Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the specification generally relates to triazolopyrimidine compounds and pharmaceutically acceptable salts thereof. These compounds and their pharmaceutically acceptable salts selectively inhibit MCT4, and the specification therefore also relates to the use of such compounds and salts thereof to treat or prevent MCT4 mediated disease, including cancer.
• the specification further relates to crystalline forms of triazolopyrimidine compounds and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds and salts; kits comprising such compounds and salts; methods of manufacture of such compounds and salts; and to methods of treating MCT4 mediated disease, including cancer, using such compounds and salts.
• Monocarboxylate transporters are encoded by the SLC16 gene family.
• the family is also known as the monocarboxylate transporter (MCT) family since the first members to be identified were demonstrated to be responsible for the proton-linked transport of monocarboxylates such as L- lactate, pyruvate and ketone bodies across the plasma membrane.
• MCT1 SLC16A1
• MCT2 monocarboxylate transporter
• CD 147 also known as basigin and EMMPRIN
• CD 147 acts as an essential chaperone to take MCT1 and MCT4 to the plasma membrane where the transporter and CD 147 remain tightly associated (Kirk et al. (2000) EMBO J.
• tumours display altered metabolism (Vander Heiden (2011) Nat. Drug Dis. 10:671-684). Tumours are composed of well oxygenated (aerobic) and poorly oxygenated (hypoxic) regions. Compared to normal cells, tumour cells have an increased dependency on the glycolytic pathway for ATP generation either via aerobic glycolysis (the Warburg effect) or anaerobic glycolysis as a consequence of tumour hypoxia. Highly proliferating tumours and hypoxic tumours appear to be particularly dependent upon glycolysis to meet their energy and biosynthetic requirements.
• FDG-PET Fluorodeoxyglucose Positron Emission Tomography
• F-18 fluorodeoxyglucose_(FDG) tracer fluorine- 18 fluorodeoxyglucose_(FDG)
• FDG-PET can be used for diagnosis, staging, and monitoring treatment of cancers.
• FDG-PET combined with computer tomography has a >90% sensitivity and specificity for the detection of metastases of most epithelial tumours (Mankoff et al. (2007) Clin. Cancer Res.
• a by-product of the increased glycolytic rates in tumours is the accumulation of lactate.
• Intracellular lactate can be transported out of tumour cells via the monocarboxylate transporters (MCTs 1, 2, 3 & 4) (Halestrap and Price, Biochem J. (1999) 343; 291-299).
• Lactate that is produced by tumour cells can be taken up by stromal and oxygenated tumour cells (via the monocarboxylate transporters MCT1 and MCT2) to regenerate pyruvate that can be used to fuel oxidative
• hypoxia-inducible factor a transcription factor that is activated by hypoxic stress.
• MCT4 is a HIF target gene and is up-regulated by hypoxia and is required to export lactate from glycolytic tumours (Ullah et al. (2006) J. Biol. Chem. 281 :9030-9037).
• MCT4 The kinetic properties of MCT4 are tuned to its role in exporting lactic acid derived from glycolysis because its very high Km for pyruvate (150 mM) ensures that pyruvate is not exported from the cell. This is essential because NADH derived from reduction of pyruvate to lactate is required to drive glycolytic flux (Halestrap and Wilson (2012) IUMBM Life 64: 109-119).
• MCT4 is over-expressed in a range of solid tumours compared to normal epithelium including renal tumours (Fisel et al. (2013) Clin. Cancer Res. 19: 5170-5181; Gerlinger et al. J. Pathol. 227: 146-156), pancreatic tumours (Baek et al. (2014) Cell Rep. 9:2233-2249), colorectal tumours (Pinheiro et al., Virchows Arch. (2008) 452; 139-146), HNSCC (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) 11 :312) and liver cancer (Gao et al. (2015) J Cancer Res. 141 : 1151-1162).
• lactate plays an important role in regulating immune cell function. Lactate has been shown to inhibit the activity of immune effector cells such as T cells and NK cells. Lactic acid suppresses the proliferation and activation of human T cells ex vivo (Fisher et al. (2007) Blood 109:3812-3819; Haas et al. (2015) PLoS Biol 13). Husain et al. have demonstrated that NK cells from LDHA-depleted tumours showed improved cytolytic function and lactate treatment ofNK cells reduced their cytotoxic activity (Husain et al. (2013) J. Immunol. 191 :1486- 1495). Furthermore, Brand et al.
• tumour associated macrophage polarisation (immunosuppressive) tumour associated macrophage polarisation (Colegio et al. (2014) Nature 513:559-563).
• Lactate accumulation in the tumour microenvironment is accompanied by acidosis (due to the co-transport with protons).
• a low pH in the tumour microenvironment has been associated with extracellular matrix degradation and migration of tumour cells (Gillies and Gatenby (2015) Cancer J. 21 : 88-96).
• R 1 and R 2 each independently represent hydrogen or methyl
• X represents C3 ⁇ 4 or O
• Ring A and Ring B each independently represent a ring selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein each of Ring A and Ring B are independently optionally substituted with one or more substituents selected from C1-3 alkyl and C1-3 alkoxy;
• Ring C represents a 5 to 9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, wherein Ring C is optionally substituted with one or more substituents selected from C1-3 alkyl, optionally substituted with methoxy or hydroxyl; dioxo, C0-2 alkyl-C(0)N(Me) 2 , C(0)Ci- 2 alkyl and S(0) 2 Ci- 2 alkyl.
• composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one
• This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
• This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
• This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer.
• This specification also describes, in part, a method for treating cancer in a warm-blooded animal in need of such treatment, which comprises administering to the warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• Figure 1 shows the X-ray powder diffraction (XRPD) pattern for Form A of (R)-4-((6-(4-(3- ((2,5,7-trimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-6-yl)oxy)pyrrolidin-l-yl)phenyl)pyridazin-3- yl)methyl)morpholine (Compound A, Example 62).
• XRPD X-ray powder diffraction
• Figure 2 shows the DSC for Form A of (R)-4-((6-(4-(3-((2,5,7-trimethyl-[l,2,4]triazolo[l,5- a]pyrimidin-6-yl)oxy)pyrrolidin- 1 -yl)phenyl)pyridazin-3-yl)methyl)morpholine (Compound A, Example 62).
• Figure 3 shows the in vivo activity of an MCT4 inhibitor (Example 62) in combination with VEGFR TKI (AZD2171, also known as cediranib) in a lung cancer xenograft model.
• Figure 4 shows the in vivo activity of an MCT4 inhibitor (Example 62) in combination with an a-CTLA4 antibody in a mouse syngeneic model.
• Figure 5 shows the in vivo activity of MCT4 inhibitor (Example 62) in combination with an aPD- 1 antibody in a mouse syngeneic model.
• R 1 and R 2 each independently represent hydrogen or methyl;
• X represents CH 2 or O;
• Ring A and Ring B each independently represent a ring selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein each of Ring A and Ring B are independently optionally substituted with one or more substituents selected from C1-3 alkyl and C1-3 alkoxy;
• Ring C represents a 5 to 9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C 1-3 alkyl, optionally substituted with methoxy or hydroxyl; dioxo, C0-2 alkyl-C(0)N(Me) 2 , C(0)Ci- 2 alkyl and S(0)2Ci-2 alkyl.
• heterocycloalkyl means a 5 to 9 membered saturated nitrogen-containing non aromatic ring (Ring C in Formula (I)) comprising one or more additional heteroatoms independently selected from nitrogen, oxygen and sulphur.
• suitable heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, diazabicyclooctanyl, octahydropyrrolo[l,2- a]pyrazinyl, pyrrolidinyl, diazepanyl, oxazepanyl and azepanyl.
• substituents on the heterocycloalkyl ring may be linked via either a carbon atom or a heteroatom.
• dioxo means two oxo substituents which are attached to the same atom.
• dioxo substitution examples include instances where Ring C represents thiomorpholinyl, where the sulphur atom is substituted with two oxo groups, i.e. where Ring C is thiomorpholine- 1,1 -dioxide.
• Ci_3 alkyl includes Ci alkyl (methyl), CF alkyl (ethyl) and C 3 alkyl (propyl as «-propyl and isopropyl).
• the C 1-3 alkyl is methyl.
• C p-q alkoxy comprises -0-C p-q alkyl groups.
• C 1-3 alkoxy includes Ci alkoxy (methoxy), C 2 alkoxy (ethoxy) and C 3 alkoxy (propoxy as n-propoxy and isopropoxy).
• the C 1-3 alkoxy is methoxy.
• a group“optionally substituted by one methoxy group” includes groups with and without a methoxy substituent.
• substituted means that one or more hydrogens (for example one or two hydrogens, or alternatively one hydrogen) on the designated group is replaced by the indicated substituent(s) (for example one or two substituents, or alternatively one substituent), provided that any atom(s) bearing a substituent maintains a permitted valency.
• Substituent combinations encompass only stable compounds and stable synthetic intermediates.“Stable” means that the relevant compound or intermediate is sufficiently robust to be isolated and have utility either as a synthetic intermediate or as an agent having potential therapeutic utility. If a group is not described as“substituted”, or “optionally substituted”, it is to be regarded as unsubstituted (i.e. that none of the hydrogens on the designated group have been replaced).
• pharmaceutically acceptable is used to specify that an object (for example a salt, dosage form, excipient) is suitable for use in patients.
• object for example a salt, dosage form, excipient
• pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H.
• a further embodiment provides any of the embodiments defined herein (for example the embodiment of claim 1) with the proviso that one or more specific Examples (for instance, one, two or three specific Examples) selected from the group consisting of Examples 1, 4, 5, 6, 7, 8, 9, 10, 11,
• X represents CFb. In another embodiment, X represents O.
• R 1 and R 2 both represent hydrogen. In another embodiment, R 1 and R 2 both represent methyl. In another embodiment, R 1 represents hydrogen and R 2 represents methyl. In one embodiment, R 1 and R 2 both represent hydrogen or R 1 represents hydrogen and R 2 represents methyl.
• Ring A is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.
• Ring B is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.
• Ring A is attached to the nitrogen of a pyrrolidine ring and to Ring B, and Ring B is attached to Ring A and to the group -C(R 1 R 2 )-Ring C.
• Ring A and Ring B may be optionally further substituted as defined herein.
• the pyrrolidine ring and Ring B are in para (i.e. 1,4) orientation on Ring A.
• Ring A and the group -C(R 1 R 2 )- Ring C are in para (i.e. 1,4) orientation on Ring B.
• the pyrrolidine ring and Ring B are in para (i.e. 1,4) orientation on Ring A and Ring A and the group -C(R 1 R 2 )-Ring C are in para (i.e.
• Ring B orientation on Ring B.
• the pyrrolidine ring and Ring B are in para (i.e. 1,4) orientation on Ring A and Ring A and the group -C(R 1 R 2 )-Ring C are in para (i.e. 1,4) orientation on Ring B and Ring A and Ring B are linked to each other via a ring carbon and are linked to the remainder of the molecule via a ring carbon.
• At least one of Ring A or Ring B is selected from pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.
• 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.
• Ring A and Ring B are optionally substituted with one or two substituents selected from Ci alkyl and Ci alkoxy. In one embodiment, Ring A and Ring B are each independently optionally substituted by one substituent selected from C 1-3 alkyl and C 1-3 alkoxy. In one embodiment, Ring A and Ring B are each independently optionally substituted by one substituent selected from methyl and methoxy.
• Ring C represents a 5 to 7 membered monocyclic saturated
• Ring C represents an 8 or 9 membered bicyclic saturated heterocycloalkyl ring.
• the bicyclic heterocycloalkyl ring may be a bridged or fused bicyclic ring.
• Ring C is selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, diazabicyclooctanyl, octahydropyrrolo[l,2-a]pyrazinyl, pyrrolidinyl, diazepanyl, oxazepanyl and azepanyl.
• Ring C is selected from the group consisting of morpholin-4-yl, piperazin-4-yl, piperidin- 1 -yl, thiomorpholine-4-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl,
• octahydropyrrolo[l,2-a]pyrazin-2-yl pyrrolidine- 1 -yl, 1 ,4-diazepan- 1 -yl, 1 ,4-oxazepan-4-yl, azepanyl- 1 -yl.
• Ring C is morpholinyl or piperazinyl. In one embodiment, Ring C is morpholin-4-yl or piperazin-4-yl.
• Ring C is morpholinyl. In one embodiment, Ring C is morpholin-4-yl.
• Ring C is piperazinyl. In one embodiment, Ring C is piperazin-4-yl.
• Ring C is optionally substituted with one or more (e.g. one, two or three) substituents independently selected from hydroxyl; ethyl optionally substituted with methoxy or hydroxyl; dioxo, C(0)N(Me) 2 , CH 2 C(0)N(Me) 2 , C(0)Me and S(0) 2 Me. In one embodiment, Ring C is substituted with C(0)Me or methyl.
• Ring C is piperazin-4-yl-ethanone. In another embodiment, Ring C is 4- methyl- 1 -piperazinyl.
• R 1 and R 2 are both hydrogen
• X represents Cffr or O
• Ring A and Ring B each independently represent a ring selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein each of Ring A and Ring B are independently optionally substituted with one or more substituents selected from C1-3 alkyl and C1-3 alkoxy;
• Ring C represents a 5 to 9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C 1-3 alkyl, optionally substituted with methoxy or hydroxyl; dioxo, C0-2 alkyl-C(0)N(Me) 2 , C(0)Ci- 2 alkyl and S(0)2Ci_2 alkyl.
• R 1 and R 2 are both hydrogen
• Ring A and Ring B are each independently selected from phenyl and pyridazinyl;
• Ring C represents morpholinyl or piperazinyl wherein the piperazinyl is optionally substituted with Ci-3 alkyl, optionally substituted with methoxy or hydroxyl; C0-2 alkyl- C(0)N(Me) 2 , C(0)Ci_ 2 alkyl and S(0)2Ci-2 alkyl.
• R 1 and R 2 are both hydrogen
• X represents CH2
• Ring A and Ring B are each independently selected from phenyl, pyridazinyl and pyrazinyl;
• Ring C represents morpholinyl, piperazinyl or pyrazinyl wherein the pyrazinyl or piperazinyl is optionally substituted with C 1-3 alkyl, optionally substituted with methoxy or hydroxyl; C0-2 alkyl- C(0)N(Me) 2 , C(0)Ci- 2 alkyl and S(0) 2 Ci- 2 alkyl.
• a further embodiment provides a compound of Formula (la):
• R 1 and R 2 each independently represent hydrogen or methyl
• X represents CFb or O
• D, E, G, J, L, M, Q and R each independently represent N or CR 3 , wherein no more than two of D, E, G and J represent N and wherein no more than two of L, M, Q and R represent N;
• R 3 represents hydrogen, C 1-3 alkyl or C 1-3 alkoxy
• Ring C represents a 5 to 9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, wherein 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(0)N(Me) 2 , C(0)Ci_ 2 alkyl and S(0)2Ci_2 alkyl.
• R 1 and R 2 both represent hydrogen. In another embodiment, R 1 and R 2 both represent methyl. In another embodiment, R 1 represents hydrogen and R 2 represents methyl. In one embodiment, R 1 and R 2 both represent hydrogen or R 1 represents hydrogen and R 2 represents methyl.
• D, E, G and J each independently represent N or CR 3 , wherein no more than two of D, E, G and J represent N.
• L, M, Q and R each independently represent N or CR 3 , wherein no more than two of L, M, Q and R represent N.
• D, E, G and J each independently represent CR 3 .
• one of D, E, G and J represents N and the remainder each independently represent CR 3 .
• two of D, E, G and J represent N and the remainder both independently represent CR 3 .
• L, M, Q and R each independently represent CR 3 .
• one of L, M, Q and R represents N and the remainder each independently represent CR 3 .
• two of L, M, Q and R represent N and the remainder both independently represent CR 3 .
• D, E, G and J each independently represent CR 3 and L, M, Q and R each independently represent N or CR 3 , wherein no more than two of L, M, Q and R represent N.
• one of D, E, G and J represents N and the remainder each independently represent CR 3 and L, M, Q and R each independently represent N or CR 3 , wherein no more than two of L, M, Q and R represent N.
• two of D, E, G and J represent N and the remainder both independently represent CR 3 and L, M, Q and R each independently represent N or CR 3 , wherein no more than two of L, M, Q and R represent N.
• D, E, G and J represent N or CR 3 , wherein no more than two of D, E, G and J represent N and L, M, Q and R each independently represent CR 3 .
• D, E, G and J represent N or CR 3 , wherein no more than two of D, E, G and J represent N and one of L, M, Q and R represents N and the remainder each independently represent CR 3 .
• D, E, G and J represent N or CR 3 , wherein no more than two of D, E, G and J represent N and two of L, M, Q and R represent N and the remainder both independently represent CR 3 .
• D, E, G and J each independently represent CR 3 and L
• M, Q and R each independently represent CR 3 .
• D, E, G and J each independently represent CR 3 and one of L, M, Q and R represents N and the remainder each independently represent CR 3 .
• D, E, G and J each independently represent CR 3 and two of L, M, Q and R represent N and the remainder both independently represent CR 3 .
• one of D, E, G and J represents N and the remainder each independently represent CR 3 and L, M, Q and R each independently represent CR 3 .
• one of D, E, G and J represents N and the remainder each independently represent CR 3 and one of L, M, Q and R represents N and the remainder each independently represent CR 3 .
• one of D, E, G and J represents N and the remainder each independently represent CR 3 and two of L, M, Q and R represent N and the remainder both independently represent CR 3 .
• two of D, E, G and J represent N and the remainder both independently represent CR 3 and L, M, Q and R each independently represent CR 3 .
• two of D, E, G and J represent N and the remainder both independently represent CR 3 and one of L, M, Q and R represents N and the remainder each independently represent CR 3 .
• two of D, E, G and J represent N and the remainder both independently represent CR 3 and two of L, M, Q and R represent N and the remainder both independently represent CR 3 .
• 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.
• 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.
• 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.
• the ring containing D, E, G and J and the ring containing L, M, Q and R are each independently optionally substituted with one or two substituents, i.e. where R 3 represents Ci alkyl and Ci alkoxy.
• the ring containing D, E, G and J and the ring containing L, M, Q and R are each independently optionally substituted with one substituent, i.e. where R 3 represents C1-3 alkyl and C1-3 alkoxy.
• the ring containing D, E, G and J and the ring containing L, M, Q and R are each independently optionally substituted with one substituent where R 3 is selected from methyl and methoxy.
• Ring C represents a 5 to 7 membered monocyclic saturated
• Ring C represents an 8 or 9 membered bicyclic saturated heterocycloalkyl ring.
• the bicyclic heterocycloalkyl ring may be a bridged or fused bicyclic ring.
• Ring C is selected from the group consisting of morpholinyl, piperazinyl, piperidinyl, thiomorpholinyl, diazabicyclooctanyl, octahydropyrrolo[l,2-a]pyrazinyl, pyrrolidinyl, diazepanyl, oxazepanyl and azepanyl.
• Ring C is selected from the group consisting of morpholin-4-yl, piperazin-4-yl, piperidin- 1 -yl, thiomorpholine-4-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl,
• octahydropyrrolo[l,2-a]pyrazin-2-yl pyrrolidine- 1 -yl, 1 ,4-diazepan- 1 -yl, 1 ,4-oxazepan-4-yl, azepanyl- 1 -yl.
• 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.
• Ring C is piperazinyl. In one embodiment, Ring C is piperazin-4-yl.
• Ring C is optionally substituted with one or more (e.g. one, two or three) substituents independently selected from hydroxyl; ethyl optionally substituted with methoxy or hydroxyl; dioxo, C(0)N(Me) 2 , CH 2 C(0)N(Me) 2 , C(0)Me and S(0) 2 Me. In one embodiment, Ring C is substituted with C(0)Me or methyl.
• Ring C is piperazin-4-yl-ethanone. In another embodiment, Ring C is 4- methyl- 1 -piperazinyl.
• R 1 and R 2 are both hydrogen
• X represents CEE or O
• D, E, G, J, L, M, Q and R each independently represent N or CR 3 , wherein no more than two of D, E, G and J represent N and wherein no more than two of L, M, Q and R represent N;
• R 3 represents hydrogen, C 1-3 alkyl or C 1-3 alkoxy
• Ring C represents a 5 to 9 membered monocyclic or bicyclic saturated heterocycloalkyl optionally containing one or more additional heteroatoms independently selected from O, N and S, wherein the heterocycloalkyl is optionally substituted with one or more substituents selected from C1-3 alkyl, optionally substituted with methoxy or hydroxyl; dioxo, C0-2 alkyl-C(0)N(Me) 2 , C(0)Ci_ 2 alkyl and S(0)2Ci_2 alkyl.
• R 1 and R 2 are both hydrogen
• X represents O
• D, E, G, J, L, M, Q and R each independently represent N or CR 3 , wherein no more than two of D, E, G and J represent N and wherein no more than two of L, M, Q and R represent N;
• R 3 represents hydrogen, methyl or methoxy
• Ring C represents morpholinyl or piperazinyl wherein the piperazinyl is optionally substituted with Ci-3 alkyl, optionally substituted with methoxy or hydroxyl; C0-2 alkyl- C(0)N(Me) 2 , C(0)Ci- 2 alkyl and S(0)2Ci-2 alkyl.
• R 1 and R 2 are both hydrogen
• X represents CEE
• D, E, G, J, L, M, Q and R each independently represent N or CR 3 , wherein no more than two of D, E, G and J represent N and wherein no more than two of L, M, Q and R represent N;
• R 3 is selected from hydrogen, methyl or methoxy
• Ring C represents morpholinyl, piperazinyl or pyrazinyl wherein the pyrazinyl or piperazinyl is optionally substituted with C1-3 alkyl, optionally substituted with methoxy or hydroxyl; C0-2 alkyl- C(0)N(Me) 2 , C(0)Ci_ 2 alkyl and S(0) 2 Ci_ 2 alkyl.
• a further embodiment provides a compound of Formula (lb):
• R 1 , R 2 , X, Ring A, Ring B and Ring C are as defined herein.
• a further embodiment provides a compound of Formula (Ic):
• R 1 , R 2 , X, D, E, G, J, L, M, Q, R and Ring C are as defined herein.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein the compound is (R)-4-((6-(4-(3-((2,5,7-trimethyl-[l,2,4]triazolo[l,5- a]pyrimidin-6-yl)oxy)pyrrolidin-l-yl)phenyl)pyridazin-3-yl)methyl)morpholine (also referred to as Compound A).
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein the compound is (R)- 1 -(4-((6-(4-(3-((2,5,7-trimcthyl- [ 1 ,2,4]triazolo [ 1 ,5-a]pyrimidin-6-yl)oxy)pyrrolidin- 1 -yl)phenyl)pyridazin-3 -yl)methyl)piperazin- 1 - yl)ethan-l-one.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein the compound is (R)-2,5,7-trimethyl-6-((l-(5-(4-((4-methylpiperazin- l-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrimidine.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein the compound is (R)-4-((6-(4-(3-((2,5,7-trimethyl-[l,2,4]triazolo[l,5- a]pyrimidin-6-yl)methyl)pyrrolidin- 1 -yl)phenyl)pyridazin-3 -yl)methyl)morpholine.
• the compound of Formula (I) is in the free base form.
• solvated forms may be a hydrated form, such as a hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or an alternative quantity thereof.
• the invention encompasses all such solvated and unsolvated forms of compounds of Formula (I), particularly to the extent that such forms possess MCT4 inhibitory activity, as for example measured using the tests described herein.
• Atoms of the compounds and salts described in this specification may exist as their isotopes.
• the invention encompasses all compounds of Formula (I) where an atom is replaced by one or more of its isotopes (for example a compound of Formula (I) where one or more carbon atom is an U C or 13 C carbon isotope, or where one or more hydrogen atoms is a 2 H or 3 H isotope, or where one or more nitrogen atoms is a 15 N isotope or where one of more oxygen atoms is an 17 0 or 18 0 isotope).
• optically active or racemic forms may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms.
• the invention includes any optically active or racemic form of a compound of Formula (I) which possesses MCT4 inhibitory activity, as for example measured using the tests described herein.
• the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis using optically active materials or by resolution of a racemic form.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof which is a single optical isomer being in an enantiomeric excess (% e.e.) of > 95%, > 98% or > 99%.
• the single optical isomer is present in an enantiomeric excess (% e.e.) of > 99%.
• Some of the compounds of Formula (I) may be crystalline and may have more than one crystalline form. It is to be understood that the invention encompasses any crystalline or amorphous form, or mixtures thereof, which possess properties useful in MCT4 inhibitory activity. It is well known how to determine the efficacy of a crystalline or amorphous form by the standard tests described hereinafter.
• crystalline materials may be analysed using conventional techniques such as, for example, X-ray powder diffraction (hereinafter XRPD) analysis and
• DSC Differential Scanning Calorimetry
• Example 62 exhibits crystallinity and a crystalline form, Form A, has been identified.
• crystalline form, Form A, of Compound A which has an XRPD pattern substantially the same as the XRPD pattern shown in Figure 1, measured by CuKa radiation.
• DSC analysis shows Compound A, Form A is a high melting solid with an onset of melting at about 2l0.2°C and a peak at about 213.2°C.
• the degree of crystallinity is conveniently greater than about 60%, more conveniently 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%.
• an XRPD pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment or machine used).
• intensities in an XRPD pattern may fluctuate depending on measurement conditions. Therefore it should be understood that Compound A, Form A of the present disclosure is not limited to the crystals that provide XRPD patterns identical to the XRPD pattern shown in Figure 1 , and any crystals providing XRPD patterns substantially the same as that shown in Figure 1 fall within the scope of the present disclosure.
• a person skilled in the art of XRPD is able to judge the substantial identity of XRPD patterns.
• a measurement error of a diffraction angle in an X-ray powder diffractogram is approximately plus or minus 0.2° 2-theta, and such degree of a measurement error should be taken into account when considering the XRPD pattern in Figure 1 and when reading Table A.
• the compounds of Formula (I) include one or more chiral centres.
• a structure or chemical name in this specification does not indicate chirality, the structure or name is intended to encompass any single stereoisomer (i.e. any single chiral isomer) corresponding to that structure or name, as well as any mixture of stereoisomers (e.g. a racemate).
• any single stereoisomer i.e. any single chiral isomer
• a racemate any mixture of stereoisomers
• a single stereoisomer can be obtained by isolating it from a mixtures of isomers (e.g. a racemate) using, for example, chiral chromatographic separation.
• a single stereoisomer is obtained through direct synthesis from, for example, a chiral starting material.
• W is a suitable leaving group, for example Cl, Br, I or OTf
• R 1 , R 2 , Ring A, Ring B and Ring C are as defined in any of the embodiments herein.
• the reaction is conveniently performed in a suitable solvent (for example 2-methyltetrahydrofuran) in the presence of a base (for example cesium carbonate) and in the presence of a suitable catalyst (for example Ruphos Pd 3 rd Generation) and ligand (for example Ruphos) at a suitable temperature (for example in the range 60°C to 80°C).
• a suitable solvent for example 2-methyltetrahydrofuran
• a base for example cesium carbonate
• a suitable catalyst for example Ruphos Pd 3 rd Generation
• ligand for example Ruphos
• the compounds of Formula (I), or pharmaceutically acceptable salt thereof may also be prepared by reaction of a compound of Formula (II), or salt thereof, and a compound of Formula (III), or salt thereof, using standard aromatic substitution conditions, well known to those skilled in the art, for example with a suitable base (for example diisopropylethylamine) in a suitable solvent (for example 1 -butanol) at a suitable temperature (for example in the range of 60°C to l20°C).
• a suitable base for example diisopropylethylamine
• a suitable solvent for example 1 -butanol
• the compounds of Formula (II) may for example be prepared by the following scheme, Scheme 1 :
• PG is a suitable nitrogen protecting group, for example Boc.
• Step 1 Performed using a suitable nucleophile (for example benzoic acid) in the presence of a suitable base (for example KOH) in a suitable solvent (for example DMF) at a suitable temperature (for example in the range of 20°C to 50°C).
• a suitable nucleophile for example benzoic acid
• a suitable base for example KOH
• a suitable solvent for example DMF
• Step 2 Performed using a suitable cyclisation substrate (for example 3 -methyl- 1 7- 1 ,2,4- triazol-5-amine) in a suitable solvent (for example AcOH) at a suitable temperature (for example in the range of 70°C to 90°C).
• a suitable cyclisation substrate for example 3 -methyl- 1 7- 1 ,2,4- triazol-5-amine
• a suitable solvent for example AcOH
• Step 3 Performed under standard hydrolysis conditions, well known to those skilled in the art, for example 1M NaOH (aq) in EtOH at RT.
• Step 4 Performed using standard conditions well known to those skilled in the art.
• the reaction may be performed using standard Mitsunobu conditions with a suitable alcohol substrate (for example /c/7-butyl-3-hydroxypyrrolidinc- 1 -carboxylatc) with triphenylphosphine and DIAD in THF at RT.
• Step 5 Performed using standard deprotection conditions well known to those skilled in the art. For example, when PG is Boc the reaction may be performed using 4M HC1 in l,4-dioxane in MeOH at RT.
• Ring A is phenyl and Ring B is pyradazinyl.
• Compounds of Formula (I), where X represents CFb may for example be prepared by the reaction of compounds of Formula (III), or a salt 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)
• reaction is conveniently performed in a suitable solvent (for example 1 ,4-dioxane) in the presence of a base (for example cesium carbonate) and in the presence of a suitable catalyst (for example Ruphos Pd 3 rd Generation) and ligand (for example Ruphos) at a suitable temperature (for example 60°C to 90°C).
• a suitable solvent for example 1 ,4-dioxane
• a base for example cesium carbonate
• a suitable catalyst for example Ruphos Pd 3 rd Generation
• ligand for example Ruphos
• PG is a suitable nitrogen protecting group, for example Boc and Y is a suitable leaving group, for example Cl, Br, I or OMs.
• Step 1 Performed using conditions that convert OH into a suitable leaving group, for example if Br is chosen as leaving group then the reaction may be performed using conditions well known to those skilled in the art for example with triphenylphosphine, tetrabromomethane, in DCM in a temperature range of 0°C to RT.
• Step 2 Performed using a suitable nucleophile (for example pentane-2, 4-dione) in the presence of a suitable base (for example potassium carbonate) in a suitable solvent (for example DMF) at a suitable temperature (for example in the range of 60°C to 80°C).
• a suitable nucleophile for example pentane-2, 4-dione
• a suitable base for example potassium carbonate
• a suitable solvent for example DMF
• Step 3 Performed using a suitable cyclisation substrate (for example 3-methyl- ⁇ H- 1,2,4- triazol-5-amine) in a suitable solvent (for example AcOH) at a suitable temperature (for example in the range of (70°C to 90°C).
• a suitable cyclisation substrate for example 3-methyl- ⁇ H- 1,2,4- triazol-5-amine
• a suitable solvent for example AcOH
• Step 4 Performed using standard deprotection conditions well known to those skilled in the art.
• PG is Boc the reaction may be performed using 4M HC1 in l,4-dioxane in MeOH at RT.
• compounds of Formula (I), where X represents CH2 may be prepared by reacting a compound of Formula (VI)
• Z is a suitable leaving group, for example, pinacol boronate ester, boronic acid or organotin and R 1 , R 2 , Ring B and Ring C are as defined in any of the embodiments herein.
• a suitable solvent for example a mixture of 1 ,4-dioxane and water
• a base for example cesium carbonate
• a suitable catalyst for example Xphos Pd 2 nd Generation
• R 1 and R 2 represent hydrogen
• Ring A is pyrazinyl
• Ring B is phenyl
• Ring C is 4-methyl- 1 -piperazinyl.
• the compounds of Formula (VI), or salt thereof may be prepared by reacting a compound of Formula (V), or salt thereof, with Ring A using standard aromatic substitution chemistry.
• Ring A will have a suitable leaving group (for example chlorine or bromine) and the reaction is conveniently performed in a suitable solvent (for example 1 -butanol) in the presence of a suitable base (for example diisopropylethylamine) at a suitable temperature (for example 60°C to l20°C).
• the compounds of Formula (VI), or salt thereof may be prepared by reacting a compound of Formula (V), or salt thereof, with Ring A using standard cross coupling conditions.
• Ring A will have a suitable leaving group (for example chlorine, bromine or iodine) in a suitable solvent (for example 1 ,4- dioxane) in the presence of a base (for example cesium carbonate) and in the presence of a suitable catalyst (for example Ruphos Pd 3 rd Generation) at a suitable temperature (for example 60°C to 90°C).
• a suitable leaving group for example chlorine, bromine or iodine
• a suitable solvent for example 1 ,4- dioxane
• a base for example cesium carbonate
• a suitable catalyst for example Ruphos Pd 3 rd Generation
• compounds of Formula (I), where X represents CFfi may be prepared by reaction of a compound with Formula (VIII)
• Ring A Ring A, Ring B and Ring C are as defined in any of the embodiments herein.
• the reaction may be performed under standard conditions, well known to those skilled in the art, for example with triethylamine in THF at 60°C.
• compounds of Formula (I), where X represents CFfi may be prepared by reaction of a compound with Formula (IX)
• Ring A Ring A, Ring B and Ring C are as defined in any of the embodiments herein.
• the reaction may be performed under standard conditions, well known to those skilled in the art, for example with sodium triacetoxyborohydride, AcOH in DCM at RT.
• BCECF AM 2',7'-Bis-(2-Carboxyethyl)-5-(and-6)-Carboxyfluorescein, Acetoxymethyl Ester;
• DMSO Dimethyl Sulphoxide
• FBS Fetal Bovine Serum
• HBSS Hanks Balanced Salt Solution
• HEPES 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid
• OD Optical Density
• RPMI Roswell Park Memorial Institute 1640 Medium.
• IC50 value the concentration of test compound that inhibited 50 % of biological activity.
• IC50 values were calculated using a smart fitting model within the Screener (Genedata AG) analysis package.
• MCT4 is predominantly expressed in normal skeletal muscle and is upregulated in a range of solid tumours where it has a role in facilitating the efflux of lactate from the cell thereby preventing intra cellular acidification. Thus inhibition of MCT4 activity represents a potential therapeutic opportunity in an oncology setting.
• MCT1 is a closely related monocarboxylate transporter and as such a key selectivity target for MCT4 inhibitors. Even though MCT4 is primarily involved in cellular efflux of lactate it is possible to drive influx of lactate in an in vitro system as described for assay systems (b) and (d) below.
• NCI-H358 cells ATCC CRL-5807
• a human lung adenocarcinoma line predominantly expressing MCT4, a small amount of MCT2 and no MCT1 (confirmed by Western blotting)
• K562 cells ATCC CCL-243
• a human erythroleukemia line predominantly expressing MCT1, a small amount of MCT2 and no MCT4 (confirmed by Western blot)
• INS-l MCT4 cells parental INS-l line gifted to AstraZeneca from the University of Geneva, Switzerland
• a rat pancreatic beta-cell line natively null for all MCT isoforms and engineered in-house to stably express human MCT4 (confirmed by Western blot).
• lactic acid present in the media was quantified via a commercial lactate detection kit (Trinity Biotech #735-10) employing the following coupled-enzymatic principle: Lactic acid is converted to pyruvate and H2O2 by lactate oxidase; in the presence of the H2O2 formed, peroxidase catalyzes the oxidative condensation of a chromogen precursor to produce a coloured dye with an absorption maximum at 540 nm (increasing absorbance being directly proportional to increasing lactate within the sample).
• the absorbance was then measured on an automated microplate reader (PerkinElmer EnVision) using a 535 nm filter and OD values normalised to control wells - treated with either DMSO (maximum assay signal) or chemistry related to that described in this patent (minimum assay signal) - before fitting concentration response curves to determine an IC50 value.
• NCI-H358 cells ATCC CRL-5807 or K562 cells (ATCC CCL-243) were defrosted directly from cryopreservation, washed and re-suspended in HBSS (Gibco #14170) with 1 mM [final] HEPES (Gibco #15630).
• the cellular fluorescence using the filter set Ex470-495_Em515-575 was measured over time and the change from base-line (pre-lactate addition) to‘lactate addition + 80 seconds’ was recorded. A percentage change from base line was calculated for each test well and values normalised to control wells - treated with either DMSO (maximum assay signal) or chemistry related to that described in this patent (minimum assay signal) - before fitting concentration response curves to determine an IC50 value.
• INS-l MCT4 cells were generated through transfection of the parental cell background with the following DNA sequence, inserted into a pcDNA3.
• l ThermoFisher #V79020 mammalian expression vector:
• the resultant cell pool was continually cultured at 37 °C and 5 % CO2 under antibiotic selection in RPMI (Sigma #R0883) medium containing 1 % L glutamine (Sigma #G75 l3), 10 % FBS (Sigma #F7524), 10 mM [final] HEPES (Gibco #15630), 0.004 % b-Mercaptoethanol (Sigma #M6250) and 100 pg/ml Geneticin (ThermoFisher #10131027). An individual clone was selected and expanded before being cryopreserved in a number of individual vials for continued use.
• NC1 H358 The in vivo efficacy of MCT4 inhibitors has been tested in human xenograft models.
• the NSCLC cell line NC1 H358 can be grown as a subcutaneous xenograft in female nude mice and tumour volume calculated from bilateral caliper measurements.
• three million NC1 H358 cells were inoculated sub-cutaneously onto the left flank of the animal in a volume of 0.1 ml serum free media (RPM1) and matrigel. Animals were assigned into treatment groups 14 days after cell implantation and received either AZD2171 (3 mg/kg QD) (Wedge et ah, (2005) Cancer Res.
• Example 62 The results of testing Example 62 are shown in Figure 3.
• VEGF inhibitor AZD2171 was effective demonstrating a 33% (p ⁇ 0.00l) tumour regression compared to the vehicle group.
• MCT4 inhibitors of Formula (I) The in vivo efficacy of MCT4 inhibitors has been tested in murine syngeneic models.
• MCT1 was knocked-out (KO) of the MC38 syngeneic cell line model using CRISPR precise genome editing.
• the MC38 MCT1 KO murine colorectal cell line can be grown sub-cutaneously in female C57.B16 mice and tumour volume calculated from bilateral caliper measurements.
• ten million cells were inoculated subcutaneously onto the left flank of the animal in a volume of 0. lml serum free DMEM media. Animals were randomised by bodyweight at the time of cell implantion and treatement started the following day.
• monotherapy treatment arms received either a compound of Formula (1) (100 mg/kg B1D) by oral gavage or aCTLA4 antibody (anti-CTLA- 4 9D9 mlgGl antibody, described in WO200712373) (10 mg/kg twice weekly) intraperitoneally.
• aCTLA4 antibody anti-CTLA- 4 9D9 mlgGl antibody, described in WO200712373
• Combination groups consisted of a compound of Formula (1) (100 or 10 mg/kg PO B1D) with aCTLA4 antibody (10 mg/kg 1P twice weekly) ln the second of these studies shown in Figure 5, monotherapy treatment arms received either a compound of Formula (1) (30 mg/kg PO B1D) with aPD-l antibody (from Bio X Cell, Catalogue # BE0146, Lot 6654l7sl, 6.78 mg/mL) (10 mg/kg 1P twice weekly) ln both studies dosing was continued for up to 6 weeks and tumour volume, body weight and tumour condition were recorded three times weekly. Vehicle was 0.5% hydroxy propyl methyl cellulose/0.1% Tween 80 given twice daily by oral gavage with PBS/a given twice weekly intraperitoneally in both studies.
• lndividual tumour growth profiles are shown with animals taken off study using time to event criteria based on a maximum tumour volume of 1.5 cm 3 , tumour condition or animal welfare limits. Due to animals coming off study during the later stages of the experiment, GeoMean percentage inhibition values were calculated on Day 15. Compared to vehicle control, Example 62 monotherapy (100 mg/kg) delivered 60.0% p£005 growth inhibition on that day. Monotherapy aCTLA4 (10 mg/kg) was ineffective with 6.1% NS .
• Example 62 For the second syngeneic study testing Example 62 the results are shown in Figure 5. Again, individual tumour growth profiles are shown with animals taken off study using time to event criteria based on a maximum tumour volume of 1.5 cm 3 , tumour condition or animal welfare limits. Due to animals reaching the time to event endpoint at different times during the later stages of the experiment GeoMean percentage inhibition values were calculated on Day 13. Compared to vehicle control, Example 62 monotherapy (30 mg/kg) delivered 30.1% (NS) growth inhibition on that day.
• Monotherapy aPD-l (10 mg/kg) efficacy was similar, delivering 33.4% NS inhibition.
• the combination of Example 62 (30 mg/kg) with aPD-l antibody was more effective than the monotherapies showing 82.3% p£0001 growth inhibition.
• Group sizes on Day 13: Vehicle n 8;
• spider plots shown in Figures 4 and 5 represent individual animal tumour growth data, comparing vehicle control growth with treatment groups.
• Compounds may be further selected on the basis of further biological or physical properties which may be measured by techniques known in the art and which may be used in the assessment or selection of compounds for therapeutic or prophylactic application.
• treatment is used synonymously with“therapy”.
• treat can be regarded as“applying therapy” where“therapy” is as defined herein.
• cancer includes both non-metastatic cancer and also metastatic cancer, such that treating cancer involves treatment of both primary tumours and also tumour metastases.
• a compound of Formula (1) or a pharmaceutically acceptable salt thereof, for use in therapy.
• a compound of Formula (I) or a
• the disease mediated by MCT4 is cancer.
• the cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, renal cancer, thyroid cancer, pancreatic cancer, small cell lung cancer and non-small cell lung cancer.
• the cancer is non-small cell lung cancer.
• the cancer is lung adenocarcinoma.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
• the disease mediated by MCT4 is cancer.
• the cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, renal cancer, thyroid cancer, pancreatic cancer, small cell lung cancer and non-small cell lung cancer.
• the cancer is non-small cell lung cancer.
• the cancer is lung adenocarcinoma.
• a method for treating a disease in which inhibition of MCT4 is beneficial in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the disease is cancer.
• the cancer is selected from the group consisting of colorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, renal cancer, thyroid cancer, pancreatic cancer, small cell lung cancer and non-small cell lung cancer.
• the cancer is non-small cell lung cancer.
• the cancer is lung adenocarcinoma.
• a method for treating cancer in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a
• Tumours that selectively express MCT4 over MCT1 have an increased likelihood of responding to treatment with a MCT4 inhibitor. Therefore, patients whose tumours express MCT1 at a low level are likely to respond better to an MCT4 inhibitor than those patients whose tumours express MCT1 at a higher level. Generally, patients whose tumours have a high MCT4:MCTl expression ratio (due to the low level of MCT1 expression), are likely to show a better response, so evaluating the relative expression levels of both MCT1 and MCT4 provides a means for selecting patients for treatment with a MCT4 inhibitor. Methods for determining the relative expression levels of MCT1 and MCT4 are known in the art and are described in W02010/089580, herein incorporated by reference.
• a method of treating cancer comprising (i) testing a tumour sample obtained from a patient suffering from or likely to suffer from cancer for selective expression of MCT4 over MCT1 and (ii) administering to the patient having the tumour which selectively expresses MCT4 over MCT1, a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in a patient wherein the cancer tumour selectively expresses MCT4 over MCT1.
• a method for treating cancer in a warm-blooded animal in need of such treatment which comprises administering to said warm-blooded animal a
• terapéuticaally effective amount refers to an amount of a compound of
• the therapeutically effective amount may cause any of the changes observable or measurable in a subject as described in the definition of“therapy”,“treatment” and“prophylaxis” above.
• the effective amount can reduce the number of cancer or tumour cells; reduce the overall tumour size; inhibit or stop tumour cell infiltration into peripheral organs including, for example, the soft tissue and bone; inhibit and stop tumour metastasis; inhibit and stop tumour growth; relieve to some extent one or more of the symptoms associated with the cancer; reduce morbidity and mortality; improve quality of life; or a combination of such effects.
• An effective amount may be an amount sufficient to decrease the symptoms of a disease responsive to inhibition of MCT4 activity.
• efficacy in vivo can, for example, be measured by assessing the duration of survival, time to disease progression (TTP), the response rates (RR), duration of response, and/or quality of life.
• effective amounts may vary depending on route of administration, excipient usage, and co-usage with other agents.
• the amount of the compound of Formula (I) or pharmaceutically acceptable salt described in this specification and the amount of the other pharmaceutically active agent(s) are, when combined, jointly effective to treat a targeted disorder in the animal patient.
• the combined amounts are in a“therapeutically effective amount” if they are, when combined, sufficient to decrease the symptoms of a disease responsive to inhibition of MCT4 activity as described above.
• such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound of Formula (I) or pharmaceutically acceptable salt thereof and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).
• Warm-blooded animals include, for example, humans.
• the anti-cancer treatment described in this specification may be useful as a sole therapy, or may involve, in addition to administration of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, conventional surgery, radiotherapy or chemotherapy; or a combination of such additional therapies.
• Such conventional surgery, radiotherapy or chemotherapy may be administered simultaneously, sequentially or separately to treatment with the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• a combination therapy is administered“simultaneously”, this includes treatment of a patient with a single dosage form (e.g. a tablet) comprising both a compound of Formula (I), or a pharmaceutically acceptable salt thereof and an additional anti-cancer substance; and also simultaneous dosing of separate dosage forms each separately comprising one of the respective combination partners.
• a single dosage form e.g. a tablet
• a single dosage form e.g. a tablet
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered before surgery.
• Administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, before surgery to entirely or partially remove a cancer may be referred to as“neo-adjuvant therapy”.
• the goal of administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof is generally to reduce the size of the target tumour in order to increase the chances of a successful resection.
• the length of time the compound of Formula (I), or a pharmaceutically acceptable salt thereof is dosed before surgery may be judged by a skilled practitioner with reference to the information within this specification.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered after surgery.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional anti-cancer substance.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered simultaneously, sequentially or separately with at least one additional anti-cancer substance.
• the anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the specification, conventional surgery or radiotherapy or
• Such chemotherapy may include one or more of the following categories of anti tumour agents:
• alkylating agents for example cis-platin, oxaliplatin, carboplatin,
• antimetabolites for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, and hydroxyurea
• antitumour antibiotics for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin
• antimitotic agents for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors
• topoisomerase inhibitors for example epipodophyll
• antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as sorafenib, axitinib, pazopanib, sunitinib and cediranib;
• immunotherapy approaches including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti- idiotypic antibodies.
• cytokines such as interleukin 2, interleukin 4 or granulocyte
• PD-l e.g. nivolumab and pembrolizumab
• PD-L1 e.g. durvalumab and atezolizumab
• CTLA4 e.g. tremelimumab and ipilimumab
• CD73 e.g. oleclumab
• inhibitors of lactate transporters including for example MCT1 inhibitors such as AZD3965;
• agents that target tumour metabolism including those that inhibit GLS 1 , Complex I, mitochondrial pyruvate carrier inhibitors.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer where the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with an additional anti-tumour substance.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof and at least one additional anti-tumour substance for use in the simultaneous, separate or sequential treatment of cancer.
• a method of treating cancer in a warm-blooded animal who is in need of such treatment which comprises administering to said warm-blooded animal a compound of Formula (I), or a pharmaceutically acceptable salt thereof and at least one additional anti-tumour substance, wherein the amounts of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect.
• a method of treating cancer in a warm-blooded animal who is in need of such treatment which comprises 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 anti-tumour substance to said warm blooded animal, wherein the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional anti-tumour substance are jointly effective in producing an anti-cancer effect.
• the additional anti-tumour substance is selected from the group consisting of one or more of the anti-tumour substances listed under points (i) - (v) above.
• CTLA4 antibodies e.g. tremelimumab and ipilimumab
• CD73 antibodies e.g. oleclumab
• CD40 ligand fusion proteins GITR ligand fusion proteins
• a compound of Formula (1) or a pharmaceutically acceptable salt thereof, and at least one additional anti-tumour substance selected from the group consisting of PD-L 1 antibodies (e.g. durvalumab and atezolizumab), for use in the treatment of cancer.
• PD-L 1 antibodies e.g. durvalumab and atezolizumab
• a compound of Formula (1) or a pharmaceutically acceptable salt thereof, and durvalumab for use in the treatment of cancer.
• the cancer is non-small cell lung cancer. In one embodiment, the cancer is lung adenocarcinoma.
• a compound of Formula (1), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer where the compound of Formula (1), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from the group consisting of PD-l antibodies (e.g. nivolumab and pembrolizumab), PD-L1 antibodies (e.g. durvalumab and
• Atezolizumab atezolizumab
• CTLA4 antibodies e.g. tremelimumab and ipilimumab
• CD73 antibodies e.g. oleclumab
• CD40 ligand fusion proteins GITR ligand fusion proteins.
• a compound of Formula (1), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer where the compound of Formula (1), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from the group consisting of PD-L 1 antibodies (e.g. durvalumab and atezolizumab).
• PD-L 1 antibodies e.g. durvalumab and atezolizumab
• a compound of Formula (1), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer where the compound of Formula (1), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately or sequentially with durvalumab.
• the cancer is non-small cell lung cancer. In one embodiment, the cancer is lung adenocarcinoma. In one embodiment there is provided use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered
• PD-l antibodies e.g. nivolumab and pembrolizumab
• PD-L1 antibodies e.g. durvalumab and atezolizumab
• CTLA4 antibodies e.g. tremelimumab and ipilimumab
• CD73 antibodies e.g. oleclumab
• CD40 ligand fusion proteins GITR ligand fusion proteins.
• a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer, where the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially with at least one additional anti-tumour substance selected from the group consisting of PD-L1 antibodies (e.g. durvalumab and atezolizumab).
• PD-L1 antibodies e.g. durvalumab and atezolizumab
• the cancer is non-small cell lung cancer. In one embodiment the cancer is lung adenocarcinoma.
• a method for treating cancer in a warm-blooded animal in need of such treatment which comprises 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 anti-tumour substance selected from the group consisting of PD-l antibodies (e.g. nivolumab and pembrolizumab), PD-L1 antibodies (e.g. durvalumab and atezolizumab), CTLA4 antibodies (e.g. tremelimumab and ipilimumab), CD73 antibodies (e.g. oleclumab), CD40 ligand fusion proteins and GITR ligand fusion proteins.
• PD-l antibodies e.g. nivolumab and pembrolizumab
• PD-L1 antibodies e.g. durvalumab and atezolizumab
• CTLA4 antibodies e.g. tre
• a method for treating cancer in a warm-blooded animal in need of such treatment which comprises 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 anti-tumour substance selected from the group consisting of PD-L 1 antibodies (e.g. durvalumab and atezolizumab).
• a method for treating cancer in a warm-blooded animal in need of such treatment which comprises adiminstering 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.
• 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 anti-tumour substance, for use in the treatment of cancer. In one embodiment the pharmaceutical composition also comprises at least one pharmaceutically acceptable excipient. In one embodiment the anti-tumour substance is an anti-neoplastic
• kits comprising:
• Container means for containing said first and further unit dosage forms; and optionally d) lnstructions for use.
• the compounds of Formula (1), and pharmaceutically acceptable salts thereof, may be administered as pharmaceutical compositions, comprising one or more pharmaceutically acceptable excipients.
• a pharmaceutical composition comprising a compound of Formula (1), or a pharmaceutically acceptable salt thereof, and at least one
• compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing.
• the compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
• compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservitol,
• a pharmaceutical composition comprising a compound of Formula (1), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in therapy.
• a pharmaceutical composition comprising a compound of Formula (1), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use in the treatment of cancer ln 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 leukaemia, acute myeloid leukaemia, head and neck squamous cell carcinoma, breast cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, renal cancer, thyroid cancer, pancreatic cancer, small cell lung cancer and non-small cell lung cancer. ln one embodiment the cancer is non-small cell lung cancer.
• the cancer is lung adenocarcinoma.
• the compound of Formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range 2.5-5000 mg/m 2 body area of the animal, or approximately 0.05-100 mg/kg, and this normally provides a therapeutically-effective dose.
• a unit dose form such as a tablet or capsule will usually contain, for example 0.1-500 mg of active ingredient.
• the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, any therapies being co-administered, and the severity of the illness being treated.
• NMR spectra were obtained at 500 MHz in d6-dimethylsulfoxide.
• the following abbreviations have been used (and derivatives thereof, e.g. dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet
• flash column chromatography was performed on Merck Kieselgel silica (Art. 9385) or on reversed phase silica (Fluka silica gel 90 Cl 8) or on Silicycle cartridges (40- 63 pm silica, 4 to 330 g weight) or on Puriflash cartridges (50 pm silica, 4 to 330 g weight) or on Grace resolv cartridges (4 to 120 g) or on RediSep Rf 1.5 Flash columns or on RediSep Rf high performance Gold Flash columns (150 to 415 g weight) or on RediSep Rf Gold C18 Reversed-phase columns (20 - 40 pm silica) either manually or automated using an Isco CombiFlash Companion system or similar system;
• hydrochloride salt or a di-hydrochloride salt 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 generally not determined, for example by means of elemental analysis data; (xii) where reactions refer to the use of a microwave, one of the following microwave reactors were used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smithcreator or CEM Explorer;
• chiral preparative chromatography was carried out using HPLC or SFC using a Waters SFC 100 or equivalent.
• a chiral stationary phase such as a cellulose or amylose chiral Daicel column or equivalent was chosen to optimise separation of isomers within the sample.
• Semi preparative separations typically used a chiral column with dimensions 30 x 250 mm, 5 micron with SFC flow rates of 100 ml/min or HPLC flow rate of 40 ml/min.
• Detection was by UV absorbance or mass spectrometric detection. For UV detection a generic wavelength, typically 220nm or 254 nm, was used or a wavelength was chosen to maximise the product response.
• a soft ionization technique such as electrospray ionization was employed allowing the product to be detected by targeting MH+ response.
• Samples were dissolved in a compatible solvent for injection into the chromatographic system.
• column temperature was held constant at
• the collimated X-ray source was passed through an automatic variable divergence slit set at V20 and the reflected radiation directed through a 5.89 mm anti scatter slit and a 9.55 mm detector slit.
• Samples were measured in reflection geometry in 0 - 20 configuration over the scan range 2° to 40° 20 with a nominal 0.12 second exposure per 0.02° increment.
• the instrument was equipped with a Position sensitive detector (Lynxeye).
• Position sensitive detector Lixeye
• 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 (1 15 g, 347.8 mmol) in DCM (1 L) at 0°C over a period of 5 min.
• 6-Bromonicotinaldehyde (3 g, 16.13 mmol) and 1 -methylpiperazine (4.85 g, 48.39 mmol) were stirred in DCM (200 mL) at rt for 2 h.
• AcOH (0.097 g, 1.61 mmol) and sodium triacetoxyborohydride (6.84 g, 32.26 mmol) were added and the mixture was stirred at rt for 16 h.
• the reaction mixture was quenched with sat. aq. NaHCCL and the organic layer was separated. The aquoues layer was extracted with EtOAc and the combined organic layers were dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
• PdCh(dppf) 21.67 mg, 0.03 mmol was added to l-((5-bromopyridin-2-yl)methyl)-4- methylpiperazine (160 mg, 0.59 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (165 mg, 0.65 mmol) and potassium acetate (1 16 mg, 1.18 mmol) in 1 ,4-dioxane (4 mL) at rt under nitrogen. The resulting mixture was stirred at 90 °C for 16 h.
• 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 rt.
• the reaction mixture was stirred at rt for 3 days, then was filtered and washed with THF.
• PdCl2(dppf)-CH2Cl2 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(l,3,2-dioxaborolane) (638 mg, 2.51 mmol) and potassium acetate (493 mg, 5.02 mmol) in l,4-dioxane (10 mL) at rt. The reaction mixture was stirred at 90°C for 16 h, then was allowed to cool to rt and was concentrate in vacuo.
• HATU (3.74 g, 9.82 mmol) was added to 2-(4-(tert-butoxycarbonyl)piperazin- l-yl)acetic acid (2 g, 8.19 mmol) in DMF (25 mL) at rt under air and the reaction mixture was stirred at rt for 30 min.
• Dimethylamine (12.28 mL, 24.56 mmol) and DIPEA (4.29 mL, 24.56 mmol) were added to the mixture at rt under air.
• the reaction mixture was stirred at rt for 2 h and then poured into sat. aq. NaHC0 3 (200 mL) and extracted with EtOAc (3 x 100 mL).
• Pd(Ph 3 P)4 (578 mg, 0.50 mmol) was added to 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)morpholine (1516 mg, 5.00 mmol), 5-bromo-2-iodopyrimidine (1424 mg, 5 mmol) and Na2C0 3 (1060 mg, 10.00 mmol) in toluene (20 mL) and water (4 mL), and the reaction mixture was stirred at l20°C for 3 days, then allowed to cool to rt and concentrated in vacuo. The residue was taken up in EtOAc (100 mL) and washed sequentially with water (2 x 20 mL).
• PdChidppfpCThCfi adduct (94 mg, 0.11 mmol) was added to (7?)-6-((l-(4-bromophenyl)pyrrolidin-3- yl)methyl)-2,5,7-trimethyl-[l,2,4]triazolo[l,5-a]pyrimidine (460 mg, 1.15 mmol), 4, 4, 4', 4', 5, 5,5', 5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (292 mg, 1.15 mmol) and potassium acetate (226 mg, 2.30 mmol) in 1 ,4-dioxane (5 mL) at rt.
• 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) under air. The resulting mixture was stirred at rt for 2 h. The solvent was removed in vacuo.
• Pd(Pli3P)4 (0.389 g, 0.34 mmol) was added to tert- butyl 4-((6-bromopyridin-3-yl)methyl)piperazine- l- 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 l,4-dioxane (12 mL) and water (3 mL) at rt. The reaction mixture was heated at 85°C in a microwave reactor for 3 h, then was allowed to cool to rt and diluted with EtOAc.
• Triphenylphosphine (5.53 ml, 23.9 mmol) was added portionwise to (4-bromo-3- methoxyphenyl)methanol (4.32 g, 20.0 mmol) and carbon tetrabromide (7.26 g, 21.9 mmol) in DCM (100 ml) at 0°C over a period of 2 min. The reaction mixture was allowed to warm to rt and was stirred at rt for 18 h, then was concentrated in vacuo.
• PdCl2(dppf)-CH2Cl2 adduct (0.464 g, 0.57 mmol) was added to l-(4-bromo-3-methoxybenzyl)-4- methylpiperazine (1.7 g, 5.68 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.89 g, 1 1.4 mmol) and potassium acetate (1.67 g, 17.1 mmol) in l,4-dioxane (25 mL) at rt.
• Triethylamine (2.10 mL, 15.1 mmol) was added to (7?)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-
• NBS 0.527 g, 2.96 mmol
• (R)-2,5,7-trimethyl-6-((l-(6-methylpyrazin-2-yl)pyrrolidin- 3-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrimidine (1 g, 2.96 mmol) in DCM (10 mL) at 0°C under air.
• the reaction mixture was stirred at 0°C for 1 h, then water was added (25 mL) and the mixture was extracted with DCM (3 x 25 mL). The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated in vacuo.
• reaction mixture was allowed to warm to rt and was stirred at rt for 3 h, then was diluted with DCM (50 mL) and adjusted to pH 8-9 with Na 2 CC> 3 (2 M aq solution). The organic layer was isolated and washed with sat. brine, passed through a phase separating cartridge and concentrated in vacuo to afford the title compound (181 mg, 87%) as a yellow solid which was used without further purification; m/z MH + 448.
• Triethylamine (1.75 mL, 12.6 mmol) was added to (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)- [l,2,4]triazolo[l,5-a]pyrimidine dihydrochloride (1 g, 3.14 mmol), 3,6-dichloropyridazine (0.468 g, 3.14 mmol) in «-propanol (10 mL) at rt under air. The reaction mixture was stirred at 90°C for 16 h, then allowed to cool to rt and partially concentrated in vacuo.
• 2,4-Dioxopentan-3-yl benzoate (58 g, 263 mmol) was added to 3-methyl-lH-l,2,4-triazol-5-amine (27.1 g, 277 mmol) in AcOH (300 mL) at rt.
• the reaction mixture was stirred at 90°C for 10 h, then was allowed to cool to rt, concentrated in vacuo and adjusted to pH>7 with sat. aq. NaHCCX
• the mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with sat.
• [l,2,4]triazolo[l,5-a]pyrimidine 500 mg, 2.02 mmol
• 5-bromopyrimidine 321 mg, 2.02 mmol
• l,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 h, then allowed to cool to rt.
• the reaction mixture was diluted with EtOAc (50 mL) and was washed with water (30 mL) and sat. brine (25 mL).
• 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 rt under air. The reaction mixture was stirred at rt for 30 min. A further 0.15 eq of trichloroisocyanuric acid was added and the reaction mixture was stirred for 30 min.
• 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 rt under air. The reaction mixture was stirred at rt for 30 min. A further 0.15 eq of trichloroisocyanuric acid was added and the reaction mixture was stirred for 30 min. Piperidine (397 m ⁇ , 4.01 mmol) was added and the reaction mixture was stirred at rt for 18 h., then diluted with DCM (20 mL), filtered and concentrated in vacuo.
• 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 rt under air. The reaction mixture was stirred at rt for 30 min. A further 0.15 eq of trichloroisocyanuric acid was added and the reaction mixture was stirred for 30 min. 1 -Methylpiperazine (445 m ⁇ , 4.01 mmol) was added and the reaction mixture was stirred at rt for 18 h, then was diluted with DCM (50 mL), filtered and concentrated in vacuo.
• Pd( PH-, 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. Na2CC>3 (2.34 mL, 4.68 mmol) in l,4-dioxane (7.8 mL) and water (1.5 mL) at rt.
• reaction mixture was stirred at 80°C for 2 h, then was allowed to cool to rt, diluted with EtOAc (75 mL), and washed sequentially with water (20 mL) and sat. brine (20 mL). The organic layer was dried over MgSCL, filtered and concentrated in vacuo.
• Example 1 (/?)-4-((6’-(3-((2, 5, 7-trimethyl- [1,2,4] triazolo [1 ,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)-[3,3'-bipyridin]-6-yl)methyl)morpholine
• Pd(Pli3P)4 (72.9 mg, 0.06 mmol) was added to (R)-6-((l-(5-bromopyridin-2-yl)pyrrolidin-3- yl)methyl)-2,5,7-trimethyl-[l,2,4]triazolo[l,5-a]pyrimidine (Intermediate 5) (253 mg, 0.63 mmol), (6- ((4-methylpiperazin-l-yl)methyl)pyridin-3-yl)boronic acid (Intermediate 9) (200 mg, 0.85 mmol) and Na2CC>3 (134 mg, 1.26 mmol) in toluene (10 mL) and water (2 mL).
• Pd(Plv,P)4 (17 mg, 0.01 mmol) was added to l-methyl-4-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)benzyl)piperazine (sourced commercially) (95 mg, 0.30 mmol), (R)-6-((l-(5-bromopyridin-2- yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[l,2,4]triazolo[l,5-a]pyrimidine (Intermediate 5) (120 mg, 0.30 mmol) and Na 2 CC> 3 (63.4 mg, 0.60 mmol) in l,4-dioxane (3 mL) and water (1.5 mL) at rt. The reaction mixture was stirred at 80°C for 16 h, allowed to cool to rt and then concentrated in vacuo.
• Example 7 (/?)-4-((5-(5-(3-((2, 5, 7-trimethyl- [1,2,4] triazolo [1 ,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)pyridin-2-yl)pyrazin-2-yl)methyl)morpholine
• Example 8 (/?)-2,5,7-trimethyl-6-((l-(6-(4-((4-methylpiperazin-l-yl)methyl)phenyl)pyridin-3- yl)pyrrolidin-3-yl)methyl)- [1 ,2,4] triazolo [1 ,5-a] pyrimidine
• Example 9 (/?)-4-((6-(5-(3-((2, 5, 7-trimethyl- [1,2,4] triazolo [1 ,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)pyridin-2-yl)pyridazin-3-yl)methyl)morpholine
• Pd(Pli3P)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-[l,2,4]triazolo[l,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 l,4-dioxane (30 mL) at rt.
• the reaction mixture was stirred at 100°C for 20 h, then allowed to cool to rt, filtered and washed with DCM (20 mL). The filtrate was concentrated in vacuo and the resulting crude product was purified by fee, eluting with 0- 10% 1 M N3 ⁇ 4 / MeOH in DCM, then further purified by preparative HPLC, then dissolved in MeOH and loaded onto a 50g SCX column. The column was washed with MeOH (2 x column volumes) then eluted with 1 M N3 ⁇ 4 / MeOH.
• Example 10 6-(((/?)-l-(2-(4-(((S)-2,4-dimethylpiperazin-l-yl)methyl)phenyl)pyrimidin-5- yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trim ethyl- [1,2,4] triazolo [1 ,5-a] pyrimidine
• Example 11 (/?)-4-((5-(5-(3-((2, 5, 7-trimethyl- [1,2,4] triazolo [1 ,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)pyrimidin-2-yl)pyridin-2-yl)methyl)morpholine
• Example 12 (/?)-6-((l-(2-(2-methoxy-4-((4-methylpiperazin-l-yl)methyl)phenyl)pyrimidin-5- yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trim ethyl- [1,2,4] triazolo [1 ,5-a] pyrimidine
• Example 13 (/?)-2,5,7-trimethyl-6-((l-(2-(2-methyl-4-((4-methylpiperazin-l- yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrimidine
• Example 14 6-(((/?)-l-(2-(4-(((3/?,5S)-3,5-dimethylpiperazin-l-yl)methyl)phenyl)pyrimidin-5- yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trim ethyl- [1,2,4] triazolo [1 ,5-a] pyrimidine
• PdCl2(dppf)-CH2Cl2 adduct (168 mg, 0.21 mmol) was added to 2-(4-(4-bromobenzyl)piperazin-l-yl)- N,N-dimethylacetamide (Intermediate 22) (700 mg, 2.06 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (627 mg, 2.47 mmol) and potassium acetate (404 mg, 4.1 1 mmol) in 1,4- dioxane (10 mL) at rt.
• Pd(Pln,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-((l-(2-bromopyrimidin-5-yl)pyrrolidin-3- yl)methyl)-2,5,7-trimethyl-[l,2,4]triazolo[l,5-a]pyrimidine (Intermediate 16) (1 10 mg, 0.27 mmol) and Na2CC>3 (58.0 mg, 0.55 mmol) in l,4-dioxane (2 mL) and water (1 mL) at rt.
• Example 16 (/?)-2-(4-(4-(5-(3-((2, 5, 7-trimethyl- [1 ,2,4] triazolo [1,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)pyrimidin-2-yl)benzyl)piperazin-l-yl)ethanol
• PdCl2(dppf)-CH2Cl2 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(l,3,2- dioxaborolane) (61 1 mg, 2.41 mmol) and potassium acetate (394 mg, 4.01 mmol) in l,4-dioxane (10 mL) at rt.
• Example 17 (/?)-l-(4-(4-(5-(3-((2, 5, 7-trimethyl- [1 ,2,4] triazolo [1,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)pyrimidin-2-yl)benzyl)piperazin-l-yl)ethanone
• Pd(Pli3P)4 (28.7 mg, 0.02 mmol) was added to l-(4-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)benzyl)piperazin-l-yl)ethanone (Intermediate 52) (86 mg, 0.25 mmol), ( /?
• Example 18 (/?)-6-((l-(2-(4-((4-(2-methoxyethyl)piperazin-l-yl)methyl)phenyl)pyrimidin-5- yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trim ethyl- [1,2,4] triazolo [1 ,5-a] pyrimidine
• RuPhos 3rd generation precatalyst 50 mg, 0.06 mmol was added to 4-(4-(5-bromopyrimidin-2- yl)benzyl)morpholine (Intermediate 24) (200 mg, 0.60 mmol), (R)-2,5,7-trimethyl-6-(pyrrolidin-3- ylmethyl)-[l,2,4]triazolo[l,5-a]pyrimidine.2HCl (Intermediate 4) (190 mg, 0.60 mmol), CS2CO3 (780 mg, 2.39 mmol) and RuPhos (55.8 mg, 0.12 mmol) in l,4-dioxane (8 mL) at rt. The reaction mixture was stirred at 90°C for 6 h, allowed to cool to rt and concentrated in vacuo. The resulting crude product was purified by flash Cl 8 chromatography, eluting with 0-100% MeOH in water (+0.1%
• Pd(Pli 3 P)4 (51.7 mg, 0.04 mmol) was added to 2-bromo-5-((4-methylpiperazin-l-yl)methyl)pyrazine (Intermediate 28) (121 mg, 0.45 mmol), (/?)-2,5,7-trimcthyl-6-(( 1 -(4-(4,4,5,5-tctramcthyl- 1 ,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrimidine (Intermediate 27) (200 mg, 0.45 mmol) and Na2C0 3 (95 mg, 0.89 mmol) in toluene (0.2 mL) and water (1 mL).
• Example 22 (/?)-2,5,7-trimethyl-6-((l-(4-(2-((4-methylpiperazin-l-yl)methyl)pyrimidin-5- yl)phenyl)pyrrolidin-3-yl)methyl)- [1 ,2,4] triazolo [1 ,5-a] pyrimidine
• Example 23 (/?)-4-((6-(4-(3-((2, 5, 7-trimethyl- [1,2,4] triazolo [1 ,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)phenyl)pyridin-3-yl)methyl)morpholine
• RuPhos 3rd generation precatalyst 39 mg, 0.05 mmol was added to (R)-2,5,7-trimethyl-6- (pyrrolidin-3-ylmethyl)-[l,2,4]triazolo[l,5-a]pyrimidine dihydrochloride (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 l,4-dioxane (3 mL) at rt.
• RuPhos 3rd generation precatalyst 36 mg, 0.04 mmol
• RuPhos (20 mg, 0.04 mmol) was added to 2-(4-bromophenyl)-5-((4-methylpiperazin-l-yl)methyl)pyrimidine (Intermediate 35) (150 mg, 0.43 mmol), (R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[l,2,4]triazolo[l,5-a]pyrimidine
• Pd(Pli3P)4 34 mg, 0.03 mmol was added to (/?)-2,5,7-trimcthyl-6-(( l -(4-(4,4,5,5-tctramcthyl- 1 ,3,2- dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[l,2,4]triazolo[l,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 Na2CC>3 (62 mg, 0.58 mmol) in l,4-dioxane (3 mL) and water (1.5 mL).
• Example 28 (/?)-4-((5-(4-(3-((2,5,7-trimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-6- yl)methyl)pyrrolidin-l-yl)phenyl)pyrimidin-2-yl)methyl)morpholine
• RuPhos 3rd generation precatalyst (53 mg, 0.06 mmol) was added to (R)-2,5,7-trimethyl-6- (pyrrolidin-3-ylmethyl)-[l,2,4]triazolo[l,5-a]pyrimidine dihydrochloride (lntermediate 4) (200 mg, 0.63 mmol), 4-((5-(4-bromophenyl)pyrimidin-2-yl)methyl)morpholine (lntermediate 39) (231 mg,
• the reaction mixture was heated at 90°C for 6 h, allowed to cool to rt, diluted with DCM (50 mL) and filtered. The filtrate was concentrated in vacuo. The resulting crude product was purified by fee, eluting with 0-5% 1 M NFP/McOH in DCM.
• Example 30 was prepared in a similar way to Example 29 in 5 steps from commercially available (S)- tert-butyl 3-(hydroxymethyl)pyrrolidine- l-carboxylate to afford the title compound (122 mg, 30% final step) as a white solid; !
• Example 31 (/?)-6-((l-(5-(2-methoxy-4-((4-methylpiperazin-l-yl)methyl)phenyl)-6- methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trimethyl- [1 ,2,4] triazolo [1 ,5-a] pyrimidine
• Example 32 2,5,7-trimethyl-6-(((/?)-l-(5-(4-(((3/?,5S)-3,4,5-trimethylpiperazin-l- yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrimidine
• (2S,6R)- 1 ,2,6-trimcthylpipcrazinc (sourced commercially) (104 mg, 0.81 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- [l,2,4]triazolo[l,5-a]pyrimidine (Intermediate 48) (181 mg, 0.40 mmol) and triethylamine (0.28 mL, 2.02 mmol) in THF (5 mL) at rt under air.
• reaction mixture was stirred at 60°C for 24 h, allowed to cool to rt, and diluted with EtOAc (50 mL) and water (15 mL). The organic layer was isolated and washed with sat. brine (15 mL), dried over MgSCL, filtered and concentrated in vacuo.
• Example 33 6-(((/?)-l-(5-(4-(((/?)-3,4-dimethylpiperazin-l-yl)methyl)phenyl)pyrazin-2- yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trim ethyl- [1,2,4] triazolo [1 ,5-a] pyrimidine
• Example 34 6-(((/?)-l-(5-(4-(((/?)-2,4-dimethylpiperazin-l-yl)methyl)phenyl)pyrazin-2- yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trim ethyl- [1,2,4] triazolo [1 ,5-a] pyrimidine
• reaction mixture was stirred at 80°C for 24 h, allowed to cool to rt and diluted with EtOAc (50 mL) and water (15 mL). The organic layer was isolated and washed with sat. brine (15 mL), dried over MgSCri, filtered and concentrated in vacuo.
• (2RJR)- 1 ,2,5-trimcthylpipcrazinc hydrochloride (sourced commercially) (147 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-[l,2,4]triazolo[l,5-a]pyrimidine (Intermediate 48) (200 mg, 0.45 mmol) and triethylamine (0.31 mL, 2.23 mmol) in l,4-dioxane (5 mL) at rt under air.
• reaction mixture was stirred at 80°C for 24 h, allowed to cool to rt and diluted with EtOAc (50 mL) and water (15 mL). The organic layer was isolated and washed with sat. brine solution (15 ml), dried over MgS0 4 , filtered and dried in vacuo.
• Example 36 2,5,7-trimethyl-6-(((/?)-l-(5-(4-(((2S,5/?)-2,4,5-trimethylpiperazin-l- yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrimidine
• Example 38 (/?)-6-((l-(5-(4-((4-ethylpiperazin-l-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3- yl)methyl)-2, 5, 7-trimethyl- [1 ,2,4] triazolo [1 ,5-a] pyrimidine
• Example 40 6-(((/?)-l-(5-(4-(((3/?,5S)-3,5-dimethylpiperazin-l-yl)methyl)phenyl)pyrazin-2- yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trim ethyl- [1,2,4] triazolo [1 ,5-a] pyrimidine
• Example 43 (/?)-6-((l-(5-(2-methoxy-4-((4-methylpiperazin-l-yl)methyl)phenyl)pyrazin-2- yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trim ethyl- [1,2,4] triazolo [1 ,5-a] pyrimidine
• Example 45 6- ⁇ [(3/?)-l-(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-a] pyrimidine
• Example 47 (/?)-4-((6-(3-methyl-5-(3-((2, 5, 7-trimethyl- [1 ,2,4] triazolo [1 ,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)pyrazin-2-yl)pyridin-3-yl)methyl)morpholine
• Example 48 6-(((/?)-l-(5-(4-(((S)-3,4-dimethylpiperazin-l-yl)methyl)phenyl)pyrazin-2- yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trim ethyl- [1,2,4] triazolo [1 ,5-a] pyrimidine
• Example 49 (/?)-4-((5-(5-(3-((2, 5, 7-trimethyl- [1,2,4] triazolo [1 ,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)pyrazin-2-yl)pyridin-2-yl)methyl)morpholine
• Example 50 6-(((/?)-l-(5-(4-(((S)-2,4-dimethylpiperazin-l-yl)methyl)phenyl)pyrazin-2- yl)pyrrolidin-3-yl)methyl)-2, 5, 7-trim ethyl- [1,2,4] triazolo [1 ,5-a] pyrimidine
• XPhos 2 nd generation precatalyst (1 1.3 mg, 0.01 mmol) was added to 4-(4-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzyl)morpholine (sourced commercially) (87 mg, 0.29 mmol), (R)-6-((l-(5- bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[l,2,4]triazolo[l,5-a]pyrimidine (Intermediate 45) (120 mg, 0.29 mmol) and CS2CO3 (188 mg, 0.58 mmol) in 1,4-dioxane (4 mL) and water (1.5 mL).
• Example 53 (/?)-N,N-dimethyl-2-(4-(4-(5-(3-((2, 5, 7-trimethyl- [1 ,2,4] triazolo [1 ,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)pyrazin-2-yl)benzyl)piperazin-l-yl)acetamide
• Example 54 (/?)-2,5,7-trimethyl-6-((l-(6-methyl-5-(4-((4-methylpiperazin-l- yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrimidine
• Example 55 N,N-dimethyl-4- [4-(5- ⁇ (3/?)-3- [(2,5,7-trimethyl [1 ,2,4] triazolo [1 ,5-a] pyrimidin-6- yl)methyl]pyrrolidin-l-yl ⁇ pyrazin-2-yl)benzyl]piperazine-l-carboxamide
• Example 56 (/?)-2,5,7-trimethyl-6-((l-(5-(3-methyl-4-((4-methylpiperazin-l- yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[l,2,4]triazolo[l,5-a]pyrimidine
• Example 58 (/?)-l-(4-(4-(5-(3-((2,5,7-trimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-6- yl)methyl)pyrrolidin-l-yl)pyrazin-2-yl)benzyl)piperazin-l-yl)ethanone
• XPhos 2 nd generation precatalyst (59 mg, 0.07 mmol) was added and the reaction mixture was stirred for 18 h at 90°C, then allowed to cool to rt and diluted with EtOAc (50 mL). The organic layer was isolated and washed with sat. brine solution and dried over MgSCfi, filtered and concentrated in vacuo. The resulting crude product was purified by fee, eluting with 0-4% 1 M NHTMcOH in DCM.
• Example 60 (/?)-4-(4-(5-(3-((2, 5, 7-trimethyl- [1 ,2,4] triazolo [1 ,5-a] pyrimidin-6- yl)methyl)pyrrolidin-l-yl)pyrazin-2-yl)benzyl)morpholine
• Example 62 (/?)-4-((6-(4-(3-((2,5,7-trimethyl-[l,2,4]triazolo[l,5-a]pyrimidin-6- yl)oxy)pyrrolidin-l-yl)phenyl)pyridazin-3-yl)methyl)morpholine

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