RU2793249C2 - Triazolpyrimidine compounds and their use in treatment of cancer - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates specifically to compounds with formula (I) and their pharmaceutically acceptable salts that selectively inhibit MCT4 (monocarboxylate transporter 4), pharmaceutical compositions based thereon, their use for obtaining a drug and a method for treating MCT4-mediated cancer.

EFFECT: development of compounds that selectively inhibit MCT4 (monocarboxylate transporter 4). In general formula (I), R¹ and R² are each independently hydrogen or methyl; X is CH₂ or O; each ring A and ring B is independently a ring selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, where each ring A and ring B is independently optionally substituted with one or more substituents selected from C_1-3 alkyl and C_{1 -3} alkoxy; ring C is a 5-9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, where ring C is optionally substituted with one or more substituents selected from C_1-3 alkyl optionally substituted with methoxy or hydroxyl; dioxo, C_0-2 alkyl-C(O)N(Me)₂, C(O)C_1-2 alkyl and S(O)₂C_1-2 alkyl.

23 cl, 5 dwg, 3 tbl, 87 ex

Description

FIELD OF THE INVENTION

This description mainly relates to triazolpyrimidine compounds and their pharmaceutically acceptable salts. These compounds and their pharmaceutically acceptable salts selectively inhibit MCT4 (monocarboxylate transporter 4) and, therefore, the description also relates to the use of such compounds and their salts for the treatment or prevention of an MCT4-mediated disease, including cancer. The description also relates to crystalline forms of triazolpyrimidine compounds and their pharmaceutically acceptable salts; pharmaceutical compositions containing such compounds and salts; kits containing such compounds and salts; methods for preparing such compounds and salts; and to methods of treating MCT4 mediated disease, including cancer, using such compounds and salts.

PRIOR ART

Monocarboxylate transporters are encoded by genes of the SLC16 family. The family is also known as the monocarboxylate transporter (MCT) family because the first identified members were shown to be responsible for the proton-coupled transport of monocarboxylates such as L-lactate, pyruvate, and ketone bodies across the cytoplasmic membrane. Direct manifestation of proton-bound lactate and pyruvate transport has been demonstrated for MCT1 (SLC16A1), MCT2 (SLC16A7), MCT3 (SLC16A8) and MCT4 (SLC16A3). The MCT family nomenclature is taken from Halestrap and Price, Biochemical Journal (1999) 343: 281-299.

MCTs have 12 transmembrane helices and functional expression requires interaction with single transmembrane domain chaperones known as CD 147 (also known as basigin and EMMPRIN (an extracellular matrix metalloproteinase inducer)) and embigin. CD 147 acts as an important chaperone for the delivery of MCT1 and MCT4 to the cytoplasmic membrane, where the transporter and CD147 remain closely associated (Kirk et al. (2000) EMBO J. 19: 3896-3904). When MCT2 is correctly expressed in the cytoplasmic membrane, there is strong preference for embigin over CD147 (Wilson et al (2005) J. Biol. Chem. 280: 27213-27221).

It is well known that tumors exhibit altered metabolism (Vander Heiden (2011) Nat. Drag Dis. 10:671-684). Tumors are composed of well oxygenated (aerobic) and poorly oxygenated (hypoxic) areas. Compared to normal cells, tumor cells have an increased dependence on the glycolytic pathway for the formation of ATP, either through aerobic glycolysis (Warburg effect) or anaerobic glycolysis as a consequence of tumor hypoxia. It appears that rapidly proliferating tumors and hypoxic tumors are particularly dependent on glycolysis for energy and biosynthetic needs. Widespread clinical use of FDG-PET (fluorodeoxyglucose positron emission tomography) PET scan with the indicator fluoro-18-fluorodeoxyglucose (F-18-FDG) has demonstrated that this glycolytic phenotype is observed in a variety of solid and hematological tumors. As a result, FDG-PET can be used to diagnose, staging, and monitor cancer treatment. FDG-PET combined with computed tomography has a sensitivity and specificity of over 90% for the detection of metastases in most epithelial tumors (Mankoffetal. (2007) Clin. Cancer Res. 13:3460-3469).

A by-product of increased rates of glycolysis in tumors is the accumulation of lactate. Intracellular lactate can be transported out of tumor cells by monocarboxylate transporters (MCTs 1, 2, 3 and 4) (Halestrap and Price, Biochem J. (1999) 343; 291-299). Lactate produced by tumor cells can be taken up by stromal and oxygenated tumor cells (via the monocarboxylate transporters MCT1 and MCT2) to regenerate pyruvate, which can be used to mediate oxidative phosphorylation (OXPHOS) (Koukouris et al., Cancer Res. (2006) 66; 632-637; Sonveaux et al., J. Clin. Invest. (2008) 118; 3930-3942). One of the key factors in the development of the glycolytic phenotype of tumors is the activation of hypoxia-inducible factor (HIF), a transcription factor that is activated by hypoxic stress. MCT4 is a HIF target gene and is activated by hypoxia and is required for lactate export from glycolytic tumors (Ullah et al. (2006) J. Biol. Chem. 281:9030-9037). The kinetic properties of MCT4 focus on its role in the export of lactic acid produced by glycolysis, as its very high Km (Michaelis constant) for pyruvate (150 mM) ensures that pyruvate is not expelled from the cell. This is important because NADH (reduced nicotinamide adenine dinucleotide) derived from the reduction of pyruvate to lactate is required to control glycolytic flux (Halestrap and Wilson (2012) IUMBM Life 64: 109-119).

Unlike normal epithelium, a number of solid tumors overexpress MCT4, including kidney tumors (Fisel et al. (2013) Clin. Cancer Res. 19: 5170-5181; Gerlinger et al. J. Pathol. 227: 146-156), pancreas (Baek et al. (2014) Cell Rep. 9:2233-2249), colorectal tumors (Pinheiro et al., Virchows Arch. (2008) 452; 139-146), HNSCC (head and neck squamous cell carcinoma) ( Zhu et al. (2014) PLoS One 9:e87904), breast cancer (Doyen et al. (2014) Biochem. Biophys. Res. Commun. 451:54-61), prostate cancer (Pertega-Gomes et al. BMC Cancer (2011) H:312) and liver cancer (Gao et al. (2015) J Cancer Res. 141: 1151-1162).

Recent evidence has shown that lactate plays an important role in regulating immune cell function. Lactate has been shown to suppress the activity of immune effector cells such as T cells and NK cells. Lactic acid inhibits ex vivo human T cell proliferation and activation (Fisher et al. (2007) Blood 109:3812-3819; Haas et al. (2015) PLoS Biol 13). Husain et al. demonstrated that NK cells from tumors lacking LDHA (lactate dehydrogenase A) showed improved cytolytic function and treatment of NK cells with lactate reduced their cytotoxic activity (Husain et al. (2013) J. Immunol. 191:1486-1495). In addition, Brand et al. demonstrated that in immunocompetent mice, LDHA knockdown reduced lactic acid production and increased infiltration of IFN-y (interferon y)-producing T and NK cells in tumors (Brand et al. (2016) Cell Metab. 24:657-671 ). Lactate has also been shown to inhibit monocyte activation and dendritic cell differentiation (Gottfried et al. (2006) Blood 107:2013-2021; Dietl et al. (2010) J. Immunol. 184:1200-1209) and also induces M2 ( immunosuppressive) polarization of tumor-associated macrophages (Colegio et al. (2014) Nature 513:559-563). Taken together, these data support the hypothesis that lactate, produced as a by-product of the glycolytic phenotype of tumors, has an immunosuppressive effect in the tumor microenvironment.

The accumulation of lactate in the tumor microenvironment is accompanied by acidosis (due to joint transport with protons). Low pH in the tumor microenvironment has been associated with extracellular matrix degradation and tumor cell migration (Gillies and Gatenby (2015) Cancer J. 21: 88-96).

Potential inhibitors of MCT1/2 have been described in WO 2004/065394, which shows that in T-lymphocytes, lactate efflux occurs via MCT1, since small molecule MCT1 inhibitors lead to the accumulation of intracellular lactate (Murray et al., Nat. Chem Biol. (2005) 1; 371-376).

However, there is a need for MCT4 inhibitors that inhibit lactate transport into MCT4 dependent cells, exhibit good bioavailability, and are suitable for administration.

SUMMARY OF THE INVENTION

Briefly, this description provides, inter alia, the compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each R ¹ and R ² independently represents hydrogen or methyl;

X is CH ₂ or O;

each ring A and ring B is independently a ring selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, where each ring A and ring B is independently optionally substituted with one or more substituents selected from C _1-3 alkyl and C _{1 -3} alkoxy;

ring C is a 5-9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, where ring C is optionally substituted with one or more substituents selected from C _{1 -3} alkyl optionally substituted with methoxy or hydroxyl; dioxo, C _0-2 alkyl-C(O)N(Me) ₂ , C(O)C _1-2 alkyl and S(O) ₂ C _1-2 alkyl.

This specification also provides, inter alia, a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

This specification also provides, inter alia, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

This specification also provides, inter alia, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

This specification also provides, inter alia, a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer.

This specification also provides, inter alia, a method of treating cancer in a warm-blooded animal in need of such treatment, comprising administering to the warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF GRAPHICS

On FIG. 1 shows the X-ray powder diffraction pattern (XRD) of form A (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1, 5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine (Compound A, Example 62).

On FIG. 2 shows a DSC (differential scanning calorimetry) thermogram of form A (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine (Compound A, Example 62).

On FIG. 3 shows the in vivo activity of an MCT4 inhibitor (Example 62) in combination with VEGFR TKI (vascular endothelial growth factor receptor 1 tyrosine kinase) (AZD2171, also known as cediranib) in a lung cancer xenograft model.

On FIG. 4 shows in vivo activity of an MCT4 inhibitor (Example 62) in combination with an anti-CTLA4 (cytotoxic T-lymphocyte antigen-4) antibody in a syngeneic mouse model.

On FIG. 5 shows in vivo activity of an MCT4 inhibitor (Example 62) in combination with an anti-PD-1 (programmed cell death protein 1) antibody in a syngeneic mouse model.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Many embodiments of the invention are described in detail in the description and will be obvious to a person skilled in the art. The invention should not be construed as being limited to any particular embodiment(s).

In a first embodiment, a compound of formula (I) is provided:

or a pharmaceutically acceptable salt thereof, wherein:

each R ¹ and R ² independently represents hydrogen or methyl;

X is CH ₂ or O;

each ring A and ring B is independently a ring selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, where each ring A and ring B is independently optionally substituted with one or more substituents selected from C _1-3 alkyl and C _{1 -3} alkoxy;

ring C is a 5-9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, where the heterocycloalkyl is optionally substituted with one or more substituents selected from C _{1- 3} alkyl optionally substituted with methoxy or hydroxyl; dioxo, C _0-2 alkyl-C(O)N(Me) ₂ , C(O)C _1-2 alkyl and S(O) ₂ C _1-2 alkyl.

The term "heterocycloalkyl" means a 5-9 membered saturated nitrogen-containing non-aromatic ring (ring C in formula (I)) containing one or more additional heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of suitable heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, diazabicyclooctanyl, octahydropyrrolo[1,2-a]pyrazinyl, pyrrolidinyl, diazepanyl, oxazepanyl and azepanyl. For the avoidance of doubt, substituents on the heterocycloalkyl ring may be bonded through either a carbon atom or a heteroatom.

The term "dioxo" means two oxo substituents that are attached to the same atom. Examples of dioxo substitution include cases where ring C is thiomorpholinyl, where the sulfur atom is substituted with two oxo groups, ie where ring C is thiomorpholine-1,1-dioxide.

The prefix C _pq in C _p-q alkyl and other terms (where p and q are integers) indicates the number of carbon atoms that are present in the group, e.g. C _1-3 alkyl includes C ₁ alkyl (methyl), C ₂ alkyl ( ethyl) and C ₃ alkyl (propyl, such as n-propyl and isopropyl). In one embodiment, C _1-3 alkyl is methyl.

The term C _p-q alkoxy includes -O-C _p-q alkyl groups. For example, C _1-3 alkoxy includes C ₁ alkoxy (methoxy), C ₂ alkoxy (ethoxy), and C ₃ alkoxy (propoxy, such as n-propoxy and isopropoxy). In one embodiment, C _1-3 alkoxy is methoxy.

Where the term "possible" is used, it is meant that the subsequent feature may or may not occur. Thus, the use of the term "may" includes cases where the feature is present as well as cases where the feature is not present. For example, the group "optionally substituted with one methoxy group" includes groups with and without a methoxy substituent.

The term "substituted" means that one or more hydrogen atoms (e.g. one or two hydrogen atoms or alternatively one hydrogen atom) in the designated group is replaced by the indicated substituent(s) (e.g. one or two substituents or alternatively one substituent ) provided that any atom(s) bearing a substituent retains a valid valence. Substituent combinations include only stable compounds and stable synthetic intermediates. "Stable" means that the respective compound or intermediate is sufficiently stable upon isolation and can be used either as a synthetic intermediate or as an agent of potential therapeutic benefit. If a group is not described as "substituted" or "possibly substituted", it should be considered as unsubstituted (ie, that none of the hydrogen atoms of the specified group has not been replaced).

The term "pharmaceutically acceptable" is used to mean that the object (eg, salt, dosage form, excipient) is suitable for use by patients. A list of examples of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.H.

In a further embodiment, any of the embodiments defined herein (e.g., an embodiment of claim 1) is provided, provided that one or more specific examples (e.g., one, two, or three specific examples) selected from the group consisting of Examples 1 , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 , 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 , 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78 , 79, 80, 81, 82, 83, 84, 85, 86 and 87, individually rejected.

In one embodiment, X is CH ₂ . In another embodiment, X is O.

In one embodiment, R ¹ and R ² are both hydrogen. In another embodiment, R ¹ and R ² are both methyl. In another embodiment, R ¹ is hydrogen and R ² is methyl. In one embodiment, R ¹ and R ² are both hydrogen, or R ¹ is hydrogen and R ² is methyl.

Ring A is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.

Ring B is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.

In formula (I), ring A is attached to the nitrogen atom of the pyrrolidine ring and to ring B, and ring B is attached to ring A and to the -C(R ¹ R ² )-ring C group. Ring A and ring B may optionally be further substituted , as defined here. In one embodiment, the pyrrolidine ring and ^ring B are para-oriented ⁽ i.e., 1,4) in the A ring. 1,4) in ring B. In one embodiment, the pyrrolidine ring and ring B are oriented in the para position (i.e., 1,4) in ring A, and ring A and the -C(R ¹ R ² )-ring C group are oriented in the para position (i.e., 1.4) in ring B. In another embodiment, the pyrrolidine ring and ring B are oriented to the para position (i.e., 1.4) in ring A, and ring A and the -C(R ¹ R ² )-ring C is oriented to the para position (i.e. 1,4) in ring B, and ring A and ring B are linked to each other via a ring carbon atom and linked to the rest of the molecule via a ring carbon atom.

In one embodiment, at least one Ring A or Ring B is selected from pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

In one embodiment, Ring A and Ring B are each independently selected from phenyl, pyridazinyl, and pyrazinyl. In another embodiment, Ring A and Ring B are each independently selected from phenyl and pyridazinyl. In another embodiment, Ring A is phenyl and Ring B is pyridazinyl. In another embodiment, Ring A is pyrazinyl and Ring B is phenyl.

In one embodiment, Ring A and Ring B are optionally substituted with one or two substituents selected from C _1-3 alkyl and C _1-3 alkoxy. In one embodiment, each ring A and ring B is independently optionally substituted with one substituent selected from C _1-3 alkyl and C _1-3 alkoxy. In one embodiment, each Ring A and Ring B are independently optionally substituted with one substituent selected from methyl and methoxy.

In one embodiment, ring C is a 5-7 membered monocyclic saturated heterocycloalkyl ring. In another embodiment, ring C is an 8- or 9-membered bicyclic saturated heterocycloalkyl ring. The bicyclic heterocycloalkyl ring may be a bridged or fused bicyclic ring.

In one embodiment, Ring C is selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, diazabicyclooctanyl, octahydropyrrolo[1,2-a]pyrazinyl, pyrrolidinyl, diazepanil, oxazepanil, and azepanil.

In one embodiment, ring C is selected from the group consisting of morpholin-4-yl, piperazin-4-yl, piperidin-1-yl, thiomorpholin-4-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl , octahydropyrrolo[1,2-a]pyrazin-2-yl, pyrrolidin-1-yl, 1,4-diazepan-1-yl, 1,4-oxazepan-4-yl, azepanyl-1-yl.

In one embodiment, Ring C is morpholinyl or piperazinyl. In one embodiment, ring C is morpholin-4-yl or piperazin-4-yl.

In one embodiment, ring C is morpholinyl. In one embodiment, ring C is morpholin-4-yl.

In one embodiment, Ring C is piperazinyl. In one embodiment, ring C is piperazin-4-yl.

In one embodiment, ring C is optionally substituted with one or more (eg one, two or three) substituents independently selected from hydroxyl; ethyl, optionally substituted with methoxy or hydroxyl; dioxo, C(O)N(Me) ₂ , CH ₂ C(O)N(Me) ₂ , C(O)Me and S(O) ₂ Me. In one embodiment, ring C is substituted with C(O)Me or methyl.

In one embodiment, Ring C is piperazin-4-yl-ethanone. In another embodiment, Ring C is 4-methyl-1-piperazinyl.

In one embodiment:

R ¹ and R ² are both hydrogen;

X is CH ₂ or O;

each ring A and ring B is independently a ring selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, where each ring A and ring B is independently optionally substituted with one or more substituents selected from C _1-3 alkyl and C _{1 -3} alkoxy;

ring C is a 5-9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, where the heterocycloalkyl is optionally substituted with one or more substituents selected from C _{1- 3} alkyl optionally substituted with methoxy or hydroxyl; dioxo, C _0-2 alkyl-C(O)N(Me) ₂ , C(O)C _1-2 alkyl and S(O) ₂ C _1-2 alkyl.

In one embodiment:

R ¹ and R ² are both hydrogen;

X is O;

each ring A and ring B is independently selected from phenyl and pyridazinyl;

ring C is morpholinyl or piperazinyl, where the piperazinyl is optionally substituted with C _1-3 alkyl, optionally substituted with methoxy or hydroxyl; C _0-2 alkyl-C(O)N(Me) ₂ , C(O)C _1-2 alkyl and S(O) ₂ C _1-2 alkyl.

In one embodiment:

R ¹ and R ² are both hydrogen;

X is CH ₂ ;

each ring A and ring B is independently selected from phenyl, pyridazinyl and pyrazinyl;

ring C is morpholinyl, piperazinyl or pyrazinyl, where pyrazinyl or piperazinyl is optionally substituted with C _1-3 alkyl, optionally substituted with methoxy or hydroxyl; C _0-2 alkyl-C(O)N(Me) ₂ , C(O)C _1-2 alkyl and S(O) ₂ C _1-2 alkyl.

According to a further embodiment, a compound of formula (Ia) is provided:

or a pharmaceutically acceptable salt thereof, wherein

each R ¹ and R ² independently represents hydrogen or methyl;

X is CH ₂ or O;

each D, E, G, J, L, M, Q and R is independently N or CR ³ where no more than two of D, E, G and J are N, and where no more than two of L, M, Q and R are N;

R ³ is hydrogen, C _1-3 alkyl or C _1-3 alkoxy;

ring C is a 5-9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, where the heterocycloalkyl is optionally substituted with one or more substituents selected from C _{1- 3} alkyl optionally substituted with methoxy or hydroxyl; dioxo, C _0-2 alkyl-C(O)N(Me) ₂ , C(O)C _1-2 alkyl and S(O) ₂ C _1-2 alkyl.

In one embodiment, R ¹ and R ² are both hydrogen. In another embodiment, R ¹ and R ² are both methyl. In another embodiment, R ¹ is hydrogen and R ² is methyl. In one embodiment, R ¹ and R ² are both hydrogen, or R ¹ is hydrogen and R ² is methyl.

D, E, G and J are each independently N or CR ³ , where no more than two of D, E, G and J are N.

L, M, Q and R are each independently N or CR ³ where no more than two of L, M, Q and R are N.

In one embodiment, D, E, G, and J are each independently CR ³ . In another embodiment, one of D, E, G, and J is N and the remainder is each independently CR ³ . In another embodiment, two of D, E, G and J are N and the remaining two are independently CR ³ .

In one embodiment, L, M, Q, and R are each independently CR ³ . In another embodiment, one of L, M, Q, and R is N and the remainder is each independently CR ³ . In another embodiment, two of L, M, Q and R are N and the remaining two are independently CR ³ .

In one embodiment, D, E, G and J are each independently CR ³ and L, M, Q and R are each independently N or CR ³ where no more than two of L, M, Q and R are N. In one embodiment, one of D, E, G and J is N and the remainder is each independently CR ³ , and L, M, Q and R are each independently N or CR ³ where no more than two of L, M , Q, and R are N. In one embodiment, two of D, E, G, and J are N, and the remaining two are independently CR ³ , and L, M, Q, and R are each independently N or CR, where no more than two of L, M, Q and R are N.

In one embodiment, D, E, G, and J are N or CR ³ , where no more than two of D, E, G, and J are N, and L, M, Q, and R are each independently CR ³ . In one embodiment, D, E, G and J are N or CR ³ where no more than two of D, E, G and J are N and one of L, M, Q and R is N and each remaining is independently CR ³ . In one embodiment, D, E, G and J are N or CR ³ where no more than two of D, E, G and J are N and two of L, M, Q and R are N and both of the remaining independently represent CR ³ .

In one embodiment, D, E, G and J are each independently CR ³ , and L, M, Q and R are each independently CR ³ .

In one embodiment, D, E, G and J are each independently CR ³ and one of L, M, Q and R is N and the remainder is each independently CR ³ .

In one embodiment, D, E, G and J are each independently CR ³ and two of L, M, Q and R are N and the remainder are both independently CR ³ .

In one embodiment, one of D, E, G and J is N and the remainder is each independently CR ³ , and L, M, Q and R are each independently CR ³ .

In one embodiment, one of D, E, G and J is N and each remaining independently is CR ³ , and one of L, M, Q and R is N and each remaining independently is CR ³ .

In one embodiment, one of D, E, G and J is N and the remainder are each independently CR ³ , and two of L, M, Q and R are N and the remainder are both independently CR ³ .

In one embodiment, two of D, E, G, and J are N, and the remaining two are independently CR ³ , and L, M, Q, and R are each independently CR ³ .

In one embodiment, two of D, E, G and J are N and the remainder are both independently CR ³ , and one of L, M, Q and R is N and each remaining independently is CR ³ .

In one embodiment, two of D, E, G and J are N and both of the remaining are independently CR ³ , and two of L, M, Q and R are N and the remainder of both are independently CR ³ .

In one embodiment, the ring containing D, E, G and J is a ring selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl. In one embodiment, the ring containing D, E, G and J is a ring selected from phenyl, pyridazinyl and pyrazinyl. In one embodiment, the ring is selected from phenyl and pyridazinyl.

In one embodiment, the ring containing L, M, Q and R is a ring selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl. In one embodiment, the ring containing L, M, Q and R is a ring selected from phenyl, pyridazinyl and pyrazinyl. In one embodiment, the ring is selected from phenyl and pyridazinyl.

In another embodiment, the ring containing D, E, G and J is phenyl and the ring containing L, M, Q and R is pyridazinyl. In another embodiment, the ring containing D, E, G and J is pyrazinyl and the ring containing L, M, Q and R is phenyl.

In one embodiment, each ring containing D, E, G and J and the ring containing L, M, Q and R is independently optionally substituted with one or two substituents, i.e. where R ³ is C _1-3 alkyl and C _{1 -3} alkoxy. In one embodiment, each ring containing D, E, G, and J and the ring containing L, M, Q, and R are independently optionally substituted with one substituent, that is, where R ³ is C _1-3 alkyl and C _1-3 alkoxy. In one embodiment, each ring containing D, E, G, and J and the ring containing L, M, Q, and R are independently optionally substituted with one substituent, where R ³ is selected from methyl and methoxy.

In one embodiment, ring C is a 5-7 membered monocyclic saturated heterocycloalkyl ring. In another embodiment, ring C is an 8- or 9-membered bicyclic saturated heterocycloalkyl ring. The bicyclic heterocycloalkyl ring may be a bridged or fused bicyclic ring.

In one embodiment, Ring C is selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, diazabicyclooctanyl, octahydropyrrolo[1,2-a]pyrazinyl, pyrrolidinyl, diazepanil, oxazepanil, and azepanil.

In one embodiment, ring C is selected from the group consisting of morpholin-4-yl, piperazin-4-yl, piperidin-1-yl, thiomorpholin-4-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl , octahydropyrrolo[1,2-a]pyrazin-2-yl, pyrrolidin-1-yl, 1,4-diazepan-1-yl, 1,4-oxazepan-4-yl, azepanyl-1-yl.

In one embodiment, Ring C is morpholinyl or piperazinyl. In one embodiment, ring C is morpholin-4-yl or piperazin-4-yl.

In one embodiment, ring C is morpholinyl. In one embodiment, ring C is morpholin-4-yl.

In one embodiment, Ring C is piperazinyl. In one embodiment, ring C is piperazin-4-yl.

In one embodiment, ring C is optionally substituted with one or more (eg one, two or three) substituents independently selected from hydroxyl; ethyl, optionally substituted with methoxy or hydroxyl; dioxo, C(O)N(Me) ₂ , CH ₂ C(O)N(Me) ₂ , C(O)Me and S(O) ₂ Me. In one embodiment, ring C is substituted with C(O)Me or methyl.

In one embodiment, Ring C is piperazin-4-yl-ethanone. In another embodiment, Ring C is 4-methyl-1-piperazinyl.

In one embodiment:

R ¹ and R ² are both hydrogen;

X is CH ₂ or O;

D, E, G, J, L, M, Q and R are each independently N or CR ³ where no more than two of D, E, G and J are N, and where no more than two of L, M, Q and R are N;

R ³ is hydrogen, C _1-3 alkyl or C _1-3 alkoxy;

ring C is a 5-9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, where the heterocycloalkyl is optionally substituted with one or more substituents selected from C _{1- 3} alkyl optionally substituted with methoxy or hydroxyl; dioxo, C _0-2 alkyl-C(O)N(Me) ₂ , C(O)C _1-2 alkyl and S(O) ₂ C _1-2 alkyl.

In one embodiment:

R ¹ and R ² are both hydrogen;

X is O;

D, E, G, J, L, M, Q and R are each independently N or CR ³ where no more than two of D, E, G and J are N, and where no more than two of L, M, Q and R are N;

R ³ is hydrogen, methyl or methoxy;

ring C is morpholinyl or piperazinyl, where the piperazinyl is optionally substituted with C _1-3 alkyl, optionally substituted with methoxy or hydroxyl; C _0-2 alkyl-C(O)N(Me) ₂ , C(O)C _1-2 alkyl and S(O) ₂ C _1-2 alkyl.

In one embodiment:

R ¹ and R ² are both hydrogen;

X is CH ₂ ;

D, E, G, J, L, M, Q and R are each independently N or CR ³ where no more than two of D, E, G and J are N, and where no more than two of L, M, Q and R are N;

R ³ is selected from hydrogen, methyl or methoxy;

ring C is morpholinyl, piperazinyl or pyrazinyl, where pyrazinyl or piperazinyl is optionally substituted with C _1-3 alkyl, optionally substituted with methoxy or hydroxyl; C _0-2 alkyl-C(O)N(Me) ₂ , C(O)C _1-2 alkyl and S(O) ₂ C _1-2 alkyl.

According to a further embodiment, a compound of formula (Ib) is provided:

or its pharmaceutically acceptable salt, where R ¹ , R ² , X, ring A, ring B and ring C are as defined here.

According to a further embodiment, a compound of formula (Ic) is provided:

or its pharmaceutically acceptable salt, where R ¹ , R ² , X, D, E, G, J, L, M, Q, R and ring C are as defined here.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

(R)-4-((6'-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1 -yl)-[3,3'-bipyridine]-6-yl)methyl)morpholine;

(R)-2,5,7-trimethyl-6-((1-(6'-((4-methylpiperazin-1-yl)methyl)-[3,3'-bipyridin]-6-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-2-yl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-(4-(2-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin- 1-yl)pyrimidin-5-yl)benzyl)morpholine;

(R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)pyridin-2-yl)pyrazin-2-yl)methyl)morpholine;

(R)-2,5,7-trimethyl-6-((1-(6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-3-yl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-((6-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)pyridin-2-yl)pyridazin-3-yl)methyl)morpholine;

6-(((R)-1-(2-(4-(((S)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)pyrimidin-2-yl)pyridin-2-yl)methyl)morpholine;

(R)-6-((1-(2-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2 ,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(2-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

6-(((R)-1-(2-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl) methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine -6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)acetamide;

(R)-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl )pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethanol;

(R)-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl )pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethenone;

(R)-6-((1-(2-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)- 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin- 1-yl)pyrimidin-2-yl)benzyl)morpholine;

(R)-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrazin-2-yl)phenyl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(4-(2-((4-methylpiperazin-1-yl)methyl)pyrimidin-5-yl)phenyl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyridin-3-yl)methyl)morpholine;

(R)-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)phenyl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyrazin-2-yl)methyl)morpholine;

(R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)phenyl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine;

(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;

(S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;

(R)-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl )-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

2,5,7-trimethyl-6-(((R)-1-(5-(4-(((3R,5S)-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin- 2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

6-(((R)-1-(5-(4-(((R)-3,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

6-(((R)-1-(5-(4-(((R)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

2,5,7-trimethyl-6-(((R)-1-(5-(4-(((2R,5R)-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin- 2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

2,5,7-trimethyl-6-(((R)-1-(5-(4-(((2S,5R)-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin- 2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

2,5,7-trimethyl-6-[[(3R)-1-[5-[4-(1-piperidylmethyl)phenyl]pyrazin-2-yl]pyrrolidin-3-yl]methyl]-[1,2 ,4]triazolo[1,5-a]pyrimidine;

(R)-6-((1-(5-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7 -trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(5-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

6-(((R)-1-(5-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl) methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

2-{4-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl] pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazin-1-yl}ethanol;

(R)-6-((1-(5-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)- 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2 ,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

{1-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin- 1-yl}pyrazin-2-yl)benzyl]piperidin-4-yl}methanol;

6-{[(3R)-1-(5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}pyrazin-2-yl)pyrrolidin-3-yl]methyl}-2,5 ,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidine;

2,5,7-trimethyl-6-({(3R)-1-[5-(4-{[4-(methylsulfonyl)piperidin-1-yl]methyl}phenyl)pyrazin-2-yl]pyrrolidin-3 -yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-((6-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl )methyl)pyrrolidin-1-yl)pyrazin-2-yl)pyridin-3-yl)methyl)morpholine;

6-(((R)-1-(5-(4-(((S)-3,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)pyrazin-2-yl)pyridin-2-yl)methyl)morpholine;

6-(((R)-1-(5-(4-(((S)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-(4-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine;

2,5,7-trimethyl-6-({(3R)-1-[5-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)pyrazin-2-yl]pyrrolidin-3 -yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine -6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)acetamide;

(R)-2,5,7-trimethyl-6-((1-(6-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

N,N-dimethyl-4-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-а]pyrimidin-6-yl )methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazin-1-carboxamide;

(R)-2,5,7-trimethyl-6-((1-(5-(3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(5-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl )pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)ethenone;

(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin- 1-yl)pyrazin-2-yl)benzyl)morpholine;

(R)-4-(4-(6-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin- 1-yl)pyridazin-3-yl)benzyl)morpholine;

(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;

(S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;

(R)-2,5,7-trimethyl-6-((1-(4-(6-(piperidin-1-ylmethyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1 ,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl) hydroxy)-[1,2,4]triazolo[1,5-a]pyrimidine;

2,5,7-trimethyl-6-(((3R)-1-(4-(6-((3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)pyridazin- 3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;

6-(((R)-1-(4-(6-(((R)-hexahydropyrrolo[1,2-а]pyrazin-2(1H)-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidine -3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

6-(((R)-1-(4-(6-(((S)-hexahydropyrrolo[1,2-а]pyrazin-2(1H)-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidine -3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine;

(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyrazin-2-yl)methyl)morpholine;

(R)-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one;

(R)-6-((1-(4-(6-((4-ethylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7 -trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-6-((1-(4-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)- 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-((6'-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1 -yl)-[2,3'-bipyridine]-5-yl)methyl)morpholine;

(R)-4-((6'-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1 -yl)-[3,3'-bipyridine]-6-yl)methyl)morpholine;

(R)-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl) hydroxy)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl) hydroxy)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin- 1-yl)pyrazin-2-yl)benzyl)morpholine;

1-[4-[[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]methyl]-1,4-diazepan-1-yl]ethenone;

(R)-2,5,7-trimethyl-6-((1-(5-(4-(pyrrolidin-1-ylmethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1 ,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl )-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-2,5,7-trimethyl-6-((1-(5-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl )-[1,2,4]triazolo[1,5-a]pyrimidine;

(R-2,5,7-trimethyl-6-((1-(5-(4-((4-methyl-1,4-diazepan-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidine -3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;

(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)-1,4-oxazepane;

(R)-6-((1-(4-(6-(Azepan-1-ylmethyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1 ,2,4]triazolo[1,5-a]pyrimidine;

4-[(1R1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholine, and

4-[(1S-1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-а]pyrimidine-6- yl)oxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholine.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;

(R)-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one;

(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; And

(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2, 4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine (also referred to as Compound A).

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-1-(4-((6-(4-(3-((2,5,7-trimethyl-[ 1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazine-1 -yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2, 4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine.

In one embodiment, the compound of formula (I) is in free base form.

The compounds and salts described in this specification may exist in solvated and unsolvated forms. For example, the solvated form may be a hydrated form such as hemihydrate, monohydrate, dihydrate, trihydrate, or an alternative amount thereof. The invention embraces all such solvated and unsolvated forms of the compounds of formula (I), especially provided that such forms have MCT4 inhibitory activity, such as, for example, measured using the tests described herein.

Atoms of the compounds and salts described in this specification may exist as isotopes. The invention covers all compounds of formula (I) in which an atom is replaced by one or more isotopes (for example, a compound of formula (I) where one or more than one carbon atom is a ¹¹ C or ¹³ C carbon isotope, or where one or more than one hydrogen atom is a ² H or ³ H isotope, or where one or more nitrogen atoms is a ¹⁵ N isotope, or where one or more oxygen atoms is a ¹⁷ O or ¹⁸ O isotope).

The compounds and salts described in this specification may exist in optically active or racemic forms due to one or more asymmetric carbon atoms. The invention includes any optically active or racemic form of a compound of formula (I) that has MCT4 inhibitory activity, eg as measured using the tests described herein. Synthesis of optically active forms can be carried out by standard methods of organic chemistry, well known in the art, for example through synthesis using optically active substances or by resolution of the racemic form.

Therefore, in one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, which is a single optical isomer present in an enantiomeric excess (% e.u.) of at least 95%, at least 98%, or at least 99%. In one embodiment, a single optical isomer is present in an enantiomeric excess (% ee) of at least 99%.

Some of the compounds of formula (I) may be crystalline and may have more than one crystalline form. It should be understood that the invention encompasses any crystalline or amorphous form, or mixtures thereof, which have properties useful for MCT4 inhibitory activity. It is well known how to determine the effectiveness of a crystalline or amorphous form using the standard tests described below.

It is well known that crystalline substances can be analyzed using conventional methods such as, for example, X-ray powder diffraction analysis (hereinafter XRD) and differential scanning calorimetry (hereinafter DSC).

For example, the compound from Example 62 exhibits crystallinity and a crystalline form, Form A, has been identified.

Therefore, an additional aspect of the disclosure is Form A of Compound A (Example 62).

The disclosure provides a crystalline form, form A, of compound A which has an XRD pattern with at least one characteristic peak at a 2-theta angle of about 7.8° measured using CuKα radiation.

The disclosure provides a crystalline form, form A, of compound A which has an XRD pattern with at least one characteristic peak at a 2-theta angle of about 19.0° measured using CuKα radiation.

The disclosure provides a crystalline form, form A, of compound A, which has an XRD pattern with at least two characteristic peaks at 2-theta angles of about 7.8° and 19.0° measured with CuKα radiation.

The disclosure provides a crystalline form, form A, of compound A, which has an XRD pattern with characteristic peaks at 2-theta angles of about 7.8; 9.2; 9.5; 10.4; 11.6; 15.8; 18.3; 19.0; 22.3 and 25.3° measured with CuKα radiation.

The disclosure provides a crystalline form, Form A, of Compound A, which has an XRD pattern substantially similar to the XRD pattern shown in FIG. 1, established using CuKα radiation.

The disclosure provides a crystalline form, form A, of compound A, which has an XRD pattern with at least one characteristic peak at a 2-theta angle of 7.8° plus or minus 0.2° as measured by CuKα radiation.

The disclosure provides a crystalline form, form A, of compound A, which has an XRD pattern with at least one characteristic peak at a 2-theta angle of 19.0° plus or minus 0.2° as measured by CuKα radiation.

According to the disclosure, a crystalline form, form A, of compound A is provided, which has an XRD pattern with at least two characteristic peaks at 2-theta angles of 7.8° and 19.0°, where these values can be greater or less than 0 ,2° measured with CuKα radiation.

According to the disclosure, a crystalline form, form A, of compound A is provided which has an XRD pattern with characteristic peaks at 2-theta angles of 7.8; 9.2; 9.5; 10.4; 11.6; 15.8; 18.3; 19.0; 22.3 and 25.3°, where the indicated values may be more or less than 0.2°, which are measured using CuKα radiation.

DSC analysis of Compound A Form A shows a melting endotherm starting at about 210.2°C and peaking at about 213.2°C (FIG. 2).

Thus, DSC analysis shows that Compound A, Form A, is a high melting solid with an onset of melting at about 210.2°C and a peak at about 213.2°C.

When the present disclosure refers to a crystalline form of Form A of Compound A, the degree of crystallinity is suitably greater than about 60%, more suitably greater than about 80%, preferably greater than about 90%, and more preferably greater than about 95%. Most preferably, the degree of crystallinity is greater than about 98%.

It should be understood that the values of the 2-theta angles of the XRD pattern may differ slightly from one instrument to another or from one sample to another, and therefore the values given should not be regarded as absolute.

It is known that an XRD pattern can be obtained that has one or more measurement errors depending on the measurement conditions (such as the equipment or instrument used). In particular, it is well known that the intensity of the XRD pattern may fluctuate depending on the measurement conditions. Therefore, it should be understood that Compound A, Form A, of the present disclosure is not limited to crystals that give XRD patterns identical to the XRD pattern shown in FIG. 1 and any crystals that give XRD patterns are essentially the same as that shown in FIG. 1. are within the scope of this disclosure. A specialist in the field of DRLP is able to assess the existing identity of the DRLP patterns.

Those skilled in the art of XRD will appreciate that the relative intensity of the peaks can be affected by, for example, grains larger than 30 microns and non-unitary aspect ratios, which can affect the analysis of the samples. One skilled in the art will also appreciate that the position of the reflections can be affected by the exact height at which the sample is in the diffractometer and the zero calibration of the diffractometer. The planarity of the sample surface can also have a small effect. Therefore, the presented data of the diffraction pattern should not be taken as absolute values. (Jenkins, R & Snyder, R.L. 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; Klug, H.P. & Alexander, L.E. (1974), X -Ray Diffraction Procedures).

Typically, the measurement error of the diffraction angle in an X-ray powder diffraction pattern is approximately plus or minus 0.2° of the 2-theta angle, and such a degree of measurement error should be taken into account when analyzing the XRD pattern in FIG. 1, and when considering Table A. In addition, it should be understood that the intensities may fluctuate depending on the experimental conditions and sample preparation (preferred orientation).

The compounds of formula (I) contain one or more chiral centers. In cases where a structure or chemical name in this specification does not indicate chirality, the structure or name is intended to include any single stereoisomer (i.e., any single chiral isomer) corresponding to that structure or name, as well as any mixture of stereoisomers (e.g., racemate) . It is well known in the art how such optically active forms can be obtained. For example, a single stereoisomer can be obtained by separating it from a mixture of isomers (eg a racemate) using, for example, chiral chromatographic separation. In other embodiments, a single stereoisomer is obtained by direct synthesis, for example from a chiral starting material.

Compounds of formula (I), where X is O, can be obtained, for example, by reacting a compound of formula (II):

or its salt with a compound of formula (III):

or a salt thereof, where W is a suitable leaving group, such as Cl, Br, I, or OTf, and R ¹ , R ² , ring A, ring B and ring C are as defined in any of the embodiments here. The reaction is conveniently carried out in a suitable solvent (eg 2-methyltetrahydrofuran) in the presence of a base (eg cesium carbonate) and in the presence of a suitable catalyst (eg Pd Ruphos 3rd generation) and ligand (eg Ruphos) at a suitable temperature (eg in the range of 60° C to 80°C).

Alternatively, depending on the nature of the A ring, compounds of formula (I) or pharmaceutically acceptable salts thereof can also be prepared by reacting a compound of formula (II) or a salt thereof and a compound of formula (III) or a salt thereof using standard aromatic substitution conditions, well known to those skilled in the art, for example with a suitable base (eg diisopropylethylamine) in a suitable solvent (eg 1-butanol) at a suitable temperature (eg in the range of 60° C. to 120° C.).

Thus, the compounds of formula (II) and (III) and their salts are used as intermediates in the preparation of compounds of formula (I) and represent a further embodiment.

Compounds of formula (II) can be obtained, for example, according to the following scheme 1:

where PG is a suitable nitrogen protecting group, for example Boc.

Stage 1: carried out using a suitable nucleophile (eg benzoic acid) in the presence of a suitable base (eg KOH) in a suitable solvent (eg DMF (dimethylformamide)) at a suitable temperature (eg in the range from 20°C to 50°C).

Step 2: carried out using a suitable cyclization substrate (eg 3-methyl-1H-1,2,4-triazol-5-amine) in a suitable solvent (eg AcOH) at a suitable temperature (eg 70°C to 90° WITH).

Step 3: Carried out under standard hydrolysis conditions well known to those skilled in the art, eg 1 M NaOH (aq.) in EHN at room temperature.

Step 4: Carried out under standard conditions well known to those skilled in the art. The reaction can be carried out under standard Mitsunobu reaction conditions with a suitable alcohol substrate (eg tert-butyl-3-hydroxypyrrolidine-1-carboxylate) with triphenylphosphine and DIAD (diisopropyl azodicarboxylate) in THF (tetrahydrofuran) at room temperature.

Step 5: Carried out under standard deprotection conditions well known to those skilled in the art. For example, when PG (protecting group) is Boc, the reaction can be carried out using 4 M HCl in 1,4-dioxane in MeOH at room temperature.

Compounds of formula (III) where R ¹ and R ² are hydrogen can be obtained, for example, by reacting a compound of formula (IV)

or a salt thereof with a suitable chlorinating agent (eg trichloroisocyanuric acid) in a suitable solvent (eg dichloroethane) followed by reaction with a suitable C-ring amine (eg morpholine) at a suitable temperature (eg room temperature) where W is a suitable leaving group , for example Cl, Br, I or OTf, and ring A, ring B and ring C are as defined in any of the embodiments here. In one embodiment, ring A is phenyl and ring B is pyradazinyl.

Compounds of formula (I), where X is CH ₂ , can be obtained, for example, by reacting compounds of formula (III) or salts thereof, where R ¹ , R ² , ring A, ring B and ring C are as defined in any of the embodiments herein, with a compound of formula (V)

or its salt. The reaction is conveniently carried out in a suitable solvent (eg 1,4-dioxane) in the presence of a base (eg cesium carbonate) and in the presence of a suitable catalyst (eg Pd Ruphos 3rd generation) and ligand (eg Ruphos) at a suitable temperature (eg in the range of 60°C to 90°C).

Therefore, compounds of formula (V) are also used as intermediates in the preparation of compounds of formula (I) and represent an additional embodiment.

Compounds of formula (V) can be obtained, for example, according to the following scheme 2:

where PG is a suitable nitrogen protecting group, eg Boc, and Y is a suitable leaving group, eg Cl, Br, I or OMs.

Step 1: Carried out under conditions that convert OH to a suitable leaving group, e.g. if Br is chosen as the leaving group, then the reaction can be carried out under conditions well known to those skilled in the art, e.g. triphenylphosphine, tetrabromomethane in DCM ( dichloromethane) at a temperature in the range from 0°C to room temperature.

Step 2: carried out using a suitable nucleophile (eg pentane-2,4-dione) in the presence of a suitable base (eg potassium carbonate) in a suitable solvent (eg DMF) at a suitable temperature (eg 60°C to 80°C) .

Step 3: carried out using a suitable cyclization substrate (eg 3-methyl-1H-1,2,4-triazol-5-amine) in a suitable solvent (eg AcOH) at a suitable temperature (eg 70°C to 90° WITH).

Step 4: carried out using standard deprotection conditions well known to those skilled in the art. For example, when PG is Boc, the reaction can be carried out using 4 M HCl in 1,4-dioxane in MeOH at room temperature.

Alternatively, compounds of formula (I) wherein X is CH ₂ can be prepared by reacting a compound of formula (VI)

or a salt thereof, where W is a suitable leaving group, for example Cl, Br, I, or OTf, and ring A is as defined in any of the embodiments herein, with a compound of formula (VII)

or a salt thereof, where Z is a suitable leaving group, such as pinacolboronate, boronic acid or an organotin compound, and R ¹ , R ² , ring B and ring C are as defined in any of the embodiments here. When Z is pinacolboronate, then the reaction is conveniently carried out in a suitable solvent (e.g. a mixture of 1,4-dioxane and water) in the presence of a base (e.g. cesium carbonate) and in the presence of a suitable catalyst (e.g. 2nd generation Pd Xphos) at a suitable temperature ( e.g. in the range of 60°C to 90°C). In one embodiment, R ¹ and R ² are hydrogen, ring A is pyrazinyl, ring B is phenyl, and ring C is 4-methyl-1-piperazinyl.

Compounds of formula (VI) or salts thereof can be prepared by reacting a compound of formula (V) or a salt thereof with ring A using standard aromatic substitution chemistries. Ring A will have a suitable leaving group (eg chlorine or bromine) and the reaction is conveniently carried out in a suitable solvent (eg 1-butanol) in the presence of a suitable base (eg diisopropylethylamine) at a suitable temperature (eg 60°C to 120°C). Alternatively, compounds of formula (VI) or salts thereof can be prepared by reacting a compound of formula (V) or a salt thereof with ring A using standard cross-coupling conditions. Ring A will have a suitable leaving group (eg chlorine, bromine or iodine) in a suitable solvent (eg 1,4-dioxane) in the presence of a base (eg cesium carbonate) and in the presence of a suitable catalyst (eg Pd Ruphos 3rd generation) at suitable temperature (eg 60°C to 90°C).

Alternatively, compounds of formula (I) wherein X is CH ₂ can be prepared by reacting a compound of formula (VIII)

or its salts with a suitable amine based ring C, where ring A, ring B and ring C are as defined in any of the embodiments here. The interaction can be carried out under standard conditions, well known to experts in the art, for example with triethylamine in THF at 60°C.

Alternatively, compounds of formula (I) wherein X is CH ₂ can be prepared by reacting a compound of formula (IX)

or its salts with a suitable amine based ring C, where ring A, ring B and ring C are as defined in any of the embodiments here. The reaction can be carried out under standard conditions well known to those skilled in the art, eg with sodium triacetoxyborohydride, AcOH in DCM at room temperature.

It should be understood that some of the various ring substituents in the compounds of the present disclosure may be introduced via standard aromatic substitution reactions or formed via conventional functional group modifications either before or immediately after the methods mentioned above, and as such are included in the method aspect of the disclosure. For example, compounds of formula (I) can be converted to other compounds of formula (I) by standard aromatic substitution reactions or by conventional functional group modifications. Such reactions and modifications include, for example, introduction of a substituent through an aromatic substitution reaction, reduction of substituents, alkylation of substituents, and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the art of chemistry.

It should also be understood that in some of the interactions mentioned here, it may be necessary/desirable to protect any sensitive groups in the compounds. Instances where protection is necessary or desirable and suitable methods of protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for an illustration, see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if the reactants include groups such as amino, carboxy, or hydroxy, it may be desirable to protect the group in some of the interactions mentioned here.

In any of the embodiments where a compound of formula (II)-(GC) or a salt thereof is mentioned, it is to be understood that such salts need not be pharmaceutically acceptable salts.

The compounds of formula (I) and any intermediates used to obtain them, can be obtained by methods similar to those shown in the "Examples" section.

Biological analyzes

The following in vitro assays were used to measure the effects of the compounds described here.

The following abbreviations were used in the description of the assays: BCECF AM - bis-(2-carboxyethyl)-5-(u-6)-carboxyfluorescein 2',7'-acetoxymethyl ester; DMSO - dimethyl sulfoxide; FBS - fetal bovine serum; HBSS - Hanks Balanced Salt Solution; HEPES - 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; OD - optical density; RPMI is a 1640 environment developed at the Roswell Park Memorial Institute.

Compound potency in assays was determined by measuring the IC ₅₀ value (concentration of test compound at which 50% of biological activity is inhibited). IC ₅₀ values were calculated using an intelligent fit model in the Screener analysis software package (Genedata AG).

Rationale:

MCT4 is predominantly expressed in normal skeletal muscle and is upregulated in a number of solid tumors, where it promotes lactate efflux from the cell, thereby preventing intracellular acidification. Thus, inhibition of MCT4 activity represents a potential increase in therapeutic efficacy in the presence of oncology. MCT1 is a closely related monocarboxylate transporter and as such is a key target for the selective action of MCT4 inhibitors. Although MCT4 is primarily involved in lactate efflux from cells, lactate influx can be controlled in an in vitro system as described for assay systems (b) and (d) below.

The purpose of these tests is to identify compounds that affect lactate efflux in a native cell line with a glycolytic phenotype predominantly expressing MCT4 and lactate transport into cells in the following in vitro assay systems:

a) SK-Br-3 cells (ATCC HTV-30) - a line of human breast adenocarcinoma with a native glycolytic phenotype, predominantly expressing MCT4 (confirmed by Western blotting)

NCI-H358 cells (ATCC CRL-5807) - a human lung adenocarcinoma line predominantly expressing MCT4, a small amount of MCT2 and not expressing MCT1 (confirmed by Western blotting)

c) K562 cells (ATCC CCL-243) - a human erythroleukemia line predominantly expressing MCT1, a small amount of MCT2 and not expressing MCT4 (confirmed by Western blotting)

d) INS-1 MCT4 cells (parent line INS-1 donated to AstraZeneca by the University of Geneva, Switzerland) - a rat pancreatic beta cell line, initially free of any MCT isoform and self-modified to stably express human MCT4 (confirmed by Western blotting).

Analysis system (a):

Formula I compounds in 100% DMSO were added to empty 384-well assay plates (Costar #3712) by sonic dosing (120 nl/well over the concentration range). SK-Br-3 cells (ATCC HTB-30) were seeded in assay plates (directly on test compound) at a density of 4000 cells/well in 40 µl of RPMI medium (Sigma #R0883) containing 1% L-glutamine (Sigma #G7513) and 20% FBS (Sigma #F7524). The assay plates were capped and incubated for 4 hours at 37° C. and 5% CO ₂ .

After incubation with test compound, 5 µl of medium was transferred to a second 384-well assay plate (Costar #3712) using an automatic tipping platform (CyBio Felix). The amount of lactic acid present in the medium was quantified using a commercial lactate assay kit (Trinity Biotech #735-10) using the following coupled enzyme principle: lactic acid is converted to pyruvate and H ₂ O ₂ by lactate oxidase; in the presence of H ₂ O ₂ formed, peroxidase catalyzes the oxidative condensation of the chromogen precursor to form a colored dye with an absorption maximum at 540 nm (the increase in absorption is directly proportional to the increase in lactate in the sample). The absorbance was then measured on an automatic microplate reader (PerkinElmer EnVisiori) using a 535 nm filter and the OD values were normalized to control wells (treated with either DMSO (maximum analyte) or a chemical related to those described in this patent (minimum analyte). signal)) before plotting concentration-effect curves to determine the IC ₅₀ value.

Analysis systems (b), (c):

Formula I compounds in 100% DMSO were added to empty 384-well assay plates (Costar #3683) by sonic dosing (90 nl/well over the concentration range).

NCI-H358 cells (ATCC CRL-5807) or K562 cells (ATCC CCL-243) were thawed immediately after cryopreservation, washed and resuspended in HBSS (Gibco #14170) with 1 mM [final] HEPES (Gibco #15630).

Cells were loaded with pH sensitive BCECF AM dye (Invitrogen #B1150) before washing to remove excess dye and seeded in assay plates (directly on test compound) at 15,000 cells/well (NCI-H358) or 30,000 cells/well (K562) in 30 µl HBSS with 1 mM [final] HEPES. The assay plates were capped and centrifuged in a plate centrifuge at 170 g for 1 minute. The plates were then wrapped in foil and incubated in the dark for 1 hour at room temperature.

After incubation with test compound, 10 µl of 25 mM sodium L-lactate (Sigma #L7022) prepared in HBSS with 1 mM [final] HEPES was directly added to 30 µl of media in the test wells to give 6.25 mM [final]. This addition was performed directly on the FLIPR Tetra platform (Molecular Devices) as part of a real-time kinetic readout protocol. Cell fluorescence using the Ex470-495_Em515-575 filter set was measured over time and the change from baseline (addition to lactate) to "add lactate plus 80 seconds" was recorded. The percent change from baseline was calculated for each test well and the values were normalized to control wells (treated with either DMSO (maximum analyte signal) or a chemical related to those described in this patent (minimum analyte signal)) before plotting effect vs. concentration to determine the IC ₅₀ value.

Analysis system (d):

Formula I compounds in 100% DMSO were added to empty 384-well assay plates (Costar #3683) by sonic dosing (90 nl/well over the concentration range).

INS-1 MCT4 cells were generated by transfecting parental cells with the following DNA sequence (deoxyribonucleic acid) inserted into the mammalian expression vector pcDNA3.1 (ThermoFisher #V79020):

.

.

The resulting cell pool was continuously cultured at 37°C and 5% CO ₂ with a selective antibiotic in RPMI medium (Sigma #R0883) containing 1% L-glutamine (Sigma #G7513), 10% FBS (Sigma #F7524), 10 mM [ final] HEPES (Gibco #15630), 0.004% p-mercaptoethanol (Sigma #M6250) and 100 μg/ml geneticin (Thermo Fisher #10131027). A single clone was selected and expanded before cryopreservation in several separate vials for further use. Prior to testing in a biological assay, a single INS-1 MCT4 cryovial was thawed and continuously subcultured for several weeks (in media with the selective antibiotic geneticin described earlier) to obtain the required number of cells. During testing, cells were harvested from the surface of culture flasks, pooled, washed and resuspended in HBSS (Gibco #14170) with 1 mM [final] HEPES (Gibco #15630).

Cells were loaded with pH sensitive BCECF AM dye (Invitrogen #B1150) before washing to remove excess dye and seeded into assay plates (directly on test compound) at a density of 15,000 cells/well in 30 μl HBSS with 1 mM [final] HEPES. The assay plates were capped and centrifuged in a plate centrifuge at 170 g for 1 minute. The plates were then wrapped in foil and incubated in the dark for 1 hour at room temperature.

After incubation with test compound, 10 µl of 25 mM sodium L-lactate (Sigma #L7022) prepared in HBSS with 1 mM [final] HEPES was directly added to 30 µl of media in the test wells to give 6.25 mM [final]. This addition was performed directly on the FLIPR Tetra platform (Molecular Devices) as part of a real-time kinetic readout protocol. Cell fluorescence using the Ex470-495_Em515-575 filter set was measured over time and the change from baseline (addition to lactate) to "add lactate plus 80 seconds" was recorded. The percent change from baseline was calculated for each test well and the values were normalized to control wells (treated with either DMSO (maximum analyte signal) or a chemical related to those described in this patent (minimum analyte signal)) before plotting effect vs. concentration to determine the IC ₅₀ value.

The following in vivo assays were used to measure the effects of the compounds described herein in combination with other agents.

Human Lung Cancer Xenograft Model - Combination with VEGFR TKI

The in vivo efficacy of MCT4 inhibitors has been tested in human xenograft models. The NSCLC cell line NCI H358 can be grown as a subcutaneous xenograft in female nude mice and the tumor volume is calculated based on bilateral caliper measurements. For efficacy studies, three million NCI H358 cells were inoculated subcutaneously on the left flank of the animal in a volume of 0.1 ml of serum-free medium (RPMI) and Matrigel. Animals were assigned to treatment groups 14 days after cell implantation and received either AZD2171 (3 mg/kg once daily) (Wedge et al., (2005) Cancer Res. 65: 4389-4400) or a compound of formula (I ) (100 mg/kg twice a day), or a combination of both through a gastric tube. Vehicle control 0.5% hydroxypropyl methylcellulose/0.1% Tween 80 (polyoxyethylene (20) sorbitan monooleate) was administered orally twice a day. Dosing was continued for 17 days and tumor volume, body weight and tumor status were recorded twice a week throughout the study.

The test results for the compound from Example 62 are shown in FIG. 3. The VEGF inhibitor AZD2171 was effective, showing 33% (p < 0.001) tumor regression compared to the vehicle group. The combination of AZD2171 with the MCT4 inhibitor of Example 62 showed a more significant change of 72% tumor regression (p <0.001 vs. control) which was also significantly different (p=0.013) from AZD2171 administered alone. Group sizes at the end of the study: vehicle (n is 11); the compound from example 62 (n is 4); AZD2171 (n is 10); AZD2171 plus the compound from example 62 (n is 9).

Mouse syngeneic model - combination with anti-CTLA4 antibodies and combinations with anti-PD-1 antibodies

The in vivo efficacy of MCT4 inhibitors has been tested in syngeneic mouse models. To test the selective effect of MCT4 inhibitors of formula (I), MCT1 was knocked out (KO) in a syngeneic model based on the MC38 cell line using precise genome editing with CRISPR (regularly spaced short palindromic repeats). The MC38 MCT1 KO mouse colorectal cell line can be grown subcutaneously in female C57.B16 mice and tumor volume calculated from bilateral caliper measurements. For efficacy studies, ten million cells were inoculated subcutaneously on the left flank of the animal in a volume of 0.1 ml of serum-free DMEM (Dulbecco's Modified Eagle's Medium). Animals were randomized according to body weight at the time of cell implantation and treatment started the following day. In the first of these studies, shown in FIG. 4, the monotherapy groups received either a compound of formula (I) (100 mg/kg twice daily) by gavage or an anti-CTLA4 antibody (aCTLA4, anti-CTLA-4 antibody 9D9 mlgGl described in WO 200712373) (10 mg/kg twice a week) intraperitoneally. The combination groups consisted of a compound of formula (I) (100 or 10 mg/kg po twice a day) with anti-CTLA4 antibody (10 mg/kg ip twice a week). In the second of these studies, shown in FIG. 5, the monotherapy groups received either a compound of formula (I) (30 mg/kg po twice a day) with an anti-PD-1 antibody (from Bio X Cell, catalog number BE0146, lot 665417s1, 6.78 mg/ml) ( 10 mg/kg ip twice a week). In both studies, dosing was continued for up to 6 weeks, and tumor volume, body weight, and tumor status were recorded three times a week. In both studies, the vehicle was a mixture of 0.5% hydroxypropyl methylcellulose/0.1% Tween 80 administered twice a day via a gastric tube with PBS/a administered twice a week intraperitoneally.

The results of testing the compound from Example 62 in the first study of syngeneic models are shown in FIG. 4. Individual tumor growth profiles are shown on withdrawal animals using time-to-event criteria based on maximum tumor volume of 1.5 cm, tumor status, or animal welfare limits. Due to the withdrawal of animals from the study during the later stages of the experiment, the geometric means of percent inhibition were calculated at day 15. Compared to vehicle control, monotherapy with Example 62 (100 mg/kg) provided 60.0% (p < 0.05) growth inhibition on that day. Monotherapy aCTLA4 (10 mg/kg) was ineffective with 6.1% (not significant). The combination of the compound from example 62 (10 and 100 mg/kg) with an anti-CTLA4 antibody showed 67.4% (p not more than 0.01) and 82.2% (p not more than 0.001) inhibition, respectively, at In this case, the combination of Example 62 (100 mg/kg twice daily) plus anti-CTLA4 antibody reached statistical significance (p=0.0311) compared to Example 62 (100 mg/kg twice daily) administered alone. Group sizes on day 15: vehicle (n is 12); the compound from example 62 (100 mg/kg) (n is 11); anti-CTLA4 antibody (10 mg/kg) (n is 11); the compound from example 62 (100 mg/kg) plus anti-CTLA4 antibody (n is 12); the compound from example 62 (10 mg/kg) plus anti-CTLA4 antibody (n is 9).

For testing the compound of Example 62 in a second syngeneic model study, the results are shown in FIG. 5. Again, individual tumor growth profiles are shown in withdrawal animals using time-to-event criteria based on maximum tumor volume of 1.5 cm, tumor status, or animal welfare limits. Due to the fact that the animals reached the end point of the event at different times in the later stages of the experiment, the geometric means of percent inhibition were calculated at day 13. Compared to vehicle control, monotherapy with Example 62 (30 mg/kg) provided 30.1% (non-significant) growth inhibition on that day. The efficacy of αPD-1 monotherapy (10 mg/kg) was similar, providing a 33.4% (non-significant) inhibition. The combination of the compound from example 62 (30 mg/kg) with anti-PD-1 antibody was more effective than monotherapy, showing 82.3% (p not more than 0.001) growth inhibition. Group sizes on day 13: vehicle (n is 8); the compound from example 62 (30 mg/kg) (n is 10); anti-PD-1 antibody (10 mg/kg) (n is 11); the compound from example 62 (30 mg/kg) plus anti-PD-1 antibody (n is 10).

It should be noted that the diagrams shown in Fig. 4 and 5 provide data on tumor growth in individual animals, comparing growth in vehicle control groups with treatment groups.

For the examples, the following data were obtained from analyzes (a)-(d) (the pIC ₅₀ values shown are the calculated average of the experiments carried out in at least triplicate, except for example 32, marked *, where the pIC ₅₀ value is the calculated average of the experiments carried out in two repetitions):

The data show that the compounds described here both affect lactate efflux from a tumor cell line predominantly expressing MCT4 and, under appropriate conditions, inhibit lactate transport into MCT4-dependent cells and are therefore useful as inhibitors of MCT4.

Compounds can be further selected based on additional biological or physical properties that can be measured by methods known in the art and that can be used in evaluating or selecting compounds for therapeutic or prophylactic use.

Due to their MCT4 inhibitory activity, the compounds of formula (I) and their pharmaceutically acceptable salts are expected to be useful in therapy.

The term "therapy" is intended to have its usual meaning in relation to a disease, with reference to the complete or partial alleviation of one, some or all of its symptoms, or the correction or compensation of the underlying pathology. The term "therapy" also includes "prophylaxis" unless otherwise noted. The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

The term "prophylaxis" is intended to have its usual meaning and includes primary prevention to prevent the development of a disease and secondary prevention in which the disease has already developed and the patient is temporarily or permanently protected from exacerbation or worsening of the disease or from developing new symptoms associated with the disease.

The term "treatment" is used as a synonym for "therapy". Similarly, the term "treat" can be considered as "the use of therapy", where "therapy" has the meaning defined here.

When the term "cancer" is mentioned, it includes both non-metastatic cancer as well as metastatic cancer, so that the treatment of cancer includes the treatment of both primary tumors and tumor metastases.

In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in therapy.

In one embodiment, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for the preparation of a medicament.

In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of an MCT4 mediated disease. In one embodiment, the MCT4 mediated disease is cancer. In one embodiment, the cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, cancer bladder, hepatocellular carcinoma, kidney cancer, thyroid cancer, pancreatic cancer, small cell lung cancer and non-small cell lung cancer.

In one embodiment, the cancer is non-small cell lung cancer.

In one embodiment, the cancer is lung adenocarcinoma.

In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of cancer.

In one embodiment, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for the manufacture of a medicament for the treatment of a disease mediated by MCT4. In one embodiment, the MCT4 mediated disease is cancer. In one embodiment, the cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, cancer bladder, hepatocellular carcinoma, kidney cancer, thyroid cancer, pancreatic cancer, small cell lung cancer and non-small cell lung cancer.

In one embodiment, the cancer is non-small cell lung cancer.

In one embodiment, the cancer is lung adenocarcinoma.

In one embodiment, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for the preparation of a medicament for the treatment of cancer.

In one embodiment, a method is provided for treating a disease in which inhibition of MCT4 is beneficial in a warm-blooded animal in need of such treatment, comprising administering to said warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the disease is cancer. In one embodiment, the cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, cancer bladder, hepatocellular carcinoma, kidney cancer, thyroid cancer, pancreatic cancer, small cell lung cancer and non-small cell lung cancer.

In one embodiment, the cancer is non-small cell lung cancer.

In one embodiment, the cancer is adenocarcinoma of the lung.

In one embodiment, a method of treating cancer in a warm-blooded animal in need of such treatment is provided, comprising administering to said warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Tumors that selectively express MCT4 over MCT1 have an increased likelihood of responding to treatment with an MCT4 inhibitor. Therefore, patients whose tumors express MCT1 at low levels are likely to respond better to an MCT4 inhibitor than those whose tumors express MCT1 at a higher level. In most cases, patients whose tumors have a high ratio of MCT4 : MCT1 expression (due to low levels of MCT1 expression) are likely to show a better response, therefore, evaluation of the relative levels of expression of both MCT1 and MCT4 provides an opportunity to select patients for treatment with an MCT4 inhibitor. . Methods for determining relative expression levels of MCT1 and MCT4 are known in the art and are described in WO 2010/089580, incorporated herein by reference.

In one embodiment, a method of treating cancer is provided, comprising (i) testing a tumor sample obtained from a patient suffering from or likely to suffer from cancer for selective expression of MCT4 over MCT1, and (ii) administering to a patient having a tumor that selectively expresses MCT4 at compared to MCT1, a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a patient in which the cancer selectively expresses MCT4 over MCT1.

In one embodiment, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for the preparation of a medicament for the treatment of cancer in a patient, wherein the cancer selectively expresses MCT4 over MCT1.

In one embodiment, a method of treating cancer in a warm-blooded animal in need of such treatment is provided, comprising administering to said warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the cancer selectively expresses MCT4 over MCT1.

The term "therapeutically effective amount" refers to an amount of a compound of formula (I), as described in any of the embodiments herein, that is effective to provide "therapy" in a subject or to "treat" a disease or disorder in a subject. In the case of cancer, a therapeutically effective amount can cause any of the observable or measurable changes in the subject, as described above in the definitions of "therapy", "treatment" and "prophylaxis". For example, an effective amount can reduce the number of cancerous or tumor cells; reduce the overall size of the tumor; suppress or stop the infiltration of tumor cells into peripheral organs, including, for example, soft tissues and bones; suppress and stop tumor metastasis; suppress and stop tumor growth; alleviate to some extent one or more of the symptoms associated with cancer; reduce morbidity and mortality; improve the quality of life; or cause a combination of these effects. An effective amount may be an amount sufficient to reduce the symptoms of a disease responsive to inhibition of MCT4 activity. In the treatment of cancer, in vivo efficacy can be measured, for example, by evaluating duration of survival, time to disease progression (TOP), response rate (RR), response duration, and/or quality of life. As will be known to those skilled in the art, effective amounts may vary depending on the route of administration, the use of the excipient, and co-use with other agents. For example, when combination therapy is used, an amount of a compound of formula (I) or a pharmaceutically acceptable salt described herein and an amount of other pharmaceutically active agent(s), when combined, are collectively effective in treating the target disorder in the affected animal. In this context, the combined amounts are in a "therapeutically effective amount" if, when combined, they are sufficient to reduce the symptoms of a disease responsive to inhibition of MCT4 activity, as described above. Typically, such amounts can be determined by one of skill in the art, for example, based on the dosage range described herein for a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the approved or otherwise advertised dosage range(s) of another pharmaceutically active connections(connections).

The term "warm-blooded animals" includes, for example, humans.

The antitumor treatment described in this specification may be useful as monotherapy or may include, in addition to administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, conventional surgery, radiation therapy or chemotherapy; or a combination of such complementary therapies. Such conventional surgery, radiation therapy or chemotherapy may be carried out simultaneously, sequentially or separately with treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

When combination therapy is used "at the same time", it includes the treatment of the patient with a single dosage form (eg tablet) containing both the formula of the compound (I) or its pharmaceutically acceptable salt, and an additional antitumor agent; as well as the simultaneous administration of separate dosage forms, each individually containing one of the respective components of the combination.

When combination therapy is administered "sequentially" or "separately", it comprises treating a patient with a first dosage form (eg, tablet) containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, followed by treating the same patient with a second dosage form containing an additional anticancer agent; or treating a patient with a single dosage form (eg, a tablet) containing a particular antitumor agent, followed by treating the same patient with a second dosage form containing a compound of formula (I) or a pharmaceutically acceptable salt thereof. The interval between successive or separate doses can be estimated by a qualified physician with reference to the information in this description.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered prior to surgery.

Administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof prior to surgery to remove all or part of a cancer may be referred to as "neoadjuvant therapy". In such a scenario, the goal of administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, is generally to reduce the size of the target tumor in order to increase the chances of successful resection. Thus, the duration of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof prior to surgery can be judged by a qualified physician with reference to the information in this specification.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered following surgery.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional anticancer agent.

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or separately with at least one additional anticancer agent.

Anticancer treatment as defined herein may be used as monotherapy or may include, in addition to the compounds mentioned in the description, conventional surgery, radiation therapy, or chemotherapy. Such chemotherapy may include one or more of the following categories of anticancer agents:

I) other antiproliferative/antineoplastic drugs and combinations thereof used in medical oncology such as alkylating agents (eg cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide and nitrosoureas); antimetabolites (eg gemcitabine and antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside and hydroxyurea); antitumor antibiotics (eg anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (eg vinca alkaloids such as vincristine, vinblastine, vindesine and vinorelbine and taxanes such as taxol and taxotere and polokinase inhibitors); and topoisomerase inhibitors (eg epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan and camptothecin);

ii) anti-angiogenic agents, such as agents that inhibit the actions of vascular endothelial growth factor, for example, the anti-vascular endothelial cell growth factor antibody, bevacizumab (Avastin™), and, for example, a VEGF receptor tyrosine kinase inhibitor, such as sorafenib, axitinib, pazopanib, sunitinib, and cediranib ;

iii) immunotherapeutic approaches, including, for example, ex vivo and in vivo approaches to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, or granulocyte-macrophage colony stimulating factor, approaches to reduce T cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies. Specific examples include monoclonal antibodies targeting PD-1 (eg nivolumab and pembrolizumab), PD-L1 (eg durvalumab and atezolizumab), CTLA4 (eg tremelimumab and ipilimumab) or CD (differentiation cluster) 73 (eg oleklumab), as well as Ligand CD40 fusion proteins and GITR ligand (glucocorticoid-induced tumor necrosis factor receptor) fusion proteins;

iv) lactate transporter inhibitors, including, for example, MCT1 inhibitors such as AZD3965;

V) agents targeting tumor metabolism, including agents that inhibit GLS1, complex I, inhibitors of the mitochondrial pyruvate transporter.

Therefore, in one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional anticancer agent for use in the treatment of cancer. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an additional anticancer agent. In one embodiment, one additional antitumor agent is present. In one embodiment, two additional antitumor agents are present. In one embodiment, three or more additional antitumor agents are present.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional anticancer agent for use in the simultaneous, separate, or sequential treatment of cancer. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with an additional anticancer agent.

In one embodiment, a method is provided for treating cancer in a warm-blooded animal in need of such treatment, comprising administering to said warm-blooded animal a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional anticancer agent, wherein the amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof an acceptable salt and an additional antitumor substance together have an effective antitumor effect.

In one embodiment, a method is provided for treating cancer in a warm-blooded animal in need of such treatment, comprising administering to said warm-blooded animal a compound of formula (I) or a pharmaceutically acceptable salt thereof, and simultaneously, separately or sequentially administering at least one additional antitumor agent to said warm-blooded animal, wherein amounts of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an additional antitumor agent together produce an effective antitumor effect.

In any embodiment, the additional antitumor agent is selected from the group consisting of one or more of the antitumor agents listed in (I)-(V) above.

One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional antitumor agent selected from the group consisting of anti-PD-1 antibodies (e.g., nivolumab and pembrolizumab), anti-PD-L1 antibodies (e.g., durvalumab and atezolizumab), anti-CTLA4 antibodies (eg tremelimumab and ipilimumab), anti-CD73 antibodies (eg olecumab), CD40 fusion protein ligand and GITR fusion protein ligand, for use in cancer treatment.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional anticancer agent selected from the group consisting of anti-PD-L1 antibodies (eg, durvalumab and atezolizumab), for use in the treatment of cancer.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, and durvalumab for use in the treatment of cancer.

In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is lung adenocarcinoma.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately, or sequentially with at least one additional antitumor agent selected from the group, consisting of anti-PD-1 antibodies (eg nivolumab and pembrolizumab), anti-PD-L1 antibodies (eg durvalumab and atezolizumab), anti-CTLA4 antibodies (eg tremelimumab and ipilimumab), anti-CD73 antibodies (eg oleklumab), CD40 fusion protein ligand and ligand of GITR fusion proteins.

In one embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately, or sequentially with at least one additional antitumor agent selected from the group, consisting of antibodies to PD-L1 (for example, durvalumab and atezolizumab).

In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with durvalumab.

In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is lung adenocarcinoma.

In one embodiment, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer is provided, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with at least one additional antitumor agent selected from from the group consisting of anti-PD-1 antibodies (eg nivolumab and pembrolizumab), anti-PD-L1 antibodies (eg durvalumab and atezolizumab), anti-CTLA4 antibodies (eg tremelimumab and ipilimumab), anti-CD73 antibodies (eg oleklumab), CD40-ligand fusion proteins; and a GITR fusion protein ligand. In one embodiment, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer is provided, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with at least one additional antitumor agent selected from from the group consisting of anti-PD-L1 antibodies (eg durvalumab and atezolizumab).

In one embodiment, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer is provided, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with durvalumab.

In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is lung adenocarcinoma.

In one embodiment, a method of treating cancer in a warm-blooded animal in need of such treatment is provided, comprising administering to said warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially with at least one additional antitumor agent selected from group consisting of anti-PD-1 antibodies (eg nivolumab and pembrolizumab), anti-PD-L1 antibodies (eg durvalumab and atezolizumab), anti-CTLA4 antibodies (eg tremelimumab and ipilimumab), anti-CD73 antibodies (eg oleklumab), CD40 ligand-fused proteins and ligand GITR-fused proteins.

In one embodiment, a method of treating cancer in a warm-blooded animal in need of such treatment is provided, comprising administering to said warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially with at least one additional antitumor agent selected from a group consisting of antibodies to PD-L1 (eg durvalumab and atezolizumab).

In one embodiment, a method of treating cancer in a warm-blooded animal in need of such treatment is provided, comprising administering to said warm-blooded animal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially with durvalumab.

In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is lung adenocarcinoma.

In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) and at least one additional anticancer agent for use in the treatment of cancer. In one embodiment, the pharmaceutical composition also contains at least one pharmaceutically acceptable excipient. In one embodiment, the antitumor agent is an antineoplastic agent. According to a further embodiment, a kit is provided comprising:

a) a compound of formula (I) or a pharmaceutically acceptable salt thereof in a first unit dosage form;

b) another additional antitumor agent in an additional unit dosage form;

c) a container designed to contain said first and additional unit dosage forms; and, perhaps

d) instructions for use.

The compounds of formula (I) and their pharmaceutically acceptable salts may be administered as pharmaceutical compositions containing one or more pharmaceutically acceptable excipients.

Therefore, in one embodiment, a pharmaceutical composition is provided comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The compositions may be in a form suitable for oral administration (e.g. tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical application (e.g. creams, ointments , gels or aqueous or oily solutions or suspensions), for administration by inhalation (eg as a fine powder or liquid aerosol), for administration by insufflation (eg as a fine powder), or for parenteral administration (eg as sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular administration) or as a suppository for rectal administration. The compositions can be prepared by well known methods using well known pharmaceutical excipients well known in the art. Thus, compositions intended for oral administration may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in therapy.

In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in the treatment of cancer. In one embodiment, said cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, kidney cancer, thyroid cancer, pancreatic cancer, small cell lung cancer and non-small cell lung cancer.

In one embodiment, the cancer is non-small cell lung cancer.

In one embodiment, the cancer is lung adenocarcinoma.

The compound of formula (I) will typically be administered to a warm-blooded animal at a unit dose in the range of 2.5-5000 mg/m ² body area of the animal, or about 0.05-100 mg/kg, and this usually provides a therapeutically effective dose. A unit dosage form, such as a tablet or capsule, will typically contain, for example, 0.1-500 mg of the active ingredient. The daily dose will necessarily vary depending on the patient being treated, the particular route of administration, any treatments used in conjunction, and the severity of the disease being treated.

EXAMPLES

Aspects of the present disclosure may be further defined by reference to the following non-limiting examples, which describe in detail the preparation of certain compounds and intermediates of the present disclosure and methods of using the compounds of the present disclosure. Those skilled in the art will appreciate that many modifications, both in materials and methods, can be made within the scope of this disclosure.

Unless otherwise stated, starting materials were commercially available. All solvents and commercial reagents were of laboratory quality and were used as shipped.

General details of experiments

The invention will now be illustrated by the following examples, in which, as a rule:

I) the processes were carried out at room temperature (rt), that is, in the range from 17 to 25°C and in an atmosphere of an inert gas such as N ₂ or Ar, unless otherwise noted;

ii) Reactions were typically followed by thin layer chromatography (TLC) and/or analytical high performance liquid chromatography (HPLC or UHPLC), which were usually combined with mass spectrometry (LC/MS). The response times given are not necessarily the minimum achievable;

iii) if necessary, the organic solutions were dried over anhydrous MgSO ₄ or Na ₂ SO ₄ , work-up procedures were carried out using traditional phase separation techniques or using SKO (strong cation exchange sorbent) as described in (XIII), evaporation was carried out either by rotary evaporation under vacuum, or in Genevac HT-4/EZ-2 or Biotage V10 evaporators;

iv) the yields, if any, are not necessarily the maximum achievable, and if necessary, the interactions were repeated if more reaction product was required;

V) as a rule, the structures of the final products of formula (I) were confirmed by methods of nuclear magnetic resonance (NMR) and/or mass spectrometry; electrospray mass spectrometry data were obtained using a Waters Acquity UHPLC system connected to a Waters single quadrupole mass spectrometer recording data for both positive and negative ions, and typically only ions related to the parent structure are reported; proton NMR chemical shift values were measured on a delta scale using either a Bruker AV500 spectrometer operating at a field strength of 500 MHz, or a Bruker AV400 operating at 400 MHz, or a Bruker AV300 operating at 300 MHz. Unless otherwise stated, NMR spectra were obtained at 500 MHz in d6-dimethylsulfoxide. The following abbreviations (and their derivatives, eg dd, doublet of doublets, etc.) have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, wide; qn, quintet; p, pentet;

vi) unless otherwise noted, compounds containing an asymmetric carbon and/or sulfur atom were not separated;

vii) the intermediates were not necessarily completely purified, but their structures and purity were assessed by TLC, analytical HPLC/UHPLC and/or NMR analysis and/or mass spectrometry;

VIII) Unless otherwise stated, flash column chromatography (FPC) was performed on Merck Kieselgel silica (Art. No. 9385), or reverse phase silica (Fluka 90 C18 silica gel), or on Silicycle cartridges (40-63 µm silica). , wt 4 to 330 g) or Puriflash cartridges (silica 50 µm, wt 4 to 330 g) or Grace Resolv cartridges (4 to 120 g) or RediSep Rf 1.5 Flash columns or high performance columns RediSep Rf Gold Flash (weight 150 to 415 g), or on RediSep Rf Gold reverse phase C18 columns (silica 20-40 µm) either manually or automatically using the Isco CombiFlash Companion or equivalent system;

IX) preparative reverse phase HPLC (RP-HPLC) was performed on C18 reversed phase silica typically using a Waters XSelect CSH C18 or Phenomenex Gemini-NX axia Prep C18 OBD column (silica 5 µm, diameter 30 mm, length 100 mm ) using mixtures of decreasing polarity as eluent, for example [containing 0.1% formic acid or 0.3-0.5% aqueous ammonium hydroxide (d is 0.91)] as solvent A and acetonitrile as solvent B ; a typical procedure would be as follows: solvent gradient over 10-20 minutes, at a rate of 40-50 ml per minute, from a mixture of solvents A and B, 95:5, respectively, to a mixture of solvents A and B, 5:95 (or an alternative ratio, if appropriate);

X) used the following UPLC analytical methods; typically, C18 reverse phase silica was used at a flow rate of 1 ml/min, and detection was performed by electrospray mass spectrometry and by UV absorption recording in the wavelength range of 220-320 nm. Analytical UHPLC was performed on CSH reversed phase C18 silica using a Waters XSelect CSH C18 column (dimensions 2.1×50 mm and particle size 1.7 microns). Gradient analysis was performed using mixtures of decreasing polarity as the eluent, for example mixtures of decreasing polarity, such as mixtures of water (containing 0.1% formic acid or 0.1% ammonia) as solvent A and acetonitrile as solvent B. B A typical 2-minute UHPLC analytical method will use a solvent gradient over 1.3 minutes at a rate of approximately 1 ml per minute from a 97:3 mixture of solvents A and B, respectively, to a 3:97 mixture of solvents A and B, respectively.

XI) in cases where certain compounds were obtained as an acid addition salt, such as hydrochloride or dihydrochloride, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was usually not determined, for example, using elemental analysis data;

xii) in cases where interactions require the use of a microwave oven, use one of the following microwave reactors: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smithcreator, or CEM Explorer;

XIII) compounds were purified by strong cation exchange sorbent (SEC) chromatography using Isolute SPE Flash SCX-2 or SCX-3 columns (International Sorbent Technology Limited, Mid Glamorgan, UK);

XIV) preparative chiral chromatography was performed using HPLC or SFC using a Waters SFC 100 system or equivalent. A chiral stationary phase, such as in a Daicel chiral cellulose or amylose column or equivalent, was chosen to optimize isomer separation in the sample. For semi-preparative separations, a 30 x 250 mm, 5 micron chiral column was typically used with a flow rate of 100 ml/min in SFC or a flow rate of 40 ml/min in HPLC. Detection was carried out by absorption in the UV region of the spectrum or by mass spectrometric detection. For UV detection, a common wavelength was used, typically 220 nm or 254 nm, or the wavelength was chosen to maximize the product signal. For mass detection, a soft ionization technique, such as electrospray ionization, was used to detect the product using a directed MH+ signal. Samples were dissolved in a compatible solvent for entry into the chromatographic system. For SFC separation, the column temperature was kept constant at about 40° C. and the back pressure was adjusted to a constant pressure of about 100-150 bar (10-15 MPa).

XV) chiral analysis was performed using SFC or HPLC using a Waters UPC2 SFC, Agilent 1200 HPLC or equivalent system. A chiral stationary phase, such as in Daicel chiral columns with cellulose or amylose or equivalent, was chosen to optimize isomer separation in the sample. For analytical separation, a 3.5×150 mm, 3 micron chiral column was typically used with a flow rate of 2 ml/min in SFC or a flow rate of 0.5 ml/min in HPLC. Detection was carried out by absorption in the UV region of the spectrum (DAD (diode array detector)) and/or by mass spectrometry (full scan). The sample was dissolved in a compatible solvent at a concentration of approximately 0.5 mg/ml and injected directly into the chromatographic system. For SFC separation, the column temperature was kept constant at about 40° C. and the back pressure was adjusted to a constant pressure of about 100-150 bar (10-15 MPa).

XVI) in most cases, the compounds from the examples and intermediate compounds were named using the ACD Name program, the item in the "Structure to Name" menu of ChemDraw Ultra (CambridgeSoft) or Biovia Draw 2016;

XVII) in cases where the reaction mixtures are meant to be degassed, this can be done, for example, by purging the reaction solvent with a constant stream of nitrogen for a suitable period of time (eg 5 to 10 minutes).

XVIII) in addition to those mentioned above, the following abbreviations have been used:

XIX) a Bruker D4 instrument was used for XRD analysis. An x-ray powder diffraction pattern was obtained by placing a sample of crystalline material on a Bruker single crystal silicon (SSC) substrate and spreading the sample in a thin layer using a glass slide. The sample was rotated at 30 rpm (to improve measurement statistics) and irradiated with X-rays generated by a finely focused copper anode tube operating at 40 kV and 40 mA at a wavelength of 1.5418 angstroms. The collimated X-ray beam was passed through an automatic slit divergence setup at V20 and reflected radiation was directed through a 5.89 mm antiscatter slit and a 9.55 mm detector slit. Samples were measured using reflection geometry in θ-2θ mode over a scan interval of 2° to 40° of 2θ angle with a nominal exposure of 0.12 seconds per scan step of 0.02°. The instrument was equipped with a position sensitive detector (Lynxeye). Those skilled in the art of X-ray powder diffraction will appreciate that the relative intensity of the peaks can be affected by, for example, grains larger than 30 microns and non-unitary aspect ratios, which can affect the analysis of the samples. One skilled in the art will also appreciate that the position of the reflections can be affected by the exact height at which the sample is in the diffractometer and the zero calibration of the diffractometer. The planarity of the sample surface can also have a small effect. Therefore, the presented diffraction pattern data should not be taken as absolute values;

XX) a TA Instruments Q2000 DSC instrument was used for differential scanning calorimetry. Typically, less than 3 mg of material, placed in a standard aluminum crucible with a lid, was heated in the temperature range from 25°C to 300°C with a constant heating rate of 10°C per minute. A nitrogen gas purge was used at a flow rate of 50 ml per minute. Temperature data were analyzed using standard software such as Universal V.4.5A from TA INSTRUMENTS®.

Intermediate 1: (R)-tert-butyl-3-(bromomethyl)pyrrolidine-1-carboxylate

Triphenylphosphine (78 g; 298.1 mmol) was added portionwise to (R)-tert-butyl-3-(hydroxymethyl)pyrrolidine-1-carboxylate (50 g; 248.4 mmol) and CBr ₄ (115 g; 347.8 mmol) in DCM (1 L) at 0°C for 5 minutes. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours, then concentrated in vacuo and purified by CPC eluting with 0-16% EtOAc in petroleum ether to give the title compound (61.6 g; 94 %) as a colorless oil; ¹ H NMR (300 MHz, CDCl ₃ ) 1.47 (9H, s), 1.72 (1H, dq), 1.99-2.16 (1H, m), 2.52-2.68 (1H, m), 3.10 (1H, dd), 3.26 -3.44 (3H, m), 3.49 (1H, ddd), 3.59 (1H, dd).

Intermediate 2: (R)-tert-butyl-3-(2-acetyl-3-oxobutyl)pyrrolidine-1-carboxylate

K ₂ CO ₃ (48.3 g; 349.8 mmol) was added to (R)-tert-butyl-3-(bromomethyl)pyrrolidine-1-carboxylate (61.6 g; 233.2 mmol) and pentane-2 ,4-dione (23.35 g; 233.2 mmol) in DMF (600 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature, diluted with EtOAc (500 ml), filtered and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 0-30% EtOAc in petroleum ether to give the title compound (43.9 g, 66%) as a pale yellow oil; m/z MH ⁺ 284.

Intermediate 3: (R)-tert-Butyl-3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1 -carboxylate

3-Methyl-1H-1,2,4-triazol-5-amine (15.20 g; 154.9 mmol) was added in one portion to (R)-tert-butyl-3-(2-acetyl-3-oxobutyl )pyrrolidine-1-carboxylate (43.9 g; 154.9 mmol) in AcOH (500 ml) at room temperature. The reaction mixture was heated at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-80% MeOH in water to give the title compound (18.00 g, 34%) as a pale yellow gum; ¹ H NMR (300 MHz, CDCl ₃ ) 1.45 (9H, s), 1.70 (1H, dt), 1.91-2.07 (1H, m), 2.32-2.44 (1H, m), 2.60 (3H, s), 2.67 (3Н, s), 2.78 (5Н, s), 3.06 (1H, dt), 3.23-3.54 (3Н, dt); m/z MN ⁺ 346.

Intermediate 4: (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (dihydrochloride salt)

4 M HCl in 1,4-dioxane (200 mL; 800 mmol) was added to (R)-tert-butyl-3-((2,5,7-trimethyl-[1.2.4]triazolo[1.5 -a]pyrimidin-6-yl)methyl)pyrrolidine-1-carboxylate (18 g; 52.11 mmol) in 1,4-dioxane (50 ml). The reaction mixture was stirred at room temperature for 16 hours. The resulting precipitate was collected by filtration, washed with 1,4-dioxane (100 mL) and dried under vacuum to give the title compound (13.80 g; 83%) as a white solid which was used without further purification; ¹ H NMR (300 MHz, DMSO) 1.63 (1H, dq), 1.90–2.05 (1H, m), 2.51 (4H, s), 2.65 (3H, s), 2.75–3.13 (7H, m), 3.26 ( 2Н, ddt), 7.30 (1H, br s) 9.28 (1H, s), 9.52 (1H, s); m/z MN ⁺ 246.

Intermediate 4B (free base of intermediate 4): (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine

1.25 M HCl in EtOAc (36.4 ml; 45.51 mmol) was added in one portion to (R)-tert-butyl-3-((2,5,7-trimethyl-[1,2,4]triazolo [1,5-a]pyrimidin-6-yl)methyl)pyrrolidine-1-carboxylate (2.62 g; 7.58 mmol) in EtOAc (15 ml) at room temperature. The resulting solution was stirred at room temperature for 5 days. The solvent was evaporated in vacuo to give the crude hydrochloride salt as an orange gum. The crude product was converted to the free base using ion exchange chromatography using a CO column. The desired product was eluted from the column using 1M NH ₃ /MeOH and the pure fractions were evaporated to dryness to give the title compound (1.77 g, 95%) as an orange gum; ^1H NMR (500 MHz, _CDCl3 ) 1.51 (1H, dq), 1.92 (1H, ddd), 2.32 (1H, р), 2.60 (3Н, s), 2.64 (1H, dd), 2.69 (3Н, s ), 2.80 (3Н, s), 2.82 (2Н, dd), 2.98 (1H, dt), 3.03–3.13 (2Н, m), NH was not detected; m/z MN ⁺ 246.

Intermediate 5: (R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidine

DIPEA (4.39 ml; 25.14 mmol), dihydrochloride (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a ]pyrimidine (2 g; 6.28 mmol) and 5-bromo-2-fluoropyridine (1.66 g; 9.43 mmol) were dissolved in n-propanol (10 ml) and sealed in a microwave tube. The reaction mixture was heated at 150°C for 2.5 hours in a microwave reactor and cooled to room temperature. The solvent was removed under reduced pressure. The reaction mixture was poured into water (100 ml), extracted with EtOAc (3×100 ml), the organic layer was dried over Na ₂ SO ₄ , filtered and evaporated to give a yellow solid. The crude product was purified by crystallization from EtOAc/petroleum ether to give the title compound (1.30 g, 52%) as a pale yellow solid; ^1H NMR (300 MHz, _CDCl3 ) 1.90 (1H, dq), 2.19 (1H, dq), 2.63 (4H, s), 2.71 (3H, s), 2.80 (3H, s), 2.93 (2H, qd ), 3.24 (1H, dd), 3.45 (1H, q), 3.63 (2H, q), 6.28 (1H, d), 7.54 (1H, dd), 8.19 (1H, d); m/z MH ⁺ 401.

Intermediate 7: 1-((6-bromopyridin-3-yl)methyl)-4-methylpiperazine

6-Bromonicotinaldehyde (3 g; 16.13 mmol) and 1-methylpiperazine (4.85 g; 48.39 mmol) were stirred in DCM (200 ml) at room temperature for 2 hours. AcOH (0.097 g; 1.61 mmol) and sodium triacetoxyborohydride (6.84 g; 32.26 mmol) were added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with sat. aq. NaHCO ₃ and the organic layer were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 0-80% MeOH in water to give the title compound (2.00 g, 46%) as a yellow oil; ¹ H NMR (300 MHz, DMSO) 2.55 (3H, s), 2.65 (4H, d), 2.91 (4H, s), 3.49 (2H, s), 7.37-7.54 (2H, m), 8.27 (1H, d); m/z MN ⁺ 270.

Intermediate 8: 1-((5-bromopyridin-2-yl)methyl)-4-methylpiperazine

5-Bromopicolinaldehyde (3.5 g; 18.82 mmol) and 1-methylpiperazine (5.65 g; 56.45 mmol) in DCM (20 ml) were stirred at room temperature for 2 hours. AcOH (0.113 g; 1.88 mmol) and sodium triacetoxyborohydride (7.98 g; 37.63 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give the title compound (2.40 g, 47%) as a yellow oil; ¹ H NMR (300 MHz, DMSO) 2.26 (3H, s), 2.47 (8H, s), 3.58 (2H, s), 7.42 (1H, m), 8.03 (1H, dd), 8.62 (1H, dd) ; m/z MN ⁺ 270.

Intermediate 9: (6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)boronic acid

PdCl ₂ (dppf) (21.67 mg; 0.03 mmol) was added to 1-((5-bromopyridin-2-yl)methyl)-4-methylpiperazine (160 mg; 0.59 mmol), 4.4, 4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (165 mg; 0.65 mmol) and potassium acetate (116 mg; 1 .18 mmol) in 1,4-dioxane (4 ml) at room temperature under nitrogen. The resulting mixture was stirred at 90°C for 16 hours.

The mixture was purified by C18 flash chromatography eluting with a gradient of 5 to 100% MeCN in water to give the crude title compound (80 mg; 58%) as a yellow gum; m/z MH ⁺ 236 (based on LC/MS data, the compound was believed to be boronic acid).

Intermediate 10: rac-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5 -a]pyrimidine

DIPEA (0.878 ml; 5.03 mmol) was added to 5-bromo-2-chloropyrimidine (486 mg; 2.51 mmol) and rac-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)- dihydrochloride [1,2,4]triazolo[1,5-a]pyrimidine (800 mg; 2.51 mmol) (prepared in 4 steps via a method similar to that of intermediate 4 with rac-tert-butyl-3-( hydroxymethyl)pyrrolidine-1-carboxylate as starting material) in EtOAc (10 ml) at room temperature. The reaction mixture was heated at 70°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 5-10% MeOH in DCM to give the title compound (350 mg; 35%) as a yellow solid; ¹ H NMR (300 MHz, CDCl ₃ ) 1.79-1.93 (1H, m), 2.09-2.27 (1H, m), 2.49-2.62 (1H, m), 2.65 (3H, s), 2.72 (3H, s) , 2.80 (3Н, s), 2.92 (2Н, dd), 3.30 (1H, dd), 3.46-3.61 (1H, m), 3.64-3.81 (2Н, m), 8.31 (2Н, s); m/z МН ⁺ 402.

Intermediate 11: (R)-2,5,7-trimethyl-6-((1-(pyridin-3-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5 -a] pyrimidine

Cs ₂ CO ₃ (1.97 g; 6.03 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1, 5-a]pyrimidine (0.74 g; 3.02 mmol) and 3-iodopyridine (0.68 g; 3.32 mmol) in 1,4-dioxane (10 ml). The reaction mixture was degassed and pre-catalyst RuPhos 3rd generation (0.25 g; 0.30 mmol) was added. The reaction mixture was heated at 90°C for 5 hours, then left to cool to room temperature and diluted with DCM and filtered. The filtrate was concentrated in vacuo and purified by CPC eluting with 0-5% 1 M NH ₃ /MeOH in DCM to give the title compound (0.413 g; 43%) as a yellow solid; ¹ H NMR (500 MHz, CDCl ₃ ) 1.88 (1H, dq), 2.18 (1H, dtd), 2.58-2.67 (4H, m), 2.70 (3H, s), 2.78 (3H, s), 2.89 (1H , dd), 2.93-3 (1H, m), 3.09 (1H, dd), 3.31-3.43 (2H, m), 3.49-3.56 (1H, m), 6.78 (1H, ddd), 7.11 (1H, ddd ), 7.92-8 (2H, m); m/z MN ⁺ 323.

Intermediate 12: (R)-6-((1-(6-Bromopyridin-3-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidine

NBS (229 mg; 1.28 mmol) was added in one portion to (R)-2,5,7-trimethyl-6-((1-(pyridin-3-yl)pyrrolidin-3-yl)methyl)-[1 ,2,4]triazolo[1,5-a]pyrimidine (414 mg; 1.28 mmol) in MeCN (5 ml) at 0° C. in air. The reaction mixture was stirred at 0°C and left to slowly warm to room temperature over 3 hours. The resulting precipitate was isolated by filtration and washed with MeCN (5 ml) to give the title compound (298 mg; 58%) as a white solid; ¹ H NMR (500 MHz, CDCl ₃ ) 1.88 (1H, dq), 2.11-2.24 (1H, m), 2.61 (3H, s), 2.62-2.67 (1H, m), 2.69 (3H, s), 2.78 (3Н, s), 2.88 (1H, dd), 2.95 (1H, dd), 3.06 (1H, dd), 3.28-3.41 (2Н, m), 3.48 (1H, td), 6.69 (1Н, dd), 7.25 (1H, dd), 7.69 (1H, d); m/z MH ⁺ 401.

Intermediate 13: 3-chloro-6-(chloromethyl)pyridazine

1,3,5-Trichloro-1,3,5-triazinan-2,4,6-trione (1.808 g; 7.78 mmol) was added in one portion to 3-chloro-6-methylpyridazine (2.00 g; 15 .56 mmol) in DCE (100 ml) at room temperature. The reaction mixture was stirred at 60°C for 2 hours, then left to cool to room temperature and filtered. The filtrate was concentrated in vacuo and purified by CPC eluting with 10-50% EtOAc in heptane to give the title compound (1.60 g, 63%) as a pale yellow oil; ¹ H NMR (500 MHz, CDCl ₃ ) 4.88 (2H, s), 7.58 (1H, d), 7.70 (1H, d); m/z MH ⁺ 163.

Intermediate 14: 4-((6-chloropyridazin-3-yl)methyl)morpholine

Morpholine (0.86 ml; 9.82 mmol) was added in one portion to 3-chloro-6-(chloromethyl)pyridazine (1.6 g; 9.82 mmol) and DIPEA (2.05 ml; 11.8 mmol) in THF (16 ml) at room temperature. The reaction mixture was stirred at room temperature for 3 days, then filtered and washed with THF. The combined filtrate was concentrated in vacuo and the resulting crude product was purified by CPC eluting with 0-5% MeOH in DCM to give the title compound (1.380 g; 66%) as a white solid; ¹ H NMR (500 MHz, CDCl ₃ ) 2.47-2.56 (4H, m), 3.68-3.76 (4H, m), 3.85 (2H, s), 7.50 (1H, d), 7.68 (1H, d); m/z MN ⁺ 214.

Intermediate 15: (R)-2,5,7-trimethyl-6-((1-(pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5 -a]pyrimidine

Cs ₂ CO ₃ (6.16 g; 18.91 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1, 5-a]pyrimidine (2.32 g; 9.46 mmol) and 5-bromopyridine (1.503 g; 9.46 mmol) in 1,4-dioxane (64 ml). The reaction mixture was degassed and pre-catalyst 3rd generation RuPhos (0.395 g; 0.47 mmol) and RuPhos (0.221 g; 0.47 mmol) were added. The reaction mixture was stirred at 90°C for 18 hours, then left to cool to room temperature, diluted with DCM and filtered. The filtrate was concentrated in vacuo and purified by CPC eluting with 0-5% 1 M NH ₃ /MeOH in DCM to give the title compound (1.160 g; 38%) as a yellow solid; ¹ H NMR (500 MHz, CDCl ₃ ) 1.88-1.95 (1H, m), 2.20 (1H, dtd), 2.61 (3H, s), 2.63-2.68 (1H, m), 2.70 (3H, s), 2.80 (3Н, s), 2.91 (1H, dd), 2.98 (1H, dd), 3.12 (1H, dd), 3.37 (1H, dt), 3.47 (1H, s), 3.54 (1H, td), 8.05 ( 2H, s), 8.60 (1H, s); m/z МН ⁺ 324.

Intermediate 16: (R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidine

(R)-2,5,7-Trimethyl-6-((1-(pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine (1.59 g; 4.92 mmol) was added to MeCN (80 ml) and the reaction mixture was cooled to 0°C. Then NBS (1.050 g; 5.90 mmol) was added in one portion. The reaction mixture was left to warm to room temperature and stirred for 2 hours. The resulting suspension was filtered and the crude solid was collected and suspended in MeCN (10 ml) and heated to reflux. The suspension was allowed to cool to room temperature and the solid was collected by filtration to give the title compound (0.652 g; 33%) as a yellow solid; ¹ H NMR (500 MHz, CDCl ₃ ) 1.90 (1H, dq), 2.16-2.25 (1H, m), 2.58-2.67 (4H, m), 2.70 (3H, s), 2.80 (3H, s), 2.88 -2.94 (1H, m), 2.98 (1H, dd), 3.10 (1H, dd), 3.34 (1H, dt), 3.44 (1H, dd), 3.51 (1H, td), 7.87 (2H, s); m/z МН ⁺ 402.

Intermediate 17: (S)-2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine

Potassium carbonate (2.43 g; 17.64 mmol) was added in one portion to 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.31 g ; 4.41 mmol) and (S)-1,3-dimethylpiperazine dihydrochloride (0.83 g; 4.41 mmol) in MeCN (40 ml) at room temperature. The reaction mixture was stirred at 80°C for 18 hours, then left to cool to room temperature and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by CPC eluting with 0-10% 1 M NH ₃ /MeOH in DCM to give the title compound (506 mg; 35%) as a colorless oil; m/z MI 331.

Intermediate 18: 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (92 mg; 0.13 mmol) was added to 4-bromo-3-methylbenzaldehyde (500 mg; 2.51 mmol), 4,4,4',4',5 ,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (638 mg; 2.51 mmol) and potassium acetate (493 mg; 5.02 mmol) in 1, 4-dioxane (10 ml) at room temperature. The reaction mixture was stirred at 90°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 10% EtOAc in petroleum ether to give the title compound (580 mg; 94%) as a yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.39 (12H, s), 2.63 (3H, s), 7.64-7.70 (2H, m), 7.92 (1H, d), 10.03 (1H, s); m/z MH ⁺ 247.

Intermediate 19: (R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)pyrimidin-2-yl)benzaldehyde

Pd(Ph ₃ P) ₄ (0.287 g; 0.25 mmol) was added to (R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2.5, 7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (1.00 g; 2.49 mmol), 4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzaldehyde (0.692 g; 2.98 mmol) and 2 M aq. a solution of sodium carbonate (2.49 ml; 4.97 mmol) in degassed 1,4-dioxane (40 ml) and water (7.5 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting residue was taken up in DCM and passed through filter paper to separate phases, then concentrated in vacuo and purified by CPC eluting with 0-10% MeOH in DCM to give the title compound (0.510 g; 48%) as a yellow solid ; ¹ H NMR (500 MHz, CDCl ₃ ) 1.88-1.96 (1H, m), 2.23 (1H, ddd), 2.62 (3H, s), 2.72 (4H, s), 2.81 (3H, s), 2.88-3.04 (2Н, m), 3.20 (1H, dd), 3.45 (1H, dt), 3.54 (1H, dd), 3.63 (1H, td), 7.9-7.99 (2Н, m), 8.16 (2Н, s), 8.42-8.53 (2H, m), 10.06 (1H, s); m/z MN ⁺ 428.

Intermediate 20: tert-Butyl 4-(2-(dimethylamino)-2-oxoethyl)piperazine-1-carboxylate

HATU (3.74 g; 9.82 mmol) was added to 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (2 g; 8.19 mmol) in DMF (25 ml) at room temperature in air atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. Dimethylamine (12.28 ml; 24.56 mmol) and DIPEA (4.29 ml; 24.56 mmol) were added to the mixture at room temperature under air. The reaction mixture was stirred at room temperature for 2 hours and then poured into sat. aq. NaHCO ₃ (200 ml) and extracted with EtOAc (3×100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give the title compound (1.65 g, 74%) as a pale yellow solid; ¹ H NMR (400 MHz, MeOD) 1.47 (9H, s), 2.49 (4H, t), 2.95 (3H, s), 3.11 (3H, s), 3.27 (2H, s), 3.43-3.50 (4H, m); m/z MN ⁺ 272.

Intermediate 21: N,N-dimethyl-2-(piperazin-1-yl)acetamide dihydrochloride

4 M HCl in EtOAc (25 ml; 100 mmol) was added to tert-butyl 4-(2-(dimethylamino)-2-oxoethyl)piperazine-1-carboxylate (1.6 g; 5.9 mmol) in EtOAc ( 25 ml) at room temperature in an air atmosphere. The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo to give the title compound (1.4 g, 100%) as a white solid; m/z MN ⁺ 172.

Intermediate 22: 2-(4-(4-bromobenzyl)piperazin-1-yl)-N,N-dimethylacetamide

N,N-dimethyl-2-(piperazin-1-yl)acetamide dihydrochloride (800 mg; 3.28 mmol) was added to 4-bromobenzaldehyde (606 mg; 3.28 mmol) in THF (25 mL) at room temperature in air atmosphere and the reaction mixture was stirred at room temperature for 3 hours. Sodium triacetoxyborohydride (1389 mg; 6.55 mmol) and AcOH (2 drops) were added to the mixture, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and concentrated under vacuum to almost dryness. The crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give the title compound (704 mg, 63%) as a brown oil; ¹ H NMR (400 MHz, _CDCl3 ) 2.49 (4H, m), 2.56 (4H, m), 2.95 (3H, s), 3.08 (3H, s), 3.18 (2H, s), 3.46 (2H, s ), 7.17-7.25 (2H, m), 7.40-7.49 (2H, m); m/z MN ⁺ 340.

Intermediate 23: 2-(4-(4-bromobenzyl)piperazin-1-yl)ethanol

2-(Piperazin-1-yl)ethanol (1.407 g; 10.81 mmol) was added to 4-bromobenzaldehyde (1 g; 5.40 mmol) in THF (25 mL) at room temperature and the reaction mixture was stirred at room temperature for within 1 hour. Sodium triacetoxyborohydride (2.291 g; 10.81 mmol) and AcOH (2 drops) were added to the mixture at room temperature under air and the reaction mixture was stirred at room temperature for 16 hours, then poured into water (20 ml) and concentrated in vacuo almost dry. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give the title compound (1.20 g, 74%) as a brown oil; ¹ H NMR (400 MHz, CDCl ₃ ) 2.23-2.57 (11H, m), 3.48 (2H, s), 3.63 (2H, t), 7.22 (2H, d), 7.46 (2H, d); m/z MN ⁺ 299.

Intermediate 24: 4-(4-(5-bromopyrimidin-2-yl)benzyl)morpholine

Pd(Ph ₃ P) ₄ (578 mg; 0.50 mmol) was added to 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine ( 1516 mg; 5.00 mmol), 5-bromo-2-iodopyrimidine (1424 mg; 5 mmol) and Na ₂ CO ₃ (1060 mg; 10.00 mmol) in toluene (20 ml) and water (4 ml) and the reaction mixture was stirred at 120°C for 3 days, then left to cool to room temperature and concentrated under vacuum. The residue was taken up in EtOAc (100 ml) and washed successively with water (2×20 ml). The organic layer was isolated and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 5-50% MeOH in water to give the title compound (510 mg, 31%) as a pale yellow solid; m/z МН ⁺ 334.

Intermediate 25: (R)-2,5,7-trimethyl-6-((1-phenylpyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Degassed tert-butanol (5 ml) was added to bromobenzene (74 μl; 0.7 mmol), dihydrochloride (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4 ]triazolo[1,5-a]pyrimidine (267 mg; 0.84 mmol), Cs ₂ CO ₃ (1368 mg; 4.20 mmol), RuPhos (65 mg; 0.14 mmol) and pre-catalyst RuPhos 3- th generation (59 mg; 0.07 mmol). The reaction mixture was heated at 90°C overnight, then left to cool to room temperature and concentrated under vacuum. The residue was dissolved in DCM (30 ml) and washed with water (30 ml). The aqueous layer was re-extracted with DCM (30 ml) and the combined organic layers were passed through a hydrophobic (phase separation) frit and concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (72 mg; 32%) as a white solid; ¹ H NMR (500 MHz, CDCl ₃ ) 1.78-1.9 (1H, m), 2.1-2.21 (1H, m), 2.55-2.64 (4H, m), 2.69 (3H, s), 2.78 (3H, s) , 2.83-2.98 (2H, m), 3.08 (1H, dd), 3.28-3.39 (2H, m), 3.45-3.55 (1H, m), 6.54 (2H, dd), 6.70 (1H, tt), 7.23 (2H, dd); m/z MN ⁺ 322.

Intermediate 26: (R)-6-((1-(4-bromophenyl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a ]pyrimidine

NBS (0.460 g; 2.58 mmol) was added to (R)-2,5,7-trimethyl-6-((1-phenylpyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1, 5-a]pyrimidine (0.83 g; 2.58 mmol) in THF (50 ml). The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 0-90% MeOH in water to give the title compound (0.750 g, 73%) as a yellow solid; m/z MN ⁺ 400.

Intermediate 27: (R)-2,5,7-trimethyl-6-((1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (94 mg; 0.11 mmol) was added to (R)-6-((1-(4-bromophenyl)pyrrolidin-3-yl)methyl)-2.5, 7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (460 mg; 1.15 mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(1,3,2-dioxaborolane) (292 mg; 1.15 mmol) and potassium acetate (226 mg; 2.30 mmol) in 1,4-dioxane (5 ml) at room temperature temperature. The reaction mixture was stirred at 90°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by CPC eluting with EtOAc to give the title compound (350 mg; 68%) as a pale yellow solid; m/z МН ⁺ 448.

Intermediate 28: 2-bromo-5-((4-methylpiperazin-1-yl)methyl)pyrazine

Potassium iodide (0.659 g; 3.97 mmol) was added to 1-methylpiperazine (0.398 g; 3.97 mmol), 2-bromo-5-(bromomethyl)pyrazine (1 g; 3.97 mmol) and K ₂ CO ₃ (0.549 g; 3.97 mmol) in DMF (30 ml) in an air atmosphere. The reaction mixture was stirred at room temperature for 4 hours then concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give the title compound (0.520 g, 48%) as a yellow oil; m/z MH ⁺ 271.

Intermediate 29: 5-bromo-2-((4-methylpiperazin-1-yl)methyl)pyrimidine

Potassium iodide (758 mg; 4.57 mmol) was added to 5-bromo-2-(bromomethyl)pyrimidine (767 mg; 3.04 mmol), 1-methylpiperazine (457 mg; 4.57 mmol) and K ₂ CO ₃ (631 mg; 4.57 mmol) in DMF (15 ml). The reaction mixture was stirred at room temperature for 2 hours then concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give the title compound (340 mg; 41%) as a white solid; m/z MH ⁺ 271.

Intermediate 30: 4-((6-bromopyridin-3-yl)methyl)morpholine

Potassium iodide (1.985 g; 11.96 mmol) was added to 2-bromo-5-(bromomethyl)pyridine (3 g; 11.96 mmol), morpholine (1.042 g; 11.96 mmol) and K ₂ CO ₃ (1.652 g; 11.96 mmol) in DMF (25 ml) and the reaction mixture was stirred at room temperature for 16 hours, then poured into water (150 ml) and extracted with EtOAc (3×50 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-75% EtOAc in petroleum ether to give the title compound (2.60 g, 85%) as a white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 2.41-2.48 (4H, m), 3.48 (2H, s), 3.68-3.75 (4H, m), 7.46 (1H, d), 7.58 (1H, dd), 8.31 (1H, d); m/z MN ⁺ 257.

Intermediate 31: 4-((6-(4-bromophenyl)pyridin-3-yl)methyl)morpholine

Pd(Ph ₃ P) ₄ (0.674 g; 0.58 mmol) was added to 4-((6-bromopyridin-3-yl)methyl)morpholine (1.5 g; 5.83 mmol), (4-bromophenyl) boronic acid (1.289 g; 6.42 mmol) and Na ₂ CO ₃ (1.237 g; 11.67 mmol) in 1,4-dioxane (14 ml) and water (7.00 ml) at room temperature. The reaction mixture was stirred at 80°C for 5 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 50% EtOAc in petroleum ether to give the title compound (1.28 g, 66%) as a white solid; ¹ H NMR (400 MHz, DMSO) 2.39 (4H, dd), 3.49-3.64 (6H, m), 7.58-7.76 (2H, m), 7.82 (1H, dd), 7.93-8.01 (1H, m), 8.01-8.09 (2H, m), 8.59 (1H, d); m/z MN ⁺ 333.

Intermediate 32: 3-chloro-6-((4-methylpiperazin-1-yl)methyl)pyridazine

Potassium iodide (1.200 g; 7.23 mmol) was added to 3-(bromomethyl)-6-chloropyridazine (1 g; 4.82 mmol), 1-methylpiperazine (0.724 g; 7.23 mmol) and K ₂ CO ₃ ( 0.999 g; 7.23 mmol) in DMF (15 ml). The reaction mixture was stirred at room temperature for 2 hours, then diluted with water and the resulting solution was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give the title compound (300 mg; 28%) as white solid; ¹ H NMR (300 MHz, DMSO) 2.19 (3H, s), 2.40 (8H, m), 3.77 (2H, s), 7.76 (1H, d), 7.88 (1H, d); m/z MN ⁺ 227.

Intermediate 33: 2-(4-bromophenyl)-5-methylpyrimidine

Pd(Ph ₃ P) ₄ (1.002 g; 0.87 mmol) was added to 2-bromo-5-methylpyrimidine (1.5 g; 8.67 mmol), (4-bromophenyl)boronic acid (1.74 g; 8.7 mmol) and Na ₂ CO ₃ (1.84 g; 17.3 mmol) in 1,4-dioxane (35 ml) and water (7 ml) in an air atmosphere. The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 2-5% EtOAc in petroleum ether to give the title compound (1.00 g, 46%) as a yellow solid; ¹ H NMR (300 MHz, CDCl ₃ ) 2.37 (3H, s), 7.55 (2H, d), 8.30 (2H, d), 8.64 (2H, s); m/z MH ⁺ 249.

Intermediate 34: 5-(bromomethyl)-2-(4-bromophenyl)pyrimidine

Benzoyl peroxide (58.3 mg; 0.24 mmol) was added to 2-(4-bromophenyl)-5-methylpyrimidine (600 mg; 2.41 mmol) and NBS (429 mg; 2.41 mmol) in CCl ₄ (12 ml) in an air atmosphere. The reaction mixture was stirred at 80°C for 4 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeOH in water to give the title compound (310 mg; 39%) as a yellow oil; m/z MN ⁺ 327.

Intermediate 35: 2-(4-bromophenyl)-5-((4-methylpiperazin-1-yl)methyl)pyrimidine

Potassium iodide (152 mg; 0.91 mmol) was added to 5-(bromomethyl)-2-(4-bromophenyl)pyrimidine (300 mg; 0.91 mmol), 1-methylpiperazine (82 mg; 0.82 mmol) and K ₂ CO ₃ (126 mg; 0.91 mmol) in DMF (10 ml) in air atmosphere. The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum. The crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give the title compound (195 mg; 61%) as a yellow oil; ¹ H NMR (300 MHz, CDCl ₃ ) 2.61 (3H, s), 2.76-3.20 (8H, m), 3.61 (2H, s), 7.54 (2H, d), 8.33 (2H, d), 8.73 (2H , s); m/z MH ⁺ 347.

Intermediate 36: tert-Butyl 4-((6-bromopyridin-3-yl)methyl)piperazine-1-carboxylate

Sodium triacetoxyborohydride (4.56 g; 21.50 mmol) was added to 6-bromonicotinaldehyde (2.00 g; 10.75 mmol), tert-butyl piperazine-1-carboxylate (4.01 g; 21.50 mmol) and AcOH (0.062 ml; 1.08 mmol) in DCM (100 ml) at 20°C. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was washed with sat. NaHCO ₃ was passed through filter paper to separate the phases and the solvent was removed under vacuum. The crude product was purified by CPC eluting with 0 to 70% EtOAc in heptane to give the title compound (2.80 g, 73.1%) as a colorless oil which crystallized on standing; ¹ H NMR (500 MHz, CDCl ₃ ) 1.45 (9H, s), 2.31-2.43 (4H, m), 3.39-3.44 (4H, m), 3.47 (2H, s), 7.45 (1H, dd), 7.55 (1H, dd), 8.29 (1H, dd); m/z МН ⁺ 356.

Intermediate 37: tert-Butyl 4-((6-(4-bromophenyl)pyridin-3-yl)methyl)piperazine-1-carboxylate

Pd(Ph ₃ P) ₄ (0.389 g; 0.34 mmol) was added to tert-butyl 4-((6-bromopyridin-3-yl)methyl)piperazine-1-carboxylate (2.40 g; 6.74 mmol), (4-bromophenyl)boronic acid (1.35 g; 6.74 mmol) and potassium carbonate (2.79 g; 20.2 mmol) in degassed 1,4-dioxane (12 ml) and water (3 ml) at room temperature. The reaction mixture was heated at 85°C in a microwave reactor for 3 hours, then left to cool to room temperature and diluted with EtOAc. The organic phase was passed through a phase separator and then concentrated under vacuum. The resulting crude product was purified by CPC eluting with 0-5% MeOH in DCM to give the title compound (1.20 g; 41%) as a yellow oil which solidified on standing; ¹ H NMR (500 MHz, CDCl ₃ ) 1.46 (9H, s), 2.36-2.47 (4H, m), 3.4-3.47 (4H, m), 3.55 (2H, s), 7.56-7.62 (2H, m) , 7.67 (1H, dd), 7.74 (1H, dd), 7.84-7.91 (2H, m), 8.57-8.63 (1H, m); m/z MH ⁺ 432.

Intermediate 38: 4-((5-bromopyrimidin-2-yl)methyl)morpholine

Potassium iodide (758 mg; 4.57 mmol) was added to 5-bromo-2-(bromomethyl)pyrimidine (767 mg; 3.04 mmol), morpholine (398 mg; 4.57 mmol) and K ₂ CO ₃ (631 mg; 4.57 mmol) in DMF (15 ml). The reaction mixture was stirred at room temperature for 2 hours, then diluted with water and concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give the title compound (720 mg; 92%) as a white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 2.55-2.63 (4H, m), 3.74-3.82 (6H, m), 8.79 (2H, s); m/z MN ⁺ 258.

Intermediate 39: 4-((5-(4-bromophenyl)pyrimidin-2-yl)methyl)morpholine

Pd(Ph ₃ P) ₄ (179 mg; 0.15 mmol) was added to 4-((5-bromopyrimidin-2-yl)methyl)morpholine (400 mg; 1.55 mmol), (4-bromophenyl)boronic acid (311 mg; 1.55 mmol) and Na ₂ CO ₃ (328 mg; 3.10 mmol) in 1,4-dioxane (5 ml) and water (2.5 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give the title compound (330 mg; 64%) as a white solid; H NMR (400 MHz, CDCl ₃ ) 2.62-2.69 (4H, m), 3.78-3.86 (4H, m), 3.90 (2H, s), 7.42-7.53 (2H, m), 7.63-7.74 (2H, m ), 8.93 (2Н, s); m/z МН ⁺ 334.

Intermediate 40: 1-bromo-4-(bromomethyl)-2-methoxybenzene

Triphenylphosphine (5.53 ml; 23.9 mmol) was added portionwise to (4-bromo-3-methoxyphenyl)methanol (4.32 g; 20.0 mmol) and tetrabromomethane (7.26 g; 21.9 mmol) in DCM (100 ml) at 0°C for 2 minutes. The reaction mixture was left to warm to room temperature and stirred at room temperature for 18 hours, then concentrated under vacuum. The resulting crude product was purified by CPC eluting with 0-50% DCM in heptane to give the title compound (5.57 g, 100%) as a colorless gum; ^1H NMR (400 MHz, _CDCl3 ) 3.91 (3H, s), 4.44 (2H, s), 6.86 (1H, dd), 6.92 (1H, d), 7.49 (1H, d).

Intermediate 41: 1-(4-bromo-3-methoxybenzyl)-4-methylpiperazine

Potassium iodide (2.135 g; 12.86 mmol) was added to 1-bromo-4-(bromomethyl)-2-methoxybenzene (3 g; 10.7 mmol), 1-methylpiperazine (1.29 g; 12.9 mmol) and K ₂ CO ₃ (1.78 g; 12.9 mmol) in DMF (50 ml). The reaction mixture was stirred at room temperature for 16 hours, then poured into water (200 ml) and extracted with EtOAc (3×100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-5% MeOH in DCM to give the title compound (1.70 g, 53%) as a pale yellow oil; ¹ H NMR (400 MHz, _CDCl3 ) 2.34 (3H, s), 2.50 (8H, br m), 3.48 (2H, s), 3.91 (3H, s), 6.82 (1H, dd), 6.91 (1H, d), 7.46 (1H, dd); m/z MN ⁺ 299.

Intermediate 42: (2-Methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid

PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.464 g; 0.57 mmol) was added to 1-(4-bromo-3-methoxybenzyl)-4-methylpiperazine (1.7 g; 5.68 mmol), 4 ,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.89 g; 11.4 mmol) and potassium acetate (1.67 g; 17.1 mmol) in 1,4-dioxane (25 ml) at room temperature. The reaction mixture was stirred at 90°C for 48 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water (with 0.5% NH ₄ HCO ₃ ) to give the title compound (1.10 g; 73%) as a red a solid; m/z MN ⁺ 265.

Intermediate 43: (R)-6-((1-(6-chloropyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidine

Triethylamine (2.10 ml; 15.1 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5- a]pyrimidine (1.2 g; 3.77 mmol) and 2,6-dichloropyrazine (0.562 g; 3.77 mmol) in n-propanol (20 ml). The reaction mixture was stirred at 90°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. Water (50 ml) was added to the residue and extracted with EtOAc (3×50 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-5% MeOH in DCM to give the title compound (1.10 g, 82%) as a pale yellow solid; ¹ H NMR (300 MHz, DMSO) 1.81 (1H, dq), 2.07 (1H, m), 2.46 (3H, s), 2.62 (4H, s), 2.73 (3H, s), 2.91 (2H, d) , 3.18 (1H, m), 3.35 (1H, q), 3.61 (2H, td), 7.75 (1H, m), 7.90 (1H, m); m/z MH ⁺ 358.

Intermediate 44: (R)-2,5,7-trimethyl-6-((1-(6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1 ,5-a]pyrimidine

Pd(Ph ₃ P) ₄ (0.355 g; 0.31 mmol) was added to (R)-6-((1-(6-chloropyrazin-2-yl)pyrrolidin-3-yl)methyl)-2.5, 7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (1.1 g; 3.07 mmol), 2,4,6-trimethyl-1,3,5,2,4, 6-trioxatriborinan in THF (50 wt.%) (1.54 g; 6.15 mmol) and Na ₂ CO ₃ (1.30 g; 12.3 mmol) in 1,4-dioxane (6 ml) and water (3 ml). The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 1-5% MeOH in DCM to give the title compound (1.00 g, 96%) as a white solid; ¹ H NMR (300 MHz, DMSO) 1.81 (1H, dq), 2.06 (1H, dq), 2.26 (3H, s), 2.54 (6H, d), 2.73 (3H, s), 2.92 (2H, m) , 3.17 (1H, m), 3.36 (2H, m), 3.59 (2H, tt), 7.63 (1H, s), 7.73 (1H, s); m/z МН ⁺ 338.

Intermediate 45: (R)-6-((1-(5-bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4 ]triazolo[1,5-а]pyrimidine

NBS (0.527 g; 2.96 mmol) was added to (R)-2,5,7-trimethyl-6-((1-(6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1 ,2,4]triazolo[1,5-a]pyrimidine (1 g; 2.96 mmol) in DCM (10 ml) at 0° C. in air. The reaction mixture was stirred at 0° C. for 1 hour, then water (25 ml) was added and the mixture was extracted with DCM (3×25 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 1-2% MeOH in DCM to give the title compound (0.90 g, 73%) as a pale yellow solid; ¹ H NMR (300 MHz, DMSO) 1.81 (1H, dq), 2.06 (1H, dq), 2.39 (3H, s), 2.48 (3H, s), 2.55 (1H, m), 2.62 (3H, s) , 2.73 (3Н, s), 2.92 (2Н, m), 3.15 (1Н, m), 3.33 (1H, q), 3.58 (2Н, ddd), 7.58 (1Н, s); m/z MH ⁺ 416.

Intermediate 46: (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidine

2,5-Dibromopyrazine (3.74 g; 15.7 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[ 1,5-a]pyrimidine (5.00 g; 15.7 mmol) and DIPEA (13.7 ml; 78.6 mmol) in n-butanol (60 ml) at room temperature. The reaction mixture was heated at reflux temperature for 2 hours, then allowed to cool to room temperature and concentrated in vacuo. The resulting crude product was triturated with water and filtered to give the title compound (4.86 g, 77%) as an off-white solid; ¹ H NMR (500 MHz, CDCl ₃ ) 1.89 (1H, dq), 2.16-2.24 (1H, m), 2.61 (4H, s), 2.70 (3H, s), 2.79 (3H, s), 2.93 (2H , tt), 3.23 (1H, dd), 3.45 (1H, dt), 3.6–3.68 (2H, m), 7.61 (1H, d), 8.10 (1H, d); m/z MH ⁺ 402.

Intermediate 47: (R)-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl) pyrrolidin-1-yl)pyrazin-2-yl)phenyl)methanol

(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (165 mg; 0.71 mmol), (R)-6-((1-( 5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (237 mg; 0.59 mmol) and Cs ₂ CO ₃ (384 mg; 1.18 mmol) were added to 1,4-dioxane (6.2 ml) and water (3.1 ml) and the reaction mixture was degassed for 10 minutes. 2nd generation XPhos pre-catalyst (23 mg; 0.03 mmol) was added and the reaction mixture was stirred for 2 hours at 90° C., then allowed to cool to room temperature. The reaction mixture was diluted with EtOAc (50 ml). The organic layer was separated and washed with sat. brine and dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-4% 1 M NH ₃ /MeOH in DCM to give the title compound (200 mg; 79%) as a white foam; ¹ H NMR (500 MHz, CDCl ₃ ) 1.74 (1H, t), 1.92 (1H, dq), 2.18-2.27 (1H, m), 2.62 (4H, s), 2.71 (3H, s), 2.80 (3H , s), 2.87-3.02 (2Н, m), 3.33 (1Н, dd), 3.55 (1H, dt), 3.68-3.8 (2Н, m), 4.74 (2Н, d), 7.41-7.47 (2Н, m ), 7.84-7.91 (2H, m), 7.95 (1H, d), 8.51 (1H, d); m/z MH ⁺ 430.

Intermediate 48: (R)-6-((1-(5-(4-(chloromethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1 ,2,4]triazolo[1,5-а]pyrimidine

(R)-(4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1 -yl)pyrazin-2-yl)phenyl)methanol (200 mg; 0.47 mmol) was dissolved in DCM (7 ml) and DMF (0.34 mg; 4.66 μmol). The reaction mixture was cooled to 0° C. and thionyl chloride (0.037 ml; 0.51 mmol) was added dropwise. The reaction mixture was left to warm to room temperature and stirred at room temperature for 3 hours, then diluted with DCM (50 ml) and adjusted to pH 8-9 with Na ₂ CO ₃ (2 M aq. solution). The organic layer was separated and washed with sat. brine, passed through a phase separation cartridge and concentrated in vacuo to give the title compound (181 mg; 87%) as a yellow solid, which was used without further purification; m/z МН ⁺ 448.

Intermediate 49: (R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)pyrazin-2-yl)-benzaldehyde

Pd(Ph ₃ P) ₄ (0.373 g; 0.32 mmol) was added to (4-formylphenyl)boronic acid (0.485 g; 3.23 mmol), (R)-6-((1-(5-bromopyrazine- 2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (1.30 g; 3.23 mmol) and Na ₂ CO ₃ (0.685 g; 6.46 mmol) in 1,4-dioxane (10 ml) and water (2 ml). The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-80% MeOH in water to give the title compound (1.20 g, 87%) as a yellow solid; ¹ H NMR (300 MHz, CDCl ₃ ) 1.94 (1H, dq), 2.25 (1H, dq), 2.57-3.07 (12H, m), 3.24-3.42 (1H, m), 3.45-3.87 (3H, m) , 7.79-8.18 (5H, m), 8.60 (1H, d), 10.04 (1H, s); m/z MH ⁺ 428.

Intermediate 50: 1-(4-bromo-2-methylbenzyl)-4-methylpiperazine

4-Bromo-2-methylbenzaldehyde (1 g; 5.02 mmol) and 1-methylpiperazine (0.503 g; 5.02 mmol) were combined with MeOH (20 ml) and the reaction mixture was stirred for 2 hours at room temperature. NaCNBH ₄ (0.631 g; 10.1 mmol) and AcOH (0.030 g; 0.50 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 1-70% MeOH in water to give the title compound (1.00 g, 70%) as a yellow solid; m/z MH ⁺ 283.

Intermediate 51: 1-methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine

PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.058 g; 0.07 mmol) was added to 1-(4-bromo-2-methylbenzyl)-4-methylpiperazine (0.2 g; 0.71 mmol), 4 ,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.215 g; 0.85 mmol) and potassium acetate (0.139 g; 1.41 mmol) in 1,4-dioxane (10 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 0-50% EtOAc in petroleum ether to give the title compound (70 mg; 30%) as a yellow solid; m/z МН ⁺ 331.

Intermediate 52: 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1-yl)ethanone

Potassium carbonate (2.23 g; 16.2 mmol) was added in one portion to 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.4 g ; 8.08 mmol) and 1-(piperazin-1-yl)ethanone (1.04 g; 8.08 mmol) in MeCN (70 ml) at room temperature. The reaction mixture was stirred at 80°C for 18 hours, then left to cool to room temperature and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by CPC eluting with 0-5% 1 M NH ₃ /MeOH in DCM to give the title compound (2.73 g, 98%) as a colorless oil; ¹ H NMR (500 MHz, CDCl ₃ ) 1.34 (12H, s), 2.07 (3H, s), 2.41 (4H, dq), 3.42-3.46 (2H, m), 3.53 (2H, s), 3.59-3.64 (2H, m), 7.33 (2H, d), 7.72-7.81 (2H, m); m/z MN ⁺ 345.

Intermediate 53: (R)-6-((1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidine

Triethylamine (1.75 ml; 12.6 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5- a] pyrimidine (1 g; 3.14 mmol), 3,6-dichloropyridazine (0.468 g; 3.14 mmol) in n-propanol (10 ml) at room temperature in an air atmosphere. The reaction mixture was stirred at 90°C for 16 hours, then left to cool to room temperature and partially concentrated under vacuum. The precipitate was collected by filtration, washed with water (50 ml) and MeOH (10 ml) and dried under vacuum to give the title compound (0.610 g; 54%) as a brown solid which was used without further purification; ¹ H NMR (400 MHz, DMSO) 1.85 (1H, dq), 2.11 (1H, ddd), 2.48 (3H, s), 2.53-2.63 (1H, m), 2.64 (3H, s), 2.75 (3H, s), 2.94 (2H, d), 3.14-3.23 (1H, m), 3.40 (1H, dt), 3.49-3.93 (2H, m), 7.00 (1H, d), 7.47 (1H, d); m/z МН ⁺ 358.

Intermediate 54: 2,4-dioxopentan-3-yl-benzoate

Potassium hydroxide (50.5 g; 901 mmol) was added to benzoic acid (100 g; 819 mmol) in DMF (1 L) at room temperature. The reaction mixture was stirred at 50° C. for 1 hour, then 3-chloropentan-2,4-dione (110 g; 819 mmol) was added and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was left to cool to room temperature, diluted with EtOAc (3 L) and washed successively with water (1 L × 2), sat. aq. NH ₄ Cl (500 ml) and sat. brine (500 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-20% EtOAc in petroleum ether to give the title compound (130 g; 72%) as a yellow oil; m/z MH ⁺ 221.

Intermediate 55: 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl-benzoate

2,4-Dioxopentan-3-yl-benzoate (58 g; 263 mmol) was added to 3-methyl-1H-1,2,4-triazol-5-amine (27.1 g; 277 mmol) in AcOH (300 ml) at room temperature. The reaction mixture was stirred at 90°C for 10 hours, then left to cool to room temperature, concentrated under vacuum and brought to a pH of more than 7 with sat. aq. _NaHC03 . The mixture was extracted with EtOAc (3×500 ml). The combined organic layers were washed with sat. brine, passed through filter paper to separate phases, and concentrated in vacuo to give the title compound (52.0 g; 70%) as a beige solid; ¹ H NMR (400 MHz, CDCl ₃ ) 2.57 (3H, s), 2.66 (3H, s), 2.70 (3H, s), 7.54-7.65 (2H, m), 7.71-7.80 (1H, m), 8.24 -8.31 (2H, m); m/z MH ⁺ 283.

Intermediate 56: 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-ol

1 M aq. NaOH (177 ml; 177.11 mmol) was added to 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl-benzoate (50 g; 177 mmol) in EtOAc (500 ml) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then partially concentrated under vacuum and the solution was slowly acidified with 6 M aq. HCl until a precipitate forms (pH approximately 7). The precipitate was isolated by filtration, washed with water and dried under vacuum to give the title compound (24 g; 76%) as an off-white solid; m/z MH ⁺ 179.

Intermediate 57: tert-Butyl-(R)-3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1 -carboxylate

Diisopropylazodicarboxylate was added dropwise (52.4 ml; 269 mmol) to 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-ol (40 g; 224 mmol), tert-Butyl-(S)-3-hydroxypyrrolidine-1-carboxylate (46.2 g; 247 mmol) and triphenylphosphine (70.7 g; 269 mmol) in THF (800 ml) at room temperature for 2 hours, and the reaction mixture was stirred at room temperature for 10 minutes and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 0-100% EtOAc in petroleum ether to give the title compound (62.0 g, 80%) as a light yellow oil; ¹ H NMR (400 MHz, DMSO) 1.42 (9H, d), 2.07-2.14 (1H, m), 2.20-2.23 (1H, m), 2.47 (3H, s), 2.51-2.54 (3H, m), 2.63 (3Н, d), 3.34 (2Н, s), 3.43-3.56 (2Н, m), 4.74 (1H, s); m/z МН ⁺ 348.

Intermediate 58: (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine dihydrochloride

4 M HCl in 1,4-dioxane (150 ml; 600 mmol) was added to tert-butyl-(R)-3-((2,5,7-trimethyl-[1.2.4]triazolo[1.5 -a]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate (52 g; 149.7 mmol) in MeOH (200 ml) and the reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. Acetone was added to the residue and stirred for 30 minutes. The precipitate was collected by filtration to give the title compound (26 g; 55%) as a white solid; ¹ H NMR (400 MHz, DMSO) 2.03-2.13 (1H, m), 2.22-2.28 (1H, m), 2.51-2.54 (3H, m), 2.62 (3H, d), 2.74 (3H, s), 3.32-3.45 (3H, m), 3.46-3.56 (1H, m), 4.90 (1H, s), 9.91 (2H, s); m/z MN ⁺ 248.

Intermediate 58B (free base of intermediate 58): (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo-[1,5-a]pyrimidine dihydrochloride (4.12 g; 16.7 mmol ) was dissolved in MeOH and loaded onto an SCX column (50 g). The column was washed with MeOH, then eluted with 1 M NH ₃ in MeOH. The solvent was removed in vacuo to give the title compound (2.73 g, 66%) as an orange gum which was used in the next step without purification; ¹ H NMR (400 MHz, CDCl ₃ ) 1.97-2.16 (2H, m, 2.60 (3H, s), 2.65 (3H, s), 2.76 (3H, s), 3.08 (2H, ddd), 3.19 (1H, s), 3.24–3.37 (2H, m), 4.62 (1H, ddt), m/z MH ⁺ 248.

Intermediate 59: (R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidine

DIPEA (0.282 ml; 1.62 mmol) was added in one portion to 5-bromo-2-fluoropyridine (0.166 ml; 1.62 mmol) and (R)-2,5,7-trimethyl-6-(pyrrolidine-3- yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine (400 mg; 1.62 mmol) in n-butanol (4 ml) at room temperature. The reaction mixture was heated at 150°C in a microwave reactor for 2 hours, then left to cool to room temperature, diluted with EtOAc (50 ml) and washed successively with water (20 ml) and sat. brine (20 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-5% MeOH in DCM to give the title compound (346 mg; 53%) as a yellow solid; m/z МН ⁺ 403.

Intermediate 60: (R)-2,5,7-trimethyl-6-((1-(pyrimidin-5-yl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5 -a]pyrimidine

Cs ₂ CO ₃ (1.98 g; 6.07 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1, 5-a]pyrimidine (500 mg; 2.02 mmol) and 5-bromopyrimidine (321 mg; 2.02 mmol) in 1,4-dioxane (20 ml). The reaction mixture was degassed and RuPhos 3rd generation precatalyst (169 mg; 0.20 mmol) and RuPhos (189 mg; 0.40 mmol) were added. The resulting suspension was stirred at 90°C for 18 hours, then left to cool to room temperature. The reaction mixture was diluted with EtOAc (50 ml) and washed with water (30 ml) and sat. brine (25 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo.

The resulting crude product was purified by CPC eluting with 0-5% 1 M NH ₃ /MeOH in DCM to give the title compound (291 mg; 44%) as an orange gum; ¹ H NMR (500 MHz, CDCl ₃ ) 2.32 (1H, dtd), 2.46-2.55 (1H, m), 2.60 (3H, s), 2.62 (3H, s), 2.67 (3H, s), 3.5-3.62 (3Н, m), 3.7-3.81 (1H, m), 4.86 (1H, s), 8.12 (2Н, s), 8.66 (1H, s); m/z MN ⁺ 326.

Intermediate 61: (R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidine

NBS (159 mg; 0.89 mmol) was added portionwise to (R)-2,5,7-trimethyl-6-((1-(pyrimidin-5-yl)pyrrolidin-3-yl)oxy)-[1, 2,4]triazolo[1,5-a]pyrimidine (291 mg; 0.89 mmol) in MeCN (10 ml) at 0°C for 10 minutes in air. The reaction mixture was stirred at 0°C for 3 hours, then diluted with DCM (50 ml) and washed successively with water (20 ml) and sat. brine (20 ml). The organic layer was separated and dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-4% 1 M NH ₃ /MeOH in DCM to give the title compound (140 mg; 39%) as a colorless gum; m/z МН ⁺ 404.

Intermediate 62: (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidine

DIPEA (1.55 ml; 8.92 mmol) was added in one portion to 2,5-dibromopyrazine (1.06 g; 4.46 mmol) and (R)-2,5,7-trimethyl-6-(pyrrolidine- 3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine (735 mg; 2.97 mmol) in n-butanol (7 ml) at room temperature. The reaction mixture was stirred at 120°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 0-4% MeOH in DCM to give the title compound (740 mg; 62%) as a yellow foam; ¹ H NMR (500 MHz, CDCl ₃ ) 2.33 (1H, dtd), 2.52 (1H, ddq), 2.60 (3H, s), 2.61 (3H, s), 2.65 (3H, s), 3.55 (1H, dd ), 3.72 (1H, td), 3.75–3.88 (2H, m), 4.81 (1H, tt), 7.70 (1H, d), 8.14 (1H, d); m/z МН ⁺ 404.

Intermediate 63: 1-(4-bromophenyl)-1,4-pentanedione

The title compound was synthesized according to reference Ryzhkov, I.O. et al. Chemistry of Heterocyclic Compounds, 47(2), 182-193; 2011. Intermediate 64: 3-(4-bromophenyl)-6-methylpyridazine

1-(4-Bromophenyl)-1,4-pentanedione (183 g; 0.717 mol) was dissolved in AcOH (1.8 L) and cooled to 0°C. Hydrazine monohydrate (35 ml; 0.717 mol) was then added and the mixture was stirred for 30 minutes. 2,3-Dichloro-5,6-dicyanobenzoquinone (244 g; 1.08 mol) was added portionwise over 30 minutes and the reaction mixture was stirred at room temperature for 40 minutes then concentrated in vacuo. The residue was partitioned between EtOAc (4 L) and sat. aq. NaHCO ₃ (4 L). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 L). The combined organic layers were washed with sat. aq. NaHCO ₃ (10×2 L) and dried over MgSO ₄ then concentrated in vacuo. The resulting crude product was purified by column under vacuum (4 L sintered glass funnel, approximately half-filled with silica, 1 L fractions, loaded onto column by dissolving in DCM), eluting with 40-60% EtOAc/petroleum ether. The resulting crude product was stirred in diethyl ether (340 ml) for 30 minutes, then filtered and washed with Et ₂ O (2×75 ml), then petroleum ether (2×75 ml) and air dried to give the title compound ( 91.2 g, 51%) as a beige solid; ¹ H NMR (400 MHz, CDCl ₃ ) 2.75 (3H, s), 7.38 (1H, d), 7.65-7.60 (2H, m), 7.71 (1H, d), 7.96-7.91 (2H, m); ¹³ C NMR (400 MHz, CDCl ₃ ) 22.1, 123.5, 124.4, 127.3, 128.4, 132.2, 135.4, 156.2, 158.6.

Intermediate 65: 4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine

1,3,5-Trichloro-1,3,5-triazinan-2,4,6-trione (20.4 g; 87.8 mmol) was added portionwise to 3-(4-bromophenyl)-6-methylpyridazine (intermediate compound 64) (50 g; 200.7 mmol) in DCM (600 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then an additional portion of 1,3,5-trichloro-1,3,5-triazinan-2,4,6-trione (0.7 g) was added and the reaction mixture was stirred for 30 minutes, then morpholine (87 ml; 1003.6 mmol) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with 300 ml of water. The organic layer was separated and washed with water (300 ml) and concentrated in vacuo. The resulting residue was suspended in refluxing EtOAc (150 ml), cooled to room temperature and filtered. The filtered solid was washed with 200 ml of MTBE and dried under vacuum to give the title compound (53.4 g, 80%) as a white solid; ¹ H NMR (400 MHz, _CDCl3 ) 2.56 (4H, m), 3.73 (4H, m), 3.91 (2H, s), 7.64 (2H, m), 7.73 (1H, d), 7.81 (1H, d ), 7.96 (2H, m); m/z МН ⁺ 334.

Intermediate 66: 8-((6-(4-bromophenyl)pyridazin-3-yl)methyl)-3-methyl-3,8-diazabicyclo[3.2.1]octane

Trichloroisocyanuric acid (65.3 mg; 0.28 mmol) was added in one portion to a solution of 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64) (200 mg; 0.80 mmol) in DCE (5.9 ml ) at room temperature under air and the reaction mixture was stirred at room temperature for 30 minutes. It was confirmed by LC/MS that a chlorine-containing intermediate had been formed. 3-Methyl-3,8-diazabicyclo[3.2.1]octane (101 mg; 0.80 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with DCM (50 ml), filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-10% 1 M NH ₃ /MeOH in DCM to give the title compound (193 mg; 64%) as a yellow solid; ¹ H NMR (400 MHz, DMSO) 1.93 (2H, q), 2.12 (2H, dd), 2.32 (3H, s), 2.37 (2H, d), 3.29 (2H, s), 4.01 (2H, s) , 7.92-7.97 (2H, m), 8.08 (1H, d), 8.29 (2H, d), 8.41 (1H, d), missing 2H was assumed to be under the DMSO peak; m/z MN ⁺ 372.

Intermediate 67: (R)-2-((6-(4-bromophenyl)pyridazin-3-yl)methyl)octahydropyrrolo[1,2-a]pyrazine

Trichloroisocyanuric acid (65.3 mg; 0.28 mmol) was added in one portion to a solution of 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64) (200 mg; 0.80 mmol) in DCE (5.2 ml ) at room temperature in air. The reaction mixture was stirred at room temperature for 30 minutes. It was confirmed by LC/MS that a chlorine-containing intermediate had been formed. DIPEA (0.7 ml; 4.01 mmol) and (R)-octahydropyrrolo[1,2-a]pyrazine dihydrochloride (240 mg; 1.20 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours, then diluted with DCM (50 ml), filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-10% 1 M NH ₃ /MeOH in DCM to give the title compound (189 mg; 63%) as a yellow solid; ¹ H NMR (400 MHz, DMSO) 1.19-1.31 (1H, m), 1.66 (3H, ddt), 1.89-2.09 (3H, m), 2.14 (1H, td), 2.27 (1H, td), 2.73 ( 1Н, d), 2.86-2.98 (3Н, m), 3.83-3.94 (2Н, m), 7.74-7.8 (3Н, m), 8.09-8.14 (2Н, m), 8.23 (1H, d); m/z МН ⁺ 373.

Intermediate 68: (S)-2-((6-(4-bromophenyl)pyridazin-3-yl)methyl)octahydropyrrolo[1,2-a]pyrazine

Trichloroisocyanuric acid (65.3 mg; 0.28 mmol) was added in one portion to a solution of 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64) (200 mg; 0.80 mmol) in DCE (5.3 ml ) at room temperature in air. The reaction mixture was stirred at room temperature for 30 minutes. It was confirmed by LC/MS that a chlorine-containing intermediate had been formed. DIPEA (0.6 ml; 3.21 mmol) and (S)-octahydropyrrolo[1,2-a]pyrazine hydrobromide (166 mg; 0.80 mmol) were added and the reaction mixture was stirred at room temperature for 3 days, then diluted with DCM (50 ml), filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-10% 1 M NH ₃ /MeOH in DCM to give the title compound (299 mg; 100%) as a yellow solid; m/z МН ⁺ 373.

Intermediate 69: 1-(4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one

Trichloroisocyanuric acid (65.3 mg; 0.28 mmol) was added in one portion to a solution of 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64) (200 mg; 0.80 mmol) in DCE (5.9 ml ) at room temperature in air. The reaction mixture was stirred at room temperature for 30 minutes. Added an additional 0.15 equiv. trichloroisocyanuric acid and the reaction mixture was stirred for 30 minutes. 1-(Piperazin-1-yl)ethan-1-one (515 mg; 4.01 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours, then diluted with DCM (20 mL), filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-4% 1 M NH ₃ /MeOH in DCM to give the title compound (246 mg; 82%) as a white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 2.09 (3H, s), 2.56 (4H, dt), 3.45-3.51 (2H, m), 3.62-3.68 (2H, m), 3.94 (2H, s), 7.63 -7.69 (2H, m), 7.71 (1H, d), 7.83 (1H, d), 7.94-8.02 (2H, m); m/z MN ⁺ 375.

Intermediate 70: 3-(4-bromophenyl)-6-(piperidin-1-ylmethyl)pyridazine

Trichloroisocyanuric acid (65.3 mg; 0.28 mmol) was added in one portion to a solution of 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64) (200 mg; 0.80 mmol) in DCE (5.5 ml ) at room temperature in air. The reaction mixture was stirred at room temperature for 30 minutes. Added an additional 0.15 equiv. trichloroisocyanuric acid and the reaction mixture was stirred for 30 minutes. Piperidine (397 μl; 4.01 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours, then diluted with DCM (20 ml), filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-4% 1 M NH ₃ /MeOH in DCM to give the title compound (246 mg; 92%) as a white solid; ¹ H NMR (400 MHz, DMSO) 1.43 (2H, q), 1.54 (4H, p), 2.38-2.48 (4H, m), 3.81 (2H, s), 7.76-7.81 (3H, m), 8.09- 8.16 (2H, m), 8.23 (1H, d); m/z МН ⁺ 332.

Intermediate 71: 3-(4-bromophenyl)-6-((4-methylpiperazin-1-yl)methyl)pyridazine

Trichloroisocyanuric acid (65.3 mg; 0.28 mmol) was added in one portion to a solution of 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64) (200 mg; 0.80 mmol) in DCE (5.5 ml ) at room temperature in air. The reaction mixture was stirred at room temperature for 30 minutes. Added an additional 0.15 equiv. trichloroisocyanuric acid and the reaction mixture was stirred for 30 minutes. 1-methylpiperazine (445 μl; 4.01 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours, then diluted with DCM (50 ml), filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-10% 1 M NH ₃ /MeOH in DCM to give the title compound (237 mg; 85%) as a yellow solid; ¹ H NMR (400 MHz, DMSO) 2.16 (3H, s), 2.28-2.4 (4H, m), 2.47 (4H, s), 3.83 (2H, s), 7.74-7.8 (3H, m), 8.09- 8.14 (2H, m), 8.23 (1H, d); m/z MH ⁺ 347.

Intermediate 72: 3-(4-bromophenyl)-6-((4-ethylpiperazin-1-yl)methyl)pyridazine

Trichloroisocyanuric acid (0.327 g; 1.40 mmol) was added in one portion to a solution of 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64) (1 g; 4.01 mmol) in DCE (27.0 ml) at room temperature in an air atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. 1-ethylpiperazine (2.55 ml; 20.1 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours, then diluted with DCM (20 ml), filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-10% 1 M NH ₃ /MeOH to give the title compound (125 mg; 9%) as a white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.08 (3H, t), 2.42 (2H, q), 2.50 (4H, s), 2.62 (4H, s), 3.93 (2H, s), 7.63-7.68 (2H , m), 7.71 (1H, d), 7.80 (1H, d), 7.94–8.00 (2H, m); m/z МН ⁺ 361.

Intermediate 73: 3-(4-bromophenyl)-6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyridazine

Trichloroisocyanuric acid (0.327 g; 1.40 mmol) was added in one portion to a solution of 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64) (1 g; 4.01 mmol) in DCE (26.5 ml) at room temperature in an air atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. 1-(2-methoxyethyl)piperazine (2.98 ml; 20.1 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours, then diluted with DCM (20 ml), filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-10% 1 M NH ₃ /MeOH in DCM to give the title compound (525 mg; 33%) as a white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 2.61 (10H, dt), 3.35 (3H, s), 3.5-3.55 (2H, m), 3.93 (2H, s), 7.62-7.67 (2H, m), 7.70 (1H, d), 7.80 (1H, d), 7.94-8 (2H, m); m/z МН ⁺ 391.

Intermediate 74: 4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)-1,4-oxazepane

Trichloroisocyanuric acid (65.3 mg; 0.28 mmol) was added in one portion to a solution of 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64) (200 mg; 0.80 mmol) in DCE (5.9 ml ) at room temperature in air. The reaction mixture was stirred at room temperature for 30 minutes. Added an additional 0.15 equiv. trichloroisocyanuric acid and the reaction mixture was stirred for 30 minutes. 1,4-oxazepane (406 mg; 4.01 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours, then diluted with DCM (50 ml), filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-4% 1 M NH ₃ /MeOH in DCM to give the title compound (200 mg; 72%) as a yellow solid; ¹ H NMR (400 MHz, DMSO) 1.83 (2H, p), 2.72 (4H, q), 3.6–3.67 (2H, m), 3.72 (2H, t), 4.01 (2H, s), 7.73–7.81 ( 2Н, m), 7.83 (1H, d), 8.07-8.16 (2Н, m), 8.24 (1H, d); m/z МН ⁺ 348.

Intermediate 75: 1-((6-(4-bromophenyl)pyridazin-3-yl)methyl)azepane

Trichloroisocyanuric acid (65.3 mg; 0.28 mmol) was added in one portion to a solution of 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64) (200 mg; 0.80 mmol) in DCE (5.5 ml ) at room temperature in air. The reaction mixture was stirred at room temperature for 30 minutes. Added an additional 0.15 equiv. trichloroisocyanuric acid and the reaction mixture was stirred for 30 minutes. Azepane (452 μl; 4.01 mmol) was added and the reaction mixture was stirred at room temperature for 3 days, then diluted with DCM (50 ml), filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-4% 1 M NH ₃ /MeOH in DCM to give the title compound (88 mg; 32%) as a yellow solid; ¹ H NMR (400 MHz, DMSO) 1.59 (8H, s), 2.64-2.7 (4H, m), 3.98 (2H, s), 7.74-7.79 (2H, m), 7.82 (1H, d), 8.09- 8.14 (2H, m), 8.23 (1H, d); m/z MH ⁺ 346.

Intermediate 76: 4-((5-chloropyrazin-2-yl)methyl)morpholine

Sodium triacetoxyborohydride (4.46 g; 21.1 mmol) was added to 5-chloropyrazine-2-carbaldehyde (1 g; 7.02 mmol) and morpholine (0.614 ml; 7.02 mmol) in DCM (10 ml) at room temperature. temperature and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with sat. aq. NaHCO ₃ and stirred for 10 minutes, then passed through filter paper to separate the phases and concentrated in vacuo to give the title compound (1.180 g; 79%) as a colorless oil; ¹ H NMR (400 MHz, CDCl ₃ ) 2.49-2.55 (4H, m), 3.69 (2H, s), 3.71-3.77 (4H, m), 8.47 (1H, d), 8.55 (1H, d); m/z MH ⁺ 214.

Intermediate 77: 4-((5-(4-bromophenyl)pyrazin-2-yl)methyl)morpholine

Pd(Ph ₃ P) ₄ (135 mg; 0.12 mmol) was added in one portion to a degassed mixture of (4-bromophenyl)boronic acid (470 mg; 2.34 mmol), 4-((5-chloropyrazin-2-yl )methyl)morpholine (500 mg; 2.34 mmol) and 2 M aq. Na ₂ CO ₃ (2.34 ml; 4.68 mmol) in 1,4-dioxane (7.8 ml) and water (1.5 ml) at room temperature. The reaction mixture was stirred at 80°C for 2 hours, then left to cool to room temperature, diluted with EtOAc (75 ml) and washed successively with water (20 ml) and sat. brine (20 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-3% MeOH in DCM to give the title compound (730 mg; 93%) as a white solid; ¹ H NMR (400 MHz, CDCl3) 2.57 (4H, q), 3.72-3.79 (6H, m), 7.62-7.66 (2H, m), 7.88-7.93 (2H, m), 8.71 (1H, d), 8.95 (1H, d); m/z МН ⁺ 334.

Intermediate 78: 2-bromo-5-(pyrrolidin-1-ylmethyl)pyridine

Potassium iodide (331 mg; 1.99 mmol) was added to 2-bromo-5-(bromomethyl)pyridine (500 mg; 1.99 mmol), pyrrolidine (142 mg; 1.99 mmol) and K ₂ CO ₃ (275 mg; 1.99 mmol) in DMF (10 ml). The reaction mixture was stirred at room temperature for 16 hours, then diluted with water (50 ml), extracted with EtOAc (3×50 ml) and the combined organic layers were washed with sat. brine (3×50 ml) and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (470 mg; 98%) as a yellow oil; m/z MH ⁺ 241.

Intermediate 79: 5-bromo-2-(bromomethyl)pyridine

Benzoyl peroxide (0.063 g; 0.26 mmol) was added to 5-bromo-2-methylpyridine (0.9 g; 5.23 mmol) and NBS (0.978 g; 5.49 mmol) in CCl ₄ (10 ml) at 15 °C. The reaction mixture was heated at reflux temperature for 15 hours, then left to cool to room temperature. The reaction mixture was diluted with DCM (100 ml) and washed successively with water (50 ml) and sat. brine (50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 5% EtOAc in petroleum ether to give the title compound (0.440 g; 34% if pure) as a crude violet oil; m/z MN ⁺ 250.

Intermediate 80: 5-bromo-2-(pyrrolidin-1-ylmethyl)pyridine

Potassium iodide (437 mg; 2.63 mmol) was added to 5-bromo-2-(bromomethyl)pyridine (660 mg; 2.63 mmol), pyrrolidine (187 mg; 2.63 mmol) and K ₂ CO ₃ (364 mg; 2.63 mmol) in DMF (10 ml). The reaction mixture was stirred at room temperature for 16 hours, then quenched with water (50 ml) and extracted with EtOAc (3×50 ml). The combined organic layers were washed with sat. brine (3×50 ml) and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (570 mg; 90%) as a black oil; m/z MH ⁺ 241.

Intermediate 81: (R)-3-methyl-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl )methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzaldehyde

Biphenyl-2-amino chloride XPhos-palladium(II) (20 mg; 0.02 mmol) was added to (R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)- 2,5,7-trimethyl-[1,2,4]-triazolo-[1,5-a]pyrimidine (intermediate 16) (200 mg; 0.50 mmol), 3-methyl-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (intermediate 18) (122 mg; 0.50 mmol) and Cs ₂ CO ₃ (324 mg; 0.99 mmol) in 1,4-dioxane (3 ml) and water (1.5 ml) at room temperature. The reaction mixture was stirred at 90°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water to give the title compound (75 mg; 34%) as a yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.90 (1H, s), 2.27 (1H, s), 2.66 (7H, d), 2.77 (3H, s), 2.86 (3H, s), 2.92-3.11 (2H , m), 3.24 (1H, s), 3.45–3.54 (1H, m), 3.59 (1H, s), 3.67 (1H, s), 7.82 (2Н, dt), 7.98 (1H, d), 8.24 ( 2Н, s), 10.06 (1H, s); m/z МН ⁺ 442.

Intermediate 82: (R)-tert-Butyl-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine -6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridin-3-yl)methyl)piperazine-1-carboxylate

Degassed 1,4-dioxane (15 ml) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a] dihydrochloride pyrimidine (intermediate 4) (500 mg; 2.04 mmol) and tert-butyl-4-((6-(4-bromophenyl)pyridin-3-yl)methyl)piperazine-1-carboxylate (intermediate 37) ( 881 mg; 2.04 mmol). Cs ₂ CO ₃ (1.99 g; 6.11 mmol) was then added followed by RuPhos (190 mg; 0.41 mmol) and 3rd generation RuPhos precatalyst (341 mg; 0.41 mmol). The reaction mixture was heated at 90°C for 24 hours, left to cool to room temperature and concentrated under vacuum. The residue was taken up in DCM, filtered through Celite, concentrated in vacuo and purified by CPC eluting with 0-10% MeOH in DCM to give the title compound (290 mg; 24%) as a beige solid; ¹ H NMR (500 MHz, CDCl ₃ ) 1.45 (9H, s), 1.82-1.94 (1H, m), 2.13-2.23 (1H, m), 2.41 (4H, s), 2.62 (4H, s), 2.70 (3Н, s), 2.78 (3Н, s), 2.86-2.99 (2Н, m), 3.14 (1H, dd), 3.37-3.47 (6Н, m), 3.52 (2Н, s), 3.57 (1H, td ), 6.58-6.64 (2H, m), 7.60 (1H, dd), 7.64 (1H, dd), 7.86-7.96 (2H, m), 8.51 (1H, d); m/z МН ⁺ 597.

Example 1: (R)-4-((6'-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl) pyrrolidin-1-yl)-[3,3'-bipyridine]-6-yl)methyl)morpholine

2nd generation XPhos pre-catalyst (29.4 mg; 0.04 mmol) was added to (R)-6-((l-(5-bromopyridin-2-yl)pyrrolidin-3-yl)methyl)-2, 5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 5) (150 mg; 0.37 mmol), (6-(morpholinomethyl)pyridin-3-yl)boronic acid (commercial sources) (83 mg; 0.37 mmol) and Cs ₂ CO ₃ (244 mg; 0.75 mmol) in 1,4-dioxane (2 ml) and water (1 ml). The reaction mixture was stirred at 80°C for 3 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound formate (80 mg; 36%) as a yellow solid; ¹ H NMR (300 MHz, MeOD) 1.89-2.08 (1H, m), 2.19-2.33 (1H, m), 2.56 (3H, s), 2.71-2.73 (4H, m), 2.77-2.89 (7H, m ), 3.04 (2Н, d), 3.24-3.33 (1Н, m), 3.44-3.57 (1Н, m), 3.57-3.75 (1H, m), 3.71-3.85 (5Н, m), 3.98 (2Н, d ), 6.67 (1H, d), 7.58 (1H, d), 7.89 (1H, dd), 8.04 (1H, dd), 8.18 (2H, s, corresponding to 2 formate equivalents), 8.33 (1H, d), 8.76 (1H, d) m/z MN ⁺ 499.

Example 4: (R)-2,5,7-trimethyl-6-((1-(6,-((4-methylpiperazin-1-yl)methyl)-[3,3,-bipyridin]-6-yl )pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph ₃ P) ₄ (72.9 mg; 0.06 mmol) was added to (R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)methyl)-2, 5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 5) (253 mg; 0.63 mmol), (6-((4-methylpiperazin-1-yl) methyl)pyridin-3-yl)boronic acid (intermediate 9) (200 mg; 0.85 mmol) and Na ₂ CO ₃ (134 mg; 1.26 mmol) in toluene (10 ml) and water (2 ml) . The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound formate (60 mg; 17%) as a yellow solid; ¹ H NMR (300 MHz, DMSO) 1.84 (1H, m), 2.10 (1H, m), 2.20 (3H, s), 2.30–2.50 (12H, m), 2.63 (3H, s), 2.74 (3H, s), 2.92 (2Н, d), 3.18 (1H, dd), 3.38 (1H, dt), 3.57 (4Н, m), 6.55 (1H, d), 7.42 (1H, d), 7.84 (1H, dd ), 7.96 (1H, dd), 8.20 (1H, s), 8.43 (1H, d), 8.72 (1H, dd); m/z МН ⁺ 512.

Example 5: (R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-2-yl)pyrrolidin-3 -yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph ₃ P) ₄ (17 mg; 0.01 mmol) was added to 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl)piperazine (commercial sources) (95mg; 0.30mmol), (R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)methyl)-2.5, 7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 5) (120 mg; 0.30 mmol) and Na ₂ CO ₃ (63.4 mg; 0.60 mmol) in 1,4-dioxane (3 ml) and water (1.5 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature and then concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA) to give the title compound formate (55 mg; 33%) as a white solid; ¹ H NMR (400 MHz, MeOD) 1.99 (1H, dq), 2.26 (1H, dq), 2.57 (3H, s), 2.70 (11H, m), 2.85 (3H, s), 3.05 (6H, m) , 3.25-3.34 (2Н, m), 3.50 (1H, m), 3.60 (1H, m), 3.70 (3Н, m), 6.63 (1H, d), 7.42 (2Н, d), 7.55(2Н, d ), 7.84 (1H, dd), 8.28 (1H, d), 8.47 (1H, s); m/z МН ⁺ 511.

Example 6: (R)-4-(4-(2-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl )pyrrolidin-1-yl)pyrimidin-5-yl)benzyl)morpholine

2nd generation XPhos precatalyst (34 mg, 0.04 mmol) was added to rac-6-((1-(5-bromopyrimidin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl -[1,2,4]triazolo-[1,5-a]pyrimidine (intermediate 10) (350 mg; 0.87 mmol), 4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)morpholine (from commercial sources) (264 mg; 0.87 mmol) and Cs ₂ CO ₃ (567 mg; 1.74 mmol) in 1,4-dioxane (3 ml) and water (1.5 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.08% NH ₄ CO ₃ ). The resulting racemic product (390 mg) was separated by preparative chiral HPLC on a Chiralpak IA column eluting with 50% EtOH in TBME (modified DEA) as eluent to give the title compound (120 mg; 31%) as a white solid; ¹ H NMR (400 MHz, MeOD) 1.90-2.04 (1H, m), 2.23 (1H, dt), 2.50 (4H, t), 2.57 (3H, s), 2.74 (4H, s), 2.86 (3H, s), 3.05 (2Н, d), 3.39 (1H, dd), 3.60 (3Н, d), 3.68-3.79 (5Н, m), 3.86 (1H, ddd), 7.45 (2Н, d), 7.55 (2Н , d), 8.61 (2Н, s); m/zMH ⁺ 499.

Example 7: (R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)pyridin-2-yl)pyrazin-2-yl)methyl)morpholine

Pd(Ph ₃ P) ₄ (46.1 mg; 0.04 mmol) was added to 4-((5-chloropyrazin-2-yl)methyl)morpholine (intermediate 76) (85 mg; 0.40 mmol), (R)-6-((1-(6-bromopyridin-3-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a ]-pyrimidine (intermediate 12) (160 mg; 0.40 mmol) and 1,1,1,2,2,2-hexamethyldistannane (131 mg; 0.40 mmol) in 1,4-dioxane (5 ml) at room temperature. The reaction mixture was stirred at 110°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA) to give the title compound (87 mg; 43%) as a yellow solid; ¹ H NMR (300 MHz, MeOD) 1.89-2.08 (1H, m), 2.18-2.31 (1H, m), 2.56 (3H, s), 2.60-2.87 (10H, m), 3.05 (2H, dd), 3.23 (1H, dd), 3.37-3.85 (10H, m), 7.10 (1H, dd), 8.03 (1H, d), 8.20 (1H, d), 8.66 (1H, d), 9.31 (1H, d) ; m/zMH ⁺ 500.

Example 8: (R)-2,5,7-trimethyl-6-((1-(6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-3-yl)pyrr o lidine -3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph ₃ P) ₄ (202 mg; 0.17 mmol) was added to (R)-6-((1-(6-bromopyridin-3-yl)pyrrolidin-3-yl)methyl)-2.5, 7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 12) (700 mg; 1.74 mmol), 1-methyl-4-(4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine (from commercial sources) (607 mg; 1.92 mmol) and 1 M aq. Na ₂ CO ₃ (3.49 ml; 3.49 mmol) in degassed 1,4-dioxane (7 ml) at room temperature. The reaction mixture was stirred at 80°C for 18 hours, then left to cool to room temperature and concentrated under vacuum. The residue was taken up in DCM, filtered and the resulting crude product was purified by CPC eluting with 0-10% 1 M NH ₃ /MeOH in DCM, then further purified by recrystallization from EtOAc (with a small amount of MeOH) to give the title compound (240 mg, 27%) as a pale yellow crystalline solid; ¹ H NMR (500 MHz, CDCl ₃ ) 1.86-1.94 (1H, m), 2.14-2.23 (1H, m), 2.28 (3H, s), 2.49 (8H, s), 2.62 (4H, s), 2.71 (3Н, s), 2.79 (3Н, s), 2.86-3.01 (2Н, m), 3.14 (1H, dd), 3.37-3.48 (2Н, m), 3.54 (2Н, s), 3.55-3.61 (1Н , m), 6.86 (1H, dd), 7.37 (2H, d), 7.59 (1H, dd), 7.82–7.88 (2H, m), 8.06 (1H, d); m/z МН ⁺ 511.

Example 9: (R)-4-((6-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)pyridin-2-yl)pyridazin-3-yl)methyl)morpholine

Pd(Ph ₃ P) ₄ (343 mg; 0.30 mmol) was added in one portion to 4-((6-chloropyridazin-3-yl)methyl)morpholine (intermediate 14) (634 mg; 2.97 mmol), (R)-6-((1-(6-bromopyridin-3-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a ]pyrimidine (intermediate 12) (1.19 g; 2.97 mmol) and 1,1,1,2,2,2-hexamethyldistannane (0.615 ml; 2.97 mmol) in 1,4-dioxane (30 ml ) at room temperature. The reaction mixture was stirred at 100°C for 20 hours, then left to cool to room temperature, filtered and washed with DCM (20 ml). The filtrate was concentrated in vacuo and the resulting crude product was purified by SPC eluting with 0-10% 1 M NH ₃ /MeOH in DCM, then further purified by preparative HPLC, then dissolved in MeOH and loaded onto an SCX column (50 g). The column was washed with MeOH (2 column volume), then eluted with 1 M NH ₃ /MeOH. The resulting resin was triturated with Et ₂ O to give a solid which was filtered off and dried under vacuum to give the title compound (608 mg; 41%) as a pale yellow solid; ¹ H NMR (500 MHz, DMSO) 1.87 (1H, dq), 2.06-2.22 (1H, m), 2.45 (7H, d), 2.64 (4H, s), 2.74 (3H, s), 2.93 (2H, d), 3.12 (1H, dd), 3.33-3.38 (1H, m), 3.48 (1H, dd), 3.51-3.64 (5H, m), 3.79 (2H, s), 7.06 (1H, dd), 7.71 (1H, d), 8.05 (1H, d), 8.33 (2H, dd); m/z MN ⁺ 500.

Example 10: 6-((R)-1-(2-(4-(((5)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl) methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-а]pyrimidine

(R)-6-((1-(2-Bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a ]pyrimidine (intermediate 16) (300 mg; 0.75 mmol), (S)-2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)benzyl)piperazine (intermediate 17) (296 mg; 0.89 mmol), Pd(Ph ₃ P) ₄ (86 mg; 0.07 mmol) and potassium carbonate (206 mg; 1.49 mmol ) was dissolved in 1,4-dioxane (12 ml) and water (4 ml) and heated at 80°C for 18 hours. The reaction mixture was left to cool to room temperature, then poured into DCM (50 ml). The aqueous layer was separated then extracted with 20% MeOH/DCM. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-5% 1 M NH ₃ /MeOH in DCM. The resulting resin was triturated with EtOAc and the resulting solid was filtered off and dried under vacuum to give the title compound (52 mg; 13%) as a white solid; ¹ H NMR (500 MHz, DMSO) 1.06 (3H, d), 1.78-1.9 (2H, m), 1.98 (1H, d), 2.10 (5H, s), 2.41 (1H, s), 2.47 (4H, s), 2.55 (2Н, d), 2.64 (4Н, s), 2.74 (3Н, s), 2.92 (2Н, d), 3.04–3.18 (2Н, m), 3.34 (1H, d), 3.46 (1H , dd), 3.5-3.58 (1H, m), 3.97 (1H, d), 7.33 (2H, d), 8.16 (2H, d), 8.20 (2H, s); m/z МН+526.

Example 11: (R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl) ha1rrolidin-1-yl) pyrimidin-2-yl) pyridin-2-yl) methyl) morpholine

2nd generation XPhos precatalyst (9 mg; 0.01 mmol) was added to (R)-6-((l-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2.5.7 -trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 16) (90 mg; 0.22 mmol), (6-(morpholinomethyl)pyridin-3-yl)boronic acid (from commercial sources) (50 mg; 0.22 mmol) and Cs ₂ CO ₃ (146 mg; 0.45 mmol) in 1,4-dioxane (3 ml) and water (1.5 ml) at room temperature. The reaction mixture was stirred at 90°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water to give the title compound (22 mg; 20%) as a white solid; ¹ H NMR (400 MHz, MeOD) 2.00 (1H, dq), 2.26 (1H, dq), 2.57 (3H, s), 2.64 (4H, s), 2.75 (4H, s), 2.86 (3H, s) , 3.08 (2Н, h), 3.25 (1H, dd), 3.46 (1H, dt), 3.54–3.72 (2Н, m), 3.72–3.83 (6Н, m), 7.63 (1H, d), 8.24 (2Н , s), 8.61 (1H, dd), 9.34 (1H, d); m/z MN ⁺ 500.

Example 12: (R)-6-((1-(2-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl )-2,5,7-trimethyl-[1,2,4]triazolo[1,5-а]pyrimidine

2nd generation XPhos precatalyst (20 mg; 0.02 mmol) was added to (R)-6-((l-(2-bromopyridin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7 -trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 16) (200 mg; 0.50 mmol), (2-methoxy-4-((4-methylpiperazin-1-yl )methyl)phenyl)boronic acid (intermediate 42) (131 mg; 0.50 mmol) and Cs ₂ CO ₃ (324 mg; 0.99 mmol) in 1,4-dioxane (3 ml) and water (1, 5 ml) at room temperature. The reaction mixture was stirred at 90°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water to give the title compound formate (56 mg, 19%) as a pale yellow solid; ¹ H NMR (400 MHz, MeOD) 2.00 (1H, dq), 2.25 (1H, ddd), 2.57 (3H, s), 2.72 (10H, m), 2.87 (3H, s), 2.99-3.15 (7H, m), 3.22 (1H, dd), 3.44 (1H, dt), 3.51-3.72 (4H, m), 3.83 (3H, s), 7.04 (1H, dd), 7.14 (1H, d), 7.49 (1H , d), 8.19 (2Н, s), 8.49 (1H, s); m/z МН ⁺ 542.

Example 13: (R)-2,5,7-trimethyl-6-((1-(2-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl )pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

1-Methylpiperazine (34 mg; 0.34 mmol) was added to (R)-3-methyl-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzaldehyde (75 mg; 0.17 mmol) in DCM (0.5 ml) at room temperature in air, and the reaction mixture was stirred for 2 hours. Sodium triacetoxyborohydride (180 mg; 0.85 mmol) was added and the reaction mixture was stirred at room temperature for 50 hours, then concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water to give the title compound (60 mg; 67%) as a yellow solid; ¹ H NMR (400 MHz, MeOD) 2.00 (1H, dq), 2.26 (1H, ddd), 2.42 (3H, s), 2.57 (3H, s), 2.72 (10H, m), 2.87 (3H, s) , 3.06 (7Н, m), 3.23 (1H, dd), 3.44 (1H, dt), 3.52–3.70 (4Н, m), 7.24–7.32 (2Н, m), 7.54 (1H, d), 8.23 (2Н , s); m/z МН ⁺ 526.

Example 14: 6-(((R)-1-(2-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3 -yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrimidin-2-yl)benzaldehyde (intermediate 19) (120 mg; 0.28 mmol) was added to (2R,6S)-2,6-dimethylpiperazine (from commercial sources) (32 mg; 0.28 mmol) in DCM (3 ml) and the reaction mixture was stirred at room temperature for 2 hours. AcOH (1.607 μl; 0.03 mmol) and sodium triacetoxyborohydride (178 mg; 0.84 mmol) were added and the reaction mixture was stirred for 2 hours, then concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (16 mg; 11%) as a white solid; ¹ H NMR (300 MHz, MeOD) 1.18 (6H, s), 1.94 (3H, ddd), 2.21 (1H, m), 2.56 (3H, s), 2.73 (4H, m), 2.84 (3H, s) , 3.08 (4Н, m), 3.18 (3Н, m), 3.58 (2Н, m), 3.62 (4Н, m), 7.41 (2Н, dd), 8.17 (4Н, dt); m/z МН ⁺ 526.

Example 15: (R)-N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)acetamide

PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (168 mg; 0.21 mmol) was added to 2-(4-(4-bromobenzyl)piperazin-1-yl)-N,N-dimethylacetamide (intermediate 22) ( 700 mg, 2.06 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (627 mg; 2.47 mmol) and potassium acetate (404 mg; 4.11 mmol) in 1,4-dioxane (10 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give (4-((4-(2-(dimethylamino)-2-oxoethyl)piperazin-1-yl)methyl)phenyl )boronic acid (186 mg; 30%), which was used immediately without a description of the properties. Pd(Ph ₃ P) ₄ (31.6 mg; 0.03 mmol) was added to (4-((4-(2-(dimethylamino)-2-oxoethyl)piperazin-1-yl)methyl)-phenyl)boronic acid (92 mg; 0.30 mmol), (R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1, 2,4]triazolo[1,5-a]pyrimidine (intermediate 16) (110 mg; 0.27 mmol) and Na ₂ CO ₃ (58.0 mg; 0.55 mmol) in 1,4-dioxane ( 2 ml) and water (1 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeCN in water (plus 0.1% FA), then further purified by preparative HPLC to give the title compound (50 mg; 31%) as white solid; ¹ H NMR (300 MHz, MeOD) 1.98 (1H, dt), 2.16-2.34 (1H, m), 2.43-2.64 (10H, m), 2.73 (4H, s), 2.84 (3H, s), 2.93 ( 3Н, s), 2.97-3.15 (5Н, m), 3.22 (3Н, d), 3.33-3.49 (2Н, m), 3.48-3.70 (4Н, m), 7.41 (2Н, d), 8.11-8.21 ( 4H, m); m/z МН ⁺ 583.

Example 16: (R)-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6- yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethanol

PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (164 mg; 0.20 mmol) was added to 2-(4-(4-bromobenzyl)piperazin-1-yl)ethanol (intermediate 23) (600 mg; 2, 01 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (611 mg; 2.41 mmol) and potassium acetate (394 mg; 4.01 mmol) in 1,4-dioxane (10 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water to give (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)boronic acid (143 mg ; 27%) as a brown solid, which was used immediately without characterization. Pd(Ph ₃ P) ₄ (31.6 mg; 0.03 mmol) was added to (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-phenyl)boronic acid (87 mg; 0 .33 mmol), (R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[ 1,5-a]pyrimidine (intermediate 16) (110 mg; 0.27 mmol) and Na ₂ CO ₃ (58.0 mg; 0.55 mmol) in 1,4-dioxane (2 ml) and water ( 1 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeCN in water (plus 0.1% FA), then further purified by preparative HPLC to give the title compound (50 mg; 34%) as white solid; ¹ H NMR (300 MHz, CDCl ₃ ) 1.88-2.02 (1H, m), 2.15-2.26 (1H, m), 2.68 (18H, m), 2.82 (3H, s), 2.87-3.05 (2H, m) , 3.18 (1H, dd), 3.36-3.58 (2H, m), 3.58-3.71 (5H, m), 7.41 (2H, d), 8.14 (2H, s), 8.21-8.30 (2H, m); m/z МН ⁺ 542.

Example 17: (R)-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6- yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethanone

Pd(Ph ₃ P) ₄ (28.7 mg; 0.02 mmol) was added to 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )benzyl)piperazin-1-yl)ethanone (intermediate 52) (86 mg; 0.25 mmol), (R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl) methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 16) (100 mg; 0.25 mmol) and Na ₂ CO ₃ (53 mg; 0.50 mmol) in 1,4-dioxane (5 ml) and water (1 ml). The reaction mixture was stirred at 80°C for 16 hours, then left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound (50 mg; 37%) as a yellow solid; ¹ H NMR (300 MHz, MeOD) 1.96 (1H, dq), 2.10 (3H, s), 2.22 (1H, m), 2.64 (11H, m), 2.84 (3H, s), 3.03 (2H, dd) , 3.20 (1H, dd), 3.60 (9H, m), 7.43 (2H, m), 8.19 (4H, d); m/z МН+540.

Example 18: (R)-6-((1-(2-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl) methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

Sodium triacetoxyborohydride (283 mg; 1.33 mmol) was added to (R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a] pyrimidin-6-yl)methyl)pyrrolidin-1-yl)-pyrimidin-2-yl)benzaldehyde (intermediate 19) (190 mg; 0.44 mmol), and 1-(2-methoxyethyl)piperazine (77 mg; 0.53 mmol), and AcOH (0.013 ml; 0.22 mmol) in DCM (20 ml) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then concentrated under vacuum, neutralized with a mixture of 1 M NH ₃ /MeOH and concentrated under vacuum. The resulting residue was taken up in DCM, filtered and purified by CPC eluting with 0-5% 1 M NH ₃ /MeOH in DCM to give the title compound (175 mg; 71%) as a pale yellow solid; ¹ H NMR (500 MHz, CDCl ₃ ) 1.86-1.96 (1H, m), 2.14-2.25 (1H, m), 2.39-2.6 (10H, m), 2.62 (3H, s), 2.64-2.69 (1H, m), 2.71 (3Н, s), 2.80 (3Н, s), 2.87-3.02 (2Н, m), 3.17 (1H, dd), 3.34 (3Н, s), 3.39-3.46 (1H, m), 3.47 -3.53 (3H, m), 3.56 (2H, s), 3.59 (1H, td), 7.39 (2H, d), 8.13 (2H, s), 8.23 (2H, d); m/z MH ⁺ 556.

Example 19: (R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl )pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)morpholine

3rd generation RuPhos precatalyst (50mg, 0.06mmol) was added to 4-(4-(5-bromopyrimidin-2-yl)benzyl)morpholine (Intermediate 24) (200mg, 0.60mmol), ( R)_2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine⋅2HCl (intermediate 4) (190 mg; 0.60 mmol), Cs ₂ CO ₃ (780 mg; 2.39 mmol) and RuPhos (55.8 mg; 0.12 mmol) in 1,4-dioxane (8 ml) at room temperature. The reaction mixture was stirred at 90°C for 6 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeOH in water (plus 0.1% FA) to give the title compound (180 mg; 60%) as a yellow solid; ¹ H NMR (300 MHz, MeOD) 1.87-2.06 (1H, m), 2.16-2.27 (1H, m), 2.53-2.62 (7H, m), 2.73 (4H, s), 2.84 (3H, s), 3.04 (2Н, dd), 3.20 (1H, dd), 3.41 (1H, dt), 3.49-3.71 (4Н, m), 3.71-3.77 (4Н, m), 7.43 (2Н, d), 8.13-8.22 ( 4H, m); m/z МН ⁺ 499.

Example 20: (R)-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3 -yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph ₃ P) ₄ (43.1 mg; 0.04 mmol) was added to (R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2, 5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 16) (300 mg; 0.75 mmol), 1-methyl-4-(4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine (from commercial sources) (236 mg; 0.75 mmol) and Na ₂ CO ₃ (158 mg; 1.49 mmol) in 1,4-dioxane (10 ml) and water (5 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1 mmol/L NH ₄ HCO ₃ ) to give the title compound (285 mg; 75%) as a white solid substances; ¹ H NMR (400 MHz, MeOD) 1.94-2.05 (1H, m), 2.31 (4H, s), 2.57 (11H, s), 2.75 (4H, s), 2.86 (3H, s), 3.06 (2H, p), 3.22 (1H, dd), 3.38-3.49 (1H, m), 3.51-3.69 (4H, m), 7.42 (2H, d), 8.14-8.22 (4H, m); m/z МН ⁺ 512.

Example 21: (R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrazin-2-yl)phenyl)pyrrolidin-3 -yl)methyl)-[1,2,4]triazolo[1,5-a]-pyrimidine

Pd(Ph ₃ P) ₄ (51.7 mg; 0.04 mmol) was added to 2-bromo-5-((4-methylpiperazin-1-yl)methyl)pyrazine (intermediate 28) (121 mg; 0. 45 mmol), (R)-2,5,7-trimethyl-6-((1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 27) (200 mg; 0.45 mmol) and Na ₂ CO ₃ (95 mg; 0. 89 mmol) in toluene (0.2 ml) and water (1 ml). The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeCN in water to give the title compound (11 mg, 5%) as a yellow solid; ^1H NMR (300 MHz, _CDCl3 ) 1.91 (1H, dq), 2.21 (1H, dq), 2.40 (3H, s), 2.67 (14H, d), 2.80 (3H, s), 2.95 (3H, s ), 3.16 (1H, dd), 3.35-3.67 (3H, m), 3.73 (2H, s), 6.59-6.68 (2H, m), 7.87-7.99 (2H, m), 8.56 (1H, d), 8.90 (1H, d); m/zMH ⁺ 512.

Example 22: (R)-2,5,7-trimethyl-6-((1-(4-(2-((4-methylpiperazin-1-yl)methyl)pyrimidin-5-yl)phenyl)pyrrolidin-3 -yl)methyl)-[1,2,4]triazolo[1,5-a]-pyrimidine

Pd(Ph ₃ P) ₄ (63.9 mg; 0.06 mmol) was added to (R)-2,5,7-trimethyl-6-((1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo-[1,5-a]pyrimidine (intermediate 27) (247 mg ; 0.55 mmol), 5-bromo-2-((4-methylpiperazin-1-yl)methyl)pyrimidine (intermediate 29) (150 mg; 0.55 mmol) and Na ₂ CO ₃ (117 mg; 1 .11 mmol) in 1,4-dioxane (2 ml) and water (1 ml). The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound (40 mg; 14%) as a yellow solid; ¹ H NMR (300 MHz, DMSO) 1.85 (1H, dq), 2.10 (1H, dq), 2.26 (3H, s), 2.49 (4H, m), 2.63 (8H, m), 2.74 (3H, s) , 2.92 (2Н, d), 3.06 (1H, dd), 3.26 (6Н, m), 3.70 (2Н, s), 6.64 (2Н, d), 7.62 (2Н, d), 8.99 (2Н, s); m/z МН ⁺ 512.

Example 23: (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)phenyl)pyridin-3-yl)methyl)morpholine

3rd generation RuPhos precatalyst (39 mg; 0.05 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1] dihydrochloride ,5-a]pyrimidine (intermediate 4) (150 mg; 0.47 mmol), 4-((6-(4-bromophenyl)pyridin-3-yl)methyl)morpholine (intermediate 31) (157 mg; 0.47 mmol), Cs ₂ CO ₃ (768 mg; 2.36 mmol) and RuPhos (44 mg; 0.09 mmol) in 1,4-dioxane (3 ml) at room temperature. The reaction mixture was stirred at 90°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound (54 mg; 23%) as a white solid; ¹ H NMR (300 MHz, MeOD) 1.87-2.05 (1H, m), 2.22 (1H, dq), 2.50 (4H, dd), 2.55 (3H, s), 2.71 (4H, s), 2.82 (3H, s), 2.94-3.09 (2H, m), 3.16 (1H, dd), 3.32-3.51 (2H, m), 3.54-3.63 (3H, m), 3.63-3.76 (4H, m), 6.61-6.73 ( 2H, m), 7.67-7.87 (4H, m), 8.44 (1H, d); m/z MH ⁺ 498.

Example 24: (R)-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3 -yl)methyl)-[1,2,4]triazolo[1,5-a]-pyrimidine

Pd(Ph ₃ P) ₄ (26 mg; 0.02 mmol) was added to (R)-2,5,7-trimethyl-6-((1-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo-[1,5-a]pyrimidine (intermediate 27) (100 mg; 0 .22 mmol), 3-chloro-6-((4-methylpiperazin-1-yl)methyl)pyridazine (intermediate 32) (51 mg; 0.22 mmol) and Na ₂ CO ₃ (47 mg; 0.45 mmol) in 1,4-dioxane (5 ml) and water (1 ml). The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound (35 mg; 31%) as a white solid; ¹ H NMR (300 MHz, DMSO) 1.87 (1H, m), 2.15 (4H, m), 2.20–2.50 (11H, m), 2.64 (4H, m), 2.75 (3H, s), 2.93 (2H, d), 3.09 (1H, dd), 3.30-3.60 (3H, m), 3.74 (2H, s), 6.65 (2H, m), 7.59 (1H, d), 8.00 (3H, m); m/z MH ⁺ 512.

Example 25: (R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)phenyl)pyrrolidin-3 -yl)methyl)-[1,2,4]triazolo[1,5-a]-pyrimidine

3rd generation RuPhos precatalyst (36 mg; 0.04 mmol) and RuPhos (20 mg; 0.04 mmol) were added to 2-(4-bromophenyl)-5-((4-methylpiperazin-1-yl)methyl) pyrimidine (intermediate 35) (150 mg; 0.43 mmol), dihydrochloride (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1, 5-a]pyrimidine (intermediate 4) (137 mg; 0.43 mmol) and Cs ₂ CO ₃ (563 mg; 1.73 mmol) in 1,4-dioxane (5 ml). The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeCN in water to give the title compound (58 mg, 26%) as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) 1.81-1.99 (2H, m), 2.19 (1H, dt), 2.35 (3H, s), 2.67 (14H, m), 2.76-3.04 (5H, m), 3.18 (1H, dd), 3.36-3.68 (5H, m), 6.55-6.66 (2H, m), 8.26-8.38 (2H, m), 8.64 (2H, s); m/z МН ⁺ 512.

Example 26: (R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)phenyl)pyrazin-2-yl)methyl)morpholine

Pd(Ph ₃ P) ₄ (34 mg; 0.03 mmol) was added to (R)-2,5,7-trimethyl-6-((1-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo-[1,5-a]pyrimidine (intermediate 27) (130 mg; 0 .29 mmol), 4-((5-chloropyrazin-2-yl)methyl)morpholine (intermediate 76) (62 mg; 0.29 mmol) and Na ₂ CO ₃ (62 mg; 0.58 mmol) in 1 ,4-dioxane (3 ml) and water (1.5 ml). The reaction mixture was stirred at 90°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeCN in water (plus 0.1% FA) to give the title compound (70 mg; 48%) as a pale yellow solid; ^1H NMR (300 MHz, _CDCl3 ) 1.91 (1H, dq), 2.21 (1H, dq), 2.67 (11H, m), 2.80 (3H, s), 2.95 (2H, m), 3.16 (1H, dd ), 3.35-3.54 (2Н, m), 3.60 (1Н, td), 3.71 (2Н, s), 3.77 (4Н, t), 6.58-6.69 (2Н, m), 7.88-8.00 (2Н, m), 8.60 (1H, s), 8.91 (1H, d); m/z МН ⁺ 499.

Example 27: (R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)phenyl)pyrrolidin-3 -yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Formaldehyde (37% in water) (5 ml; 67.2 mmol) was added in one portion to (R)-tert-butyl-4-((6-(4-(3-((2,5,7-trimethyl- [1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1-yl)phenyl)pyridin-3-yl)methyl)piperazine-1-carboxylate (intermediate 82) (290 mg; 0.49 mmol) in formic acid (10 ml) at room temperature. The reaction mixture was stirred at 55°C for 4 hours, left to cool to room temperature and concentrated under vacuum. The residue was redissolved in 2 M NH ₃ /MeOH and purified by preparative HPLC to give the title compound (58 mg; 26%) as a white solid; ¹ H NMR (500 MHz, CDCl ₃ ) 1.83-1.93 (1H, m), 2.12-2.22 (1H, m), 2.29 (3H, s), 2.53 (8H, d), 2.62 (4H, s), 2.70 (3Н, s), 2.79 (3Н, s), 2.85-2.99 (2Н, m), 3.14 (1H, dd), 3.37-3.47 (2Н, m), 3.52 (2Н, s), 3.57 (1H, td ), 6.55-6.65 (2H, m), 7.59 (1H, dd), 7.65 (1H, dd), 7.87-7.95 (2H, m), 8.51 (1H, d); m/z МН ⁺ 511.

Example 28: (R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine

3rd generation RuPhos precatalyst (53 mg; 0.06 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1] dihydrochloride ,5-a]pyrimidine (intermediate 4) (200 mg; 0.63 mmol), 4-((5-(4-bromophenyl)pyrimidin-2-yl)methyl)morpholine (intermediate 39) (231 mg; 0.69 mmol), Cs ₂ CO ₃ (819 mg; 2.51 mmol) and RuPhos (59 mg; 0.13 mmol) in 1,4-dioxane (8 ml). The reaction mixture was stirred at 90°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 0-100% MeCN in water (plus 0.1% FA) to give the title compound (180 mg; 57%) as a white solid; ¹ H NMR (300 MHz, MeOD) 1.88-2.06 (1H, m), 2.22 (1H, dq), 2.55 (3H, s), 2.60-2.69 (4H, m), 2.71 (4H, m), 2.82 ( 3Н, s), 3.02 (2Н, dd), 3.15 (1H, dd), 3.31–3.50 (2Н, m), 3.52–3.66 (1Н, m), 3.69–3.79 (4Н, m), 3.83 (2Н, s), 6.67-6.77 (2H, m), 7.52-7.63 (2H, m), 8.97 (2H, s); m/z МН ⁺ 499.

Example 29: (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine

Degassed 1,4-dioxane (10 ml) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 4) (257 mg; 1.05 mmol) and 4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine (intermediate 65) (350 mg; 1.05 mmol). Cs ₂ CO ₃ (1.02 g; 3.14 mmol) was then added followed by the addition of RuPhos (24 mg; 0.05 mmol) and 3rd generation RuPhos precatalyst (44 mg; 0.05 mmol). The reaction mixture was heated at 90°C for 6 hours, left to cool to room temperature, diluted with DCM (50 ml) and filtered. The filtrate was concentrated under vacuum. The resulting crude product was purified by CPC eluting with 0-5% 1 M NH ₃ /MeOH in DCM. The resulting oil was triturated with EtOAc:heptane (4:1, 10 mL) and the precipitate was filtered off and dried under vacuum to give the title compound (270 mg; 52%) as a yellow solid; ^1H NMR (500 MHz, _CDCl3 ) 1.90 (1H, dq), 2.20 (1H, td), 2.56 (4H, q), 2.62 (4H, s), 2.70 (3H, s), 2.79 (3H, s ), 2.93 (2H, qd), 3.15 (1H, dd), 3.37–3.49 (2H, m), 3.55–3.63 (1H, m), 3.69–3.77 (4H, m), 3.87 (2H, s), 6.59-6.68 (2H, m), 7.59 (1H, d), 7.75 (1H, d), 7.98-8.06 (2H, m); m/z МН ⁺ 499.

Example 30: (S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine

The compound of Example 30 was obtained by a method similar to that of Example 29 in 5 steps from commercially available (S)-tert-butyl-3-(hydroxymethyl)pyrrolidine-1-carboxylate to give the title compound (122 mg; 30% at the final stage) as a white solid; ¹ H NMR (500 MHz, DMSO) 1.86 (1H, dq), 2.07-2.16 (1H, m), 2.38-2.45 (4H, m), 2.47 (3H, s), 2.59 (1H, d), 2.64 ( 3Н, s), 2.74 (3Н, s), 2.93 (2Н, d), 3.09 (1H, dd), 3.32 (1H, d), 3.43 (1H, dd), 3.46-3.53 (1H, m), 3.54 -3.63 (4H, m), 3.75 (2H, s), 6.65 (2H, d), 7.62 (1H, d), 7.98 (2H, d), 8.02 (1H, d); m/z МН ⁺ 499.

Example 31: (R)-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-6-methylpyrazin-2-yl)pyrrolidin-3- yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-а]pyrimidine

XPhos 2nd generation precatalyst (30 mg; 0.04 mmol) was added to (2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid (intermediate 42) (112 mg; 0 .42 mmol), (R)-6-((1-(5-bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2, 4]triazolo[1,5-a]pyrimidine (intermediate 45) (160 mg; 0.38 mmol) and Cs ₂ CO ₃ (250 mg; 0.77 mmol) in 1,4-dioxane (2 ml) and water (1 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound (90 mg; 42%) as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) 1.78-2.24 (3H, m), 2.27 (3H, s), 2.31-2.77 (17H, m), 2.82 (3H, s), 2.87-3.06 (2H, m) , 3.34 (1H, dd), 3.45-3.61 (3H, m), 3.66-3.83 (5H, m), 6.93-7.04 (2H, m), 7.22 (1H, d), 7.77 (1H, s); m/z МН ⁺ 556.

Example 32 2,5,7-trimethyl-6-(((R)-1-(5-(4-(((3R,5S)-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl )pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]-pyrimidine

(2S,6R)-1,2,6-Trimethylpiperazine (from commercial sources) (104 mg; 0.81 mmol) was added in one portion to (R)-6-((1-(5-(4-(chloromethyl) phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 48) (181 mg; 0.40 mmol) and triethylamine (0.28 ml; 2.02 mmol) in THF (5 ml) at room temperature under air. The reaction mixture was stirred at 60°C for 24 hours, left to cool to room temperature, and diluted with EtOAc (50 ml) and water (15 ml). The organic layer was separated and washed with sat. brine (15 ml), dried over MgSO ₄ , filtered and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 0-4% 1 M NH3/MeOH in DCM to give the title compound (115 mg; 53%) as a pale yellow solid; ¹ H NMR (500 MHz, DMSO) 0.92 (6H, d), 1.75 (2H, m), 1.8-1.91 (1H, m), 2.06-2.16 (5H, m), 2.46 (3H, s), 2.5- 2.52 (1H, m), 2.63 (6Н, d), 2.74 (3Н, s), 2.93 (2Н, d), 3.2-3.26 (1H, m), 3.37-3.47 (3Н, m), 3.63 (1H, dd), 3.66-3.73 (1H, m), 7.32 (2H, d), 7.87 (2H, d), 8.02 (1H, d), 8.61 (1H, d); m/z MH ⁺ 540.

Example 33: 6-((R)-1-(5-(4-((R)-3,4-dimethylpiperazin-1-yl)methyl)phenyl)-pyrazin-2-yl)pyrrolidin-3-yl) methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]-pyrimidine

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (200 mg; 0.47 mmol) and (R)-1,2-dimethylpiperazine (from commercial sources) (267 mg; 2.34 mmol) in MeOH ( 10 ml) was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (397 mg; 1.87 mmol) and AcOH (2.81 mg; 0.05 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours, then concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound (126 mg; 51%) as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) 1.06 (3H, d), 1.93 (2H, dq), 2.22 (3H, dt), 2.33 (4H, s), 2.56-3.06 (15H, m), 3.34 (1H , dd), 3.56 (3H, d), 3.67-3.84 (2H, m), 7.40 (2H, d), 7.78-7.88 (2H, m), 7.95 (1H, d), 8.51 (1H, d); m/z MH ⁺ 526.

Example 34: 6-((R)-1-(5-(4-((R)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)-pyrazin-2-yl)pyrrolidin-3-yl) methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]-pyrimidine

(R)-1,3-dimethylpiperazine dihydrochloride (from commercial sources) (167 mg; 0.89 mmol) was added in one portion to (R)-6-((1-(5-(4-(chloromethyl)phenyl)- pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 48) (200 mg; 0. 45 mmol) and triethylamine (0.31 ml; 2.23 mmol) in 1,4-dioxane (5 ml) at room temperature in an air atmosphere. The reaction mixture was stirred at 80°C for 24 hours, left to cool to room temperature and diluted with EtOAc (50 ml) and water (15 ml). The organic layer was separated and washed with sat. brine (15 ml), dried over MgSO ₄ , filtered and concentrated under vacuum. The resulting crude product was purified by SPC eluting with 0-4% 1 M NH ₃ /MeOH in DCM, then further purified by preparative HPLC to give the title compound (32 mg; 14%) as a yellow foam; ¹ H NMR (500 MHz, DMSO) 1.06 (3H, d), 1.79–1.91 (2H, m), 1.99 (1H, s), 2.10 (5H, s), 2.41 (1H, s), 2.46 (4H, s), 2.52-2.62 (3H, m), 2.63 (3H, s), 2.74 (3H, s), 2.93 (2H, d), 3.12 (1H, d), 3.23 (1H, dd), 3.4-3.49 (1Н, m), 3.63 (1H, dd), 3.65-3.74 (1H, m), 3.95 (1H, d), 7.32 (2Н, d), 7.82-7.90 (2Н, m), 8.02 (1H, d ), 8.60 (1H, d); m/z МН ⁺ 526.

Example 35 2,5,7-trimethyl-6-(((R)-l-(5-(4-(((2R,5R)-2,4,5-trimethylpiperazin-l-yl)methyl)phenyl )pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

(2R,5R)-1,2,5-trimethylpiperazine hydrochloride (from commercial sources) (147 mg; 0.89 mmol) was added in one portion to (R)-6-((1-(5-(4-(chloromethyl )phenyl)-pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 48) (200 mg; 0.45 mmol) and triethylamine (0.31 ml; 2.23 mmol) in 1,4-dioxane (5 ml) at room temperature in an air atmosphere. The reaction mixture was stirred at 80°C for 24 hours, left to cool to room temperature and diluted with EtOAc (50 ml) and water (15 ml). The organic layer was separated and washed with sat. brine (15 ml), dried over MgSO ₄ , filtered and dried under vacuum. The resulting crude product was purified by CPC eluting with 0-4% 1 M NH ₃ /MeOH in DCM, then further purified by trituration with MeOH to give the title compound (78 mg; 32%) as a pale yellow solid; ¹ H NMR (500 MHz, DMSO) 0.90 (3H, d), 1.03 (3H, d), 1.8–1.91 (1H, m), 2.10 (5H, s), 2.22–2.32 (3H, m), 2.46 ( 4Н, s), 2.57-2.61 (1H, m), 2.63 (3Н, s), 2.74 (4Н, s), 2.93 (2Н, d), 3.23 (1H, dd), 3.41-3.48 (2Н, m) , 3.55-3.66 (2H, m), 3.66-3.73 (1H, m), 7.35 (2H, d), 7.86 (2H, d), 8.02 (1H, d), 8.60 (1H, d); m/z MN ⁺ 540.

Example 36 2,5,7-trimethyl-6-(((R)-1-(5-(4-(((2S,5R)-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl )pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

(2R,5S)-1,2,5-trimethylpiperazine dihydrochloride (commercial sources) (180 mg; 0.89 mmol) was added in one portion to (R)-6-((l-(5-(4-(chloromethyl )phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine (intermediate 48) (200 mg; 0.45 mmol) and triethylamine (0.31 ml; 2.23 mmol) in 1,4-dioxane (5 ml) at room temperature in an air atmosphere. The reaction mixture was stirred at 80°C for 24 hours, left to cool to room temperature and diluted with EtOAc (50 ml) and water (15 ml). The organic layer was separated and washed with sat. brine (15 ml), dried over MgSO ₄ , filtered and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 0-4% 1 M NH ₃ /MeOH in DCM, then further purified by preparative HPLC to give the title compound (81 mg; 34%) as a pale yellow solid; ¹ H NMR (500 MHz, DMSO) 0.83 (3H, d), 1.07 (3H, d), 1.73 (1H, t), 1.80–1.93 (3H, m), 2.09 (4H, s), 2.35 (1H, s), 2.46 (3Н, s), 2.63 (5Н, s), 2.74 (3Н, s), 2.93 (2Н, d), 3.01 (1H, d), 3.20-3.26 (1H, m), 3.43 (1Н , d), 3.59–3.74 (2Н, m), 4.02 (1H, d), 7.32 (2Н, d), 7.86 (2Н, d), 8.02 (1H, s), 8.61 (1H, s), that the missing 1H is under the DMSO peak; m/z MN ⁺ 540.

Example 37: 2,5,7-trimethyl-6-[[(3R)-1-[5-[4-(1-piperidylmethyl)phenyl]-pyrazin-2-yl]pyrrolidin-3-yl]methyl]- [1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (30 mg; 0.07 mmol), piperidine (12 mg; 0.14 mmol), DCM (2 ml) and AcOH (2 drops) were combined and the reaction the mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (45 mg; 0.21 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The resulting crude product was purified by preparative HPLC to give the title compound (15 mg; 44%); ¹ H NMR (400 MHz, DMSO) 1.47 (6H, d), 1.82-1.92 (1H, m), 2.12 (1H, dd), 2.36 (4H, s), 2.48 (3H, s), 2.65 (4H, s), 2.76 (3Н, s), 2.95 (2Н, d), 3.25 (2Н, dd), 3.41-3.51 (2Н, m), 3.62-3.75 (2Н, m), 7.37 (2Н, s), 7.90 (2Н, s), 8.04 (1H, d), 8.64 (1H, s); m/z МН ⁺ 497.

Example 38: (R)-6-((1-(5-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2, 5,7-trimethyl-[1,2,4]triazolo[1,5-а]pyrimidine

1-Ethylpiperazine (136 mg; 1.19 mmol) was added to (R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a ]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)-benzaldehyde (intermediate 49) (170 mg; 0.40 mmol) in MeOH (5 ml) at room temperature and the reaction mixture was stirred within 1 hour. Sodium triacetoxyborohydride (421 mg; 1.99 mmol) was added. The reaction mixture was stirred at room temperature for 60 hours then concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA) to give the title compound formate (114 mg; 51%) as a pale yellow solid. ; 1Н NMR (300 MHz, CDCl ₃ ) 1.25 (3Н, t), 1.93 (1Н, dq), 2.15-2.32 (1Н, m), 2.56-3.06 (22Н, m), 3.34 (1Н, dd), 3.48- 3.65 (3H, m), 3.76 (2H, ddt), 7.34-7.44 (2H, m), 7.78-7.89 (2H, m), 7.95 (1H, d), 8.47-8.55 (2H, m); m/z МН ⁺ 526.

Example 39: (R)-2,5,7-trimethyl-6-((1-(5-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)pyrazin-2-yl )pyrrolidin-3-yl)methyl)-[1,2,4]triazolo-[1,5-a]pyrimidine

Bis(triphenylphosphoranyl)palladium(IV) chloride (35 mg; 0.05 mmol) was added to 1-((6-bromopyridin-3-yl)methyl)-4-methylpiperazine (intermediate 7) (135 mg; 0.50 mmol), 1,1,1,2,2,2-hexamethyldistannane (180 mg; 0.55 mmol) in THF (3 ml) at room temperature. The reaction mixture was stirred at 85°C for 16 hours. (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5- a] pyrimidine (intermediate 46) (200 mg; 0.50 mmol) and Pd(Ph ₃ P) ₄ (57.4 mg; 0.05 mmol) and THF (5 ml). The reaction mixture was transferred to a microwave tube and heated at 100° C. for 10 hours in a microwave reactor and then allowed to cool to room temperature and concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA) to give the title compound (59 mg; 23%) as a yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.95 (1H, dq), 2.25 (1H, tt), 2.47 (3H, s), 2.60-2.75 (15H, m), 2.82 (3H, s), 2.97 (2H , qd), 3.38 (1H, dd), 3.54-3.65 (3H, m), 3.80 (2H, td), 7.73 (1H, dd), 7.92 (1H, d), 8.11 (1H, d), 8.53- 8.59 (1H, m), 9.09 (1H, d); m/z MH ⁺ 513.

Example 40: 6-(((R)-1-(5-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3 -yl)methyl)-2,5,7-trimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (200 mg; 0.47 mmol) was added to (2R,6S)-1,2,6-trimethylpiperazine (from commercial sources) (120 mg; 0.94 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature for 2 hours. AcOH (2.7 μl; 0.05 mmol) and sodium cyanoborohydride (118 mg; 1.87 mmol) were added and the reaction mixture was stirred for 16 hours, then concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (75 mg; 31%) as a white solid; ^1H NMR (300 MHz, _CDCl3 ) 1.06 (6H, d), 1.73 (2H, t), 1.93 (1H, dq), 2.23 (1H, dq), 2.82 (17H, m), 3.34 (1H, dd ), 3.55 (3Н, d), 3.75 (2Н, m), 7.40 (2Н, m), 7.83 (2Н, m), 7.95 (1H, d), 8.51 (1Н, d); m/z MH ⁺ 526.

Example 41 2-{4-[4-(5-{(3R)-3-[(2,5,7-trimethyl[l,2,4]triazolo[1,5-a]pyrimidin-6-yl )methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazin-1-yl}ethanol

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (30 mg; 0.07 mmol), 2-piperazin-1-ylethanol (18.23 mg; 0.14 mmol), DCM (2 ml) and AcOH (2 drops) were combined and the reaction mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (45 mg; 0.21 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. The resulting crude product was purified by preparative HPLC to give the title compound (8 mg; 20%); ¹ H NMR (400 MHz, DMSO) 1.81-1.93 (1H, m), 2.12 (1H, d), 2.31-2.44 (10H, m), 2.48 (3H, s), 2.65 (4H, s), 2.76 ( 3Н, s), 2.95 (2Н, d), 3.22-3.27 (2Н, m), 3.47 (4Н, s), 3.62-3.76 (2Н, m), 4.32 (1H, s), 7.34 (2H, d) , 7.88 (2H, d), 8.04 (1H, d), 8.62 (1H, d); m/z MH ⁺ 542.

Example 42: (R)-6-((1-(5-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl) methyl)-2,5,7-trimethyl-[1,2,4]triazolo-[1,5-а]pyrimidine

1-(2-Methoxyethyl)piperazine (202 mg; 1.40 mmol) was added to (R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[ 1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)-benzaldehyde (intermediate 49) (200 mg; 0.47 mmol) in DCM (5 ml) at room temperature temperature in air atmosphere and the reaction mixture was stirred for 1 hour. Sodium triacetoxyborohydride (496 mg; 2.34 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA) to give the title compound formate (194 mg; 70%) as a yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.89-2.01 (1H, m), 2.18-2.31 (1H, m), 2.59-3.05 (22H, m), 3.35 (4H, s), 3.52-3.67 (3H, m), 3.67-3.83 (4H, m), 7.38-7.46 (2H, m), 7.82-7.90 (2H, m), 7.97 (1H, s), 8.45 (1H, s), 8.54 (1H, d) ; m/z МН ⁺ 556.

Example 43: (R)-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl )-2,5,7-trimethyl-[1,2,4]triazolo[1,5-а]pyrimidine

2nd generation XPhos precatalyst (14.7 mg; 0.02 mmol) was added to (R)-6-((l-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2.5 ,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 46) (150 mg; 0.37 mmol), (2-methoxy-4-((4-methylpiperazine-1 -yl)methyl)phenyl)boronic acid (intermediate 42) (108 mg; 0.41 mmol) and Cs ₂ CO ₃ (243 mg; 0.75 mmol) in 1,4-dioxane (3 ml) and water ( 1.5 ml) at room temperature. The reaction mixture was stirred at 90°C for 4 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA) to give the title compound formate (168 mg; 79%) as a pale yellow solid. ; ¹ H NMR (400 MHz, CDCl ₃ ) 1.93 (1H, dq), 2.23 (1H, dq), 2.54-3.05 (24H, m), 3.34 (1H, dd), 3.51-3.65 (3H, m), 3.76 (2Н, ddd), 3.89 (3Н, s), 6.96-7.06 (2Н, m), 7.73 (1H, d), 7.98 (1H, d), 8.69 (1H, d); m/z МН ⁺ 542.

Example 44: {1-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl ]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperidin-4-yl}methanol

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (30 mg; 0.07 mmol), 4-piperidylmethanol (16.12 mg; 0.14 mmol), DCM (2 ml) and AcOH (2 drops) were combined and the reaction mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (45 mg; 0.21 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC to give the title compound (17.4 mg; 47%); ¹ H NMR (400 MHz, DMSO) 1.07-1.2 (2H, m), 1.34 (1H, s), 1.62 (2H, d), 1.85-1.95 (3H, m), 2.12 (1H, dd), 2.48 ( 3Н, s), 2.65 (4Н, s), 2.76 (3Н, s), 2.82 (2Н, d), 2.95 (2Н, d), 3.21-3.28 (4Н, m), 3.45 (2Н, s), 3.62 -3.75 (2H, m), 4.37 (1H, s), 7.34 (2H, d), 7.88 (2H, d), 8.04 (1H, d), 8.62 (1H, d); m/z МН ⁺ 527.

Example 45: 6-{[(3R)-1-(5-{4-[(l,l-dioxidothiomorpholin-4-yl)methyl]phenyl}-pyrazin-2-yl)pyrrolidin-3-yl]methyl} -2,5,7-trimethyl[1,2,4]triazolo[1,5-а]pyrimidine

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (30 mg; 0.07 mmol), 1,4-thiazinan-1,1-dioxide hydrochloride (24.03 mg; 0.14 mmol), DCM ( 2 ml) and AcOH (2 drops) were combined and the mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (45 mg; 0.21 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC to give the title compound (12 mg; 30%); ¹ H NMR (400 MHz, DMSO) 1.87 (1H, dd), 2.12 (1H, dd), 2.48 (3H, s), 2.65 (4H, s), 2.76 (3H, s), 2.86-2.93 (4H, m), 2.95 (2Н, d), 3.09-3.14 (4Н, m), 3.25 (1H, dd), 3.45 (1H, dt), 3.62-3.76 (4Н, m), 7.39 (2Н, d), 7.91 (2Н, d), 8.04 (1H, d), 8.64 (1H, d); m/z МН ⁺ 547.

Example 46 2,5,7-trimethyl-6-({(3R)-1-[5-(4-{[4-(methylsulfonyl)piperidin-1-yl]methyl}phenyl)pyrazin-2-yl] pyrrolidin-3-yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (30 mg; 0.07 mmol), 4-methylsulfonylpiperidine (22.9 mg; 0.14 mmol), DCM (2 ml) and AcOH (2 drops) was combined and the mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (45 mg; 0.21 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC and lyophilized to give the title compound (15 mg; 38%); ¹ H NMR (500 MHz, DMSO) 1.56 (2H, tt), 1.76-1.85 (1H, m), 1.92 (4H, t), 2.05 (1H, dd), 2.41 (3H, s), 2.58 (4H, s), 2.69 (3H, s), 2.84 (3H, s), 2.88 (4H, d), 2.98 (1H, ddt), 3.18 (1H, dd), 3.38 (1H, dt), 3.44 (2H, s ), 3.55-3.68 (2H, m), 7.28 (2H, d), 7.82 (2H, d), 7.97 (1H, d), 8.55 (1H, d); m/z MH ⁺ 575.

Example 47: (R)-4-((6-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine- 6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)pyridin-3-yl)methyl)-morpholine

Bis(triphenylphosphoranyl)palladium(IV) chloride (164mg; 0.23mmol) was added to 4-((6-bromopyridin-3-yl)methyl)morpholine (Intermediate 30) (600mg; 2.33mmol), 1,1,1,2,2,2-hexamethyldistannane (841 mg; 2.57 mmol) in THF (8 ml) at room temperature. The reaction mixture was stirred at 85°C for 16 hours. (R)-6-((1-(5-bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[ 1,5-a]pyrimidine (intermediate 45) (300 mg; 0.72 mmol) and Pd(Ph ₃ P) ₄ (83 mg; 0.07 mmol) and the mixture was transferred to a microwave tube with THF (10 ml). The reaction mixture was heated at 100°C for 5 hours in a microwave reactor and left to cool to room temperature, then concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA), then further purified by preparative HPLC to give the title compound (160 mg; 43%) as white solid; ¹ H NMR (300 MHz, MeOD) 1.97 (1H, dq), 2.24 (1H, dq), 2.47–2.59 (10H, m), 2.73 (4H, s), 2.84 (3H, s), 3.04 (2H, dd), 3.32-3.42 (1H, m), 3.47-3.66 (3H, m), 3.66-3.87 (6H, m), 7.72 (1H, dd), 7.81 (1H, s), 7.91 (1H, dd) , 8.53-8.60 (1H, m); m/z МН ⁺ 514.

Example 48: 6-(((R)-1-(5-(4-(((S)-3,4-dimethylpiperazin-1-yl)methyl)phenyl)-pyrazin-2-yl)pyrrolidin-3- yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-а]pyrimidine

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (200 mg; 0.47 mmol) was added to (S)-1,2-dimethylpiperazine dihydrochloride (350 mg; 1.87 mmol) in MeOH (10 ml) . The reaction mixture was stirred at room temperature for 2 hours. AcOH (2.81 mg; 0.05 mmol) and sodium triacetoxyborohydride (397 mg; 1.87 mmol) were added and the reaction mixture was stirred for 16 hours. The reaction mixture was quenched with water and the resulting solution was purified by preparative HPLC to give the title compound (132 mg; 54%) as a white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.07 (3H, d), 1.94 (2H, dq), 2.18-2.35 (6H, m), 2.39 (1H, s), 2.59-2.85 (13H, m), 2.97 (2Н, qd), 3.35 (1H, dd), 3.56 (3Н, d), 3.76 (2Н, ddt), 7.38-7.45 (2Н, m), 7.80-7.88 (2Н, m), 7.96 (1Н, d ), 8.52 (1H, d); m/z МН ⁺ 526.

Example 49: (R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)pyrazin-2-yl)pyridin-2-yl)methyl)morpholine

2nd generation XPhos precatalyst (19.6 mg; 0.02 mmol) was added to (R)-6-((l-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2.5 ,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 46) (200 mg; 0.50 mmol), (6-(morpholinomethyl)pyridin-3-yl)boronic acid (from commercial sources) (110 mg; 0.50 mmol) and Cs ₂ CO ₃ (324 mg; 0.99 mmol) in 1,4-dioxane (4 ml) and water (2 ml) at room temperature. The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound (172 mg; 69%) as a yellow solid; ¹ H NMR (400 MHz, MeOD) 1.91-2.06 (1H, m), 2.23-2.29 (1H, m), 2.53-2.57 (7H, m), 2.66-2.74 (4H, m), 2.85 (3H, d ), 2.97-3.11 (2Н, m), 3.35-3.38 (1Н, m), 3.53-3.59 (1Н, m), 3.67-3.85 (8Н, m), 7.61 (1H, d), 8.05 (1H, s ), 8.30 (1H, dd), 8.56 (1H, s), 9.01–9.02 (1H, m); m/z MH ⁺ 500.

Example 50: 6-(((R)-1-(5-(4-(((S)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)-pyrazin-2-yl)pyrrolidin-3- yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-а]pyrimidine

(S)-1,3-dimethylpiperazine dihydrochloride (167 mg; 0.89 mmol) was added in one portion to (R)-6-((1-(5-(4-(chloromethyl)phenyl)pyrazin-2-yl) pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 48) (200 mg; 0.45 mmol) and triethylamine ( 0.31 ml; 2.23 mmol) in 1,4-dioxane (5 ml) at room temperature in an air atmosphere. The reaction mixture was stirred at 80°C for 24 hours, left to cool to room temperature and diluted with EtOAc (50 ml) and water (15 ml). The organic layer was separated and washed with sat. brine (15 ml), dried over MgSO ₄ , filtered and concentrated under vacuum. The resulting crude product was purified by CPC eluting with 0-4% 1 M NH ₃ /MeOH in DCM to give the title compound (54 mg; 23%) as a pale yellow solid; ¹ H NMR (500 MHz, DMSO) 1.06 (3H, d), 1.80-1.91 (2H, m), 1.94-2.04 (1H, m), 2.05-2.14 (5H, m), 2.37-2.43 (1H, m ), 2.46 (4Н, s), 2.52-2.61 (3Н, m), 2.63 (3Н, s), 2.74 (3Н, s), 2.93 (2Н, d), 3.12 (1Н, d), 3.23 (1H, dd), 3.43 (1Н, dt), 3.63 (1H, dd), 3.66-3.73 (1Н, m), 3.95 (1Н, d), 7.33 (2Н, d), 7.82-7.91 (2Н, m), 8.02 (1H, d), 8.60 (1H, d); m/z МН ⁺ 526.

Example 51: (R)-4-(4-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6 -yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine

2nd generation XPhos precatalyst (11.3 mg; 0.01 mmol) was added to 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (from commercial sources) (87 mg; 0.29 mmol), (R)-6-((1-(5-bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2.5 ,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 45) (120 mg; 0.29 mmol) and Cs ₂ CO ₃ (188 mg; 0.58 mmol) in 1,4-dioxane (4 ml) and water (1.5 ml). The reaction mixture was stirred at 90°C for 16 hours, left to cool to room temperature and filtered through celite. as a pale yellow solid; ¹ H NMR (300 MHz, MeOD) 1.92-1.99 (1H, m), 2.17-2.27 (1H, m), 2.41 (3H, s), 2.55 (3H, s), 2.61-2.83 (11H, m), 2.96-3.03 (2H, m), 3.29-3.35 (1H, m), 3.47-3.55 (1H, m), 3.65-3.79 (6H, m), 3.86 (2H, s), 7.47-7.53 (4H, m ), 7.75 (1H, s); m/z MH ⁺ 513.

Example 52 2,5,7-trimethyl-6-({(3R)-1-[5-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)pyrazin-2-yl] pyrrolidin-3-yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (30 mg; 0.07 mmol), 1-methylsulfonylpiperazine (22.99 mg; 0.14 mmol), DCM (2 ml) and AcOH (2 drops) was combined and the mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (45 mg; 0.21 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC to give the title compound (11.9 mg; 30%); ¹ H NMR (400 MHz, DMSO) 1.87 (1H, dd), 2.12 (1H, dd), 2.48 (7H, s), 2.65 (4H, s), 2.76 (3H, s), 2.87 (3H, s) , 2.95 (2Н, d), 3.09-3.16 (4Н, m), 3.25 (1H, dd), 3.41-3.50 (1H, m), 3.55 (2Н, s), 3.62-3.75 (2Н, m), 7.37 (2Н, d), 7.90 (2Н, d), 8.04 (1Н, d), 8.63 (1H, d); m/z MH ⁺ 576.

Example 53: (R)-N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo-[1,5 -a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)acetamide

N,N-Dimethyl-2-(piperazin-1-yl)acetamide (intermediate 21) (240 mg; 1.40 mmol) was added to (R)-4-(5-(3-((2.5, 7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (200 mg; 0 .47 mmol) in DCM (5 ml) at room temperature and the reaction mixture was stirred for 1 hour. Sodium triacetoxyborohydride (496 mg; 2.34 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA) to give partial (0.6 equivalents) formate of the title compound (172 mg; 60%) as a yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.87-2.01 (1H, m), 2.18-2.30 (1H, m), 2.64 (3H, s), 2.60-2.71 (1H, m), 2.72-2.78 (11H, m), 2.83 (3H, s), 2.96 (3H, s), 2.88-3.05 (2H, m), 3.05 (3H, s), 3.24 (2H, s), 3.35 (1H, dd), 3.52-3.63 (1H, m), 3.72-3.81 (1H, m), 3.78 (3H, s), 7.45 (2H, d), 7.87 (2H, d), 7.97 (1H, d), 8.42 (0.6H, s, corresponds to 0.6 equiv. formate), 8.52 (1H, d); m/z МН ⁺ 583.

Example 54: (R)-2,5,7-trimethyl-6-((1-(6-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl )pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

2nd generation XPhos pre-catalyst (28 mg; 0.04 mmol) was added to 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl)piperazine (125mg; 0.40mmol), (R)-6-((1-(5-bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2.5.7 -trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 45) (150 mg; 0.36 mmol) and Cs ₂ CO ₃ (235 mg; 0.72 mmol) in 1, 4-dioxane (3 ml) and water (1.5 ml) at room temperature. The reaction mixture was stirred at 90°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound (110 mg; 58%) as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) 1.81-2.00 (1H, m), 2.20 (1H, dq), 2.31-2.76 (21H, m), 2.82 (3H, s), 2.94 (2H, qd), 3.34 (1H, dd), 3.46-3.61 (3H, m), 3.74 (2H, ddd), 7.38 (2H, d), 7.43-7.53 (2H, m), 7.79 (1H, s); m/z МН ⁺ 526.

Example 55 N,N-dimethyl-4-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidine- 6-yl)methyl)pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazin-1-carboxamide

(R)-4-(5-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)-pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (30 mg; 0.07 mmol), N,N-dimethylpiperazin-1-carboxamide (23 mg; 0.14 mmol), DCM (2 ml) and AcOH (2 drops) were combined and the mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (45 mg; 0.21 mmol) was then added and the reaction mixture was stirred at room temperature for 16 hours. The mixture was purified by preparative HPLC to give the title compound (13 mg; 33%); ¹ H NMR (400 MHz, DMSO) 1.82-1.92 (1H, m), 2.07-2.17 (1H, m), 2.35-2.41 (4H, m), 2.48 (3H, s), 2.65 (4H, s), 2.72 (6H, s), 2.76 (3H, s), 2.95 (2H, d), 3.07–3.15 (4H, m), 3.22–3.27 (1H, m), 3.41–3.54 (3H, m), 3.68 ( 2H, ddd), 7.36 (2H, d), 7.89 (2H, d), 8.04 (1H, d), 8.63 (1H, d); m/zMH ⁺ 569.

Example 56: (R)-2,5,7-trimethyl-6-((1-(5-(3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl )pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph ₃ P) ₄ (35 mg; 0.03 mmol) was added to (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2.5, 7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 46) (122 mg; 0.30 mmol), 1-methyl-4-(2-methyl-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine (intermediate 51) (100 mg; 0.30 mmol) and Na ₂ CO ₃ (64.2 mg; 0 .61 mmol) in toluene (4 ml) and water (1 ml). The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by preparative HPLC to give the title compound (15 mg; 9%) as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) 1.94 (1Н, m), 2.22 (1H, dt), 2.30–2.75 (21Н, m), 2.81 (3H, s), 2.95 (2Н, t), 3.34 (1H , dd), 3.54 (3H, m), 3.75 (2H, m), 7.34 (1H, m), 7.65 (2H, m), 7.94 (1H, d), 8.50 (1H, s); m/z МН ⁺ 526.

Example 57: (R)-2,5,7-trimethyl-6-((1-(5-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)1 shrazin-2- yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo-[1,5-a]pyrimidine

2nd generation XPhos pre-catalyst (10.76 mg; 0.01 mmol) was added to (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2, 5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 46) (110 mg; 0.27 mmol), (6-((4-methylpiperazin-1-yl) methyl)pyridin-3-yl)boronic acid (intermediate 9) (71 mg; 0.30 mmol) and Cs ₂ CO ₃ (178 mg; 0.55 mmol) in 1,4-dioxane (3 ml) and water (1.5 ml) at room temperature. The reaction mixture was stirred at 80°C for 4 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA) to give partial (0.5 equiv.) formate of the title compound (141 mg; 96% ) as a white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.96 (1H, dq), 2.25 (1H, dt), 2.62-2.76 (10H, m), 2.83 (3H, s), 2.89-3.06 (10H, m), 3.36 (1H, dd), 3.59 (1H, dt), 3.71-3.84 (4H, m), 7.41 (1H, d), 7.99 (1H, d), 8.18 (1H, dd), 8.40 (0.5H, s, from 0.5 equiv. formate), 8.53 (1H, d), 9.11 (1H, d); m/z МН ⁺ 513.

Example 58: (R)-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6- yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)ethanone

1-(4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1-yl)-ethanone (intermediate 52) (667 mg; 1.94 mmol), (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo [1,5-a]pyrimidine (intermediate 46) (600 mg; 1.49 mmol) and Cs ₂ CO ₃ (972 mg; 2.98 mmol) were added to 1,4-dioxane (30 ml) and water ( 15 ml) and the mixture was degassed for 10 minutes. 2nd generation XPhos pre-catalyst (59 mg; 0.07 mmol) was added and the reaction mixture was stirred for 18 hours at 90° C., then allowed to cool to room temperature and diluted with EtOAc (50 ml). The organic layer was separated, washed with sat. brine and dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-4% 1 NH ₃ /MeOH in DCM. The product was dissolved in EtOAc (2 ml) and stirred for 2 hours and the resulting precipitate was isolated by filtration and dried under vacuum to give the title compound (209 mg; 26%) as a white solid; ¹ H NMR (500 MHz, DMSO) 1.78-1.91 (1H, m), 1.96 (3H, s), 2.03-2.16 (1H, m), 2.26-2.33 (2H, m), 2.34-2.4 (2H, m ), 2.46 (3H, s), 2.55-2.67 (4H, m), 2.74 (3H, s), 2.93 (2H, d), 3.2-3.26 (1H, m), 3.35-3.47 (5H, m), 3.50 (2H, s), 3.59-3.75 (2H, m), 7.34 (2H, d), 7.88 (2H, d), 8.02 (1H, s), 8.62 (1H, s); m/z MN ⁺ 540.

Example 59: (R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3 -yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

2nd generation XPhos pre-catalyst (0.780 g; 0.99 mmol) was added to a mixture of (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2.5 ,7-trimethyl-[1,2,4]triazolo-[1,5-a]pyrimidine (intermediate 46) (7.98 g; 19.84 mmol), 1-methyl-4-(4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine (from commercial sources) (7.53 g; 23.8 mmol) and Cs ₂ CO ₃ (12.93 g ; 39.7 mmol) in 1,4-dioxane (187 ml) and water (75 ml). The reaction mixture was heated at 90°C for 3 hours, left to cool to room temperature and concentrated under vacuum. The residue was taken up in water (1 L) and extracted with DCM (3×800 ml). The combined organic layers were washed with water, sat. brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with 0-15% MeOH in DCM. The product was taken up in MeCN (150 ml) and stirred for 2 hours after sonication. The resulting precipitate was isolated by filtration, washed with diethyl ether and then with n-heptane, and dried under vacuum to give the title compound (6.30 g; 62%) as a pale cream solid; ¹ H NMR (500 MHz, DMSO) 1.82-1.88 (1H, m), 2.10-2.14 (1H, m), 2.15 (3H, s), 2.30-2.34 (4H, m), 2.37-2.41 (4H, m ), 2.47 (3H, s), 2.58-2.64 (1H, m), 2.64 (3H, s), 2.75 (3H, s), 2.91-2.95 (2H, m), 3.23-3.26 (1H, m), 3.43-3.46 (1H, m), 3.47 (2H, s), 3.64-3.67 (1H, m), 3.68-3.72 (1H, m), 7.32 (2H, d), 7.85 (2H, d), 8.00 ( 1H, s), 8.56 (1H, s); m/z MH ⁺ 512.

Example 60: (R-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl) pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine

2nd generation XPhos pre-catalyst (24.45 mg; 0.03 mmol) was added to (R-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2.5 ,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 46) (250 mg; 0.62 mmol), 4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (from commercial sources) (188 mg; 0.62 mmol) and Cs ₂ CO ₃ (405 mg; 1.24 mmol) in 1,4- dioxane (5 ml) and water (2.5 ml) at room temperature.The reaction mixture was stirred at 80°C for 16 hours, left to cool to room temperature, filtered through celite and concentrated under vacuum.The resulting crude product was purified by preparative HPLC to give the title compound (191 mg; 56%) as a pale yellow solid, ¹ NMR (300 MHz, MeOD) 1.93-2.02 (1H, m), 2.18-2.28 (1H, m), 2.55 ( 3H, s), 2.65-2.74 (4H, m), 2.78-2.83 (7H, m), 3.02-3.04 (2H, m), 3.29-3.35 (1H, m), 3.49-3.58 (1H, m), 3.66-3.81 (6H, m), 3.86 (2H, s), 7.47 (2H, d), 7.90 (2H, d), 7.99 (1H, s), 8.49 (1H, s); m/z NH ⁺ 499.

Example 61: (R)-4-(4-(6-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl )pyrrolidin-1-yl)pyridazin-3-yl)benzyl)morpholine

2nd generation XPhos pre-catalyst (11 mg; 0.01 mmol) was added to (R)-6-((l-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)methyl)-2.5, 7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 53) (100 mg; 0.28 mmol), 4-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)benzyl)morpholine (from commercial sources) (85 mg; 0.28 mmol) and Cs ₂ CO ₃ (182 mg; 0.56 mmol) in 1,4-dioxane (2 ml) and water (1 ml) at room temperature. The reaction mixture was stirred at 90°C for 2 hours, left to cool to room temperature and concentrated under vacuum. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.08% NH ₄ HCO ₃ ) to give the title compound (101 mg; 73%) as a white solid ; ¹ H NMR (400 MHz, MeOD) 2.01 (1H, dq), 2.26 (1H, dt), 2.54 (7H, d), 2.75 (4H, s), 2.86 (3H, s), 3.07 (2H, dd) , 3.38 (1Н, dd), 3.52-3.63 (3H, m), 3.68-3.86 (6Н, m), 7.04 (1H, d), 7.44-7.51 (2Н, m), 7.82-7.95 (3H, m) ; m/z МН ⁺ 499.

Example 62: (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine

Combined Cs ₂ CO ₃ (50 g; 153 mmol), 4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine (10 g; 29.80 mmol) (intermediate 65) and dihydrochloride ( R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 58) (10 g; 29.80 mmol ), 3rd generation RuPhos pre-catalyst (1.87 g; 2.24 mmol) and RuPhos (1.04 g; 2.24 mmol). A degassed mixture of 2-methyltetrahydrofuran (80 ml) and water (40 ml) was added and the reaction mixture was heated at reflux temperature for 17 hours, then left to cool to room temperature and diluted with DCM (250 ml) and water (250 ml). The organic layer was separated and washed with a mixture of sat. brine:water, 1:1 (100 ml), then filtered through a silica pad, then concentrated in vacuo to give the crude product. The reaction was then repeated using the following: Cs ₂ CO ₃ (75 g; 230 mmol), 4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine (15 g; 44.70 mmol), dihydrochloride (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine (15 g; 44.7 mmol), precatalyst 3rd generation RuPhos (2.80 g; 3.35 mmol) and RuPhos (1.56 g; 3.35 mmol) in a degassed mixture of 2-methyltetrahydrofuran (120 mL) and water (60 mL). The second interaction was carried out by a method similar to the method described for the first interaction. Two portions of the crude product were combined and purified by SFC (Kromasil SIL column 250×50 mm, 10 μm, at a flow rate of 450 ml/min using 33% MeOH in supercritical CO ₂ at a pressure of 130 bar (13 MPa) and an oven temperature of 30° C) to give the title compound (29 g; 80% yield based on two batches combined) as a white solid; ¹ H NMR (600 MHz, DMSO) 2.31 (1H, dtd), 2.42 (5H, d), 2.46 (3H, s), 2.52 (3H, s), 2.58 (3H, s), 3.45 (1H, dd) , 3.54 (1H, td), 3.58 (5H, q), 3.62-3.68 (1H, m), 3.77 (2H, s), 4.96 (1H, s), 6.74 (2H, d), 7.65 (1H, d ), 8.03 (2H, d), 8.07 (1H, d); m/z MH ⁺ 501.

Form A

End product, (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine was analyzed by XRD and DSC and found to be crystalline. XRD of the substance sample gave a diffraction pattern, which is shown in Fig. 1. (R)-4-((6-(4-(3-((2,5,7-Trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy )pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine Form A has at least one peak at a 2θ angle of 7.8° or 19.0° measured using CuKα radiation. The ten most important DRLP peaks are shown in Table A.

Example 62.1: Scaling up (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6- yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine

The way of synthesis of 1 part of the compound:

Step 1: 1-(4-bromophenyl)-1,4-pentanedione (intermediate 63)

2-Bromo-1-(4-bromophenyl)ethenone (12.2 kg; 43.89 mol), 2,4-pentanedione (9.2 kg; 91.89 mol) and potassium carbonate (12.2 kg; 88 .27 mol) was suspended in ethanol (72.25 L) for approximately 24 hours at room temperature. Ethyl acetate (84.26 L) and water (74 L) were added to effect phase separation in which the lower phase was discarded. Changing the solvent of the organic phase to n-heptane (2 x 84.8 L and 1 x 73.1 L) resulted in the formation of a solid, which was separated by filtration and washed with n-heptane (17.54 L) to give the title compound (7.26 kg; 59.4% yield based on an analysis value of 91.6% (w/w)). ^1H NMR (400 MHz, _CDCl3 ) 2.15 (3H, s), 2.56 (2H, t), 3.07 (2H, t), 7.44 (2H, d), 7.89 (2H, d).

Stage 2: 3-(4-bromophenyl)-6-methylpyridazine (intermediate 64)

1-(4-Bromophenyl)-1,4-pentadione (13.2 kg; 51.74 mol) and hydrazine hydrate (10.9 kg; 217.74 mol) were mixed in ethanol (54.5 L) for approximately 6 hours at room temperature. Addition of water gave a solid which was separated by filtration and washed with water (3×66 L) and n-heptane (2×36.5 L). The solid was mixed with tetrachloro-1,4-benzoquinone (14.5 kg; 58.97 mol) and acetonitrile (137.4 L) for approximately 6 hours at room temperature. The reaction was stopped by adding 12.5% (w/w) sodium sulfite solution (85 L) and the acetonitrile was removed by distillation. Addition of water (66 L) and 2 M sodium hydroxide solution (66 L) gave a solid, which was separated by filtration and washed with 2 M sodium hydroxide (2×40 L) and water (2×145 L). The solid was mixed with dichloromethane (140 L) and filtered again before washing with water (3×145 L). The organic phase was then treated with activated charcoal followed by a solvent exchange with methyl tert-butyl ether (100 L) and a final wash with methyl tert-butyl ether (2×55 L). This gave the title compound (8.25 kg; 61% yield based on an assay value of 95.2% (w/w)). ¹ H NMR (400 MHz, CDCl ₃ ) 2.75 (3H, s), 7.38 (1H, d), 7.65-7.60 (2H, m), 7.71 (1H, d), 7.96-7.91 (2H, m); ¹³ C NMR (400 MHz, CDCl ₃ ) 22.1, 123.5, 124.4, 127.3, 128.4, 132.2, 135.4, 156.2, 158.6.

Step 3: 4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine (Intermediate 65)

1,3,5-Trichloro-1,3,5-triazinan-2,4,6-trione (2.8 kg; 12.05 mol) was added portionwise to 3-(4-bromophenyl)-6-methylpyridazine (intermediate compound 64) (7.15 kg; 27.32 mol) in DCM (338.35 L) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then an additional portion of 1,3,5-trichloro-1,3,5-triazinan-2,4,6-trione (0.31 kg; 1.33 mol) was added and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was filtered and the organic filtrate was washed with water (68 L) before changing the solvent to acetonitrile (55 L). Morpholine (4.75 kg; 54.52 mol) was added and the mixture was heated for 4 hours before concentration and filtration to give a solid which was washed with acetonitrile (6 L) and water (6 L). The solid was dissolved using 4 N hydrochloric acid (7.5 kg) and water (45 L). The acidic solution was washed with ethyl acetate (2 x 2.5 L) before adjusting the pH with 15% (w/w) sodium hydroxide (11 kg) to give a solid which was isolated by filtration. This gave the title compound (6.2 kg; 67% yield based on an assay value of 98.7% (w/w)). ¹ H NMR (400 MHz, _CDCl3 ) 2.56 (4H, m), 3.73 (4H, m), 3.91 (2H, s), 7.64 (2H, m), 7.73 (1H, d), 7.81 (1H, d ), 7.96 (2H, m); m/z МН ⁺ 334.

The way of synthesis of 2 parts of the compound:

Stage 4: 3-methyl-1H-1,2,4-triazol-5-amine

Aminoguanidine bicarbonate (17.7 kg; 130.04 mol) was mixed with nitric acid (165 g; 2.62 mol) in acetic acid (29.8 L; 521.21 mol) for 64 hours at 90°C. The mixture was cooled and diluted with isopropyl acetate (30 L) and filtered to give the title compound. The crude material (13.9 kg; 36.7% yield based on an analysis value of 33.7% (w/w)) was used directly in step 5.

Step 5: 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-ol (intermediate 56)

2,4-Pentanedione (5.6 kg; 55.93 mol) and tetra-n-butylammonium bromide (0.9 kg; 2.79 mol) were cooled in acetonitrile (39.44 L). Slow addition of trimethylsilyl chloride (7.3 kg; 67.19 mol) and dimethyl sulfoxide (4.4 kg; 56.32 mol) gave intermediate 3-chloro-2,4-pentanedione as an acetonitrile solution. This solution was loaded with benzoic acid (4.9 kg; 40.12 mol) and diisopropylethylamine (8.6 kg; 66.54 mol) to give 2,4-dioxopentan-3-ylbenzoate (intermediate 54). Changing the solvent to 2-methyltetrahydrofuran (28.1 L) followed by washing with 5% sodium sulfate was followed by the addition of 3-methyl-1H-1,2,4-triazol-5-amine (12.8 kg; 43.97 mole). Addition of acetic acid (32.19 L) and heating at 90°C for 20 hours gave 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-ylbenzoate (intermediate compound 55). Changing the solvent to toluene (25 L) and stirring at room temperature with 5 M sodium hydroxide (63 L) for 20 hours at room temperature gave the title compound. Addition of 6M hydrochloric acid gave a solid which was isolated by filtration and washed with water (16 L). The solid was suspended in water (40 L) and toluene (15 L) and filtered, then washed with water (16 L) and dried to give 5.8 kg (94.6% w/w analysis); 30.79 mol; yield 76.7% based on benzoic acid).

Step 6: Intermediate 58: (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine dihydrochloride (Intermediate 58 )

Diisopropylazodicarboxylate (6.9 kg; 34.12 mol) in THF (14.62) was added dropwise to 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6- ol (4.55 kg; 24.16 mol), tert-butyl-(S)-3-hydroxypyrrolidine-1-carboxylate (5.3 kg; 28.31 mol) and triphenylphosphine (7.3 kg; 27.83 mol) in THF (85.49 L) at 0°C and then stirred at room temperature for 20 hours. This was followed by a solvent change to 2-methyl-THP (46.84 L) and washing with 25% (w/w) sodium chloride (2×22 kg). 2-Methyl-THF was removed by changing the solvent to isopropyl alcohol (45 L) and the Boc group was removed by adding 15% hydrochloric acid in isopropyl alcohol (73.8 kg) and stirring for 15 hours at room temperature. Cooling and seeding with (11)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1.5-a]pyrimidine dihydrochloride (120 g; 370 mmol) gave a solid a substance which was isolated by filtration and washed with isopropyl alcohol. Finally, the solid was suspended in ethyl acetate (45 L) before final filtration and washing with ethyl acetate (45 L) to give 5.35 kg (analysis* 74% (w/w); 16.01 mol; 66% yield). ¹ H NMR (400 MHz, DMSO) 2.03-2.13 (1H, m), 2.22-2.28 (1H, m), 2.51-2.54 (3H, m), 2.62 (3H, d), 2.74 (3H, s), 3.32-3.45 (3H, m), 3.46-3.56 (1H, m), 4.90 (1H, s), 9.91 (2H, s); m/z MH ⁺ 248. ^* The analysis is performed based on the equivalent of the free base.

An association:

Step 7: (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine (Example 62)

Combined Cs ₂ CO ₃ (23.8 kg; 73.0 mol), 4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine (4.89 kg; 14.63 mol) (intermediate compound 65), and (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine dihydrochloride (intermediate 58) ( 4.33 kg; 17.51 mol*), 2-ditert-butylphosphino-2'-methylbiphenyl (0.23 kg; 736 mmol), and tris(dibenzylideneacetone) dipalladium(0) (0.33 kg; 360 mmol) . A degassed mixture of 2-methyltetrahydrofuran (80 L) and water (40 L) was added and the reaction mixture was heated at reflux for 24 hours, then allowed to cool to room temperature and diluted with DCM (100 L) and water (50 L) . The reaction mixture was filtered and the solvent in the organic phase was changed to ethyl acetate to give 8.4 kg of crude material. This was dissolved in DCM (200 L) and washed successively with 2 M hydrochloric acid (2×90 L), 2 M sodium hydroxide (140 L) and 5% sodium thiosulfate (2×50 L). The resulting DCM solution was passed through silica gel resin with thiol groups (0.5 kg) before changing the solvent to ethyl acetate to obtain 5 kg of crude material. This was dissolved in DCM (25 L) and the true form A was obtained by adding n-heptane (25 L) with seeding (Form A (R)-4-((6-(4-(3-((2,5,7 -trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)-pyrrolidin-1-yl)phenyl)-pyridazin-3-yl)methyl)morpholine), used for control nucleation points. Filtration and drying (30° C.) gave the title compound (4.06 kg; 8.11 mol; 55% yield) as a white solid; ¹ H NMR (600 MHz, DMSO) 2.31 (1H, dtd), 2.42 (5H, d), 2.46 (3H, s), 2.52 (3H, s), 2.58 (3H, s), 3.45 (1H, dd) , 3.54 (1H, td), 3.58 (5H, q), 3.62-3.68 (1H, m), 3.77 (2H, s), 4.96 (1H, s), 6.74 (2H, d), 7.65 (1H, d ), 8.03 (2Н, d), 8.07 (1Н, d); m/z MH ⁺ 501. *3load is the amount of base substance corrected for the free base of intermediate 58, minus the total load and is 5.85 kg of the dihydrochloride salt.

Example 63: (S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine

The compound of Example 63 was obtained by a method similar to that of Example 62 in 3 steps from commercially available tert-butyl-(R)-3-hydroxypyrrolidine-1-carboxylate to give the title compound (125 mg; 31% per final stage) as a white solid; ¹ H NMR (400 MHz, DMSO) 2.26-2.47 (9H, m), 2.52 (3H, s), 2.58 (3H, s), 3.45 (1H, dd), 3.5-3.61 (6H, m), 3.61- 3.69 (1H, m), 3.77 (2H, s), 4.96 (1H, s), 6.73 (2H, d), 7.64 (1H, d), 8.04 (3H, dd); m/z MH ⁺ 501.

Example 64: (R)-2,5,7-trimethyl-6-((1-(4-(6-(piperidin-1-ylmethyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy) -[1,2,4]triazolo[1,5-a]pyrimidine

Cs ₂ CO ₃ (593 mg; 1.82 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a] pyrimidine (intermediate 58B) (150 mg; 0.61 mmol) and 3-(4-bromophenyl)-6-(piperidin-1-ylmethyl)pyridazine (intermediate 70) (202 mg; 0.61 mmol) in 2-methyltetrahydrofuran (1.6 ml) and water (0.8 ml). The reaction mixture was degassed and pre-catalyst 3rd generation RuPhos (38 mg; 0.05 mmol) and RuPhos (21 mg; 0.05 mmol) were added. The reaction mixture was heated at reflux for 18 hours, left to cool to room temperature, and then diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (83 mg, 27%) as a white solid; ¹ H NMR (400 MHz, DMSO) 1.37-1.45 (2H, m), 1.52 (4H, p), 2.32 (1H, dt), 2.40 (5H, s), 2.47 (3H, s), 2.53 (3H, s), 2.59 (3H, s), 3.46 (1H, dd), 3.51-3.61 (2H, m), 3.66 (1H, q), 3.74 (2H, s), 4.98 (1H, s), 6.75 (2H , d), 7.63 (1H, d), 8-8.07 (3H, m); m/z МН ⁺ 499.

Example 65: (R)-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3 -yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine

Cs ₂ CO ₃ (593 mg; 1.82 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a]pyrimidine (Intermediate 58 B) (150 mg; 0.61 mmol) and 3-(4-bromophenyl)-6-((4-methylpiperazin-1-yl)methyl)pyridazine (Intermediate 71) (211 mg ; 0.61 mmol) in 2-methyltetrahydrofuran (1.6 ml) and water (0.8 ml). The reaction mixture was degassed and RuPhos 3rd generation precatalyst (38 mg; 0.05 mmol) and RuPhos (21 mg; 0.05 mmol) were added. The reaction mixture was heated at reflux for 18 hours, allowed to cool to room temperature, and then diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (154 mg; 49%) as an off-white solid; ¹ H NMR (400 MHz, DMSO) 2.16 (3H, s), 2.27-2.38 (5H, m), 2.38-2.48 (8H, m), 2.53 (3H, s), 2.59 (3H, s), 3.46 ( 1H, dd), 3.51-3.61 (2H, m), 3.66 (1H, q), 3.77 (2H, s), 4.97 (1H, s), 6.74 (2H, d), 7.62 (1H, d), 8.01 -8.09 (3H, m); m/z МН ⁺ 514.

Example 66: 2,5,7-trimethyl-6-(((3R)-1-(4-(6-((3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl )pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine

Cs ₂ CO ₃ (494 mg; 1.52 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a]pyrimidine (intermediate 58B) (125 mg; 0.51 mmol) and 8-((6-(4-bromophenyl)pyridazin-3-yl)methyl)-3-methyl-3,8-diazabicyclo[3.2. 1]octane (intermediate 66) (189 mg; 0.51 mmol) in 2-methyltetrahydrofuran (1.6 ml) and water (0.8 ml). The reaction mixture was degassed and 3rd generation RuPhos precatalyst (31.7 mg; 0.04 mmol) and RuPhos (17.69 mg; 0.04 mmol) were added. The reaction mixture was heated at reflux for 18 hours, left to cool to room temperature, then diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (121 mg; 44%) as an off-white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.86 (2H, q), 2.05 (2H, dd), 2.23 (3H, s), 2.27-2.39 (3H, m), 2.46-2.54 (1H, m), 2.57 -2.63 (8H, m), 2.65 (3H, s), 3.13 (2H, s), 3.48-3.65 (3H, m), 3.73-3.82 (1H, m), 3.87 (2H, s), 4.85 (1H , s), 6.68 (2H, d), 7.74-7.82 (2H, m), 8.04 (2H, d); m/z MN ⁺ 540.

Example 67: 6-(((R)-1-(4-(6-(((R)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyridazin-3-yl) phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine

Cs ₂ CO ₃ (494 mg; 1.52 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a]pyrimidine (intermediate 58B) (125 mg; 0.51 mmol) and (R)-2-((6-(4-bromophenyl)pyridazin-3-yl)methyl)octahydropyrrolo[1,2-a]pyrazine (intermediate 67) (189 mg; 0.51 mmol) in 2-methyltetrahydrofuran (1.6 ml) and water (0.8 ml). The reaction mixture was degassed and RuPhos 3rd generation precatalyst (31.7 mg; 0.04 mmol) and RuPhos (17.7 mg; 0.04 mmol) were added. The reaction mixture was heated at reflux for 18 hours, allowed to cool to room temperature, and then diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (33 mg; 12%) as an off-white solid; ¹ H NMR (400 MHz, DMSO) 1.20-1.31 (1H, m), 1.66 (3H, ttd), 1.87-2.06 (3H, m), 2.14 (1H, td), 2.25 (1H, td), 2.33 ( 1H, dtd), 2.42 (1H, dd), 2.47 (3H, s), 2.53 (3H, s), 2.59 (3H, s), 2.73 (1H, d), 2.86-2.98 (3H, m), 3.46 (1H, dd), 3.51-3.62 (2H, m), 3.62-3.71 (1H, m), 3.77-3.87 (2H, m), 4.97 (1H, s), 6.75 (2H, d), 7.62 (1H , d), 8.05 (3H, t); m/z MN ⁺ 540.

Example 68: 6-(((R)-1-(4-(6-(((S)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyridazin-3-yl) phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine

Cs ₂ CO ₃ (494 mg; 1.52 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a]pyrimidine (intermediate 58B) (125 mg; 0.51 mmol) and (S)-2-((6-(4-bromophenyl)pyridazin-3-yl)methyl)octahydropyrrolo[1,2-a]pyrazine (intermediate 68) (189 mg; 0.51 mmol) in 2-methyltetrahydro-furan (1.6 ml) and water (0.8 ml). The reaction mixture was degassed and pre-catalyst 3rd generation RuPhos (31.7 mg; 0.04 mmol) and RuPhos (17.7 mg; 0.04 mmol) were added. The reaction mixture was heated at reflux for 18 hours, left to cool to room temperature, then diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (76 mg; 28%) as an off-white solid; ¹ H NMR (400 MHz, DMSO) 1.20-1.32 (1H, m), 1.66 (3H, dqd), 1.88-2.06 (3H, m), 2.14 (1H, td), 2.25 (1H, td), 2.3- 2.37 (1H, m), 2.42 (1H, d), 2.47 (3H, s), 2.53 (3H, d), 2.60 (3H, s), 2.73 (1H, d), 2.85-2.98 (3H, m) , 3.47 (1H, dd), 3.51-3.62 (2H, m), 3.66 (1H, q), 3.77-3.87 (2H, m), 4.98 (1H, s), 6.75 (2H, d), 7.62 (1H , d), 8.01–8.09 (3H, m); m/z MN ⁺ 540.

Example 69: (R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy)pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine

Cs ₂ CO ₃ (401 mg; 1.23 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a]pyrimidine (intermediate 58B) (101 mg; 0.41 mmol) and 4-((5-(4-bromophenyl)pyrimidin-2-yl)methyl)morpholine (intermediate 39) (137 mg; 0.41 mmol) in 2-methyltetrahydrofuran (1.4 ml) and water (0.7 ml). The reaction mixture was degassed and RuPhos 3rd generation precatalyst (25.7 mg; 0.03 mmol) and RuPhos (14.4 mg; 0.03 mmol) were added. The reaction mixture was heated at reflux for 18 hours, left to cool to room temperature, then diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (82 mg, 40%) as a white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 2.34 (1H, dp), 2.47-2.55 (1H, m), 2.60 (3H, s), 2.61-2.65 (7H, m), 2.65 (3H, s), 3.45 -3.54 (2H, m), 3.58 (1H, td), 3.72-3.78 (1H, m), 3.78-3.83 (4H, m), 3.85 (2H, s), 4.83-4.89 (1H, m), 6.65 -6.72 (2H, m), 7.46-7.53 (2H, m), 8.89 (2H, s); m/z MH ⁺ 501.

Example 70: (R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy) pyrrolidin-1-yl) phenyl) pyrazin-2-yl) methyl) morpholine

Cs ₂ CO ₃ (668 mg; 2.05 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a]pyrimidine (intermediate 58B) (169 mg; 0.68 mmol) and 4-((5-(4-bromophenyl)pyrazin-2-yl)methyl)morpholine (intermediate 77) (228 mg; 0.68 mmol) in 2-methyltetrahydrofuran (2.3 ml) and water (1.1 ml). The reaction mixture was degassed and RuPhos 3rd generation precatalyst (42.9 mg; 0.05 mmol) and RuPhos (23.9 mg; 0.05 mmol) were added. The reaction mixture was heated at reflux for 18 hours, left to cool to room temperature, then diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (104 mg, 30%) as an off-white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 2.33 (1H, dtd), 2.50 (1H, dd), 2.53-2.57 (4H, m), 2.60 (3H, s), 2.61 (3H, s), 2.64 (3H , s), 3.46-3.6 (2Н, m), 3.61 (1H, td), 3.70 (2Н, s), 3.72-3.83 (5Н, m), 4.85 (1H, dt), 6.63-6.71 (2Н, m ), 7.91-8.00 (2H, m), 8.60 (1H, d), 8.91 (1H, d); m/z MH ⁺ 501.

Example 71: (R)-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6 -yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)-piperazin-1-yl)ethan-1-one

Cs ₂ CO ₃ (632 mg; 1.94 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a]pyrimidine (intermediate 58B) (160 mg; 0.65 mmol) and 1-(4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1- onu (intermediate 69) (243 mg; 0.65 mmol) in 2-methyltetrahydrofuran (1.7 ml) and water (0.9 ml). The reaction mixture was degassed and RuPhos 3rd generation precatalyst (40.6 mg; 0.05 mmol) and RuPhos (22.6 mg; 0.05 mmol) were added. The resulting suspension was heated at reflux for 18 hours, left to cool to room temperature, diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (154 mg; 44%) as a pale yellow solid; ¹ H NMR (400 MHz, DMSO) 1.99 (3H, s), 2.33 (1H, d), 2.37–2.43 (3H, m), 2.47 (5H, s), 2.53 (3H, s), 2.59 (3H, s), 3.46 (5Н, dd), 3.56 (2Н, q), 3.66 (1H, q), 3.82 (2Н, s), 4.98 (1H, s), 6.75 (2Н, d), 7.66 (1H, d ), 8.06 (3H, dd); m/z МН ⁺ 542.

Example 72: (R)-6-((1-(4-(6-((4-ethylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2, 5,7-trimethyl-[1,2,4]triazolo[1,5-а]pyrimidine

Cs ₂ CO ₃ (336 mg; 1.03 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a] pyrimidine (intermediate 58 B) (85 mg; 0.34 mmol) and 3-(4-bromophenyl)-6-((4-ethylpiperazin-1-yl)methyl) pyridazine (intermediate 72) (124 mg ; 0.34 mmol) in 2-methyltetrahydrofuran (0.9 ml) and water (0.5 ml). The reaction mixture was degassed and RuPhos 3rd generation precatalyst (21.6 mg; 0.03 mmol) and RuPhos (12.0 mg; 0.03 mmol) were added. The reaction mixture was heated at reflux for 18 hours, left to cool to room temperature, diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (65 mg; 36%) as a pale yellow solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.08 (3H, t), 2.33 (1H, dtd), 2.42 (3H, q), 2.45-2.54 (4H, m), 2.57-2.64 (JH, m), 2.65 (3H, s), 3.52 (2H, dd), 3.57-3.65 (1H, m), 3.78 (1H, td), 3.89 (2H, s), 4.85 (1H, dt), 6.68 (2H, d), 7.60 (1H, d), 7.74 (1H, d), 8-8.08 (2H, m); m/z МН ⁺ 528.

Example 73: (R)-6-((1-(4-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl) hydroxy)-2,5,7-trimethyl-[1,2,4]-triazolo[1,5-а]pyrimidine

Cs ₂ CO ₃ (870 mg; 2.67 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a]pyrimidine (Intermediate 58B) (220 mg; 0.89 mmol) and 3-(4-bromophenyl)-6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyridazine (Intermediate 73 ) (348 mg; 0.89 mmol) in 2-methyltetrahydrofuran (2.4 ml) and water (1.1 ml). The reaction mixture was degassed and RuPhos 3rd generation precatalyst (55.8 mg; 0.07 mmol) and RuPhos (31.1 mg; 0.07 mmol) were added. The reaction mixture was heated at reflux for 18 hours, left to cool to room temperature, diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (211 mg; 43%) as a pale yellow foamy solid; ¹ H NMR (400 MHz, CDCl ₃ ) 2.33 (1H, dtd), 2.49 (1H, dd), 2.51-2.64 (16H, m), 2.65 (3H, s), 3.35 (3H, s), 3.46-3.56 (4Н, m), 3.57-3.64 (1H, m), 3.78 (1H, td), 3.89 (2Н, s), 4.84 (1H, dd), 6.68 (2Н, d), 7.59 (1H, d), 7.74 (1H, d), 8.00-8.07 (2H, m); m/zMH ⁺ 558.

Example 74: (R)-4-((6'-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy) pyrrolidin-1-yl)-[2,3'-bipyridin]-5-yl)methyl)morpholine

B (R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5- a] pyrimidine (intermediate 59) (190 mg; 0.47 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3 ,2-dioxaborolane) (144 mg; 0.57 mmol) and potassium acetate (92 mg; 0.94 mmol) in 1,4-dioxane (5 ml) PdCl ₂ (dppf)-CH adduct was added in a microwave tube ₂ Cl ₂ (19 mg; 0.02 mmol) and the reaction mixture was heated at 90°C overnight, then left to cool to room temperature. 4-((6-Bromopyridin-3-yl)methyl)morpholine (Intermediate 30) (121 mg; 0.47 mmol) was added followed by Cs ₂ CO ₃ (307 mg; 0.94 mmol), XPhos 2 precatalyst -th generation (74 mg; 0.05 mmol) and water (3 ml). The reaction mixture was heated at 90°C for 18 hours, then left to cool to room temperature and diluted with EtOAc (50 ml) and water (10 ml) and the layers were separated. The aqueous layer was further extracted with DCM (50 ml) and the combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by preparative HPLC to give the title compound (44 mg; 19%) as a pale brown foam; ¹ H NMR (400 MHz, CDCl ₃ ) 2.34 (1H, dtd), 2.42-2.56 (5H, m), 2.60 (3H, s), 2.61 (3H, s), 2.64 (3H, s), 3.53 (2H , s), 3.61 (1H, dd), 3.68-3.73 (4H, m), 3.74-3.92 (3H, m), 4.82 (1H, s), 6.51 (1H, d), 7.60 (1H, d), 7.70 (1H, dd), 8.21 (1H, dd), 8.55 (1H, d), 8.76 (1H, d); m/z МН ⁺ 501.

Example 75: (R)-4-((6'-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy) pyrrolidin-1-yl)-[3,3'-bipyridin]-6-yl)methyl)morpholine

Cs ₂ CO ₃ (242 mg; 0.74 mmol) was added to (6-(morpholinomethyl)pyridin-3-yl)boronic acid (83 mg; 0.37 mmol) and (R)-6-((1-( 5-Bromopyridin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 59) (150 mg; 0.37 mmol) in 1,4-dioxane (2.5 ml) and water (1.2 ml). The reaction mixture was degassed and the 2nd generation XPhos precatalyst (59 mg; 0.04 mmol) was added. The reaction mixture was stirred at 80° C. for 18 hours, left to cool to room temperature, diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was dissolved in DMSO (2 mL) and purified by preparative HPLC, then further purified by SPC eluting with 0-3% 1 M NH ₃ /MeOH in DCM to give the title compound (18 mg; 10%) in the form of a colorless resin; ¹ H NMR (400 MHz, CDCI3) 2.34 (1H, dtd), 2.48-2.53 (1H, m), 2.52-2.57 (4H, m), 2.60 (3H, s), 2.62 (3H, s), 2.65 ( 3H, s), 3.60 (1H, dd), 3.69 (2H, s), 3.76 (5H, h), 3.8-3.89 (2H, m), 4.83 (1H, dt), 6.48-6.54 (1H, m) , 7.46 (1H, d), 7.72 (1H, dd), 7.78 (1H, dd), 8.41 (1H, dd), 8.74 (1H, dd); m/z MH ⁺ 501.

Example 76: (R)-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)-phenyl)pyrimidin-5-yl)pyrrolidin- 3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine

1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine (131 mg; 0.42 mmol), (R)-6 -((1-(2-bromopyridin-5-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 61) (140 mg; 0.35 mmol) and Cs ₂ CO ₃ (226 mg; 0.69 mmol) were added to 1,4-dioxane (3.7 ml) and water (1.8 ml) and the mixture was degassed into within 10 minutes. 2nd generation XPhos precatalyst (13.62 mg; 0.02 mmol) was added and the reaction mixture was stirred for 2 hours at 85°C, left to cool to room temperature, and poured into water (25 ml) and extracted with EtOAc( 2x50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by preparative HPLC, then further purified by SPC eluting with 0-5% 1 M NH ₃ /MeOH in DCM to give the title compound (54 mg; 30%) as a white foam; ¹ H NMR (500 MHz, DMSO) 2.16 (3H, s), 2.24-2.46 (9H, m), 2.48 (3H, s), 2.52-2.54 (1H, m), 2.55 (3H, s), 2.60 ( 3H, s), 3.44-3.52 (3H, m), 3.57-3.64 (1H, m), 3.69 (2H, dd), 5.00 (1H, s), 7.37 (2H, d), 8.18-8.24 (2H, m), 8.31 (2H, s); m/z МН ⁺ 514.

Example 77: (R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)-phenyl)pyrazin-2-yl)pyrrolidin- 3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine

Palladium(II) acetate (3.2 mg; 0.01 mmol) was added to (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)oxy)-2.5, 7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 62) (115 mg; 0.28 mmol), 1-methyl-4-(4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine (117 mg; 0.37 mmol), potassium phosphate (151 mg; 0.71 mmol) and dicyclohexyl (2',4', 6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (13.6 mg; 0.03 mmol) in degassed water (1.6 ml) and THF (5 ml) at room temperature. The reaction mixture was heated at reflux for 1 hour, left to cool to room temperature, diluted with EtOAc (50 ml) and washed with water (50 ml). The organic layer was separated and dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was dissolved in DCM (1 ml) and purified by CPC eluting with 0-5% 1 M NH ₃ /MeOH in DCM to give the title compound (83 mg; 57%) as a yellow foam; ¹ H NMR (500 MHz, CDCl ₃ ) 2.29 (3H, s), 2.3-2.59 (10H, m), 2.60 (3H, s), 2.63 (3H, s), 2.66 (3H, s), 3.55 (2H , s), 3.63 (1H, dd), 3.78-3.93 (3H, m), 4.84 (1H, s), 7.41 (2H, d), 7.79-7.88 (2H, m), 8.02 (1H, d), 8.53 (1H, d); m/z МН ⁺ 514.

Example 78: (R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy )pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine

Palladium(II) acetate (6.9 mg; 0.03 mmol) was added to (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)oxy)-2.5, 7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 62) (250 mg; 0.62 mmol), 4-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)benzyl)morpholine (225 mg; 0.74 mmol), potassium phosphate (328 mg; 1.55 mmol) and dicyclohexyl (2',4',6'-triisopropyl -[1,1'-biphenyl]-2-yl)phosphine (29.5 mg; 0.06 mmol) in degassed water (3.33 ml) and THF (10 ml) at room temperature. The reaction mixture was heated at reflux for 1 hour, left to cool to room temperature, diluted with EtOAc (50 ml) and washed with water (50 ml). The organic layer was isolated and dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was dissolved in DCM (1 ml) and purified by CPC eluting with 0-5% 1 M NH ₃ /MeOH in DCM to give the title compound (58 mg; 19%) as a yellow foam; ¹ H NMR (500 MHz, CDCl ₃ ) 2.35 (1H, dtd), 2.44-2.5 (4H, m), 2.50-2.58 (1H, m), 2.60 (3H, s), 2.62 (3H, s), 2.66 (3H, s), 3.54 (2H, s), 3.63 (1H, dd), 3.70-3.75 (4H, m), 3.82 (1H, td), 3.85-3.93 (2H, m), 4.83 (1H, d ), 7.42 (2H, d), 7.81-7.88 (2H, m), 8.02 (1H, d), 8.53 (1H, d); m/z MH ⁺ 501.

Example 79: 1-[4-[[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6 -yl)methyl]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]methyl]-1,4-diazepan-1-yl]ethanone

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1- yl)pyrazin-2-yl)benzaldehyde (intermediate 49) (30 mg; 0.07 mmol), 1-(1,4-diazepan-1-yl)ethanone (19.9 mg; 0.14 mmol), DCM (2 ml) and AcOH (2 drops) and the reaction mixture was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (45 mg; 0.21 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was purified by preparative HPLC to give the title compound (18 mg; 47%); ¹ H NMR (400 MHz, DMSO) 1.71 (1H, s), 1.81 (1H, d), 1.87 (1H, dd), 2.00 (3H, d), 2.14 (1H, dd), 2.48 (3H, s) , 2.54-2.62 (4H, m), 2.65-2.69 (4H, m), 2.76 (3H, s), 2.95 (2H, d), 3.25 (1H, dd), 3.41-3.52 (5H, m), 3.61 -3.75 (4H, m), 7.37 (2H, dd), 7.89 (2H, dd), 8.04 (1H, d), 8.63 (1H, d); m/z MH ⁺ 554.

Example 80: (R)-2,5,7-trimethyl-6-((1-(5-(4-(pyrrolidin-1-ylmethyl)phenyl)-pyrazin-2-yl)pyrrolidin-3-yl)methyl )-[1,2,4]triazolo[1,5-a]pyrimidine

2nd generation XPhos pre-catalyst (19.56 mg; 0.02 mmol) was added to (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2, 5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (200 mg; 0.50 mmol), 1-(4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)benzyl)pyrrolidine (143 mg; 0.50 mmol) and Cs ₂ CO ₃ (324 mg; 0.99 mmol) in degassed 1,4-dioxane (4 ml) and water ( 2 ml) at room temperature. The reaction mixture was stirred at 90° C. for 16 hours, left to cool to room temperature and purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.08% NH ₄ HCO ₃ ) to give the title compound (63 mg; 26%) as a pale yellow solid; ¹ H NMR (400 MHz, MeOD) 1.85 (4H, p), 1.99 (1H, dq), 2.26 (1H, dq), 2.59 (7H, d), 2.75 (4H, s), 2.86 (3H, s) , 3.05 (2Н, dt), 3.33-3.42 (1H, m), 3.56 (1H, dt), 3.66-3.85 (4Н, m), 7.41-7.48 (2Н, m), 7.81-7.90 (2Н, m) , 8.01 (1H, d), 8.50 (1H, d); m/z МН ⁺ 483.

Example 81: (R)-2,5,7-trimethyl-6-((1-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin-3- yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Bis(triphenylphosphine)palladium(II) chloride (137 mg; 0.19 mmol) was added to 2-bromo-5-(pyrrolidin-1-ylmethyl)pyridine (intermediate 78) (470 mg; 1.95 mmol), 1 ,1,1,2,2,2-hexamethyldistannane (702 mg; 2.14 mmol) in THF (6 ml) at room temperature. The reaction mixture was stirred at 85°C for 16 hours. The reaction mixture was transferred to a microwave tube and (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2 ,4]triazolo[1,5-a]pyrimidine (300 mg; 0.75 mmol) and Pd(Ph ₃ P) ₄ (86 mg; 0.07 mmol). The reaction mixture was heated at 100°C for 5 hours in a microwave reactor, then left to cool to room temperature. The resulting mixture was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA), then further purified by preparative HPLC eluting with mixtures of water (containing 10 mmol NH ₄ HCO ₃ ) and MeCN with decreasing polarity to give the title compound (115 mg; 32%) as a pale yellow solid; ¹ H NMR (400 MHz, MeOD) 1.86 (4H, p), 2.00 (1H, dq), 2.26 (1H, dq), 2.60 (7H, d), 2.75 (4H, s), 2.86 (3H, s) , 3.07 (2Н, dd), 3.38 (1H, dd), 3.58 (1Н, dt), 3.71-3.88 (4Н, m), 7.87 (1H, dd), 8.04 (1H, d), 8.14 (1Н, d ), 8.51-8.57 (1H, m), 8.92 (1H, d); m/z МН ⁺ 484.

Example 82: (R)-2,5,7-trimethyl-6-((1-(5-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (85 mg; 0.12 mmol) was added to 5-bromo-2-(pyrrolidin-1-ylmethyl)pyridine (intermediate 80) (560 mg; 2.32 mmol) , 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (590 mg; 2.32 mmol) and potassium acetate (456 mg; 4.64 mmol) in 1,4-dioxane (10 ml) at room temperature. The reaction mixture was stirred at 90°C for 16 hours and left to cool to room temperature. The reaction mixture was purified by C18 flash chromatography eluting with 5-100% MeOH in water to give crude 2-(pyrrolidin-1-ylmethyl)-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyridine (280 mg; 42% pure) as a yellow solid. 2nd generation XPhos precatalyst (29.3 mg; 0.04 mmol) was added to (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2.5 ,7-trimethyl-[1,2,4]triazolo[1,5-a]-pyrimidine (300 mg; 0.75 mmol), crude 2-(pyrrolidin-1-ylmethyl)-5-(4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine from the first stage (258 mg; 0.89 mmol in the case of pure) and Cs ₂ CO ₃ (486 mg; 1.49 mmol) in 1 ,4-dioxane (4 ml) and water (2 ml) at room temperature. The reaction mixture was stirred at 90°C for 16 hours. The crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA) to give the title compound (54 mg; 15%) as a pale yellow solid; ¹ H NMR (400 MHz, MeOD) 1.87-2.07 (5H, m), 2.27 (1H, dq), 2.57 (3H, s), 2.67-2.89 (11H, m), 3.07 (2H, dd), 3.34- 3.42 (1H, m), 3.54-3.64 (1H, m), 3.69-3.88 (2H, m), 3.98 (2H, s), 7.58 (1H, d), 8.08 (1H, d), 8.33 (1H, dd), 8.54-8.61 (1H, m), 9.06 (1H, dd); m/z МН ⁺ 484.

Example 83: (R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methyl-1,4-diazepan-1-yl)methyl)phenyl)pyrazine- 2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

1-Methyl-1,4-diazepane (53 mg; 0.47 mmol) was added to (R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo [1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde (Intermediate 49) (200 mg; 0.47 mmol) in DCM (5 ml) at room temperature temperature in air atmosphere, and the reaction mixture was stirred for 1 hour. Sodium triacetoxyborohydride (496 mg; 2.34 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resulting crude product was purified by C18 flash chromatography eluting with 5-100% MeCN in water (plus 0.1% FA) to give the title compound formate (129 mg; 48%) as a white solid; ¹ H NMR (400 MHz, CDCl ₃ ) 1.88-2.02 (1H, m), 2.08 (2H, dt), 2.25 (1H, dq), 2.60-2.76 (10H, m), 2.79-3.06 (11H, m) , 3.14-3.22 (2H, m), 3.35 (1H, dd), 3.58 (1H, dt), 3.69-3.84 (4H, m), 7.38-7.45 (2H, m), 7.81-7.89 (2H, m) , 7.97 (1H, d), 8.52 (1H, d), 8.60 (1H, s); m/z МН ⁺ 526.

Example 84: (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy) pyrrolidin-1-yl) phenyl) pyridazin-3-yl) methyl) -1,4-oxazepan

Cs ₂ CO ₃ (553 mg; 1.70 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a]pyrimidine (Intermediate 58B) (140 mg; 0.57 mmol) and 4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)-1,4-oxazepan (Intermediate 74) ( 197 mg; 0.57 mmol) in 2-methyltetrahydrofuran (1.5 ml) and water (0.76 ml). The reaction mixture was degassed and RuPhos 3rd generation precatalyst (35.5 mg; 0.04 mmol) and RuPhos (19.8 mg; 0.04 mmol) were added. The reaction mixture was stirred at 88° C. for 18 hours, left to cool to room temperature, diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was dissolved in DMSO (2 ml) and purified by preparative HPLC to give the title compound (136 mg; 47%) as a pale yellow solid; ¹ H NMR (400 MHz, DMSO) 1.84 (2Н, р), 2.35 (1Н, tt), 2.43 (1Н, dd), 2.48 (3H, s), 2.54 (3H, s), 2.60 (3H, s) , 2.72 (4Н, q), 3.47 (1H, dd), 3.56 (2Н, dd), 3.60–3.69 (3H, m), 3.72 (2Н, t), 3.95 (2Н, s), 4.98 (1H, s ), 6.75 (2Н, d), 7.69 (1H, d), 8.02–8.11 (3H, m); m/z MN ⁺ 515.

Example 85: (R)-6-((1-(4-(6-(Azepan-1-ylmethyl)pyridazin-3-yl)phenyl)-pyrrolidin-3-yl)oxy)-2,5,7- trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

Cs ₂ CO ₃ (249 mg; 0.76 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5- a]pyrimidine (intermediate 58B) (63 mg; 0.25 mmol) and 1-((6-(4-bromophenyl)pyridazin-3-yl)methyl)azepane (intermediate 75) (88 mg; 0. 25 mmol) in 2-methyltetrahydrofuran (0.6 ml) and water (0.3 ml). The reaction mixture was degassed and RuPhos 3rd generation precatalyst (16 mg; 0.02 mmol) and RuPhos (9 mg; 0.02 mmol) were added. The reaction mixture was stirred at 88° C. for 18 hours, left to cool to room temperature, diluted with DCM (10 ml) and water (5 ml) and passed through a phase separation cartridge. The resulting DCM layer was concentrated in vacuo. The resulting crude product was dissolved in DMSO (2 ml) and purified by preparative HPLC. The resulting product was loaded onto an SCX column (5 g), washing with MeOH (2×column volume), then eluting with 1 M NH ₃ in MeOH (2×column volume), and concentrated in vacuo to give the title compound (35 mg; 27 %) as a white solid; ¹ H NMR (400 MHz, DMSO) 1.60 (8H, s), 2.3-2.37 (1H, m), 2.43 (1H, d), 2.48 (3H, s), 2.54 (3H, d), 2.61 (3H, s), 2.66 (4Н, d), 3.48 (1H, dd), 3.52-3.63 (2Н, m), 3.67 (1H, q), 3.92 (2Н, s), 4.99 (1H, s), 6.76 (2Н , d), 7.68 (1H, d), 8.01–8.11 (3H, m); m/z МН ⁺ 513.

Example 86 and 87: 4-[(1R)-1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5- a]pyrimidin-6-yl)oxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholine and 4-[(1S)-1-[4-[5-[(3R)-3- [(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy]-pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl] morpholine

Tetrakis(triphenylphosphine)palladium(0) (157 mg; 0.14 mmol) was added to a degassed solution of 4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)-phenyl)ethyl)morpholine (commercial sources) (432mg; 1.36mmol), (R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)oxy) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine (intermediate 62) (550 mg; 1.36 mmol) and sodium carbonate (2.0 ml; 4. 1 mmol) in 1,4-dioxane (7.7 ml) and water (3.9 ml) under nitrogen atmosphere. The resulting solution was stirred at 80°C for 2 hours, then left to cool to room temperature. The reaction mixture was diluted with EtOAc (50 ml) and washed successively with water (25 ml) and sat. brine (25 ml). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting crude product was purified by CPC eluting with a gradient of 0-5% MeOH in DCM to give the title compound as a mixture of two diastereomers (355 mg). The isomers were separated by chiral SFC (Phenomonex C1 column, 30×250 mm, 5 microns, at a flow rate of 80 ml/min using 40% IPA plus 0.1% DEA/60% supercritical CO ₂ at 120 bar (12 MPa) and column temperature 40°C) to give one diastereomer (unknown alpha chirality with respect to morpholine) 4-(1-(4-(5-((R)-3-((2,5,7-trimethyl-[1,2 ,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)pyrazin-2-yl)phenyl)ethyl)morpholine (62 mg; 18%); ^1H NMR (400 MHz, _CDCl3 ) 1.38 (3H, d), 2.28-2.47 (3H, m), 2.47-2.58 (3H, m), 2.60 (3H, s), 2.62 (3H, s), 2.66 (3H, s), 3.35 (1H, q), 3.59-3.75 (5H, m), 3.77-3.96 (3H, m), 4.84 (1H, s), 7.40 (2H, d), 7.84 (2H, d ), 8.01 (1H, d), 8.52 (1H, d); m/z MH ⁺ 515; and then the second diastereomer (unknown alpha chirality with respect to morpholine) 4-(1-(4-(5-((R)-3-((2,5,7-trimethyl-[1,2,4]triazolo[1 ,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)pyrazin-2-yl)phenyl)ethyl)morpholine (68 mg; 19%); ^1H NMR (400 MHz, _CDCl3 ) 1.38 (3H, d), 2.27-2.46 (3H, m), 2.46-2.58 (3H, m), 2.60 (3H, s), 2.62 (3H, s), 2.66 (3H, s), 3.35 (1H, q), 3.57-3.76 (5H, m), 3.77-3.96 (3H, m), 4.84 (1H, s), 7.40 (2H, d), 7.84 (2H, d ), 8.01 (1H, d), 8.52 (1H, d); m/z MN ⁺ 515.

Claims (125)

1. Compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ² are each independently hydrogen or methyl; X is CH ₂ or O; each ring A and ring B is independently a ring selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, where each ring A and ring B is independently optionally substituted with one or more substituents selected from C _1-3 alkyl and C _{1 -3} alkoxy; ring C is a 5-9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, where ring C is optionally substituted with one or more substituents selected from C _{1 -3} alkyl optionally substituted with methoxy or hydroxyl; dioxo, C _0-2 alkyl-C(O)N(Me) ₂ , C(O)C _1-2 alkyl and S(O) ₂ C _1-2 alkyl. 2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is CH ₂ . 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is O. 4. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of paragraphs. 1-3, where R ¹ and R ² are both hydrogen. 5. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of paragraphs. 1-4, wherein ring C is selected from morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, diazabicyclooctanyl, octahydropyrrolo[1,2-a]pyrazinyl, pyrrolidinyl, diazepanil, oxazepanil and azepanil. 6. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of paragraphs. 1-5, where each ring A and ring B is independently optionally substituted with one or more substituents selected from methyl and methoxy. 7. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of paragraphs. 1-6, where ring C is optionally substituted with one or more substituents selected from methyl, optionally substituted with hydroxyl; ethyl, optionally substituted with methoxy or hydroxyl; dioxo, C(O)N(Me) ₂ , CH ₂ C(O)N(Me) ₂ , C(O)Me and S(O) ₂ Me. 8. The compound of formula (I) according to any one of paragraphs. 1-7, where the compound of formula (I) is a compound of formula (Ia):

or its pharmaceutically acceptable salt, where X, R ¹ , R ² and ring C are as defined in any of paragraphs. 1-5 or 7, and where each D, E, G, J, L, M, Q, and R is independently N or CR ₃ , where no more than two of D, E, G, and J are N and where not more than two of L, M, Q and R are N, and R ₃ is hydrogen, C _1-3 alkyl or C _1-3 alkoxy. 9. The compound of formula (I) according to any one of paragraphs. 1-7, where the compound of formula (I) is a compound of formula (Ib):

or its pharmaceutically acceptable salt, where R ¹ , R ² , X, ring A, ring B and ring C are as defined in any of paragraphs. 1-7. 10. The compound of formula (I) according to claim 8, where the compound of formula (I) is a compound of formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , X, D, E, G, J, L, M, Q, R, ring A, ring B and ring C are as defined in clause 8. 11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of: ( R )-4-((6'-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1 -yl)-[3,3'-bipyridine]-6-yl)methyl)morpholine; ( R )-2,5,7-trimethyl-6-((1-(6'-((4-methylpiperazin-1-yl)methyl)-[3,3'-bipyridin]-6-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-2-yl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-(4-(2-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin- 1-yl)pyrimidin-5-yl)benzyl)morpholine; ( R )-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)pyridin-2-yl)pyrazin-2-yl)methyl)morpholine; ( R )-2,5,7-trimethyl-6-((1-(6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-3-yl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((6-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)pyridin-2-yl)pyridazin-3-yl)methyl)morpholine; 6-((( R )-1-(2-(4-((( S )-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)pyrimidin-2-yl)pyridin-2-yl)methyl)morpholine; ( R )-6-((1-(2-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2 ,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(2-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; 6-((( R )-1-(2-(4-(((3 R ,5 S )-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3- yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine -6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)acetamide; ( R )-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl )pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethanol; ( R )-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl )pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethenone; ( R )-6-((1-(2-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)- 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin- 1-yl)pyrimidin-2-yl)benzyl)morpholine; ( R )-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrazin-2-yl)phenyl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(4-(2-((4-methylpiperazin-1-yl)methyl)pyrimidin-5-yl)phenyl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyridin-3-yl)methyl)morpholine; ( R )-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)phenyl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyrazin-2-yl)methyl)morpholine; ( R )-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)phenyl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine; ( R )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine; ( S )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine; ( R )-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl )-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; 2,5,7-trimethyl-6-((( R )-1-(5-(4-(((3 R ,5 S )-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl) pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; 6-((( R )-1-(5-(4-((( R )-3,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; 6-((( R )-1-(5-(4-((( R )-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; 2,5,7-trimethyl-6-((( R )-1-(5-(4-(((2 R ,5 R )-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl) pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; 2,5,7-trimethyl-6-((( R )-1-(5-(4-(((2 S ,5 R )-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl) pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; 2,5,7-trimethyl-6-[[(3 R )-1-[5-[4-(1-piperidylmethyl)phenyl]pyrazin-2-yl]pyrrolidin-3-yl]methyl]-[1, 2,4]triazolo[1,5-a]pyrimidine; ( R )-6-((1-(5-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7 -trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(5-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; 6-((( R )-1-(5-(4-(((3 R ,5 S )-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3- yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; 2-{4-[4-(5-{(3 R )-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl ]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazin-1-yl}ethanol; ( R )-6-((1-(5-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)- 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2 ,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; {1-[4-(5-{(3 R )-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidine -1-yl}pyrazin-2-yl)benzyl]piperidin-4-yl}methanol; 6-{[(3 R )-1-(5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}pyrazin-2-yl)pyrrolidin-3-yl]methyl}-2, 5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidine; 2,5,7-trimethyl-6-({(3 R )-1-[5-(4-{[4-(methylsulfonyl)piperidin-1-yl]methyl}phenyl)pyrazin-2-yl]pyrrolidin- 3-yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((6-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl )methyl)pyrrolidin-1-yl)pyrazin-2-yl)pyridin-3-yl)methyl)morpholine; 6-((( R )-1-(5-(4-((( S )-3,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)pyrazin-2-yl)pyridin-2-yl)methyl)morpholine; 6-((( R )-1-(5-(4-((( S )-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl) -2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-(4-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine; 2,5,7-trimethyl-6-({(3 R )-1-[5-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)pyrazin-2-yl]pyrrolidin- 3-yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine -6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)acetamide; ( R )-2,5,7-trimethyl-6-((1-(6-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; N,N-dimethyl-4-[4-(5-{(3 R )-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidine-6- yl)methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazin-1-carboxamide; ( R )-2,5,7-trimethyl-6-((1-(5-(3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(5-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin- 3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl )pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)ethenone; ( R )-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin- 1-yl)pyrazin-2-yl)benzyl)morpholine; ( R )-4-(4-(6-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin- 1-yl)pyridazin-3-yl)benzyl)morpholine; ( R )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine; ( S )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine; ( R )-2,5,7-trimethyl-6-((1-(4-(6-(piperidin-1-ylmethyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1 ,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl) hydroxy)-[1,2,4]triazolo[1,5-a]pyrimidine; 2,5,7-trimethyl-6-(((3 R )-1-(4-(6-((3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)pyridazine -3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine; 6-((( R )-1-(4-(6-((( R )-hexahydropyrrolo[1,2-a]pyrazin-2(1 H )-yl)methyl)pyridazin-3-yl)phenyl) pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; 6-((( R )-1-(4-(6-((( S )-hexahydropyrrolo[1,2-a]pyrazin-2(1 H )-yl)methyl)pyridazin-3-yl)phenyl) pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine; ( R )-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyrazin-2-yl)methyl)morpholine; ( R )-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one; ( R )-6-((1-(4-(6-((4-ethylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7 -trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-6-((1-(4-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)- 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((6'-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1 -yl)-[2,3'-bipyridine]-5-yl)methyl)morpholine; ( R )-4-((6'-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1 -yl)-[3,3'-bipyridine]-6-yl)methyl)morpholine; ( R )-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl) hydroxy)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl) hydroxy)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin- 1-yl)pyrazin-2-yl)benzyl)morpholine; 1-[4-[[4-[5-[(3 R )-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl )methyl]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]methyl]-1,4-diazepan-1-yl]ethenone; ( R )-2,5,7-trimethyl-6-((1-(5-(4-(pyrrolidin-1-ylmethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1 ,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl )-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(5-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl )-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-2,5,7-trimethyl-6-((1-(5-(4-((4-methyl-1,4-diazepan-1-yl)methyl)phenyl)pyrazin-2-yl) pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)-1,4-oxazepane; ( R )-6-((1-(4-(6-(azepan-1-ylmethyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1 ,2,4]triazolo[1,5-a]pyrimidine; 4-[(1R)-1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6 -yl)oxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholine; And 4-[(1S)-1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-6 -yl)oxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholine. 12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from: ( R )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine; ( R )-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl) hydroxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one; ( R )-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl) methyl)-[1,2,4]triazolo[1,5-a]pyrimidine; ( R )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine; And ( S )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine -1-yl)phenyl)pyridazin-3-yl)methyl)morpholine. 13. The compound of formula (I) according to any one of paragraphs. 1-12 where the compound is ( R )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine -6-yl)oxy)-pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine or a pharmaceutically acceptable salt thereof. 14. The compound of formula (I) according to any one of paragraphs. 1-12 where the compound is ( S )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine -6-yl)oxy)-pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine or a pharmaceutically acceptable salt thereof. 15. The compound of formula (I) according to any one of paragraphs. 1-12 where the compound is ( R )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine -6-yl)oxy)-pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine. 16. The compound of formula (I) according to any one of paragraphs. 1-12 where the compound is ( S )-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine -6-yl)oxy)-pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine. 17. The compound of formula (I) according to claim 15, wherein the compound is in crystalline form with an x-ray powder diffraction (XRD) pattern substantially as shown in FIG. 1, installed using CuKα radiation. 18. A pharmaceutical composition that selectively inhibits MCT4 (monocarboxylate transporter 4), which contains an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-17 and at least one pharmaceutically acceptable excipient. 19. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of paragraphs. 1-17 for use as an MCT4 inhibitor. 20. The compound of formula (I) or its pharmaceutically acceptable salt according to any one of paragraphs. 1-17 for use in the treatment of MCT4 mediated cancer. 21. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-17 to obtain a drug for the treatment of cancer mediated by MCT4. 22. A method of treating MCT4-mediated cancer in a warm-blooded animal in need of such treatment, comprising administering to said warm-blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-17. 23. Connection for use, application or method according to any one of paragraphs. 20-22, where the cancer is a non-small cell lung cancer, such as lung adenocarcinoma.

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