms. Heterocycloalkyl radicalThe groups may be fully saturated or contain unsaturation, and may be bridged, spiro, and/or fused ring systems. In some cases, a heterocycloalkyl group can contain at least two heteroatoms, which can be the same or different. The heterocycloalkyl group may be substituted or unsubstituted. In some cases, the heterocycloalkyl group may contain from 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Representative examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S, S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S, S-dioxide, oxazolidonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidyl, dihydrofuranyl, dihydropyranyl, tetrahydrothienyl-5-oxide, tetrahydrothienyl-S, s-dioxide, homothiomorpholinyl-5-oxide, quinuclidinyl, 2-oxa-5-azabicyclo [2.2.1]Heptyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 3, 8-diaza-bicyclo [3.2.1]Octyl, 2, 5-diaza-bicyclo [2.2.1]Heptyl, 3, 8-diaza-bicyclo [3.2.1]Octyl, 3, 9-diaza-bicyclo [4.2.1]Nonyl, 2, 6-diaza-bicyclo [3.2.2]Nonyl, [1, 4]]Oxaphosphacyclohexyl-4-oxide, [1, 4] n]Azaphosphorocyclohexyl-4-oxide, [1, 2] 2]Oxaphosphol-2-oxide, phosphohexyl-1-oxide, [1, 3]]Azaphospholane-3-oxides, [1, 3]]Oxaphosphole-3-oxides, 7-oxabicyclo [2.2.1]]Heptyl, 6, 8-dihydro-5H- [1,2,4]]Triazolo [4,3-a]Pyrazin-7-yl, 6, 8-dihydro-5H-imidazo [1,5-a ]]Pyrazin-7-yl, 6, 8-dihydro-5H-imidazo [1,2-a ]]Pyrazin-7-yl, 5,6,8, 9-tetrahydro- [1,2,4]Triazolo [4,3-d][1,4]Diaza derivatives

-7-yl and 6, 8-dihydro-5H- [1,2,4]Triazolo [4,3-a]Pyrazin-7-yl. Suitably, a heterocycloalkyl group as defined herein is a monocyclic, bicyclic or spiro heterocyclic group containing one, two or three heteroatoms selected from N, O or S.

As used herein by itself or in combination with another term or terms, the heterocycloalkylene (heterocycloalkylene) ginger and heterocycloalkylene groups ginger refer to 3-to 15-membered monocyclic, bicyclic, or tricyclic non-aromatic ring systems that contain at least one heteroatom such as nitrogen, oxygen, sulfur, or phosphorus in addition to one or more carbon atoms. The heterocycloalkylene group may be fully saturated or contain unsaturation, and may be bridged, spiro and/or fused. The heterocycloalkylene group may be substituted or unsubstituted. In some cases, a heterocycloalkylene group may contain from 3 to 10 ring atoms; such as from 3 to 7 ring atoms. In other instances, a heterocycloalkylene group can contain from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.

As used herein by itself or in combination with another term or terms, alkylheterocycloalkyl ginger and alkylheterocycloalkyl group ginger refer to alkyl groups in which a hydrogen atom is replaced by a heterocycloalkyl group, where alkyl and heterocycloalkyl groups are as previously defined, such as, for example, pyrrolidinylmethyl (C₄H₈NCH₂-). The alkyl heterocycloalkyl group may be substituted or unsubstituted. When the number of carbons is provided, e.g. (C)_n-m) Alkyl heterocycloalkyl, range refers to the entire group. Suitably, the alkyl groups formed have from 1 to 6 carbons, suitably from 1 to 3 carbons.

pharmaceutically acceptable ginger, as used herein by itself or in combination with another term or terms, refers to a material that is generally chemically and/or physically compatible with other ingredients such as, for example, with respect to formulation ; and/or materials that are generally physiologically compatible with its recipient (such as, for example, a subject).

As used herein, the pharmaceutical composition ginger refers to a composition that can be used to treat a disease, condition, or disorder in a subject, including a human, by itself or in combination with another term or terms.

As used herein by itself or in combination with another term or terms, -stable ginger and chemically stable ginger refer to compounds of useful purity that are sufficiently robust when isolated from a reaction mixture. The present application relates only to the preparation of stable compounds. When a list of optional substituents includes members that cannot be used to replace a particular group due to valence requirements, chemical stability, or other reasons, the list is intended to be read in context to include those members of the list that are suitable for replacing the particular group. For example, when considering the degree of optional substitution of a particular moiety, it is to be understood that the number of substituents does not exceed the valency suitable for use in that moiety. For example, if R¹Is a methyl group (-CH)₃) It may optionally be substituted with 1 to 3R⁵And (4) substitution.

As used herein by itself or in combination with another term or terms, substituted ginger indicates that a hydrogen atom on a molecule has been replaced by a different atom or group of atoms, and the atom or group of atoms replacing the hydrogen atom is the substituent ginger. It is to be understood that the terms substituent (substituents) ginger, substituent (substituents) ginger, moiety (molienty) ginger, moiety (molienties) ginger, group (groups) ginger, or group (groups) ginger refer to one or more substituents.

As used herein, pharmaceutical product ginger refers to a product that contains a drug. For example, examples of pharmaceutical products include medical devices, pharmaceutical compositions, and kits comprising one or more medical devices and/or pharmaceutical compositions. Suitably, the pharmaceutical product is a pharmaceutical composition.

Methods of treatment and medical uses

In one aspect, the present invention provides a method for treating estrogen receptor positive breast cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an MPS1 inhibitor, wherein:

(i) the subject has been previously treated with endocrine therapy; and/or

(ii) The breast cancer is resistant to endocrine therapy.

In another aspect, the present invention provides an MPS1 inhibitor for use in treating an estrogen receptor positive breast cancer in a subject in need thereof, wherein:

(i) the subject has been previously treated with endocrine therapy; and/or

(ii) The breast cancer is resistant to endocrine therapy.

In another aspect, the present invention provides the use of an MPS1 inhibitor in the manufacture of a medicament for the treatment of an estrogen receptor positive breast cancer in a subject in need thereof, wherein:

(i) the subject has been previously treated with endocrine therapy; and/or

(ii) The breast cancer is resistant to endocrine therapy.

In one embodiment of each of the aspects above, the subject has been previously treated with endocrine therapy. Typically, the need for further treatment suggests that previous endocrine therapy has failed.

Examples

Materials and methods

17- β -estradiol (E2) and 4-hydroxytamoxifen (4-OHT) were purchased from Sigma-Aldrich (Dorset, UK), fulvestrant (ICI182780) was purchased from Tocrisis Bioscience (Bristol, UK), paclitaxel (paclitaxel) was purchased from Selleckchem (Suffolk, UK), Perspertiril (PD-0332991) was synthesized and provided by Pfizer (Tadworth, UK). MPS1 inhibitors CCT289346, BAY1161909 and BAY 1217389 were synthesized and provided by ICR Cancer Therapeutics (Sutton, UK). The 1 inhibitor NMS-P715 was purchased from Calbiochem (Hertfordshire, UK).

Tissue culture

ER + BC lines wild-type (wt) MCF7, wt-HCC1428, wt-SUM44, wt-T47D, and wt-ZR75.1 cells were obtained from ATCC and at 37 ℃ at 5% CO₂In RPMI1640 medium (Gibco, Thermo Fisher Scientific, Loughborough, UK) without phenol red, supplemented with 10% fetal bovine serum (Gibco, Thermo Fisher Scientific) and 1nM E2. Cell line identity was analyzed by short tandem repeat spectroscopy (short tandem repeat)profiling) (Promega, Madison, Wis., USA). Long-term estrogen deprived cells (MCF 7-LTED) that model resistance to endocrine therapy^wtESR1 and MCF7-LTED^Y537CThe mutants, HCC1428-LTED, SUM44-LTED and ZR75.1-LTED) were cultured in phenol red free RPMI1640 supplemented with 10% dextran activated charcoal stripped fetal bovine serum (DCC-FBS).

Cell viability assay (2D and 3D)

To evaluate the effect of MPS1 inhibition on 2D-grown BC cells, cells were seeded in RPMI1640 supplemented with 10% DCC-FBS in white 96-well plates (GreinerBio-One, gloucentershire, UK). Wt cells were stripped of E2 for 72 hours prior to the experiment. After 24 hours, cells were treated with increasing doses of MPS1 inhibitor ± 4-OHT or fulvestrant in the presence or absence of E2. The medium was changed after 3 days and used after 6 days

Luminescent Cell Viability Assay (Promega) Cell Viability was assessed according to the manufacturer's instructions.

To assess the viability of MPS1 inhibitors on ER + BC in 3D sphere cultures, wt-MCF7 and MCF7-LTED^wtESR1 cells and MCF7-LTED^Y537CCells were seeded at 2500 cells/well in minimal medium in ultra-low adsorption 96-well plates (Corning) and centrifuged at 900rpm for 10 min. After 3 days of incubation, the newly formed spheroids were treated with increasing doses of CCT289346 or BAY 1217389 and retreated every 3-4 days. The effect of treatment on cell viability was assessed after 10 days. Images of the spheres were taken using CeligoS (Nexcelome Bioscience, Lawrence, MA, US) and performed according to the manufacturer's protocol

Luminescent 3D cell viability assay (Promega) as a quantitative readout. Each experiment was performed at least twice, with eight technical replicates per treatment. In a Victor spectrophotometer (Per)kin Elmer, Wokingham, UK) and the values are expressed as fold changes relative to vehicle-treated controls.

siRNA kinase group (kineme) library

A set of LTED cell lines, including MCF7-LTED, SUM44-LTED, HCC1428-LTED, ZR75-LTED and T47D-LTED and MCF7-991R, MCF7-LTED 991R, T47D-991R, T47D-LTED 991R and MCF7-LTED ICIR991R, were transfected with ON-TARGETplus siRNA library-human protein kinase (G-103505, GE Dharmacon, Buckinghamshire, UK). An siRNA library consisting of 9 96-well plates containing SMART pool (pool) siRNAs targeting 709 protein kinases was transferred onto 3 white-walled 384-well plates with clear bottoms (Greiner Bio-One) using a Hamilton Microlab Star liquid handling robot (Hamilton, Bonaduz, Switzerland). The library was supplemented with non-targeted siRNA and PLK1 siRNA (two SMART pools from GE Dharmacon) as positive and negative controls, respectively, and the plates were frozen.

For reverse transfection, plates containing 200nM siRNA were thawed, 10 μ l of RNAiMax (Invitrogen, Paisley, UK) per well was added using a Multidrop Combi (ThermoFisher Scientific), and incubated at room temperature for 30 min. Next, the cells were seeded in 35. mu.l of basal growth medium per well using the Multidrop comb. After 6 days, use

Luminescent cell viability assay (Promega) cell viability was assessed according to the manufacturer's protocol and luminescence was measured using a Victor spectrophotometer (Perkin Elmer, wokinggam. Luminescence readings for each well of the plate were logarithmically converted, the median of the plate was centered, and then the median of the replicates was calculated. This was finally used to calculate the Z-score using the median absolute deviation (mean absolute deviation) for the cell line. The kinetics (dynamic) of each library screen was evaluated by calculating the basic value of Z (prime value). Setting a threshold value of acceptability to Z'>0.3(Brough et al, 2011). Each screen consisted of at least two biological experiments, which included technical replicates of the library. The resultant combination was then generated using Venny 2.1.0 (comparative Genomics, CNB-CSIC, Spain)Wien maps of targets for different BC models.

Immunoblotting

To compare the expression level of MPS1 across our BC line, wt-MCF7, wt-HCC1428, wt-SUM44, wt-T47D, wt-ZR75.1, MCF7-LTED grown in basal medium at 70% confluence (confluence)^wtESR1 and MCF7-LTED^Y537CCell extracts were prepared from HCC1428-LTED, SUM44-LTED and ZR75.1-LTED and SKBR 3.

Protein extracts were generated as previously described (Martin et al, 2003), equal amounts of protein (25 μ g) were resolved by SDS-PAGE (resolve) and immunoblot analysis was performed protein was detected using antibodies against MPS1 (NT clone 3-472-1IgG1,05-682,1:1000, Millipore, Walford, UK) and α -tubulin (T9026, mouse IgG1,1:4000, Sigma-Aldrich.) the disambiguated antibody (Dako/Agilent, Santa Clara, CA, UK) was used at 1:2000 dilution and antigen-antibody interactions were detected with ECL reagent (Amersham).

To detect PARP lysis, cells were seeded into 10cm dishes and allowed to acclimate (acclimate) overnight before 72 hours of treatment with CCT289346 or vehicle control proteins were separated by SDS-PAGE, immunoblotted, and the membrane incubated with antibodies against lysed Poly ADP Ribose Polymerase (PARP) (Santa Cruz Biotechnology, Santa Cruz, CA, UK) and α -tubulin (T9026, mouse IgG1,1:4000, Sigma-Aldrich).

Knockdown of 709 kinases identified MPS1 as a co-determinant of E-deprivation tolerance

To identify targets that drive hormone-independent growth in estrogen deprived (LTED) cells, a library with pools of siRNA targeting 709 kinases was used for screening (FIG. 1A). Cell viability was measured using titerGlo. In this screen, we identified and validated MPS1/TTK as the most common hit (hit) in our LTED cell line group, regardless of ER expression status (fig. 1B). Evaluation of global (global) gene expression data and protein abundance using dimethyl-labeled MCF7 cells versus MCF7-LTED cells showed an increase in MPS1 at both mRNA and protein levels (fig. 1C), which was verified by immunoblot analysis (fig. 1D). Notably, SUM44-LTED showed a similar increase in MPS1 abundance compared to the parental control (parental control), whereas T47D and T47D-LTED appeared similar and HCC1428-LTED appeared to have lower levels of MPS1 compared to their parental cell lines.

The expression of MPS1 correlates with an adverse response to endocrine therapy

To assess the clinical relevance of MPS1, a comprehensive gene expression dataset was assessed for ER + BC patients treated with the new adjuvant anastrozole or letrozole. Clinical response data were available for 72 patients treated with anastrozole, of which 55 were classified as responders (responders) based on a 2-week residual Ki67 score < 10% and 17 were classified as non-responders.

In this case, gene expression in the treatment of MPS1(p <0.0001) was significantly correlated with an adverse response to anastrozole (fig. 2A). It was also found that increased gene expression in treatment of MPS1(p <0.0001) correlated with higher Ki67 expression 2 weeks after treatment when expressed as a continuous variable (fig. 2B).

In the second cohort (cohort), data were available for 52 tumor patients, of which 37 were classified as responders based on tumor shrinkage ≧ 50%. While baseline MPS1 expression showed a trend towards an adverse response (p 0.13) (fig. 3C), increased in-treatment expression of MPS1(p 0.018) was significantly correlated with an adverse response to letrozole (fig. 3D).

Next it was evaluated whether the expression of MPS1 also correlated with long-term results for the adjuvant tamoxifen. MPS1(p ═ 3.14e-02) was shown to be closely associated with poor Relapse Free Survival (RFS) after 10 years of follow-up in 747 ER + patients treated with tamoxifen (figure 4).

MPS1 inhibition inhibited proliferation of endocrine tolerant cell lines in 2D and globular cultures

Sensitivity of wt-MCF7 cells and MCF7-LTED cells to increasing concentrations of MPS1 inhibitor CCT289346 in the presence or absence of estradiol (E2). CCT289346 resulted in a concentration-dependent decrease in proliferation of wt-MCF7 cells in the presence of E2 (IC)₅₀100nM) (fig. 5). Furthermore, CCT289346 resulted in a significant reduction of proliferation of two MCF7-LTED models, one MCF7-LTThe ED model contained wt-ESR1 and another MCF7-LTED model contained a hot-spot mutation (Y537C) (with IC's of 60nM and 40nM, respectively)₅₀Value).

Next, the efficacy of CCT289346 in spherical cultures was evaluated (fig. 6). In agreement with previous observations, CCT289346 reduced the sphere size, which was confirmed using TiterGlo to assess viability.

Subsequently, the wt-MCF7 model and the MCF7-LTED model were treated with the following three alternative MPS1 inhibitors: NMS-P715, BAY1161909 and BAY 1217389. All three agents resulted in similar concentration-dependent reduction of proliferation of wt-MCF7 cells in the presence of E2 and similar concentration-dependent reduction of proliferation of both MCF7-LTED models in the presence and absence of E2 (fig. 7-9).

Notably, IC of response to BAY 1217389₅₀Values are much lower than about 20 times the other agents tested. Moreover, BAY 1217389 was particularly potent in spherical cultures (fig. 9). To explore the possibility that these observations were cell line specific, we processed two additional LTED models, SUM44 LTED and HCC1428 LTED, and these showed similar sensitivity patterns (fig. 10). In the presence of E2, both wt-SUM44 and wt-HCC1428 showed concentration-dependent reduction of proliferation. Concentrations above 250nM showed an induced feedback cycle (feedback loop) and associated proliferation rise. Modeling additive endocrine therapy in the absence of E2; note that the data is normalized to vehicle and thus expressed as 100%, CCT289346 resulted in a 30% reduction in proliferation, again supporting the ability of CCT289346 to target de novo tolerance. Both HCC1428 LTED and SUM44 LTED showed concentration-dependent reduction of proliferation in the absence or presence of E2.

Taken together, these data show a class-specific effect of MPS1 inhibition, confirming that it is a clinically relevant target in endocrine therapy-resistant breast cancer.

We next investigated the potential role of MPS1 as a target for de novo tolerance. Previously, we showed that using the E2F mid-treatment ginger signature score (E2F "on-treatment" signature score) in patients treated with anastrozole, we could identify patients with breast cancer with ligand-independent ER activity (Miller et al 2011). To address this issue, we cultured wt-MCF7 cells in the presence or absence of E2, modeling additive endocrine therapy. In the presence of E2, CCT289346 resulted in a concentration-dependent decrease in proliferation. Addition of CCT289346 to DCC (modeling in combination with endocrine therapy) showed a further 20% decrease in proliferation, indicating that MPS1 inhibits targeted de novo tolerance (fig. 11).

Effect of CCT289346 in combination with endocrine therapy

The potential of combining CCT289346 with fulvestrant or 4-hydroxy tamoxifen (4-OHT) to improve efficacy was investigated. MCF7-LTED cells were treated with increasing concentrations of endocrine agent alone or with CCT289346 (defined IC)₅₀Concentration) of the endocrine agent. As expected, the two endocrine agents combined with CCT289346 resulted in a concentration-dependent decrease in cell proliferation, confirming that proliferation was dependent on ER (fig. 12). Taken together, this data suggests that CCT289346 in combination with either endocrine agent may provide clinical utility in endocrine therapy resistant breast cancer patients.

Genomic profiling (genomic profiling) revealed that loss of RB is associated with irreversible tolerance to CDK4/6 inhibition

A panel of breast cancer cell lines with different phenotypic backgrounds (wt-MCF7, MCF7 LTED, wt-T47D and T47DLTED) were chronically treated in the presence of CDK4/6 inhibitor (1 μ M Periplaneta). Tolerance was verified by culturing tolerant cell lines with increasing concentrations of piparix in comparison to their wild type progenitors (figure 13).

Subsequently, the piparix tolerogenic cell line was cultured both short and long term in the absence of drug to assess the stability of the tolerogenic phenotype. Notably, wt-MCF7^991RDerivatives and MCF7 LTED^991R -derived washed-out (waspout) gingers rendered them again susceptible to the antiproliferative effect of thujaplicin, indicating that the phenotype was plastic. In contrast, wt-T47D^991RCell line and T47D LTED^991RThe cell line remained tolerant (fig. 13).

Targeted tolerance to thujaplici

To investigate which kinases are commonly associated with the CDK4/6 tolerant phenotype, a kinase panel knock-down screen (siRNA) targeting 709 kinases in a piparix tolerant cell line was used (fig. 14). All cell lines showed varying degrees of dependence on G2/M checkpoint regulators, however, MPS1 was a common determinant in all cell line models regardless of RB or ESR1 status. This observation was next validated by comparing the effect of siRNA targeted MPS1 versus targeted PLK in cell lines. The inhibitory effect varies between cell lines, with a reduction in proliferation ranging between 20% and 40%.

The piparide-tolerant cell line is sensitive to the antiproliferative effect of CCT289346

To address the usefulness of MPS1 as a co-determinant of resistance to CDK4/6 inhibition, proliferation assays were performed using MPS1 inhibitors CCT289346 and NMS-P715 in a variety of breast cancer cell lines, including wild-type cell lines (fig. 15) and LTED cell lines (fig. 16), in the presence or absence of thujaplici.

All cell lines showed varying degrees of concentration-dependent reduction in proliferation in response to the two MPS1 inhibitors (fig. 15 and 16). Addition of CCT289346 to piparide shows a lower IC₅₀Value (for wt-MCF7^991R、MCF7LTED^991RAnd wt-T47D^991RAbout 50nM) was used. T47D-LTED^991RShowed the most sensitive inhibition to MPS1 with an IC of 25nM₅₀The value is obtained.

To date, MPS1 inhibitors have only been studied in triple negative breast cancer models in combination with chemotherapy. As demonstrated herein, MPS1 is also a suitable target in ER + breast cancer models for endocrine therapy and/or pipbicril tolerance. The data herein show that MPS1 inhibitors reduce tumor cell growth, particularly in endocrine tolerance models of endocrine-resistant cancer and of periphe-resistant diseases. These findings are of significant clinical importance, at least in part, because little is currently known about appropriate therapies for patients with relapsed CDK4/6 inhibitors.

In vivo studies

Method of producing a composite material

In vivo efficacy study-MCF 7-LTED

In vivo studies were performed according to the british ministry of medicine (Home Office) guidelines in female NCr outbred nude mice aged 8 to 12 weeks from ovariectomy and approved by the institutes of Cancer research ethics Committee. Xenograft modeling in patients resistant to aromatase treatment by modeling MCF7-LTED (5X 10) in basement membrane matrix (1:1 Matrigel; BD Biosciences)⁶) Cell inoculation into the right flank of each animal was initiated. After the tumor size reached 7mm, mice were randomized and treated with the following treatments for 40 days: 200mg/kg of fulvestrant (formulated in peanut oil) injected subcutaneously once a week (day 5), 50mg/kg of CCT289346 administered by oral gavage twice a week (days 1 and 4) or a combination of the two. The control group was treated with two vehicles. Tumors were measured twice weekly for 40 days.

In all groups, tumor growth was assessed by caliper measurements of the two largest diameters twice a week. The volume is then calculated according to the following formula: a x b²X pi/6, where a and b are orthogonal tumor diameters. For each tumor, the volume is reported as the initial volume as a Relative Tumor Volume (RTV). The mean (and SE) of RTV in the same treatment group was calculated and growth curves were established as a function of time.

PDX establishment

Female swiss nude mice were purchased from Charles River (Les arbres, France) and maintained under specific pathogen-free conditions. Their care and housing complies with the institutional guidelines and rules of the French Ethics Committee (French Ethics Committee) (project authorization number 02163.02). PDX was established from primary surgical samples (primarysurgical specs) with informed consent of the patients, as described elsewhere (Marangoni et al 2007). As previously disclosed (Cottu et al 2014), HBCx-34 OvaR PDX was established from ER + breast cancer xenografts with acquired tolerance to estrogen deprivation (absence of estrogen supplementation associated with ovarian ablation). As described in Hatem et al (Hatem et al, 2016), HBCx-86 PDX was established from early ER + PI3KCA mutated breast cancer, which was rendered estrogen-independent by serial tumor passage without estrogen supplementation.

In vivo efficacy studies in PDX

Fulvestrant (Faslodex, AstraZeneca, Macclesfield, UK) was administered by intramuscular injection once a week (day 5) with a 273/4 gauge needle at a dose of 50 mg/kg. CCT289346 was administered by oral gavage at 25mg/kg twice weekly (day 1 and day 4). When the tumor reaches 60mm³To 200mm³At volume (v), mice were individually identified and randomly assigned to either control or treatment groups (10 mice/group) and treatment was initiated. Treatment is administered over a period of 5-6 weeks. Tumor growth was assessed by caliper measurement of two perpendicular diameters of the tumor twice a week. The tumor volume alone was calculated as V a b2/2, with a being the largest diameter and b being the smallest diameter. For each tumor, V is reported as the initial volume as a Relative Tumor Volume (RTV). The mean (and SE) of RTV in the same treatment group was calculated and growth curves were established as a function of time.

Results

Analysis of the MCF7-LTED model showed that both fulvestrant and CCT289346 significantly reduced tumor volume as monotherapies compared to controls, but there were no statistical differences between the drugs. The combination shows a trend towards statistical significance (p ═ 0.066) compared to fulvestrant alone (fig. 17).

Evaluation of the PDX model HBCx-34 showed a significant reduction in tumor volume in response to both fulvestrant and CCT 289346. Strikingly, a suboptimal concentration of CCT289346(25mg/kg), as monotherapy, reduced tumor volume to a similar extent to fulvestrant. The combination of CCT289346 and fulvestrant showed a significant reduction (p ═ 0.024) compared to fulvestrant alone (fig. 18).

Evaluation of the PDX model HBCx-86 showed a significant reduction in tumor volume with both CCT289346 and fulvestrant, although fulvestrant performed well as monotherapy. Strikingly, the combination of fulvestrant and CCT289346 showed a significant reduction in tumor volume (p <0.0001) compared to fulvestrant alone (fig. 19).

In summary, the MPS1 inhibitors shown above were effective in vivo in a model resistant to estrogen deprivation.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).

All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.

This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

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