CN116209655A - Mutant IDH1 and IDH2 inhibitors and application thereof - Google Patents

Abstract

The present invention relates to a compound as a mutant isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) inhibitor represented by formula (I), its preparation method and pharmaceutical composition. The present invention also relates to the use of the above compound or its pharmaceutical composition in treating diseases mediated by mutant IDH1 and IDH2.

Description

Mutant IDH1 and IDH2 inhibitors and applications thereof technical field

The invention relates to a series of compounds used as mutant isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) inhibitors, a preparation method and a pharmaceutical composition thereof. The present invention also relates to the use of the above compound or its pharmaceutical composition in treating diseases mediated by mutant IDH1 and IDH2.

Background technique

In recent years, three metabolic enzymes, fumarate dehydrogenase, succinate dehydrogenase, and isocitrated dehydrogenase (IDH), have been found in tumors. The gene mutations of these enzymes change cell metabolism and may be related to the occurrence and development of tumors. .

There are three types of human IDH, namely IDH1, IDH2, and IDH3. IDH1 is localized in the cytoplasm and peroxisomes, and IDH2 and IDH3 are localized in mitochondria. This class of proteases can oxidize isocitrate to oxalosuccinate and then to α-ketoglutarate (α-KG).

In 2008, a mutation in the IDH1 gene was accidentally discovered during gene sequencing of human glioblastoma, which opened the prelude to IDH in tumor research. Subsequent large-scale clinical glioma case-control studies found that IDH1 gene mutations occur in more than 75% of low-grade gliomas and 90% of secondary glioblastomas; IDH2 gene mutations occur in About 20% of acute myeloid leukemia. In addition, IDH gene mutations have also been reported in cholangiocarcinoma (10%-23%), melanoma (10%) and chondroid tumors (75%). It can be seen that IDH mutations exist in a variety of tumors. Common mutation sites are arginine residues located in the catalytic center (IDH1/R132H, IDH1/R132C, IDH2/R140Q, IDH2/R172K). The mutated IDH can catalyze the conversion of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). Studies have shown that α-KG is similar in structure to 2-HG, and 2-HG competes with α-KG, thereby reducing the activity of α-KG-dependent enzymes, resulting in hypermethylation of chromatin, which is overmethylated It is thought to interfere with normal cell differentiation, leading to excessive proliferation of immature cells, which can lead to cancer.

Agios Pharmaceuticals published its research results in Science magazine in 2013: the mutant IDH1 enzyme inhibitor AGI-5198 developed by the company (Science, 2013, 340, 626-630) and the mutant IDH2 enzyme inhibitor AGI-6780 (Science, 2013, 340, 622-626) can effectively inhibit the production of 2-HG mediated by mutant IDH1/IDH2 in cells, and induce the differentiation of abnormally proliferating cancer cells. Treatment of glioma cells harboring IDH1 mutations with AGI-5198 and leukemia cells harboring IDH2 mutations with AGI-6780 both resulted in increased expression of maturation markers in the cells.

The phase I clinical trial of AG-120, a mutant IDH1 inhibitor developed by Agios Pharmaceuticals, showed that 98 α-Hydroxyglutaric acid (2-HG) levels decreased in % of patients.

In 2013, Agios Pharmaceuticals reported the IDH2 ^R140Q inhibitor AGI-6780 and the IDH2 ^R132H inhibitor AGI-5198, as well as another IDH2 ^R140Q inhibitor AG-221 that the company later marketed. AGI-6780 and AGI-5198 are able to inhibit 2-HG production in cells carrying common IDH1 and IDH2 mutants, respectively.

2017年，礼来公司就报道了一种IDH1和IDH2抑制剂

申请了专利WO2018111707A1；和记黄埔公司于2019年就一种IDH1和IDH2抑制剂

申请WO2019047909A1专利。 Agios Pharmaceuticals also applied for patent WO2015003640A1 in 2014, disclosing an IDH1 and IDH2 inhibitor

In 2017, Eli Lilly reported an IDH1 and IDH2 inhibitor

Application for patent WO2018111707A1; Hutchison Whampoa in 2019 on an IDH1 and IDH2 inhibitor

Apply for WO2019047909A1 patent.

For cancers caused by IDH1 and IDH2 mutations, such as glioma, acute myeloid leukemia, cholangiocarcinoma, melanoma, etc., the IDH1 mono-inhibitor AG120 and IDH2 mono-inhibitor AG221 are currently on the market, providing clinical medicine choose. New studies have found that IDH1 and IDH2 mutations may coexist in the same tumor, resulting in limited efficacy of IDH1 or IDH2 single inhibitors and acquired drug resistance. Although it has been reported that drug research on simultaneously inhibiting mutant IDH1 and IDH2 for the treatment of cancer has been reported, there is still a need to develop novel mutant IDH1 and IDH2 dual inhibitors with strong target inhibition ability and excellent selectivity for the treatment of cancer caused by mutants. Related diseases mediated by IDH1 and IDH2 can overcome the problem of acquired drug resistance after long-term use of single inhibitors, and provide a new drug option for the clinic.

Contents of the invention

The present invention relates to a compound as an inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, Chelates, non-covalent complexes or prodrugs. Compound structural formula of the present invention is as shown in formula (I):

in,

R is selected from -CN, C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclyl, C ₆ - C ₁₂ aryl, 5-12 membered heteroaryl; said C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, 3- 12-membered heterocyclic group, C ₆ -C ₁₂ aryl group, 5-12 membered heteroaryl group are optionally substituted by m R ₇ ;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are the same or different, each independently selected from hydrogen, halogen, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, -OC ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocyclic group; said C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocyclic group replaced by one or more halogens, -OH, -NH ₂ , -CN, C ₁ -C ₄ alkyl, -OC ₁ -C ₄ alkyl, -NH(C ₁ -C ₄ alkyl) or -N(C ₁ -C ₄ alkyl) ₂ substitutions;

R _{and R} optionally together with the carbon atom to which they are attached form C(=O); or

R and _R optionally together with the carbon atom to _which they are attached form C(=O); or

R ₂ and R ₃ optionally form a C ₃ -C ₁₀ membered cycloalkyl group, a 3-10 membered heterocyclic group, a C ₆ -C ₁₀ membered aryl group or a 5-10 membered heteroaryl group together with the carbon atoms to which they are attached; Wherein, the C ₃ -C ₁₀ membered cycloalkyl group, 3-10 membered heterocyclic group, C ₆ -C ₁₀ membered aryl group, 5-10 membered heteroaryl group are optionally replaced by one or more -OH, - NH ₂ , -CN, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy substituted; or

R ₅ and R ₆ optionally form a C ₃ -C ₁₀ cycloalkyl group, a 3-10 membered heterocyclyl group, a C ₆ -C ₁₀ membered aryl group or a 5-10 membered heteroaryl group together with the carbon atoms to which they are attached; wherein , the C ₃ -C ₁₀ membered cycloalkyl group, 3-10 membered heterocyclic group, C ₆ -C ₁₀ membered aryl group, 5-10 membered heteroaryl group are optionally replaced by one or more -OH, -NH _2. -CN, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy;

Each R ₇ is independently selected from hydrogen, deuterium, -CN, halogen, oxo, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Alkynyl, -NR ₁₁ R ₁₂ , -OR ₁₃ , -(CO)OR ₁₄ , -(CO)NR ₁₅ R ₁₆ , -(CO)R ₁₇ , 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl base, 5-10 membered heteroaryl, C ₃ -C ₆ alkenylalkyl or C ₃ -C ₁₀ alkynylalkyl; said C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₃ -C ₆ alkenylalkyl or C ₃ -C ₁₀ alkynylalkyl is optionally substituted by one or more hydrogen, -CN, halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy;

Each R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ Halocycloalkyl, 3-10 membered heterocyclyl, C ₃ -C ₆ alkenyl alkyl or C ₃ -C ₁₀ alkynyl alkyl;

m is selected from any integer of 1-8 (for example: m is 1, 2, 3, 4, 5, 6, 7 or 8).

-CH ₂OCH ₃。 In some embodiments, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ in formula (I) are the same or different, each independently selected from hydrogen, -CN, -CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CHF ₂ , -CF ₃ , -CF ₂ CH ₃ , -CH ₂ CF ₃ ,

_{-CH2OCH3 .}

In some embodiments, R ₂ , R ₃ , R ₅ , and R ₆ in formula (I) are independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or C ₃ -C ₆ cycloalkyl .

In some embodiments, R ₂ , R ₃ , R ₅ , and R ₆ in formula (I) are independently selected from CF ₃ , CH ₃ or cyclopropyl; further, R ₂ is different from R ₃ , and R ₅ is different from R ₆ different.

In some embodiments, R ₁ and R ₄ in formula (I) are independently selected from hydrogen.

In some embodiments, R ₂ and R ₃ in formula (I) form cyclopropane and cyclobutane together with the carbon atoms they are connected to; said cyclopropane and cyclobutane are optionally substituted by one or more hydrogen or halogen .

In some embodiments, R ₅ and R ₆ in formula (I) form cyclopropane, cyclobutane together with the carbon atoms they are connected to; said cyclopropane, cyclobutane are optionally substituted by one or more hydrogen, halogen .

In some embodiments, R in formula (I) is selected from -CN, C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkynyl, -OR ₁₀ , C ₃ -C ₁₂ cycloalkyl, 3-12 membered Heterocyclyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl; said C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, 3-12 Membered heterocyclyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl are optionally substituted by m R ₇ .

In some embodiments, R in formula (I) is selected from C ₁ -C ₁₀ alkyl; said C ₁ -C ₁₀ alkyl is optionally substituted by m R ₇ .

In some embodiments, R in formula (I) is selected from C ₃ -C ₁₂ cycloalkyl; said C ₃ -C ₁₂ cycloalkyl is optionally substituted by m R ₇ .

In some embodiments, each R ₇ in formula (I) is independently selected from hydrogen, -CN, halogen, oxo, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -NR ₁₁ R ₁₂ , -OR ₁₃ , -(CO)OR ₁₄ , -(CO)NR ₁₅ R ₁₆ , C ₆ -C ₁₀ aryl or C ₃ -C ₁₀ alkynyl alkyl; the C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, C ₃ -C ₁₀ alkynylalkyl optionally replaced by hydrogen, -CN, halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy substitution.

-Ph、

In some embodiments, each R ₇ in formula (I) is independently selected from hydrogen, -CN, -F, -Cl, -Br, oxo, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CHFCH ₃ , -CHFCH ₂ CH _3. -CF ₂ CH ₂ CH ₃ , -NH ₂ , -OCH ₃ , -OH, -COOH, -COCH ₃ , -COOCH 3 , -CONHCH _{3 ,} -CON(CH ₃ ) ₂ ,

-Ph,

-OCH ₂CH ₃、

-CH ₂OCH ₃、

In some embodiments, R in formula (I) is selected from -CH ₃ , -CN,

-OCH ₂ CH ₃ ,

-CH ₂ OCH ₃ ,

In some embodiments, the compound represented by formula (I), or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug selection Since formula (II):

in,

R is selected from -CN, C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclyl, C ₆ - C ₁₂ aryl, 5-12 membered heteroaryl; said C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, 3- 12-membered heterocyclic group, C ₆ -C ₁₂ aryl group, 5-12 membered heteroaryl group are optionally substituted by m R ₇ ;

R ₃ and R ₆ are the same or different, each independently selected from hydrogen, halogen, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, -OC ₁ -C ₄ alkyl, C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocyclic group; said C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, 3-6 membered heterocyclic group is replaced by one or more halogen, -OH, -NH ₂ , -CN, C ₁ -C ₄ alkyl, -OC ₁ -C ₄ alkyl, -NH (C ₁ -C ₄ alkyl) or -N (C ₁ -C ₄ alkyl) ₂ substituted;

Each R ₇ is independently selected from hydrogen, deuterium, -CN, halogen, oxo, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Alkynyl, -NR ₁₁ R ₁₂ , -OR ₁₃ , -(CO)OR ₁₄ , -(CO)NR ₁₅ R ₁₆ , -(CO)R ₁₇ , 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl radical or 5-10 membered heteroaryl; said C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 3-10 membered hetero Cyclic, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl optionally substituted by hydrogen, -CN, halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy ;

Each R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ Halocycloalkyl, 3-10 membered heterocyclyl, C ₃ -C ₆ alkenyl alkyl or C ₃ -C ₁₀ alkynyl alkyl;

m is selected from any integer of 1-8.

In some embodiments, R ₃ and R ₆ in formula (I) are the same or different, and are independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or C ₃ -C ₆ cycloalkyl.

In some embodiments, R ₃ and R ₆ in formula (II) are the same or different, and are independently selected from CF ₃ , CH ₃ or cyclopropyl.

In some embodiments, R in formula (II) is selected from -CN, C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkynyl, -OR ₁₀ , C ₃ -C ₁₂ cycloalkyl, 3-12 membered Heterocyclyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl; said C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, 3-12 Membered heterocyclyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl are optionally substituted by m R ₇ .

In some embodiments, R in formula (II) is selected from C ₁ -C ₁₀ alkyl; said C ₁ -C ₁₀ alkyl is optionally substituted by m R ₇ .

In some embodiments, R in formula (II) is selected from C ₃ -C ₁₂ cycloalkyl; said C ₃ -C ₁₂ cycloalkyl is optionally substituted by m R ₇ .

In some embodiments, each R ₇ in formula (II) is independently selected from hydrogen, -CN, halogen, oxo, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -NR ₁₁ R ₁₂ , -OR ₁₃ , -(CO)OR ₁₄ , -(CO)NR ₁₅ R ₁₆ or C ₆ -C ₁₀ aryl; the C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl is optionally substituted by hydrogen, -CN, halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy.

-Ph、

In some embodiments, each R ₇ in formula (II) is independently selected from hydrogen, -CN, -F, -Cl, -Br, oxo, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CH ₂ F, -CH ₂ CHF ₂ , -CHFCH ₃ , -CHFCH ₂ CH _3. -CF ₂ CH ₂ CH ₃ , -NH ₂ , -OCH ₃ , -OH, -COOH, -COCH ₃ , -COOCH 3 , -CONHCH _{3 ,} -CON(CH ₃ ) ₂ ,

-Ph,

-OCH ₂CH ₃、

-CH ₂OCH ₃、

In some embodiments, R in formula (II) is selected from -CH ₃ , -CN,

-OCH ₂ CH ₃ ,

-CH ₂ OCH ₃ ,

In some embodiments, the compound represented by formula (I), or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug selection Since formula (III):

in,

R is selected from -CN, C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, 3-12 membered heterocyclyl, C ₆ - C ₁₂ aryl, 5-12 membered heteroaryl; said C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, 3- 12-membered heterocyclic group, C ₆ -C ₁₂ aryl group, 5-12 membered heteroaryl group are optionally substituted by m R ₇ ;

Each R ₇ is independently selected from hydrogen, deuterium, -CN, halogen, oxo, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ Alkynyl, -NR ₁₁ R ₁₂ , -OR ₁₃ , -(CO)OR ₁₄ , -(CO)NR ₁₅ R ₁₆ , -(CO)R ₁₇ , 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl base, 5-10 membered heteroaryl, C ₃ -C ₆ alkenylalkyl or C ₃ -C ₁₀ alkynylalkyl; said C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₃ -C ₆ alkenylalkyl or C ₃ -C ₁₀ alkynylalkyl is optionally substituted by one or more hydrogen, -CN, halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy;

Each R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ is independently selected from hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ Halocycloalkyl, 3-10 membered heterocyclyl, C ₃ -C ₆ alkenyl alkyl or C ₃ -C ₁₀ alkynyl alkyl;

m is selected from any integer of 1-8.

In some embodiments, R in formula (III) is selected from -CN, C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkynyl, -OR ₁₀ , C ₃ -C ₁₂ cycloalkyl, 3-12 membered Heterocyclyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl; said C ₁ -C ₁₀ alkyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₂ cycloalkyl, 3-12 Membered heterocyclyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl are optionally substituted by m R ₇ .

In some embodiments, R in formula (III) is selected from C ₁ -C ₁₀ alkyl; said C ₁ -C ₁₀ alkyl is optionally substituted by m R ₇ .

In some embodiments, R in formula (III) is selected from C ₃ -C ₁₂ cycloalkyl; said C ₃ -C ₁₂ cycloalkyl is optionally substituted by m R ₇ .

In some embodiments, each R ₇ in formula (III) is independently selected from hydrogen, -CN, halogen, oxo, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, -NR ₁₁ R ₁₂ , -OR ₁₃ , -(CO)OR ₁₄ , -(CO)NR ₁₅ R ₁₆ or C ₆ -C ₁₀ aryl; the C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl is optionally substituted by hydrogen, -CN, halogen, hydroxyl, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy.

-Ph或

In some embodiments, each R ₇ in formula (III) is independently selected from hydrogen, -CN, -F, -Cl, -Br, oxo, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ F, -CHF ₂ , -CF ₃ , -NH ₂ , -OCH ₃ , -OH, -COOH, -COOCH ₃ , -CONHCH ₃ , CON(CH ₃ ) ₂ ,

-Ph or

-OCH ₂CH ₃、

-CH ₂OCH ₃、

In some embodiments, R in formula (III) is selected from -CH ₃ , -CN,

-OCH ₂ CH ₃ ,

-CH ₂ OCH ₃ ,

In some embodiments, the compound represented by formula (I), or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug selection Since formula (IV):

The present invention further provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

6-(prop-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine- 2,4-diamine;

4-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-methylbutyl -3-yn-2-ol;

4-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)but-3-yne- 1-alcohol;

6-(3,3-Dimethylbut-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1, 3,5-triazine-2,4-diamine;

3-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)ethynyl)oxetane Butan-3-ol;

1-((4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)acetylene)cyclopropane- 1-alcohol;

6-(oxetan-3-ylacetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine- 2,4-diamine;

6-(azetidin-3-ylacetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine- 2,4-diamine;

6-(3,4,4,4-tetrafluoro-3-(trifluoromethyl)but-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1 -trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine;

1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)ethynyl)cyclobutane- 1-alcohol;

5-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2-methylpentane -4-yn-2-ol;

6-(cyclopropylacetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4- Diamine;

6-(cyclobutylacetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-di amine;

6-(Phenylacetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine ;

6-((1H-pyrazol-4-yl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-tri Oxyzine-2,4-diamine;

6-((3-methyloxetan-3-yl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3 ,5-triazine-2,4-diamine;

6-(cyclopentylacetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-di amine;

3-(4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)propionitrile;

6-(3-methoxyprop-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3, 5-triazine-2,4-diamine;

6-((1-methoxycyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5- Triazine-2,4-diamine;

6-(pyridin-2-ylacetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4 - diamines;

1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)acetylene)cyclohexyl- 1-alcohol;

6-(thiophen-2-ylacetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4 - diamines;

6-(Cyclohexylacetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine ;

6-((4-chlorophenyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2 ,4-diamine;

6-(3-aminobut-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5- Triazine-2,4-diamine;

6-(3,3-Dimethylbut-1-yn-1-yl)-N ² ,N ⁴ -bis(2,2,2-trifluoroethyl)-1,3,5-triazine- 2,4-diamine;

6-(3-methoxy-3-methylbut-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl) -1,3,5-triazine-2,4-diamine;

6-(3-Methylbut-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5 - Triazine-2,4-diamine;

6-(4-Methylpent-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5 - Triazine-2,4-diamine;

6-(3-fluoro-3-methylbut-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine;

6-((1-methylcyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine -2,4-diamine;

6-((1-aminocyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine- 2,4-diamine;

6-((1-(trifluoromethyl)cyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3, 5-triazine-2,4-diamine;

6-((2,2-difluoro-1-methylcyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1 ,3,5-triazine-2,4-diamine;

1-((4,6-bis(((R)-1,1,1-trifluoroprop-2-yl)amino)-1,3,5-triazin-2-yl)acetylene)cyclopropane- 1-nitrile;

6-((2,2-difluoro-1-methylcyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1 ,3,5-triazine-2,4-diamine;

6-((2-methylcyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine -2,4-diamine;

6-((2,2-difluorocyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5- Triazine-2,4-diamine;

6-((2-fluorocyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine- 2,4-diamine;

6-((3,3-difluorocyclobutyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5- Triazine-2,4-diamine;

6-((1-(trifluoromethyl)cyclobutyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3, 5-triazine-2,4-diamine;

6-((3-fluorocyclobutyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine- 2,4-diamine;

6-((3-fluorocyclobutyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine- 2,4-diamine;

6-((3-fluorobicyclo[1.1.1]pent-1-yl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1 ,3,5-triazine-2,4-diamine;

4-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,2-di Methylbut-3-yn-1-ol;

6-(4-fluoro-3,3-dimethylbut-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl )-1,3,5-triazine-2,4-diamine;

6-(3,3-Dimethylpent-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1, 3,5-triazine-2,4-diamine;

N ² , N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-6-(3,3,4-trimethylpent-1-yn-1-yl)- 1,3,5-triazine-2,4-diamine;

6-((1-(methoxymethyl)cyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1, 3,5-triazine-2,4-diamine;

6-(But-1,3-diyn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5- Triazine-2,4-diamine;

6-((1-fluorocyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine -2,4-diamine;

4-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-1,1,1 - Trifluoro-2-methylbut-3-yn-2-ol;

4-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-1,1,1 - Trifluoro-2-(trifluoromethyl)but-3-yn-2-ol;

1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)ethynyl)cyclobutane Base-1-ol;

1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)ethynyl)cyclopenta Base-1-ol;

6-((1-fluorocyclobutyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine -2,4-diamine;

6-((1-fluorocyclopentyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine -2,4-diamine;

4-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,2-di Methylbut-3-ynecarboxylic acid;

Methyl 4-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2,2 - methyl dimethylbut-3-ynoate;

4-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-N,2,2 - Trimethylbut-3-yneamide;

4-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-N,N,2 ,2-Tetramethylbut-3-yneamide;

6-((2,2-Dimethylcyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3, 5-triazine-2,4-diamine;

6-(4,4,4-trifluoro-3,3-dimethylbut-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoro Propan-2-yl)-1,3,5-triazine-2,4-diamine;

6-(4,4,4-Trifluoro-3-methyl-3-(trifluoromethyl)but-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1, 1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine;

6-((1-ethylcyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-tri Oxyzine-2,4-diamine;

6-(3,3-Dimethylbut-1-yn-1-yl)-N ² ,N ⁴ -diisopropyl-1,3,5-triazine-2,4-diamine;

6-((1-isopropylcyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5- Triazine-2,4-diamine;

(1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)ethynyl)ring Propyl) Methanol;

6-((1-(fluoromethyl)cyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3, 5-triazine-2,4-diamine;

6-((1-(Difluoromethyl)cyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3 ,5-triazine-2,4-diamine;

6-((1-phenylcyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-tri Oxyzine-2,4-diamine;

6-((1-phenylcyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-tri Oxyzine-2,4-diamine;

6-((1-cyclobutylcyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine -2,4-diamine;

6-((1-(3,3-difluorocyclobutyl)cyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl )-1,3,5-triazine-2,4-diamine;

(R)-6-(3,3-Dimethylbutyl-1-yn-1-yl)-N ² -isopropyl-N ⁴ -(1,1,1-trifluoropropyl-2- base)-1,3,5-triazine-2,4-diamine;

6-((1-methylcyclobutyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-tri Oxyzine-2,4-diamine;

(R)-6-(3,3-Dimethylbut-1-yn-1-yl)-N ² -(2,2,2-trifluoroethyl)-N ⁴ -(1,1,1 -trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine;

(R)-N ² -([1,1'-bis(cyclopropyl)]-1-yl)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ⁴ - (1,1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine;

N ² , N ⁴ -bis(R)-1-cyclopropylethyl)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-1,3,5-triazine-2 ,4-diamine;

6-((1-(Difluoromethyl)cyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroisopropan-2-yl)-1,3 ,5-triazine-2,4-diamine;

N ² -((R)-1-cyclopropylethyl)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ⁴ -((R)-1,1,1 -trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine;

(R)-N ² -(3,3-difluorocyclobutyl)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ⁴ -(1,1,1-tri Fluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine;

6-(3,3-Dimethylbutyl-1-yn-1-yl)-N ² ,N ⁴ -bis(2,2,2-trifluoroethyl)-1,3,5-triazine -2,4-diamine;

6-(3-methoxy-3-methylbutyl-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropyl-2- base)-1,3,5-triazine-2,4-diamine;

6-((1-(2-fluoroethyl)cyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3 ,5-triazine-2,4-diamine;

6-((1-(2,2-difluoroethyl)cyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)- 1,3,5-triazine-2,4-diamine;

6-(((3R,5R,7R)-adamantan-1-yl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)- 1,3,5-triazine-2,4-diamine;

6-([1,1'-bis(cyclopropane)]-1-ylethynyl)-N ² ,N ⁴ -bis((R))-1,1,1-trifluoropropan-2-yl) -1,3,5-triazine-2,4-diamine;

6-((3-fluorofuran-3-yl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5- Triazine-2,4-diamine;

6-(3-Fluoro-3-methylpent-4-1-en-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropane-2- Base)-1,3,5-triazine-2,4-diamine 5-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amine)-1 ,3,5-triazin-2-yl)-3-methyl-1-ene-4-yne-3-pentanol;

N ² , N ⁴ -bis((R)-1-cyclopropylethyl)-6-(3,3-dimethylbut-1-yn-1-yl)-1,3,5-triazine -2,4-diamine;

N ² , N ⁴ -bis(3,3-difluorocyclobutyl)-6-(3,3-dimethylbut-1-yn-1-yl)-1,3,5-triazine-2 ,4-diamine;

N ² , N ⁴ -bis((R)-1-cyclopropyl)-6-((1-ethylcyclopropyl)acetylene)-1,3,5-triazine-2,4-diamine;

6-((1-(1-fluoropropyl)cyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3 ,5-triazine-2,4-diamine;

6-((1-(1,1-dicyclopropyl)cyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)- 1,3,5-triazine-2,4-diamine;

2-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopentanol ;

6-((2-fluorocyclopentyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-triazine- 2,4-diamine;

6-(3-Ethyl-3-fluoropent-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1 ,3,5-triazine-2,4-diamine;

6-((1-(1-fluoroethyl)cyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3 ,5-triazine-2,4-diamine;

6-((1-(1-fluoropropynyl)cyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1, 3,5-triazine-2,4-diamine;

2-(1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)acetylene) Cyclopropyl) isopropanol;

1-(1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl ) cyclopropyl) ethanol;

1-(1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl )cyclopropyl)-2,2,2-trifluoroethyl-1-alcohol;

1-(1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl ) cyclopropyl) ethyl ketone;

(R)-N ² -(3,3-difluorocyclobutyl)-6-(3,3-dimethylbut-1-yn-1-yl)-N ⁴ -(1,1,1- Trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine;

(R)-6-((1-(Difluoromethyl)cyclopropyl)acetylene)-N ² -isopropyl-N ⁴ -(1,1,1-trifluoroprop-2-yl)-1 ,3,5-triazine-2,4-diamine;

(R)-(1-((4-((3,3-difluorocyclobutyl)amine)-6-((1,1,1-trifluoropropyl)amine)-1,3,5- Triazinyl)ethynyl)methanol;

N ² , N ⁴ -bis(3,3-difluorocyclobutyl)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-1,3,5-triazine-2, 4-diamine;

(R)-N ² -cyclopropyl-6-((1-(difluoromethyl)cyclopropyl)acetylene)-N ⁴ -(1,1,1-trifluoropropyl-2-yl)- 1,3,5-triazine-2,4-diamine;

(R)-6-((1-(Difluoromethyl)cyclopropyl)acetylene)-N ² -(1-methylcyclopropyl)-N ⁴ –(1,1,1-trifluoropropyl -2-yl)-1,3,5-triazine-2,4-diamine;

(R)-1-((4-((1-difluoromethyl)cyclopropyl)ethynyl)-6-(1,1,1-trifluoropropan-2-yl)amine)cyclopropyl- 1-cyano;

6-((1-(Difluoromethyl)cyclopropyl)acetylene)-N ² -(1,1-difluoropropyl)-N ⁴ -(R)-1,1,1-trifluoropropyl )-1,3,5-triazine-2,4-diamine;

N ² -(3,3-difluorobutyl-6-((1-(difluoromethyl)cyclopropyl)acetylene)-N ⁴ -(R)-1,1,1-trifluoropropyl) -1,3,5-triazine-2,4-diamine;

6-((1-(Difluoromethyl)cyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-N ⁴ - ((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine;

(R)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ² -propyl-N ⁴ -(1,1,1-trifluoroprop-2-yl)-1 ,3,5-triazine-2,4-diamine;

(R)-N ² -butyl-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ⁴ -(1,1,1-trifluoroprop-2-yl)-1 ,3,5-triazine-2,4-diamine;

(R)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ² -(1,1,1-trifluoroprop-2-yl-N ⁴ -(3,3, 3-trifluoropropyl)-1,3,5-triazine-2,4-diamine;

(R)-N ² -(cyclopropylmethyl)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ⁴ -(1,1,1-trifluoropropane-2 -yl)-1,3,5-triazine-2,4-diamine;

(R)-6-((1-(Difluoromethyl)cyclopropyl)ethynyl)-N ² -(2-methylethyl)-N ⁴ -(1,1,1-trifluoropropane- 2-yl)-1,3,5-triazine-2,4-diamine;

(R)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ² -(2,2-difluoropropyl)-N ⁴ -(1,1,1-trifluoro Propan-2-yl)-1,3,5-triazine-2,4-diamine;

(1-((4,6-bis(((R)-1-cyclopropylethyl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol;

6-((1-propenylcyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3,5-tri Oxyzine-2,4-diamine;

(R)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ² -(1,3-difluoropropane2-yl)-N ⁴ -(1,1,1- Trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine; or

6-((1-(Difluoromethyl)cyclopropyl)ethynyl)-N ² -(1-fluoroprop-2-yl)-N ⁴ -((R)-1,1,1-trifluoro Propan-2-yl)-1,3,5-triazine-2,4-diamine.

The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of at least one compound mentioned above and at least one pharmaceutically acceptable auxiliary material.

The present invention provides the application of the compound represented by the structural formula (I) or the pharmaceutical composition in the preparation of medicine.

The present invention further provides the preferred technical scheme of said application:

Preferably, the application is treating, preventing, delaying or arresting the occurrence or progression of cancer or cancer metastasis.

Preferably, the application is used for treating diseases mediated by mutant IDH1 and IDH2.

Preferably, said disease is cancer.

Preferably, the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, lung cancer, breast cancer, sarcoma, glioma, glioblastoma multiforme, acute myeloid leukemia, non-Hodgkin Lymphoma etc. In specific embodiments, the cancer to be treated is glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML) , sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic lymphoma. In a more specific embodiment, the cancer to be treated is glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML ), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin's lymphoma (NHL).

Preferably, the application is as an inhibitor of mutant IDH1 and IDH2.

The present invention also provides a method for treating and/or preventing diseases mediated by IDH1 and IDH2 by administering a therapeutically effective amount of at least one compound or pharmaceutical composition represented by structural formula (I) to a subject.

Preferably, in the above method, the disease mediated by IDH1 and IDH2 is cancer.

The present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least one compound or pharmaceutical composition represented by the structural formula (I) to the subject. In some embodiments, the present invention relates to a method of treating cancer characterized by the presence of mutant IDH1 and IDH2, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound represented by general formula I or an isomer thereof, A pharmaceutically acceptable salt, crystal, solvate or prodrug, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, lung cancer, breast cancer, sarcoma, nerve Glioma, glioblastoma multiforme, acute myeloid leukemia, non-Hodgkin's lymphoma, etc.

Preferably, in the above method, the treatment object is human.

definition

The general chemical terms used in the above general structural formulas have their usual meanings.

For example, the terms "halo" and "halogen" as used herein refer to fluorine, chlorine, bromine or iodine, unless otherwise specified. Preferred halo groups include fluorine, chlorine and bromine.

In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. Alkyl groups as used herein may be optionally substituted with one or more substituents. Non-limiting examples of alkyl groups include, for example, alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-( 2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and the like. Similarly, "C _1-8 " in "C _1-8 alkyl" refers to a straight chain or branched chain arrangement containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms group.

Alkenyl and alkynyl groups include straight or branched chain alkenyl and alkynyl groups. Similarly, "C _2-8 alkenyl" and "C _2-8 alkynyl" refer to alkenyl groups containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight or branched chain or alkynyl.

"Haloalkyl" means that the aforementioned linear or branched alkyl is substituted by one or more halogens.

"Alkoxy" refers to the oxygen ether form of the aforementioned linear or branched alkyl, ie -O-alkyl.

In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient may be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.

The term "aromatic ring", in the present invention, unless otherwise stated, refers to an unsubstituted or substituted monocyclic, fused or condensed ring aromatic group including carbon atoms, or an unsubstituted or substituted heteroatom, for example N, O or S monocyclic, parallel ring or condensed ring aromatic group, when it is a parallel ring or condensed ring, at least one ring has aromaticity. Preferably, the aromatic ring is a 5- to 10-membered monocyclic or bicyclic aromatic ring group. Examples of such aromatic rings include, but are not limited to, phenyl, pyridyl, pyrazolyl, pyrimidinyl, chroman, indolyl.

The term "cycloalkyl" refers to monocyclic and polycyclic ring systems containing only carbon atoms in the ring and which may be optionally substituted with one or more substituents. Cycloalkyl as used herein refers to and includes saturated or unsaturated non-aromatic ring systems. The term cycloalkyl additionally includes bridged, fused and spiro ring systems. Non-limiting examples of cycloalkyl include, eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, spiro[3.4]octyl, bicyclo[2.2.1]heptane, and the like.

The term "heterocyclyl", in the present invention, unless otherwise stated, refers to unsubstituted or substituted monocyclic and polycyclic ring systems consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S , and includes saturated or unsaturated ring systems as well as polycyclic ring systems having unsaturated and/or aromatic moieties. Wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized. The heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure. It should be understood that polycyclic heterocycloalkyl groups additionally include fused, bridged and spiro ring systems. A heterocycloalkyl group as used herein may be optionally substituted with one or more substituents. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro Oxadiazolyl.

As used herein, unless otherwise indicated, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing carbon ring atoms, at least one ring being aromatic. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl is phenyl.

The term "heteroaryl", in the present invention, unless otherwise stated, refers to an unsubstituted or substituted stable 5-membered or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-membered or 10-membered benzo A fused heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms can optionally be replaced by Oxygenated, the nitrogen heteroatoms can optionally be quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl, Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzotriazolyladenine, quinolinyl or isoquinolinyl.

The term "substituted" means that one or more hydrogen atoms in the group are respectively replaced by the same or different substituents. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), C _1-8 alkyl, C _{3- 12} cycloalkyl, -OR ₁ , -SR ₁ , =O, =S, -C (O)R ₁ , -C(S)R ₁ , =NR ₁ , -C(O)OR ₁ , -C(S)OR ₁ , -NR ₁ R ₂ , -C(O)NR ₁ R ₂ , Cyano, Nitro, -S(O) ₂ R ₁ , -OS(O ₂ )OR ₁ , -OS(O) ₂ R ₁ , -OP(O)(OR ₁ )(OR ₂ ); where R ₁ and R ₂ are independently selected from -H, C _1-6 alkyl, C _1-6 haloalkyl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy Butyl, isobutoxy, tert-butoxy, -SCH ₃ , -SC ₂ H ₅ , formaldehyde, -C(OCH ₃ ), cyano, nitro, -CF ₃ , -OCF ₃ , amino, dimethyl Amino, methylthio, sulfonyl and acetyl groups.

Examples of substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.

Examples of substituted alkoxy include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.

When the compound provided by the present invention is a base, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.

Since the compound shown in formula (I) will be used as a medicine, preferably, a certain purity is used, for example, at least 60% purity, more suitable purity is at least 75%, particularly suitable purity is at least 98% (% is weight) Compare).

The prodrugs of the compounds of the present invention are included in the protection scope of the present invention. In general, the prodrugs refer to functional derivatives that are readily converted in vivo into the desired compound. For example, any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application, which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite or Residues. Particularly preferred derivatives or prodrugs are those compounds which, when administered to a patient, increase the bioavailability of the compounds of the present application (e.g., allow an orally administered compound to be more readily absorbed into the blood), or promote the delivery of the parent compound to a biological organ or Those compounds delivered at a site of action such as the brain or lymphatic system. Therefore, the term "administering" in the treatment methods provided by the present invention refers to the administration of the compounds disclosed in the present invention that can treat different diseases, or the compounds disclosed in the present invention, although not explicitly disclosed, can be converted into compounds disclosed in the present invention after administration to the subject. compounds of compounds. Routine methods for selecting and preparing suitable prodrug derivatives are described, for example, in such books as Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

Clearly, any substituent or variable at a particular position in a molecule is defined independently of other positions in the molecule. It is easy to understand that those skilled in the art can select the substituents or substitution forms of the compounds in the present invention through prior art means and the methods described in the present invention, so as to obtain chemically stable and easy-to-synthesize compounds.

The compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and optical isomers. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

The above formula (I) does not exactly define the three-dimensional structure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula (I) and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During the synthesis of such compounds, or using racemization or epimerization procedures well known to those skilled in the art, the products obtained may be mixtures of stereoisomers.

When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and their mixtures.

When the compound represented by formula (I) and its pharmaceutically acceptable salts have solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming a solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.

The term "composition", in the present invention, is meant to include products comprising the specified amounts of each of the specified ingredients, as well as any product produced directly or indirectly from the combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients as well as processes for the preparation of the compounds of the invention are also part of the invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of the present invention.

The pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories. Although the most suitable mode of administration of the active ingredient in any given case depends on the particular subject to be administered, the nature of the subject and the severity of the condition, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical compositions of the present invention may conveniently be presented in unit dosage forms and prepared by any methods of preparation well known in the art of pharmacy.

In fact, according to conventional drug mixing techniques, the compound represented by formula (I) of the present invention, or drug prodrugs, or metabolites, or pharmaceutically acceptable salts, can be used as active components and mixed with drug carriers to form a drug combination thing. The pharmaceutical carrier can take a wide variety of forms depending on the mode of administration desired, for example, oral or parenteral (including intravenous). Accordingly, the pharmaceutical compositions of the present invention may be presented as discrete units suitable for oral administration such as capsules, cachets or tablets containing predetermined doses of the active ingredient. Furthermore, the pharmaceutical composition of the present invention may be in the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered by controlled release and/or delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. In general, such methods include a step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions are prepared by uniform and intimate admixture of the active ingredient with liquid carriers or finely divided solid carriers or a mixture of both. In addition, the product can be easily prepared to a desired appearance.

Therefore, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and the compound shown in formula (I) or its stereoisomer, tautomer, polymorph, solvate, its pharmaceutically acceptable Salts, their prodrugs. The combination of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and one or more other therapeutically active compounds is also included in the pharmaceutical composition of the present invention.

The pharmaceutical carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gaseous carrier. Solid carriers include, but are not limited to, lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid. Liquid carriers include, but are not limited to, syrup, peanut oil, olive oil and water. Gas carriers include, but are not limited to, carbon dioxide and nitrogen. For the preparation of pharmaceutical oral preparations, any pharmaceutically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used in oral liquid preparations such as suspensions, elixirs, and solutions; and carriers, such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like can be used in oral solid preparations such as powders, capsules and tablets. Considering ease of administration, tablets and capsules are preferred for oral formulations, where solid pharmaceutical carriers are used. Alternatively, tablets may be coated using standard aqueous or non-aqueous formulation techniques.

Tablets containing a compound of this invention or a pharmaceutical composition may be formed by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be obtained by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be obtained by moistening the powdered compound or pharmaceutical composition with an inert liquid diluent and then molding in a suitable machine.

The pharmaceutical composition suitable for parenteral administration provided by the present invention can be prepared by adding the active component into water to prepare an aqueous solution or suspension. Suitable surfactants such as hydroxypropylcellulose may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, preservatives may also be included in the pharmaceutical composition of the present invention to prevent the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems. Furthermore, the above pharmaceutical composition can be prepared in the form of sterile powder for immediate preparation of sterile injection or dispersion. In any event, the final injectable form must be sterile and, for easy syringability, must be fluid. Furthermore, the pharmaceutical composition must be stable during manufacture and storage. Thus, preferably, the pharmaceutical composition is preserved against contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention can be in a form suitable for topical administration, for example, aerosol, cream, ointment, lotion, dusting powder or other similar dosage forms. Furthermore, the pharmaceutical composition provided by the present invention can be in a form suitable for use in transdermal drug delivery devices. These preparations can be prepared by using the compound represented by formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, by conventional processing methods. As an example, a cream or ointment is prepared with the desired consistency by adding about 5% to 10% by weight of the hydrophilic material and water.

The pharmaceutical composition provided by the invention may be in a form suitable for rectal administration with solid as carrier. Unit dose suppositories are the most typical dosage form. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories are conveniently prepared by first mixing the pharmaceutical composition with softened or melted excipients, followed by cooling and moulding.

In addition to the adjuvant components mentioned above, the formulation of the above preparation may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, Thickeners, lubricants and preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that adjust the isotonic pressure between the drug and the blood. The pharmaceutical composition comprising the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, can be prepared in the form of powder or concentrated solution.

However, it will be appreciated that lower or higher dosages than those recited above may be required. The specific dosage level and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combinations condition and the severity of the particular disease being treated.

Detailed ways

In order to make the above content more clear and definite, the present invention will use the following examples to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the protection scope of the present invention. In the specific embodiment of the present invention, the technical means or methods, etc. that are not specifically described are conventional technical means or methods in the art, and the used raw materials, reagents, etc. are all commercially available products.

Unless otherwise indicated, all parts and percentages herein are by weight and all temperatures are in degrees Celsius.

The following abbreviations are used in the examples:

Pd(dppf)Cl ₂ .CH ₂ Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex;

DMF: N,N-dimethylformamide;

DMSO: dimethyl sulfoxide;

EA: ethyl acetate;

THF: Tetrahydrofuran;

AsPh ₃ : triphenylarsenic;

n-Bu: n-butyl;

DIEA: Diisopropylethylamine;

DAST: diethylaminosulfur trifluoride;

TBAF: Tetrabutylammonium fluoride;

α-KG: α-ketoglutarate;

2-HG: 2-hydroxyglutarate;

LC-MS or LCMS: Liquid Chromatography-Mass Spectrometry.

Example 1: 6-(prop-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5 - Preparation of triazine-2,4-diamine

Step 1: Intermediate 6-chloro-N,N-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine ( Preparation of Int-1)

A mixture of cyanuric chloride (18.4g, 0.1mol), (R)-1,1,1-trifluoroisopropylamine hydrochloride (29.9g, 0.2mol) and 1,4-dioxane (200mL) , DIEA (100 mL, 0.6 mol) was slowly added dropwise with stirring in an ice bath. After the dropwise addition, the reaction system was naturally warmed up to room temperature, continued to stir for 30 min, and then heated to 80 ^o C and continued to stir for 2 h. The completion of the reaction was monitored by TLC, the reaction mixture was concentrated under reduced pressure, and the concentrated residue was purified by column chromatography (ethyl acetate: n-hexane = 5% to 10%) to obtain compound Int-1 (26.5g, 78.5%), white to light yellow solid.

LCMS [M+H ⁺ ] 338.05.

Step 2: 6-(prop-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)-1,3,5- Preparation of Triazine-2,4-Diamine (Compound 1)

Under nitrogen protection, the intermediate Int-1 (0.03g, 0.09mmol), tributyl propargyl stannane (0.06g, 0.18mmol), triphenylarsenic (0.05g, 0.18mmol) and 3mL 1,4-bis The mixture of oxane was heated at 100 ^o C for 4 hours. After the reaction was completed, the reaction mixture was quenched with water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by Prep-TLC (n-hexane:ethyl acetate=10:1) to obtain compound 1 (3 mg, 9.9%) as an off-white solid.

LCMS [M+H ⁺ ] 342.11.

Example 2: 4-(4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amino)-1,3,5-triazin-2-yl)-2 - Preparation of methylbut-3-yn-2-ol

Under the protection of nitrogen, the intermediate compound Int-1 (0.1g, 0.3mmol), 2-methyl-3-butyn-2-ol (0.05g, 0.59mmol), CuI (0.01g, 0.06mmol), Pd ( A mixture of PPh ₃ ) ₂ Cl ₂ (0.02 g, 0.03 mmol), TEA (0.13 mL, 0.9 mmol) and DMF (2 mL) was stirred at 80 ^o C for 2 hours. After the reaction was completed, the reaction system was diluted with water, extracted twice with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by PrepTLC (n-hexane:ethyl acetate=10:1) to obtain compound 2 (72 mg, 63.1%) as a white solid.

LCMS [M+H ⁺ ] 386.13.

¹ H NMR (500 MHz, CD ₃ OD) δ 5.01-4.88 (m, 2H), 1.60-1.52 (m, 6H), 1.40-1.32 (m, 6H).

Example 4: 6-(3,3-Dimethylbut-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl )-1,3,5-triazine-2,4-diamine preparation

Under nitrogen protection, the intermediate Int-1 (0.05g, 0.15mmol), 3,3-dimethyl-1-butyne (0.024g, 0.3mmol), CuI (0.01g, 0.03mmol), Pd (PPh ₃ ) ₂ Cl ₂ (0.02g, 0.015mmol), TEA (0.045, 0.45mmol) and DMF (2mL) were stirred at 70 ^o C for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, the reaction mixture was diluted with water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with aqueous sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-TLC (n-hexane:ethyl acetate=10:1), and then prepared by Prep-HPLC to obtain compound 4 (24 mg, 42.3%) as a white solid.

LCMS [M+H ⁺ ] 384.15.

¹ H NMR (500 MHz, CD ₃ OD) δ 5.01 - 4.88 (m, 2H), 1.40 - 1.18 (m, 15H).

Example 31: 6-(3-Fluoro-3-methylbut-1-yn-1-yl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2- Preparation of base)-1,3,5-triazine-2,4-diamine

Under ice-water bath cooling, DAST (0.05 g, 0.34 mmol) was added dropwise to a solution of compound 2 (0.064 g, 0.17 mmol) in DCM (2 mL). After the dropwise addition was completed, the reaction solution was warmed up to room temperature, and the stirring reaction was continued for 30 min. After the reaction was completed, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution dropwise under cooling in an ice-water bath, extracted with dichloromethane, and the organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep_TLC (n-hexane:ethyl acetate=10:1) to obtain compound 31 (19.7 mg, 30.6%) as a white solid.

LCMS [M+H ⁺ ] 388.10.

Example 32: 6-((1-methylcyclopropyl)acetylene)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoroprop-2-yl)-1,3, Preparation of 5-triazine-2,4-diamine

Under the protection of nitrogen, the intermediate compound Int-1 (0.2g, 0.59mmol), CuI (0.023g, 0.12mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.042g, 0.06mmol), TEA (0.3mL, 1.77mmol ), TBAF (0.5mL, 1M in THF), a mixture of (1-methylcyclopropyl)ethynyl)trimethylsilane (0.3g, 1.77mmol) and DMF (2mL) was stirred at 90°C for reaction 2 Hour. After the reaction was completed, cool down to room temperature, dilute the reaction system with water, extract twice with ethyl acetate, wash the organic phase with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by Prep-TLC (n-hexane:ethyl acetate=10:1) to obtain compound 32 (8 mg, 3.5%) as a white solid.

LCMS [M+H ⁺ ] 382.14.

Example 123: (1-((4,6-bis(((R)-1-cyclopropylethyl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl ) Methanol

Step 1: Preparation of intermediate 6-chloro-N,N-bis[(R)-cyclopropan-2-yl]-1,3,5-triazine-2,4-diamine (Int-2)

A mixture of cyanuric chloride (2.0g, 10.85mmol), (R)-cyclopropylethylamine hydrochloride (2.77g, 22.78mmol) and 1,4-dioxane (60mL) was slowly dropped in an ice bath Add DIEA (8.96 mL, 54.23 mmol). After the dropwise addition, the reaction system was naturally warmed up to room temperature, continued to stir for 1 h, and then heated to 60° C. and continued to stir for 1 h. The completion of the reaction was monitored by TLC, the reaction was cooled to room temperature, poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was spin-dried. The concentrated residue was purified by column chromatography (ethyl acetate: n-hexane = 0%-20%) to obtain compound Int-2 (2.76 g, 90.3%), a white to pale yellow solid.

LCMS[M+H ⁺ ]282.14

Step 2: (1-((4,6-bis(((R)-1-cyclopropylethyl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl) Preparation of Methanol

Under the protection of nitrogen, the intermediate compound Int-2 (2.76g, 9.79mmol), (1-ethynylcyclopropyl) methanol (1.13g, 11.75mmol),) CuI (0.37g, 1.96mmol), Pd (PPh ₃ ) ₂ Cl ₂ (0.69 g, 0.98 mmol), TEA (4.08 mL, 29.38 mmol) and DMF (40 mL) were stirred at 60° C. overnight. After the reaction was completed, the reaction system was diluted with water, washed with ethyl acetate (60mL x 4), saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the concentrated residue was purified by column chromatography (ethyl acetate: n-hexane = 0%-75%) to obtain compound 123 (2.76 g, 82.5%) as a yellow solid.

LCMS [M+H ⁺ ] 342.22.

Example 80: N ² ,N ⁴ -bis((R)-1-cyclopropylethyl)-6-((1-(difluoromethyl)cyclopropyl)acetylene)-1,3,5- Triazine-2,4-diamine

Step 1: (1-((4,6-bis(((R)-1-cyclopropylethyl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl) Preparation of formaldehyde

Compound (1-((4,6-bis(((R)-1-cyclopropylethyl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol ( 2.76 g, 8.08 mmol) was dissolved in DCM (100 mL). Dess-Matin (4.11 g, 9.70 mmol) was added to the above solution under ice cooling and stirred overnight at room temperature. After the completion of the reaction monitored by LCMS, saturated sodium thiosulfate solution and saturated sodium bicarbonate solution were added to the reaction solution, and stirred for 20 min. The organic phase was separated, the aqueous DCM was extracted twice, the organic phases were combined, dried, and spin-dried to obtain compound (1-((4,6-bis(((R)-1-cyclopropylethyl)amine)-1, 3,5-Triazin-2-yl)ethynyl)cyclopropyl)carbaldehyde (2.57 g, crude product) was used directly in the next step. LCMS[M+H ⁺ ]340.21

Step 2: N ² , N ⁴ -bis((R)-1-cyclopropylethyl)-6-((1-(difluoromethyl)cyclopropyl)acetylene)-1,3,5-tri Preparation of oxazine-2,4-diamine

Compound (1-((4,6-bis(((R)-1-cyclopropylethyl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)formaldehyde ( 2.57g, 7.57mmol) was dissolved in 80mL of dichloromethane, and DAST (7.32g, 45.43mmol) was added dropwise under ice bath. Stir at room temperature for 2h. After the reaction was completed, the excess DAST was spun out, the residue was dissolved in DCM, and saturated aqueous sodium bicarbonate solution was slowly added dropwise until neutral. The organic phase was separated, the aqueous phase was extracted three times with DCM, and the combined organic phase was spin-dried. The crude product was purified by column chromatography (ethyl acetate:n-hexane=0%-40%) to obtain the target compound 80 (1.18g, 43.1%) as a light yellow solid.

LCMS[M+H ⁺ ]362.21

¹ H NMR (500MHz, DMSO-d ₆ )δ7.48–7.22(m,2H),5.74(td,J＝55.3,13.1Hz,1H),3.43(m,2H),1.27–1.06(m,10H ),0.94–0.84(m,2H),0.42-0.36(m,2H),0.35-0.23(m 4H),0.16-0.07(m,2H).

Example 81: 6-((1-(Difluoromethyl)cyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl) - Preparation of 1,3,5-triazine-2,4-diamine

Step 1: (1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)acetylene Base) the preparation of cyclopropyl) methanol

Referring to the operation method of step 2 of Example 123, (1-((4,6-bis(((R)-1,1,1-trifluoropropane- 2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol (2.0 g, 68%) as a white solid.

LCMS[M+H ⁺ ]398.33

Step 2: (1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)acetylene Base) the preparation of cyclopropyl) formaldehyde

Referring to the operation method of step 1 of Example 80, (1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5- Triazin-2-yl)ethynyl)cyclopropyl)methanol (2.0g, 5.04mmol) was used as starting material to synthesize (1-((4,6-bis(((R)-1,1,1-trifluoro Propan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)carbaldehyde to obtain 1.5 g of brown solid (yield 75%).

LCMS[M+H ⁺ ]396.31

Step 3: 6-((1-(Difluoromethyl)cyclopropyl)ethynyl)-N ² ,N ⁴ -bis((R)-1,1,1-trifluoropropan-2-yl)- Preparation of 1,3,5-triazine-2,4-diamine

Referring to the operation method of step 2 of Example 80, (1-((4,6-bis(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5- Starting from triazin-2-yl)ethynyl)cyclopropyl)carbaldehyde (1.6g, 4.05mmol), compound 81 (1.4g, 82%) was synthesized as a white solid.

LCMS[M+H ⁺ ]418.31

¹ H NMR (500MHz, CDCl ₃ )δ5.88–5.58(m,1H), 4.92-4.82(m,2H), 1.45–1.33(m,6H), 1.26-1.22(m,4H).

Example 83: (R)-N ² -(3,3-difluorocyclobutyl)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ⁴ -(1,1 ,1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine preparation

Step 1: Preparation of (R)-4,6-dichloro-N-(1,1,1-trifluoropropan-2-yl)-1,3,5-triazin-2-amine

A mixture of cyanuric chloride (2.0 g, 10.8 mmol), (R)-1,1,1-trifluoroisopropylamine hydrochloride (1.6 g, 10.8 mmol) and 1,4-dioxane (20 mL) DIEA (5.4 mL, 32.5 mmol) was slowly added dropwise under ice bath. After the dropwise addition, the reaction system was naturally warmed up to room temperature and stirred for 60 min. The completion of the reaction was monitored by TLC, water was added to the reaction liquid, and ethyl acetate extracted three times. The combined organic phases were concentrated under reduced pressure, and the concentrated residue Int-3 (2.7 g, 78.5%) was a brown oil which was directly used in the next step.

LCMS[M+H ⁺ ]260.98

Step 2: (R)-6-Chloro-N ² -(3,3-difluorocyclobutyl)-N ⁴ -(1,1,1-trifluoropropan-2-yl)-1,3,5 - Preparation of triazine-2,4-diamine

DIEA (3.8mL, 22.9mmol) was added to intermediate Int-3 (3.0g, 11.5mmol), difluorocyclobutylamine hydrochloride (1.6g, 11.5mmol) in 1,4-dioxane (30mL) Solution, react at room temperature for 5h. The reaction was monitored by TLC. After the reaction was completed, water was added to the above reaction solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was filtered and spin-dried. The residue was purified by column chromatography (ethyl acetate: n-hexane = 0-30%) to obtain the intermediate Int-4 (3.0 g, 78%) as a brown solid.

LCMS[M+H ⁺ ]332.68

Step 3: (R)-(1-((4-((3,3-difluorocyclobutyl)amine)-6-((1,1,1-trifluoropropan-2-yl)amine)- Preparation of 1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol

Referring to the operation method of step 2 of Example 123, (R)-(1-((4-((3,3-difluorocyclobutyl)amine)- 6-((1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol (2.7 g, 76%), For oil.

LCMS[M+H ⁺ ]392.35

Step 4: (R)-(1-((4-((3,3-difluorocyclobutyl)amine)-6-((1,1,1-trifluoropropan-2-yl)amine)- Preparation of 1,3,5-triazin-2-yl)ethynyl)cyclopropyl)formaldehyde

Referring to the operation method of step 1 of Example 80, with (R)-(1-((4-((3,3-difluorocyclobutyl)amine)-6-((1,1,1-trifluoropropane -2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol (2.7g, 6.9mmol) as starting material, synthesis of (R)-(1-((4 -((3,3-difluorocyclobutyl)amine)-6-((1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl) Ethynyl)cyclopropyl)carbaldehyde (2.6 g, 96%) as a white solid.

LCMS[M+H ⁺ ]390.33

Step 5: (R)-N ² -(3,3-difluorocyclobutyl)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ⁴ -(1,1, Preparation of 1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine

Referring to the operation method of step 2 of Example 80, with (R)-(1-((4-((3,3-difluorocyclobutyl)amine)-6-((1,1,1-trifluoropropane -2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)formaldehyde (2.6g, 6.7mmol) as raw material, compound 83 (1.3g, 47%) was synthesized, It is a white solid.

LCMS[M+H ⁺ ]412.33

¹ H-NMR (500MHz, CD ₃ OD) δ5.84-5.57(m,1H),4.93-4.90(m,1H),4.35-4.21(m,1H),3.0-2.83(m,2H),2.70 -2.47(m,2H),1.39-1.32(m,3H),1.28-1.21(m,4H).

Example 82: N ² -((R)-1-cyclopropylethyl)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ⁴ -((R)-1 , Preparation of 1,1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine

Step 1: 6-Chloro-N ² -((R)-1-cyclopropylethyl)-N ⁴ -((R)-1,1,1-trifluoropropan-2-yl)-1,3 , Preparation of 5-triazine-2,4-diamine

DIEA (3.8mL, 22.9mmol) was added to intermediate Int-3 (3.0g, 11.5mmol), difluorocyclobutylamine hydrochloride (1.4g, 11.5mmol) in 1,4-dioxane (20mL) In the solution, react overnight at 50 ^o C. The reaction was monitored by TLC. After the reaction was completed, water was added to the above reaction solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was filtered and spin-dried. The residue was purified by column chromatography (ethyl acetate:n-hexane=0~30%) to obtain the compound 6-chloro-N ² -((R)-1-cyclopropylethyl)-N ⁴ -((R) -1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (3.0 g, 84%) as a brown solid.

LCMS[M+H ⁺ ]310.72

Step 2: (1-((4-(((R)-1-cyclopropylethyl)amine)-6-(((R)-1,1,1-trifluoropropan-2-yl)amine )-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol

Referring to the operation method of step 2 of Example 123, 6-chloro-N ² -((R)-1-cyclopropylethyl)-N ⁴ -((R)-1,1,1-trifluoropropane- 2-yl)-1,3,5-triazine-2,4-diamine (3.0g, 9.7mmol) was used as raw material to synthesize (1-((4-(((R)-1-cyclopropylethyl base)amine)-6-(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl) Methanol (3.0 g, 83%) as a colorless oil.

LCMS[M+H ⁺ ]370.39

Step 3: (1-((4-(((R)-1-cyclopropylethyl)amine)-6-(((R)-1,1,1-trifluoropropan-2-yl)amine )-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)formaldehyde

Referring to the operation method of step 1 of Example 80, with (1-((4-(((R)-1-cyclopropylethyl)amine)-6-(((R)-1,1,1-tri Fluoroprop-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol (3.0g 8.1mmol) as raw material, synthesis (1-((4-(( (R)-1-cyclopropylethyl)amine)-6-(((R)-1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazine-2 -yl)ethynyl)cyclopropyl)carbaldehyde (2.7 g, 90%), white solid.

LCMS[M+H ⁺ ]368.38

Step 4: N ² -((R)-1-cyclopropylethyl)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ⁴ -((R)-1, Preparation of 1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

Referring to the operation method of step 2 of Example 80, (1-((4-(((R)-1-cyclopropylethyl)amine)-6-(((R)-1,1,1-tri Fluoroprop-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)formaldehyde (2.7g, 7.34mmol) was used as raw material to synthesize compound 82 (1.5g, 52% ), as a white solid.

LCMS[M+H ⁺ ]390.37

¹ H-NMR (500MHz, CD ₃ OD) δ5.86-5.56 (m, 1H), 4.87-4.78 (m, 1H), 3.54-3.39 (m, 1H), 1.44-1.17 (m, 10H), 1.10 -0.88(m,1H),0.57-0.14(m,4H).

Example 124: (R)-6-((1-(Difluoromethyl)cyclopropyl)ethynyl)-N ² -(1,3-difluoropropane2-yl)-N ⁴ -(1, Preparation of 1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine

Step 1: 1,3-Difluoropropylamine Hydrochloride

1,3-Difluoroacetone (0.46g, 4.9mmol), ammonium acetate (3.8g, 49mmol), and NaBH ₃ CN (0.92g, 14.7mmol) in methanol were stirred at 60 ^o C overnight. After the reaction was completed, water was added to the reaction liquid, extracted three times with ethyl acetate, and the organic phases were combined. Adjust the pH of the organic phase to 3-4 with dilute hydrochloric acid. Spin-dry to obtain compound 1,3-difluoropropylamine hydrochloride (0.4 g, 62%) as a white solid.

Step 2: (R)-6-Chloro-N ² -(1,3-difluoropropan-2-yl)-N ⁴ -(1,1,1-trifluoropropan-2-yl)-1,3 , Preparation of 5-triazine-2,4-diamine

DIEA (1.5 mL, 9.12 mmol) was added to 1,4-dioxane ( 5 mL) solution, stirred at room temperature for 3 hours. The reaction was monitored by TLC. After the reaction was completed, water was added to the above reaction solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was filtered and spin-dried. The residue was purified by Prep-TLC (ethyl acetate: n-hexane=1/3) to obtain compound (R)-6-chloro-N ² -(1,3-difluoropropan-2-yl)-N ⁴ -(1 , 1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine (0.18 g, 37%), white solid.

LCMS[M+H ⁺ ]320.66

Step 3: (R)-(1-((4-((1,3-difluoropropan-2-yl)amine)-6-((1,1,1-trifluoropropan-2-yl)amine )-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol

Referring to the operation method in step 2 of Example 123, (R)-6-chloro-N ² -(1,3-difluoropropan-2-yl)-N ⁴ -(1,1,1-trifluoropropane- 2-yl)-1,3,5-triazine-2,4-diamine (0.18g, 0.56mmol) was used as raw material to synthesize (R)-(1-((4-((1,3-difluoro Propan-2-yl)amine)-6-((1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl) Methanol (0.17 g, 79%).

LCMS[M+H ⁺ ]380.34

Step 4: (R)-(1-((4-((1,3-difluoropropan-2-yl)amine)-6-((1,1,1-trifluoropropan-2-yl)amine )-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)formaldehyde

Referring to the operation method of step 1 of Example 80, with (R)-(1-((4-((1,3-difluoropropan-2-yl)amine)-6-((1,1,1-tri Fluoroprop-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol (0.17g, 0.45mmol) was used as raw material to synthesize (R)-(1-( (4-((1,3-difluoropropan-2-yl)amine)-6-((1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazine- 2-yl)ethynyl)cyclopropyl)carbaldehyde (0.16 g, crude).

LCMS[M+H ⁺ ]378.32

Step 5: (R)-6-((1-(difluoromethyl)cyclopropyl)ethynyl)-N ² -(1,3-difluoropropane2-yl)-N ⁴ -(1,1 , Preparation of 1-trifluoroprop-2-yl)-1,3,5-triazine-2,4-diamine

Referring to the operation method of step 2 of Example 80, with (R)-(1-((4-((1,3-difluoropropan-2-yl)amine)-6-((1,1,1-tri Fluoroprop-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)formaldehyde (0.16 g, crude) starting material, synthesis of (R)-6-((1- (Difluoromethyl)cyclopropyl)ethynyl)-N ² -(1,3-difluoropropane-2-yl)-N ⁴ -(1,1,1-trifluoroprop-2-yl)-1 , 3,5-Triazine-2,4-diamine (20 mg), white solid.

LCMS[M+H ⁺ ]400.32

Example 125: 6-((1-(Difluoromethyl)cyclopropyl)ethynyl) ^-N2- (1-fluoropropyl-2yl) ^-N4 -((R)-1,1, 1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine

Step 1: 1-fluoropropan-2-amine hydrochloride

1-Fluoroacetone (1 g, 13.15 mmol), benzylamine (1.41 g, 13.15 mmol) were dissolved in DCM (50 mL). NaBH(OAc) ₃ (8.36 g, 39.44 mmol) was added in portions and stirred at room temperature for 18 h. The reaction solution was diluted with DCM (160 mL), washed with saturated Na ₂ CO ₃ (150 mL) and brine (150 mL). The layers were separated, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was dissolved in methanol (30 mL), 10% Pd/C (300 mg) was added, and the reaction mixture was reacted under nitrogen protection for 4 d. The reaction mixture was filtered through celite, the filter cake was washed with methanol, and the filtrate was collected. Hydrochloric acid (4M dioxane solution) was added to the filtrate and stirred at room temperature for 1 h, then concentrated under reduced pressure to obtain 1-fluoropropan-2-amine hydrochloride (0.93 g, 92%).

Step 2: 6-chloro-N ² -(1-fluoropropyl-2-yl)-N ⁴ -((R)-1,1,1-trifluoropropyl-2-yl)-1,3, Preparation of 5-triazine-2,4-diamine

DIEA (2.09 mL, 12.64 mmol) was slowly added to intermediate Int-3 (1.1 g, 4.21 mmol), 1-fluoropropylamine hydrochloride (0.62 g, 5.48 mmol) in 1,4-dioxane (30 mL) Solution, react at room temperature for 16h. The reaction was monitored by TLC. After the reaction was completed, water was added to the above reaction solution, extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was collected and spin-dried. The crude product was purified by column chromatography (EA:PE=0-30%) to obtain 6-chloro-N ² -(1-fluoropropyl-2-yl)-N ⁴ -((R)-1,1,1 -Trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine (1.15 g, 91%), white solid.

LCMS[M+H ⁺ ]302.67

Step 3: (1-((4-((1-fluoropropyl-2-yl)amine)-6-(((R)-(1,1,1-trifluoropropan-2-yl)amine) Preparation of -1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol

Referring to the operation method of step 2 of Example 123, 6-chloro-N ² -(1-fluoropropyl-2-yl)-N ⁴ -((R)-1,1,1-trifluoropropyl-2 -yl)-1,3,5-triazine-2,4-diamine (1.15g, 3.8mmol) was used as raw material to synthesize (1-((4-((1-fluoropropyl-2-yl)amine )-6-(((R)-(1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol ( 1.18 g, 86%), white solid.

LCMS[M+H ⁺ ]362.34

Step 4: (1-((4-((1-fluoropropyl-2-yl)amine)-6-(((R)-(1,1,1-trifluoropropan-2-yl)amine) Preparation of -1,3,5-triazin-2-yl)ethynyl)cyclopropyl)formaldehyde

Referring to the operation method of step 1 of Example 80, with (1-((4-((1-fluoropropyl-2-yl)amine)-6-(((R)-(1,1,1-trifluoro Propan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)methanol (1.18g, 86%) as raw material, synthesis (1-((4-(( 1-fluoropropyl-2-yl)amine)-6-(((R)-(1,1,1-trifluoropropan-2-yl)amine)-1,3,5-triazine-2- ethynyl)cyclopropyl)carbaldehyde (1.15 g, crude), yellow solid.

LCMS[M+H ⁺ ]360.33

Step 5: 6-((1-(Difluoromethyl)cyclopropyl)ethynyl)-N ² -(1-fluoropropyl-2-yl)-N ⁴ -((R)-1,1, Preparation of 1-trifluoropropyl-2-yl)-1,3,5-triazine-2,4-diamine

Referring to the operation method of step 2 of Example 80, (1-((4-((1-fluoropropyl-2-yl)amine)-6-(((R)-(1,1,1-trifluoro Propan-2-yl)amine)-1,3,5-triazin-2-yl)ethynyl)cyclopropyl)formaldehyde (1.15g, crude product) was used as raw material to synthesize 125 (0.8g, 65%), white solid.

LCMS [M+H ⁺ ] 382.33.

¹ H NMR (500MHz, DMSO-d6) δ8.27–7.91(m,1H),7.85–7.56(m,1H),5.75(td,J＝55.3,14.4Hz,1H),4.81(m,1H) ,4.47–4.11(m,3H),1.37–1.00(m,10H).

Select corresponding intermediates and reagents to synthesize the example compounds in the table referring to the methods of Examples 1, 2, 4, 31, 32, 80, 81, 82 and 123, 124, 125.

The NMR data of Compound 3, Compound 31, Compound 32, Compound 46, Compound 69, Compound 79, Compound 81, and Compound 82 are as follows:

Compound 3: ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.25-8.10(m,2H),4.95-4.91(m,1H),4.92-4.75(m,2H),3.56(m,2H), 2.54(m,2H),1.36–1.25(m,6H);

Compound 31: ¹ H-NMR (500MHz, CDCl ₃ ) δ5.40-5.39 (m, 1H), 5.33-5.14 (m, 1H), 5.04-4.75 (m, 2H), 1.76-1.70 (m, 6H) ,1.40-1.37(m,6H);

Compound 32: ¹ H-NMR (500MHz, CDCl ₃ ) δ5.40-5.25 (m, 2H), 4.89-4.73 (m, 2H), 1.44-1.35 (m, 6H), 1.14 (s, 3H), 0.92 -0.87(m,4H);

Compound 46: ¹ H-NMR (500MHz, CDCl ₃ ) δ5.39-5.37(m, 1H), 5.28-2.11(m, 1H), 5.00-4.73(m, 2H), 3.54-3.52(d, J= 5.95Hz, 2H), 1.34-1.29(m, 6H), 1.25-1.21(m, 6H);

Compound 69: ¹ H NMR (500MHz, CDCl ₃ ) δ5.41–5.04(m,2H),5.04–4.71(m,2H),3.60(s,2H),2.12(s,1H),1.38(d, J＝6.8Hz, 6H), 1.28–1.24(m, 2H), 0.96–0.92(m, 2H);

Compound 79: ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.23–7.80(m,2H),5.92–5.58(m,1H),5.02–4.64(m,1H),1.58–1.12(m,8H ), 0.65–0.46(m,4H), 0.35–0.28(m,2H), 0.19–0.07(m,2H).

Pharmacological experiment

Example A: Enzyme Activity Inhibition Test

The inhibitory ability of the test compounds on IDH1 ^R132H and IDH2 ^R140Q enzyme activities was expressed as half inhibitory concentration (IC ₅₀ ) value. In this experiment, the method of fluorescence was used to screen compounds on IDH1 ^R132H and IDH2 ^R140Q enzymes, and the testing process was as follows.

1. IDH1 ^R132H test process

(1) Prepare 1×Assay buffer.

(2) Compound concentration gradient preparation: the initial concentration of the test compound on the IDH1 ^R132H enzyme is 10000 nM, 3-fold dilution, 10 concentrations, single well detection. Dilute the solution to a final concentration of 200 times in a 384-well plate, and then use Echo550 to transfer 250nL to the 384 reaction plate for use. Add 250 nL of 100% DMSO to negative control wells and positive control wells, respectively.

(3) Add 40 μL of 1.25-fold final concentration enzyme mix and NADPH mix, and incubate for 60 minutes.

(4) Add 10 μL of 5-fold final concentration of substrate mix and incubate for 90 minutes.

(5) Add 25 μL of 3-fold final concentration Detection buffer to the reaction well and shake for 1 min.

(6) Ensight, Ex544/Em590 cutoff 590 is used for reading.

2.IDH2 R140Q test process

(1) Prepare 1×Assay buffer.

(2) Compound concentration gradient preparation: the initial concentration of the test compound on the IDH2 ^R140Q enzyme is 10000 nM, 3-fold dilution, 10 concentrations, single well detection. 100% DMSO solution diluted to 50-fold final concentration in a 96-well plate.

(3) Add 1 μL of DMSO or 1 μL of the diluted compound to the reaction well.

(4) Add 25μL enzyme Mix and 1*buffer(max), and incubate for 60 minutes.

(5) Add 25 μL substrate mix and incubate for 150 minutes.

(6) Add 25μL Detection buffer to the reaction well, shake for 1min, and incubate for 60 minutes.

(7) Ensight, Ex544/Em590 cutoff 590 is used for reading.

3. Data Analysis

(1) Calculation of inhibition rate

Formula: %Inhibition=(RFU_sample-RFU_min)/(RFU_max-RFU_min)*100%. Among them: RFU-sample is the fluorescence intensity of the sample; RFU-min is the average value of negative control wells, representing the fluorescence intensity with enzyme; RFU-max is the average value of positive control wells, representing the fluorescence intensity without enzyme.

(2) Fit the dose-effect curve: take the log value of the concentration as the X-axis, and the percentage inhibition rate as the Y-axis, and use the log (inhibitor) vs.response-Variable slope of the analysis software GraphPad Prism 5 to fit the dose-effect curve, thereby obtaining The _IC50 value of each compound on the enzyme activity was shown.

The results of enzyme activity inhibition experiments were expressed by IC ₅₀ , as shown in Table 1. As shown by the compounds of the present invention illustrated in the Examples, the IC ₅₀ values are in the following ranges: "A" stands for "IC ₅₀ ≤ 200nM";"B" stands for "200nM<IC ₅₀ <1000nM";"C" stands for "1000nM< IC ₅₀ ≤5000nM”; “D” stands for “IC ₅₀ >5000nM”.

Table 1

Note: "/" means not detected.

Example B: Cell 2-HG experiment

The inhibitory effect of compounds on the production of 2-HG in the culture supernatant of U87 cell line stably transfected with IDH1 ^R132H and TF-1 cells stably transfected with IDH2 ^R140Q or IDH2 ^R172K was detected.

1. Collect the cultured cells by centrifugation, then suspend them with cell culture medium, inoculate the cells in a 96-well cell culture plate after cell counting, and finally seed the plate with 160 μL of cell suspension/well (U87-IDH1-R132H is 20,000 cells/well). well, 10000 cells/well for TF-1-IDH2-R140Q and TF-1-IDH2-R172K).

2. Take a 96-well dilution plate, dilute the compound to be tested by DMSO and cell culture medium, and then take 40 μL of the compound to be tested after the serial dilution and add it to the 96-well culture plate where the cells have been plated, with a final volume of 200 μL per well. . The final concentration of the compound in the detection of cell TF-1-IDH2-R140Q and TF-1-IDH2-R172K was 10000, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, 4.6,

1.5, 0 nM (the final concentration of DMSO is 0.2%), the final concentration of the compound in the detection of cell U87-IDH1-R132H is 2000, 666.7, 222.2, 74.1, 24.7, 8.2, 2.7, 0.9, 0.3, 0.1 nM. Finally, it was placed in a 37°C incubator containing 5% CO ₂ for cultivation.

3. After the compound was co-incubated with the cells for 72 hours, the cell culture plate was taken out, centrifuged at 2500 rpm for 5 minutes, and then 100 μL of the culture medium supernatant was drawn for 2-HG determination.

4. Dilute the supernatant with pure water, take 30 μL of the diluted sample into a 1.5ml centrifuge tube, add 200 μL of internal standard solution, vortex to mix, and centrifuge at 4°C and 13,000 rpm for 15 minutes. Take 100 μL of the supernatant solution in a 96-well plate, dilute it with purified water at a ratio of 1:1, and detect it with LC-MS. The value of Analyte Peak Area represents the level of 2-HG.

5. Calculation of inhibition rate, formula: %Inhibition=(1-Analyte Peak Area_sample/Analyte Peak Area_max)*100%. Curve fitting was performed with Graphpad Prism software to obtain IC ₅₀ values.

The results of cell 2-HG inhibition assay are expressed by IC ₅₀ , as shown in Table 2. As shown by the compounds of the present invention illustrated in the Examples, the IC ₅₀ values are in the following ranges: "A" stands for "IC ₅₀ ≤ 200nM";"B" stands for "200nM<IC ₅₀ <1000nM";"C" stands for "1000nM< IC ₅₀ ≤5000nM”; “D” stands for “IC ₅₀ >5000nM”.

Table 2

Embodiment: mouse PO-Cassette experimental method

1. Preparation of compounds (solvent: 15% DMSO/10% Solutol/75% physiological saline).

2. Mice were intragastrically administered (dose: 5 mg/kg), blood was collected 0.5, 2, and 4 hours after administration, and the plasma supernatant was obtained by centrifugation at 4000 rpm for 10 minutes.

3. After taking 30 μl plasma supernatant sample, add 200 μl internal standard solution, centrifuge at 12000 rpm for 10 minutes, take 100 μl of supernatant solution and dilute it with water 1:1 and inject the sample, the injection volume is 10 μl. The drug concentration in plasma was detected by LC-MS.

4. Each parameter (t _1/2 , C _max , AUC _last ) was calculated with Winnonln software, and the test results are shown in Table 3.

table 3

While the invention has been fully described by way of the embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should all be included within the scope of the appended claims of the present invention.

Claims (31)

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof:

   

   wherein,

   r is selected from-CN, C ₁ -C ₁₀ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₂ Cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ Aryl, 5-12 membered heteroaryl; the C is ₁ -C ₁₀ Alkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₂ Cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ Aryl, 5-12 membered heteroaryl optionally substituted with m R ₇ Substitution;

   R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ and R is ₆ The same or different are each independently selected from hydrogen, halogen,CN、C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, -O-C ₁ -C ₄ Alkyl, C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocyclyl; the C is ₁ -C ₄ Alkyl, C ₃ -C ₆ Cycloalkyl, 3-6 membered heterocyclyl is substituted with one or more halo, -OH, -NH ₂ 、-CN、C ₁ -C ₄ Alkyl, -O-C ₁ -C ₄ Alkyl, -NH (C) ₁ -C ₄ Alkyl) or-N (C) ₁ -C ₄ Alkyl group ₂ Substitution;

   R ₂ and R is ₃ Optionally together with the carbon atom to which it is attached form C (=o); or (b)

   R ₅ And R is ₆ Optionally together with the carbon atom to which it is attached form C (=o); or (b)

   R ₂ And R is ₃ Optionally together with the carbon atom to which it is attached form C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ A membered aryl or 5-10 membered heteroaryl; wherein the C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ The membered aryl, 5-10 membered heteroaryl is optionally substituted with one or more-OH, -NH ₂ -CN, halogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy substitution; or (b)

   R ₅ And R is ₆ Optionally together with the carbon atom to which it is attached form C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ A membered aryl or 5-10 membered heteroaryl; wherein the C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ Meta-arylThe 5-to 10-membered heteroaryl is optionally substituted with one or more-OH, -NH ₂ -CN, halogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Alkoxy substitution;

   each R is ₇ Independently selected from hydrogen, deuterium, -CN, halogen, oxo, C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ Cycloalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, -NR ₁₁ R ₁₂ 、-OR ₁₃ 、-(CO)OR ₁₄ 、-(CO)NR ₁₅ R ₁₆ 、-(CO)R ₁₇ 3-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, C ₃ -C ₆ Alkenyl alkyl or C ₃ -C ₁₀ Alkynyl alkyl; the C is ₁ -C ₆ Alkyl, C ₃ -C ₁₀ Cycloalkyl, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, C ₃ -C ₆ Alkenyl alkyl or C ₃ -C ₁₀ Alkynyl alkyl is optionally substituted with one or more hydrogen, -CN, halogen, hydroxy, amino, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy substitution;

   each R is ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ 、R ₁₅ 、R ₁₆ 、R ₁₇ Independently selected from hydrogen, C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ Cycloalkyl, C ₃ -C ₁₀ Halogenated cycloalkyl, 3-10 membered heterocyclic group, C ₃ -C ₆ Alkenyl alkyl or C ₃ -C ₁₀ Alkynyl alkyl;

   m is selected from any integer from 1 to 8.
2. The compound according to claim 1, wherein the compound of formula (I) is selected from the group consisting of formula (II):

   
3. the compound according to claim 1, wherein the compound of formula (I) or formula (II) is selected from the group consisting of formula (III):

   
4. the compound according to claim 1, wherein the compound of formula (I) is selected from the group consisting of formula (IV):

   
5. a compound according to claim 1, wherein R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ And R is ₆ Identical or different, each independently selected from hydrogen, -CN, -CH ₃ 、-CH ₂ CH ₂ CH ₃ 、-CH ₂ CH ₂ CH ₂ CH ₃ 、-CHF ₂ 、-CF ₃ 、-CF ₂ CH ₃ 、-CH ₂ CF ₃ 、

   

   -CH ₂ OCH ₃ 。
6. A compound according to claim 1, wherein R ₂ 、R ₃ 、R ₅ 、R ₆ Independently selected from C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl or C ₃ -C ₆ Cycloalkyl groups.
7. A compound according to claim 1 or 3, wherein R ₂ 、R ₃ 、R ₅ 、R ₆ Independently selected from CF ₃ 、CH ₃ Or cyclopropyl; further, R ₂ And R is R ₃ Different, R ₅ And R is R ₆ Different.
8. The compound according to any one of claims 1 to 4, wherein R in formula (I) ₁ 、R ₄ Independently selected from hydrogen.
9. A compound according to claim 1, wherein R ₂ And R is ₃ Together with the carbon atom to which it is attached, form a cyclopropane, cyclobutane; the cyclopropane, cyclobutane are optionally substituted with one or more hydrogen, halogen.
10. The compound of claim 1 or 6, wherein R ₅ And R is ₆ Together with the carbon atom to which it is attached, form a cyclopropane, cyclobutane; the cyclopropane, cyclobutane are optionally substituted with one or more hydrogen, halogen.
11. The compound according to any one of claims 1 to 7, wherein R is selected from-CN, C ₁ -C ₁₀ Alkyl, C ₂ -C ₆ Alkynyl, -OR ₁₀ 、C ₃ -C ₁₂ Cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ Aryl, 5-12 membered heteroaryl; the C is ₁ -C ₁₀ Alkyl, C ₂ -C ₆ Alkynyl, C ₃ -C ₁₂ Cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ Aryl, 5-12 membered heteroaryl optionally substituted with m R ₇ And (3) substitution.
12. A compound according to any one of claims 1 to 11, wherein R is selected from C ₁ -C ₁₀ An alkyl group; the C is ₁ -C ₁₀ Alkyl is optionally substituted with m R ₇ And (3) substitution.
13. A compound according to any one of claims 1 to 11, wherein R is selected from C ₃ -C ₁₂ Cycloalkyl; the C is ₃ -C ₁₂ Cycloalkyl is optionally substituted with m R ₇ And (3) substitution.
14. The compound of any one of claims 1-13, wherein each R ₇ Independently selected from hydrogen, -CN, halogen, oxo, C ₁ -C ₆ Alkyl, C ₃ -C ₁₀ Cycloalkyl, -NR ₁₁ R ₁₂ 、-OR ₁₃ 、-(CO)OR ₁₄ 、-(CO)NR ₁₅ R ₁₆ 、C ₆ -C ₁₀ Aryl or C ₃ -C ₁₀ Alkynyl alkyl; the C is ₁ -C ₆ Alkyl, C ₃ -C ₁₀ Cycloalkyl, C ₆ -C ₁₀ Aryl, C ₃ -C ₁₀ Alkynyl alkyl is optionally substituted with hydrogen, -CN, halogen, hydroxy, amino, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy substitution.
15. The compound of any one of claims 1-14, wherein each R ₇ Independently selected from hydrogen, -CN, -F, -Cl, -Br, oxo, -CH ₃ 、-CH ₂ CH ₃ 、-CH(CH ₃ ) ₂ 、-CH ₂ OH、-CH ₂ CH ₂ OH、-CH ₂ F、-CHF ₂ 、-CF ₃ 、-CH ₂ CH ₂ F、-CH ₂ CHF ₂ 、-CHFCH ₃ 、-CHFCH ₂ CH ₃ 、-CF ₂ CH ₂ CH ₃ 、-NH ₂ 、-OCH ₃ 、-OH、-COOH、-COCH ₃ 、-COOCH ₃ 、-CONHCH ₃ 、-CON(CH ₃ ) ₂ 、

    

    -Ph、

    
16. A compound according to any one of claims 1 to 15, wherein R is selected from-CH ₃ 、-CN、

    

    

    

    -OCH ₂ CH ₃ 、

    

    

    -CH ₂ OCH ₃ 、

    

    

    
17. The compound according to any one of claims 1-2, 4, wherein R ₃ 、R ₆ Identical or different, independently selected from C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl or C ₃ -C ₆ Cycloalkyl groups.
18. The compound according to any one of claims 1-2, 4, 17, wherein R in formula (II) ₃ 、R ₆ Identical or different, independently selected fromCF ₃ 、CH ₃ Or cyclopropyl.
19. A compound according to any one of claims 1 to 18, wherein the compound of formula (I) is selected from:

    6- (prop-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    4- (4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) -2-methylbutan-3-yn-2-ol;

    4- (4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) but-3-yn-1-ol;

    6- (3, 3-dimethylbut-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    3- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) acetylene) oxetan-3-ol;

    1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) acetylene) cyclopropan-1-ol;

    6- (Oxetan-3-ylacetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (azetidin-3-ylacetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (3, 4-tetrafluoro-3- (trifluoromethyl) but-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) acetylene) cyclobutan-1-ol;

    5- (4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) -2-methylpent-4-yn-2-ol;

    6- (cyclopropylacetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropyl-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (cyclobutylacetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (Phenylacetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1H-pyrazol-4-yl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((3-Methyloxetan-3-yl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (cyclopentylacetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    3- (4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) propionitrile;

    6- (3-methoxyprop-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1-methoxycyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (pyridin-2-ylacetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) acetylene) cyclohex-1-ol;

    6- (thiophen-2-ylacetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (Cyclohexylacetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((4-chlorophenyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (3-aminobut-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (3, 3-dimethylbut-1-yn-1-yl) -N ² ,N ⁴ -bis (2, 2-trifluoroethyl) -1,3, 5-triazine-2, 4-diamine;

    6- (3-methoxy-3-methylbut-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (3-methylbut-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (4-methylpent-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (3-fluoro-3-methylbut-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1-methylcyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1-aminocyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (trifluoromethyl) cyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((2, 2-difluoro-1-methylcyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) acetylene) cyclopropane-1-carbonitrile;

    6- ((2, 2-difluoro-1-methylcyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((2-methylcyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((2, 2-difluorocyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((2-fluorocyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((3, 3-difluorocyclobutyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (trifluoromethyl) cyclobutyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((3-fluorocyclobutyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((3-fluorocyclobutyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((3-Fluorobicyclo [ 1.1.1)]Pent-1-yl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    4- (4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) -2, 2-dimethylbut-3-yn-1-ol;

    6- (4-fluoro-3, 3-dimethylbut-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (3, 3-dimethylpent-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    N ² ,N ⁴ -bis ((R) -1, 1-trifluoroprop-2-yl) -6- (3, 4-trimethylpent-1-yn-1-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (methoxymethyl) cyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (but-1, 3-diyn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1-fluorocyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    4- (4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) -1, 1-trifluoro-2-methylbutan-3-yn-2-ol;

    4- (4, 6-bis (((R) -1, 1-trifluoroprop-2-yl) amino) -1,3, 5-triazin-2-yl) -1, 1-trifluoro-2- (trifluoromethyl) but-3-yn-2-ol;

    1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) ethynyl) cyclobutyl-1-ol;

    1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) ethynyl) cyclopentyl-1-ol;

    6- ((1-fluorocyclobutyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1-fluorocyclopentyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    4- (4, 6-bis (((R) -1, 1-trifluoroprop-2-yl) amino) -1,3, 5-triazin-2-yl) -2, 2-dimethylbut-3-ynecarboxylic acid;

    methyl 4- (4, 6-bis (((R) -1, 1-trifluoroprop-2-yl) amino) -1,3, 5-triazin-2-yl) -2, 2-dimethylbut-3-ynoic acid methyl ester;

    4- (4, 6-bis (((R) -1, 1-trifluoroprop-2-yl) amino) -1,3, 5-triazin-2-yl) -N, 2-trimethylbut-3-yninamide;

    4- (4, 6-bis (((R) -1, 1-trifluoroprop-2-yl) amino) -1,3, 5-triazin-2-yl) -N, 2-tetramethylbut-3-yninamide;

    6- ((2, 2-dimethylcyclopropyl) ethynyl) -N ² ,N ⁴ -double (-)R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (4, 4-trifluoro-3, 3-dimethylbut-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (4, 4-trifluoro-3-methyl-3- (trifluoromethyl) but-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1-ethylcyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (3, 3-dimethylbut-1-yn-1-yl) -N ² ,N ⁴ -diisopropyl-1, 3, 5-triazine-2, 4-diamine;

    6- ((1-isopropylcyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amino) -1,3, 5-triazin-2-yl) ethynyl) cyclopropyl) methanol;

    6- ((1- (fluoromethyl) cyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1-phenylcyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1-phenylcyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1-cyclobutylcyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (3, 3-difluorocyclobutyl) cyclopropyl) ethynyl))-N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R) -6- (3, 3-dimethylbutyl-1-yn-1-yl) -N ² -isopropyl-N ⁴ - (1, 1-trifluoropropyl-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1-methylcyclobutyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R) -6- (3, 3-dimethylbut-1-yn-1-yl) -N ² - (2, 2-trifluoroethyl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R)-N ² - ([ 1,1' -bis (cyclopropyl))]-1-yl) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    N ² ,N ⁴ -bis (R) -1-cyclopropylethyl) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (difluoromethyl) cyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoroisopropyl-2-yl) -1,3, 5-triazine-2, 4-diamine;

    N ² - ((R) -1-cyclopropylethyl) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ⁴ - ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R)-N ² - (3, 3-difluorocyclobutyl) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ⁴ - (1, 1-trifluoropropyl-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (3, 3-dimethylbutyl-1-yn-1-yl) -N ² ,N ⁴ -bis (2, 2-trifluoroethyl) -1,3, 5-triazine-2, 4-diamine;

    6- (3-methoxy-3-methylbut-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropyl-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (2-fluoroethyl)) Cyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (2, 2-difluoroethyl) cyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (((3R, 5R, 7R) -adamantan-1-yl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ([ 1,1' -bis (cyclopropyl)]-1-ylethynyl) -N ² ,N ⁴ -bis ((R)) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((3-fluorofuran-3-yl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (3-fluoro-3-methylpent-4-1-en-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoroprop-2-yl) -1,3, 5-triazine-2, 4-diamine 5- (4, 6-bis (((R) -1, 1-trifluoroprop-2-yl) amine) -1,3, 5-triazin-2-yl) -3-methyl-1-en-4-yn-3-pentanol;

    N ² ,N ⁴ -bis ((R) -1-cyclopropylethyl) -6- (3, 3-dimethylbut-1-yn-1-yl) -1,3, 5-triazine-2, 4-diamine;

    N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- (3, 3-dimethylbut-1-yn-1-yl) -1,3, 5-triazine-2, 4-diamine;

    N ² ,N ⁴ -bis ((R) -1-cyclopropyl) -6- ((1-ethylcyclopropyl) acetylene) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (1-fluoropropyl) cyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (1, 1-dicyclohexyl) cyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    2- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amine) -1,3, 5-triazin-2-yl) acetylene) cyclopentanol;

    6- ((2-fluorocyclopentyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- (3-ethyl-3-fluoropent-1-yn-1-yl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (1-fluoroethyl) cyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (1-fluoropropynyl) cyclopropyl) acetylene) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    2- (1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amine) -1,3, 5-triazin-2-yl) acetylene) cyclopropyl) isopropanol;

    1- (1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amine) -1,3, 5-triazin-2-yl) ethynyl) cyclopropyl) ethanol;

    1- (1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amine) -1,3, 5-triazin-2-yl) ethynyl) cyclopropyl) -2, 2-trifluoroethyl-1-ol;

    1- (1- ((4, 6-bis (((R) -1, 1-trifluoropropan-2-yl) amine) -1,3, 5-triazin-2-yl) ethynyl) cyclopropyl) ethanone;

    (R)-N ² - (3, 3-difluorocyclobutyl) -6- (3, 3-dimethylbut-1-yn-1-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R) -6- ((1- (difluoromethyl) cyclopropyl) acetylene) -N ² -isopropyl-N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazin-2, 4-diamine;

    (R) - (1- ((4- ((3, 3-difluorocyclobutyl) amine) -6- ((1, 1-trifluoropropyl) amine) -1,3, 5-triazinyl) ethynyl) methanol;

    N ² ,N ⁴ -bis (3, 3-difluorocyclobutyl) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -1,3, 5-triazine-2, 4-diamine;

    (R)-N ² -cyclopropyl-6-(1- (difluoromethyl) cyclopropyl) acetylene) -N ⁴ - (1, 1-trifluoropropyl-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R) -6- ((1- (difluoromethyl) cyclopropyl) acetylene) -N ² - (1-methylcyclopropyl) -N ⁴ - (1, 1-trifluoropropyl-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R) -1- ((4- ((1-difluoromethyl) cyclopropyl) ethynyl) -6- (1, 1-trifluoropropan-2-yl) amine) cyclopropyl-1-cyano;

    6- ((1- (difluoromethyl) cyclopropyl) acetylene) -N ² - (1, 1-difluoropropyl) -N ⁴ - (R) -1, 1-trifluoropropyl) -1,3, 5-triazine-2, 4-diamine;

    N ² - (3, 3-difluorobutyl-6- ((1- (difluoromethyl) cyclopropyl) acetylene) -N ⁴ - (R) -1, 1-trifluoropropyl) -1,3, 5-triazine-2, 4-diamine;

    6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -N ⁴ - ((S) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ² -propyl-N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R)-N ² -butyl-6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ² - (1, 1-trifluoropropan-2-yl-N) ⁴ - (3, 3-trifluoropropyl) -1,3, 5-triazine-2, 4-diamine;

    (R)-N ² - (cyclopropylmethyl) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ² - (2-methylethyl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ² - (2, 2-difluoropropyl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (1- ((4, 6-bis (((R) -1-cyclopropylethyl) amine) -1,3, 5-triazin-2-yl) ethynyl) cyclopropyl) methanol;

    6- ((1-propenyl cyclopropyl) ethynyl) -N ² ,N ⁴ -bis ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine;

    (R) -6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ² - (1, 3-difluoropropan-2-yl) -N ⁴ - (1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine; or (b)

    6- ((1- (difluoromethyl) cyclopropyl) ethynyl) -N ² - (1-fluoroprop-2-yl) -N ⁴ - ((R) -1, 1-trifluoropropan-2-yl) -1,3, 5-triazine-2, 4-diamine.
20. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of claims 1-19 and at least one pharmaceutically acceptable excipient.
21. Use of a compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20 in the manufacture of a medicament.
22. The use according to claim 21, wherein the use is the treatment, prevention, delay or prevention of the occurrence or progression of cancer or cancer metastasis.
23. The use according to claim 21 or 22, for the treatment of diseases mediated by mutant IDH1 and IDH 2.
24. The use according to claim 23, wherein the disease is cancer.
25. The use according to claim 22 or 24, wherein the cancer is selected from melanoma, papillary thyroid tumours, cholangiocarcinomas, lung cancer, breast cancer, sarcomas, gliomas, glioblastoma multiforme, acute myelogenous leukemias, non-hodgkin lymphomas and the like. In specific embodiments, the cancer to be treated is glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute Myelogenous Leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinoma, or angioimmunoblastic lymphoma. In more specific embodiments, the cancer to be treated is glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute Myelogenous Leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-hodgkin's lymphoma (NHL).
26. The use according to claim 21, wherein the use is as a mutant IDH1 and IDH2 inhibitor.
27. A method of treating and/or preventing IDH 1-and IDH 2-mediated diseases by administering a therapeutically effective amount of at least one compound of any one of claims 1-19 or a pharmaceutical composition of claim 20 to a subject.
28. The method of claim 27, wherein the IDH1 and IDH2 mediated disease is cancer.
29. A method of treating cancer comprising administering to a subject a therapeutically effective amount of at least one compound of any one of claims 1-19 or the pharmaceutical composition of claim 20.
30. A method of treating a cancer characterized by the presence of mutant IDH1 and IDH2, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-19, or an isomer, pharmaceutically acceptable salt, crystal, solvate or prodrug thereof, or the pharmaceutical composition of claim 20, wherein said cancer is selected from the group consisting of melanoma, papillary thyroid tumor, cholangiocarcinoma, lung cancer, breast cancer, sarcoma, glioma, glioblastoma multiforme, acute myelogenous leukemia, non-hodgkin's lymphoma.
31. The method of claim 30, wherein the subject is a human.