WO2022195499A1 - Substituted pyridazine compounds as cd73 inhibitors - Google Patents
Substituted pyridazine compounds as cd73 inhibitors Download PDFInfo
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- WO2022195499A1 WO2022195499A1 PCT/IB2022/052369 IB2022052369W WO2022195499A1 WO 2022195499 A1 WO2022195499 A1 WO 2022195499A1 IB 2022052369 W IB2022052369 W IB 2022052369W WO 2022195499 A1 WO2022195499 A1 WO 2022195499A1
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- Prior art keywords
- cancer
- compound
- azaspiro
- leukemia
- alkyl
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- TZOMMLNZMGRSRT-UHFFFAOYSA-N tert-butyl-dimethyl-[2-(1h-pyrazol-4-yl)ethoxy]silane Chemical compound CC(C)(C)[Si](C)(C)OCCC=1C=NNC=1 TZOMMLNZMGRSRT-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- GVIJJXMXTUZIOD-UHFFFAOYSA-N thianthrene Chemical compound C1=CC=C2SC3=CC=CC=C3SC2=C1 GVIJJXMXTUZIOD-UHFFFAOYSA-N 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- MHNHYTDAOYJUEZ-UHFFFAOYSA-N triphenylphosphane Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MHNHYTDAOYJUEZ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
Definitions
- Q represents 4- to 8-membered heterocycloalkyl selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl or octahydrocyclopenta[c]pyrrolyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo.
- the present invention provides a use of compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, in the manufacture of a medicament for treating or preventing a disease or disorder mediated by CD73.
- Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, such as, but not limited to, a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol;
- Step 2 Synthesis of (S)-5-(5-(3-fluoropyrrolidin-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 12)
- MeOH MeOH
- 1 N HCl 3 mL
- Step 2 Synthesis of 5-(6-methyl-5-(4-methyl-1H-imidazol-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 15)
- MeOH MeOH
- 1 N HCl 1 mL
- Step 3 Synthesis of 5-(5-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione (Example 22)
- MeOH 3 mL
- 1 N HCl 2 mL
- the reaction mixture was concentrated under reduced pressure to remove excess HCl.
- Step 2 Synthesis of 5-(6-methyl-5-(6-azaspiro[2.5]octan-6-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 33) To a stirred solution of intermediate 85 (0.05 g, 0.146 mmol, 1 eq) in MeOH (5 mL) in a sealed tube was added conc.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides pyridazine compounds represented by formula (I), which are therapeutically useful as CD73 inhibitors. These compounds are useful in the treatment and/or prevention of diseases or disorders dependent upon CD73 in a subject. The present invention also provides preparation of the compounds and pharmaceutical compositions comprising at least one of compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof.
Description
SUBSTITUTED PYRIDAZINE COMPOUNDS AS CD73 INHIBITORS RELATED APPLICATION This application claims the benefit of Indian provisional patent application number 202141011717, filed on March 19th, 2021, the contents of which are hereby incorporated by reference in their entirety. FIELD OF THE INVENTION The present invention relates to pyridazine compounds and a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof which are useful as CD73 inhibitors and for the treatment of diseases or disorders dependent on modulation of CD73. The present invention also relates to a method of preparation of the said pyridazine compounds and pharmaceutical compositions comprising the said compounds. BACKGROUND OF THE INVENTION The anticancer immune response involves extracellular ATP to block cell proliferation through T-cell activation. However, in the tumor micro-environment, two extracellular membrane- bound enzymes, CD39 and CD73 are overexpressed and hydrolyze efficiently ATP into AMP then further into immune-suppressive adenosine once generated through the activity of CD39 and CD73, adenosine binds to A2A and A2B receptors expressed on tumor cells. This signaling can enhance tumor growth and directly promotes tumor cell proliferation. Additionally, adenosine inhibits anti-tumor cell activity through the inhibition of CD4+ cells, T cells, CTLs, dendritic cells, and NK cells. Adenosine also activates immunosuppressive cells such as Tregs, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), allowing additional suppression of anti-tumor activity. CD73 (designated also as ecto-5’nucleotidase or ecto5’NTase) appears to be a clinically key target in the management of cancer. Targeting A2A or A2B receptors or inhibiting adenosine signaling, via CD73 blockade, can represent a promising adjunct to tumor immunotherapy since several immunotherapeutic approaches to curb neoplasia have failed due to CD73 over expression in cancer cells or high adenosine levels within tumor microenvironment. This indicates a crucial role of the CD73 in protecting normal and cancerous tissues from collateral damage during
immune responses. In particular, evidence for the role of extracellular adenosine, and thus for the relevance of CD73 in tumor protection. The key factor influenced in the design of CD73 inhibitor: a) with antibodies targeting CD73, as with other antibody targets, the capacity for engaging Fc receptors can be reduced by antibody engineering. In that case, the widespread expression of CD73 in normal tissues could lead to safety concerns using an antibody capable of Fc receptor-mediated antibody-dependent cellular cytotoxicity. For example, considering the above reason, MEDI9447 was introduced with mutations abrogating Fc engagement, but in contrast this reduced the efficacy of MEDI9447 which shows the clear positive role in antitumor immunity demonstrating for Fc engagement with anti- CD73 antibodies; b) on contrast, small molecules display several advantages as compared with mAb approaches, such as oral bioavailability, a greater exposure of the tumor microenvironment and the chance of different formulations to overcome pharmacokinetic and/or pharmacodynamic challenges. For small molecules, it is important to consider whether the molecule is competitive or noncompetitive with AMP in the tumor microenvironment as noncompetitive inhibitors are expected to be active independently of extracellular AMP but, by contrast, the efficacy of competitive inhibitors could be reduced by the presence of a high concentration of the endogenous substrate. International applications WO2021041319, WO2020046813, WO2020210970, WO2019168744, and WO2019090111 report several small molecule compounds and their derivatives capable of targeting CD73. However, there is a need for the development of small molecule CD73 inhibitors with the potential to dampen CD73 signalling in various proliferative disorders and autoimmune diseases. SUMMARY OF THE INVENTION Provided herein is compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof and pharmaceutical compositions comprising compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof that are useful as CD73 inhibitors and for the treatment of diseases or disorders dependent on or mediated
by CD73. The present invention also provides a preparation of compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof. In one aspect, the present invention provides a compound of formula (I):
or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein, dotted lines ----- represents a bond or absent; R1 is hydrogen, alkyl, halogen, haloalkyl, cyano or -NRxRy; R2 represents hydrogen or alkyl; R3 represents cycloalkyl or alkyl; or R2 and R3 combine together with the N atom to which they are attached to form ring Q; Q represents 5- to 9-membered heteroaryl, 7- to 10-membered spiroheterocycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl or oxo; R4a represents alkoxy or hydroxy; R4b is absent; alternatively, R4a and R4b together represent an oxo group; R4c represents alkoxy or hydroxy; R4d is absent; alternatively, R4c and R4d together represent an oxo group; R4e and R4f independently are hydrogen or absent; and Rx and Ry independently represents hydrogen or alkyl. In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
In yet another aspect, the present invention relates to the preparation of compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for use as a medicament. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating diseases or disorders that are dependent upon or mediated by CD73. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating diseases or disorders that have altered CD73 including mutations and overexpression thereof. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for treating diseases or conditions wherein inhibition of CD73 proteins provides a benefit. In another aspect, the present invention provides methods of treating a disease or a disorder comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof to a subject, e.g., a human, in need thereof. The disease or disorder, for example, cancer is treatable by inhibition of CD73. In another aspect, the present invention provides a use of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof for the manufacture of a medicament for treating a disease or condition, e.g., cancer. DETAILED DESCRIPTION OF THE INVENTION The present invention provides pyridazinyl derivative compounds, referred as a compound of formula (I), which are useful as CD73 inhibitors and for the treatment of conditions dependent on or mediated by CD73. The present invention further provides pharmaceutical compositions comprising the said compound or a stereoisomer or a tautomer thereof as therapeutic agents. Each embodiment is provided by way of explanation of the invention and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions and methods described
herein without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus, it is intended that the present invention includes such modifications and variations and their equivalents. Other objects, features and aspects of the present invention are disclosed in or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not to be construed as limiting the broader aspects of the present invention. In one embodiment, the present invention provides compound of formula (I):
or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein, dotted lines ----- represents a bond or absent; R1 is hydrogen, alkyl, halogen, haloalkyl, cyano or -NRxRy; R2 represents hydrogen or alkyl; R3 represents cycloalkyl or alkyl; or R2 and R3 combine together with the N atom to which they are attached to form ring Q; Q represents 5- to 9-membered heteroaryl, 7- to 10-membered spiroheterocycloalkyl or 4- to 8-membered heterocycloalkyl; wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo; R4a represents alkoxy or hydroxy; R4b is absent; alternatively R4a and R4b combine together to form an oxo group; R4c represents alkoxy or hydroxy; R4d is absent; alternatively R4c and R4d combine together to form an oxo group; R4e and R4f independently are hydrogen or absent; and
Rx and Ry independently represents hydrogen or alkyl. In one embodiment, dotted lines ----- represents a bond or absent. In one embodiment, dotted lines ----- represents a bond. In one embodiment, dotted lines ----- represents absent. In one embodiment, R1 is hydrogen, alkyl, halogen, haloalkyl, cyano or -NRxRy. In one embodiment, Rx and Ry independently represents hydrogen or alkyl. In one embodiment, R1 is hydrogen, (C1-C4)alkyl, halogen, -CF3, -CN, -NH2, -NH(CH3) or -N(CH3)2. In one embodiment, R1 is hydrogen, (C1-C4)alkyl, -F, -Cl, -CF3, -CN, -NH2, -NH(CH3) or -N(CH3)2. In one embodiment, R2 represents hydrogen or alkyl. R3 represents cycloalkyl or alkyl; or R2 and R3 combine together with the N atom to which they are attached to form ring Q. In one embodiment, R2 represents hydrogen or (C1-C6)alkyl. In one embodiment, R3 represents (C3-C5)cycloalkyl or (C1-C6)alkyl. In one embodiment, R2 represents hydrogen or (C1-C4)alkyl; and R3 represents cyclopropyl or (C1-C4)alkyl In one embodiment, Q represents 5- to 9-membered heteroaryl, 7- to 10-membered spiroheterocycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo. In one embodiment, Q represents 5- to 9-membered heteroaryl selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl (pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl and purinyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo. In one embodiment, Q represents 7- to 10-membered spiroheterocycloalkyl selected from 2-azaspiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 6- azaspiro[2.5]octanyl, 5-azaspiro[2.4]heptanyl, 2,7-diazaspiro[4.4]nonanyl, 1,7- diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 2-oxa-7- azaspiro[4.4]nonanyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo.
In one embodiment, Q represents 4- to 8-membered heterocycloalkyl selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl or octahydrocyclopenta[c]pyrrolyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo. In one embodiment, Q represents pyrrolidinyl, pyrazolyl, piperidinyl, imidazolyl, azetidinyl, indazolyl, 2-azaspiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 6- azaspiro[3.4]octanyl, 5-azaspiro[2.4]heptanyl, 2,7-diazaspiro[4.4]nonanyl, 1,7- diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, or 2-oxa-7-azaspiro[4.4]nonanyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino halo, haloalkyl, hydroxyalkyl and oxo. In one embodiment, R2 represents hydrogen or alkyl. In one embodiment, R3 represents hydrogen, cycloalkyl or alkyl. In one embodiment, R2 represents hydrogen or (C1-C4)alkyl and R3 represents cyclopropyl or (C1-C4)alkyl. In one embodiment, R4a and R4c independently represents alkoxy or hydroxy; alternatively R4a and R4b together represent an oxo group; and R4c and R4d together represent an oxo group. In one embodiment, R4a and R4c independently represents methoxy. In one embodiment, R4b and R4d are absent. In one embodiment, R4e and R4f independently are hydrogen or absent. In one embodiment of compound of formula (I), if both R4e and R4f are absent, dotted lines ------ represents bond. In one embodiment, the present invention provides compound of formula (IA) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof:
; wherein R1, R2, R3, and Q are as defined in compound of formula (I). In one embodiment of compound of formula (IA), Q represents pyrrolidinyl, pyrazolyl, piperidinyl, imidazolyl, azetidinyl, indazolyl, 2-azaspiro[4.4]nonanyl, 2,6- diazaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 6-azaspiro[2.5]octanyl, 5-azaspiro[2.4]heptanyl, 2,7-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-6- azaspiro[3.4]octanyl or 2-oxa-7-azaspiro[4.4]nonanyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from -CH3, -(CH2)3-CH3, gemdimethyl, -F, -Cl, gemdifluoro, -CF3, -(CH2)2OH, amino and oxo. In one embodiment of compound of formula (IA), Q represents 5- to 9-membered heteroaryl, 7- to 10-membered spiroheterocycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo; Rx and Ry independently represents hydrogen or alkyl. In one embodiment the present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy; Q represents pyrrolidinyl, pyrazolyl, piperidinyl, imidazolyl, azetidinyl, indazolyl, 2-azaspiro[4.4]nonanyl, 2,6- diazaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 6-azaspiro[2.5]octanyl, 5-azaspiro[2.4]heptanyl, 2,7-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-6- azaspiro[3.4]octanyl or 2-oxa-7-azaspiro[4.4]nonanyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from -CH3, -CH2(CH2)2-CH3, gemdimethyl, -F, -Cl, gemdifluoro, -CF3, -(CH2)2OH, amino and oxo; and
Rx and Ry independently represents hydrogen or -CH3. In one embodiment, the present invention provides a compound of formula (IB) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof:
R1, R2, R3, and Q are as defined in compound of formula (I). In one embodiment of compound of formula (IB), R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy. In one embodiment of compound of formula (IB), Q represents 5- to 9-membered heteroaryl, 7- to 10-membered spiroheterocycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo; and Rx and Ry independently represents hydrogen or alkyl. In one embodiment, the present invention provides a compound of formula (IA) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy; Q represents pyrrolidinyl, pyrazolyl, piperidinyl, imidazolyl, azetidinyl, indazolyl, 2- azaspiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 6- azaspiro[2.5]octanyl, 5-azaspiro[2.4]heptanyl, 2,7-diazaspiro[4.4]nonanyl, 1,7- diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl or 2-oxa-7- azaspiro[4.4]nonanyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from -CH3, -CH2(CH2)2-CH3, gemdimethyl, -F, -Cl, gemdifluoro, -CF3, - (CH2)2OH, amino and oxo; and Rx and Ry independently represents hydrogen or -CH3
In one embodiment, the present invention provides compound of formula (IC) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof:
; wherein R1, R2, R3, and Q are as defined in compound of formula (I). In one embodiment, the present invention provides a compound of formula (IC) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof: wherein R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy; Q represents 5- to 9-membered heteroaryl, 7- to 10-membered spiroheterocycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo; and Rx and Ry independently represents hydrogen or alkyl. In one embodiment, the present invention provides compound of formula (ID) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof:
Wherein
ring Z represents (C3-C5) cycloalkyl or 3- to 5-membered heterocycloalkyl containing 1-2 heteroatoms selected from O, N or S; m represents 1, 2 or 3; n represents 1, 2 or 3; and R1 is as defined in compound of formula (I). In one embodiment, the present provides a compound of formula (ID) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy; ring Z represents (C3-C5) cycloalkyl or 3- to 5-membered heterocycloalkyl containing 1-2 heteroatoms selected from O, N or S; or ring Z is absent; and Rx and Ry independently represents hydrogen or alkyl. In one embodiment, the present invention provides compound of formula (IE) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof:
wherein ring Z represents (C3-C5) cycloalkyl or 3- to 5-membered heterocycloalkyl containing 1-2 heteroatoms selected from O, N or S; or ring Z is absent; m represents 1, 2 or 3; n represents 1, 2 or 3; and R1 is as defined in compound of formula (I). In one embodiment, ring Z represents (C3-C5) cycloalkyl or 3- to 5-membered heterocycloalkyl containing 1-2 heteroatoms selected from O, N or S;. In one embodiment, ring Z is absent.
In one embodiment, the formula
represents
, ,
, , , , , ; wherein each group is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from -CH3, -CH2(CH2)2-CH3, gemdimethyl, -F, -Cl, gemdifluoro, -CF3, -(CH2)2OH, amino and oxo. In one embodiment, the present provides a compound of formula (IE) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy; ring Z represents (C3-C5) cycloalkyl or 3- to 5-membered heterocycloalkyl containing 1-2 heteroatoms selected from O, N or S; or ring Z is absent; and Rx and Ry independently represents hydrogen or alkyl. In one embodiment, the present invention provides a compound or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein the compound is selected from:
Method of treatment In certain embodiment, the present invention provides a compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use in the manufacture of medicament for the treatment of diseases or disorders dependent upon CD73. In certain embodiment, the present invention provides a pharmaceutical composition comprising compound of formula (I) or a pharmaceutical acceptable salt or a stereoisomer or a tautomer thereof, for use in the manufacture of medicament for the treatment of diseases or disorders dependent upon CD73. In certain embodiment, the present invention provides a method of inhibiting a target protein comprising administering to a cell therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein the compound is effective for inhibiting the target protein. In certain embodiment, wherein the target protein is CD73. In certain embodiment, the present invention provides a method for treating a disease or disorder mediated by CD73, in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof. In one embodiment, diseases or disorders dependent on CD73, include cancer. In one embodiment, cancer is selected from brain gliomas, glioblastomas, astrocytomas, multiforme, bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer vulval cancer, uterine/cervical cancer,
endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers, testicular cancer or virus-related cancer. In certain embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer or a tautomer thereof as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described in the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. In certain embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), for use in inhibiting a target protein in a cell comprising contacting the cell with an effective amount of the compound, wherein the compound effectuates the inhibition of the target protein. In certain embodiment, the present invention provides a compound or a pharmaceutically acceptable salt or a stereoisomer or a tautomer or a tautomer thereof, for use as a medicament. In certain embodiment, the present invention provides a use of pharmaceutical composition comprising a compound of formula (I), in the manufacture of a medicament for treating or preventing a disease or disorder mediated by CD73. In certain embodiments, the present invention provides a use of compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, in the manufacture of a medicament for treating or preventing a disease or disorder mediated by CD73. In one embodiment, the present invention provides a use of compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, in the manufacture of a medicament for treating or preventing cancer selected from brain gliomas, glioblastomas, astrocytomas, multiforme, bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma adenosquamous carcinoma, acinar cell carcinoma,
glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, uterine/cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers, testicular cancer or virus-related cancer. In certain embodiments, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use in treating or preventing of a disease or disorder mediated by CD73. In one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use in treating or preventing cancer selected from brain gliomas, glioblastomas, astrocytomas, multiforme, bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, uterine/cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer salivary gland cancer hepatocellular cancer, gastric
cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers, testicular cancer or virus-related cancer. Pharmaceutical compositions Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this application with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient
temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, including but not limited to tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Dosage forms for topical or transdermal administration of a compound of this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this application. The ointments, pastes, creams and gels may contain, in addition to an active compound of this application, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof. Powders and sprays can contain, in addition to the compounds of this application, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound
across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Administration of the disclosed compounds and pharmaceutical compositions can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. Depending on the intended mode of administration, the disclosed compounds or pharmaceutical compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts. Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, such as, but not limited to, a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algiic acid or its sodium salt or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that
enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200. Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, one or more disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles or serum proteins can be used to solubilize the disclosed compounds. One or more disclosed compounds or compositions can be delivered by parental administration. The parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use in treating or preventing cancer selected from brain gliomas, glioblastomas, astrocytomas, multiforme, bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, uterine/cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer,
cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers, testicular cancer or virus-related cancer. DEFINITIONS Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present invention. The singular forms “a”, “an” and “the” encompass plural references unless the context clearly indicates otherwise. As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to an event or circumstance in which the said alkyl may be substituted as well as the event or circumstance in which the alkyl is not substituted. The term “optionally substituted alkyl” can also be referred to ‘unsubstituted or substituted alkyl’ group, wherein the substituents are described herein. The term “substituted” refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Unless specifically stated, the substituents can include any substituents described herein, for example, a halogen, a
hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl or an acyl), a thiocarbonyl (such as a thioester, a thioacetate or a thioformate), an alkoxyl, an oxo, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heteroaryl, a heterocycloalkyl, an aralkyl or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C3-C10 branched-chain alkyl groups. Preferably, the “alkyl” group refers to C1-C6 straight-chain alkyl groups including C3-C6 branched-chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C4 straight-chain alkyl groups including C3-C4 branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3- octyl and 4-octyl. The “alkyl” group may be unsubstituted or substituted. As used herein, the term “halo” or “halogen” alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine. As used herein, the term “haloalkyl” refers to alkyl substituted with one or more halogen atoms, wherein the halogen and alkyl groups are as defined above. Examples of “haloalkyl” include but are not limited to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl and 2,2,2-trifluoroethyl. As used herein, the term “hydroxyalkyl” refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms have been replaced with hydroxyl group. Examples of hydroxyalkyl moieties include but are not limited to -CH2OH, -CH2CH2OH, - CH2CH2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH) CH3, -CH(CH3)CH2OH. As used herein the term “cycloalkyl” alone or in combination with other term(s) means - C3-C10 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls.
As used herein, the term “heterocycloalkyl” refers to a non-aromatic, saturated or partially saturated, bridged bicyclic, monocyclic or polycyclic ring system of 3- to 15-member, unless the ring size is specifically mentioned, having at least one heteroatom selected from O, N, and S, with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. The term “heterocycloalkyl” also refers to the bridged bicyclic ring system having at least one heteroatom selected from O, N or S. Examples of “heterocycloalkyl” include, but not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl, isoindolinyl, oxoisoindolinyl, dioxoisoindolinyl, aza- bicyclooctanyl, diazabicyclooctanyl, azocinyl, chromanyl, isochromanyl, xanthenyl and octahydrocyclopenta[c]pyrrolyl. Attachment of a heterocycloalkyl substituent with other portion can occur via either a carbon atom or a heteroatom. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups by one or more aforesaid groups. Preferably “heterocycloalkyl” refers to 4- to 8-membered ring (unless the ring size is specifically mentioned) selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and octahydrocyclopenta[c]pyrrolyl. All heterocycloalkyl are unsubstituted or substituted by one or more aforesaid groups. As used herein, the term “spiroheterocycloalkyl” refers to saturated bicyclic ring systems containing 4 to 9 carbon atoms and at least one heteroatom independently selected from oxygen, sulphur and nitrogen, in which the two rings are linked by a common atom. Examples of “spiroheterocycloalkyl” include, but not limited to, 2,6-diazaspiro[3.3]heptanyl, 2,6- diazaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 2-azaspiro[3.5]-nonanyl, 2,7- diazaspiro[4.4]nonanyl, 2-azaspiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 6- azaspiro[3.4]octanyl, 6-azaspiro[2.5]octanyl, 5-azaspiro[2.4]heptanyl, 2,7- diazaspiro[4.4]nonanyl, 1,7-diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-6- azaspiro[3.4]octanyl or 2-oxa-7-azaspiro[4.4]nonanyl and the like. As used herein, the term “heteroaryl” refers to a completely unsaturated ring system containing a total of 5 to 14 ring atoms, unless the ring size is specifically mentioned. At least one
of the ring atoms is a heteroatom (i.e., O, N or S), with the remaining ring atoms/groups being independently selected from C, N, O or S. A heteroaryl may be a single-ring (monocyclic) or multiple rings (bicyclic, tricyclic or polycyclic) fused together or linked covalently. Preferably, “heteroaryl” is a 5- to 6-membered ring, unless the ring size is specifically mentioned. The rings may contain from 1 to 4 additional heteroatoms selected from N, O and S, wherein the N atom is optionally quarternized. Any suitable ring position of the heteroaryl moiety may be covalently linked to the defined chemical structure. Examples of “heteroaryl” include but not limited to furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl (pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, α-carbolinyl, indolizinyl, benzoisothiazolyl, benzoxazolyl, pyrrolopyridyl, purinyl, benzothiadiazolyl, benzooxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl, dibenzothienyl, acridinyl and the like. Heteroaryl group may be unsubstituted or further substituted with the substituted as defined herein. As used herein, the term “amino” refers to an –NH2 group. As used herein, the term “hydroxy” or “hydroxyl” alone or in combination with other term(s) means –OH. As used herein, the term “oxo” refers to =O group. As used herein, the term “alkoxy” refers to the group -O-alkyl, where alkyl groups are as defined above. The groups “alkoxy” includes C1-C6 alkoxy, particularly C1-C4 alkoxy groups. Exemplary C1-C10 alkoxy group include but are not limited to methoxy, ethoxy, n-propoxy, n- butoxy or t-butoxy. An alkoxy group can be unsubstituted or substituted with one or more suitable groups. The term “heteroatom” as used herein designates a sulfur, nitrogen or oxygen atom. As used herein, the term 'compound(s)' comprises the compound(s) disclosed in the present invention. As used herein, the term “comprise” or “comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. As used herein, the term “or” means “and/or” unless stated otherwise.
As used herein, the term “including” as well as other forms, such as “include”, “includes” and “included” is not limiting. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As used herein, the term “pharmaceutical composition” refers to a composition(s) containing a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition(s) usually contain(s) about 1% to 99%, for example, about 5% to 75% or from about 10% to about 30% by weight of the compound of formula (I) or (II) or pharmaceutically acceptable salts thereof. The amount of the compound of formula (I) or pharmaceutically acceptable salts thereof in the pharmaceutical composition(s) can range from about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg or from about 5 mg to about 250 mg or in any range falling within the broader range of 1 mg to 1000 mg or higher or lower than the aforementioned range. As used herein, “pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavour enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant or emulsifier that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. The term “administer,” “administering,” or “administration” as used in this disclosure refers to either directly administering one or more disclosed compounds or a pharmaceutically acceptable salt of one or more disclosed compounds or a composition comprising one or more disclosed compounds to a subject or analog of the compound or a pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body. The term “carrier” as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ or portion of the body to another organ or portion of the body of a subject. As used herein, the term “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. As used herein, the term “prevent”, “preventing” and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent”, “preventing” and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease. As used herein, the term “subject” that may be interchangeable with ‘patient’, refers to an animal, preferably a mammal, and most preferably a human. As used herein, the term, “therapeutically effective amount” refers to an amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; or a composition comprising the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, effective in producing the desired therapeutic response in a particular patient suffering from a diseases or disorder, in particular their use in diseases or disorder associated with cancer. Particularly, the term “therapeutically effective amount” includes the amount of the compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, when administered, that induces a positive modification in the disease or disorder to be treated or is sufficient to prevent development of or alleviate to some extent, one or more of the symptoms of the disease or disorder being treated in a subject. In respect of the therapeutic amount of the compound, the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgment can also be considered. The therapeutically effective amount of the compound or composition will be varied with the particular condition being treated, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the age and physical condition of the end user, the specific compound or composition employed the particular pharmaceutically acceptable carrier utilized. “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
The term “pharmaceutically acceptable salt” refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base. In some cases, a medicament can be present in the form of a pharmaceutically acceptable salt. In some instances, a pharmaceutically acceptable salt can be a salt described in Berge et al, J. Pharm. Sci, 1977. In some instances, a pharmaceutically acceptable salts can include those salts derived from a mineral, organic acid or inorganic base. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the non- toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be prepared from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 2002). The present invention also provides methods for formulating the disclosed compounds as for pharmaceutical administration. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery
system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop. The term “stereoisomers” refers to any enantiomers, diastereoisomers or geometrical isomers of the compound of formula (I), wherever they are chiral or when they bear one or more double bonds. When the compounds of the formula (I) and related formulae are chiral, they can exist in racemic or in optically active form. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-Isomers and l-Isomers and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centres or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the present invention may exist as geometric Isomers. The present invention includes all cis, trans, syn, anti, entgegen (E) and zusammen (Z) Isomers as well as the appropriate mixtures thereof. The term “enantiomers” refers to a pair of stereoisomers which are non-superimposable mirror images of one another. The term “enantiomer” refers to a single member of this pair of stereoisomers. The term “racemic” refers to a 1: 1 mixture of a pair of enantiomers. The disclosure includes enantiomers of the compounds described herein. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form or any other form in terms of stereochemistry. In some embodiments the compounds are the (R, S)-enantiomer. The term “diastereomers” refers to the set of stereoisomers which cannot be made superimposable by rotation around single bonds. For example, cis- and trans- double bonds, endo- and exo- substitution on bicyclic ring systems, and compounds containing multiple stereogenic centres with different relative configurations are considered to be diastereomers. The term “diastereomer” refers to any member of this set of compounds. In some examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers. The disclosure includes diastereomers of the compounds described herein
The term “tautomer” refers to compounds in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms. It is understood that all tautomeric forms, insofar as they may exist, are included within the invention. The compounds of the present invention may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable excipients. The compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents and solvents. The pharmaceutical composition can be administered by oral, parenteral or inhalation routes. Examples of the parenteral administration include administration by injection, percutaneous, transmucosal, transnasal and transpulmonary administrations. Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters and polyoxyethylene. The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing. The pharmaceutical compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topical application. Further, the
pharmaceutical composition of the present invention may be formulated so as to provide desired release profile. Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of pharmaceutical compositions. The route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or topical. Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions. Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration. The pharmaceutical compositions of the present patent application may be prepared by conventional techniques known in literature. Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application. EXPERIMENTAL The following abbreviations refer respectively to the definitions below: MeCN – Methyl cyanide; DMSO – Dimethylsulfoxide; DIPEA - N,N-Diisopropylethylamine; NaHCO3 – Sodium bicarbonate; EtOH – Ethanol; MeOH – Methanol; THF – Tetrahydrofuran;
IPA – Isopropyl alcohol; TFA – Trifluoro acetic acid; K2CO3 – Potassium carbonate; Pd(dppf)Cl2 – [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II)dichloride; Cs2CO3 – Caesium carbonate; PPh3 – Triphenyl phosphine; dppf – 1,1'-Bis(diphenylphosphino)ferrocene; PddppfCl2.DCM - [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; NH4Cl – Ammonium chloride; Dioxane.HCl; – Hydrochloric acid in dioxane; Na2SO4 – Sodium sulphate; H2O – water; br – Broad; Å– Angstrom ; oC - Degree Celsius ; conc – Concentrated; DMSO-d6- Deuterated dimethylsulfoxide; CH2Cl2 _ DCM – Dichloromethane; DMF- N, N- Dimethylformamide; Et2O – Diethyl ether; g- Gram; h – Hours; 1H- Proton; HCl- Hydrochloric acid; Hz- Hertz; J - Coupling Constant; LC–MS - Liquid Chromatography- Mass Spectroscopy; HPLC - High-performance liquid chromatography; chiral HPLC - chiral high-performance liquid chromatography; M – Molar; MHz – Mega Hertz (frequency); MS - Mass Spectroscopy; mmol - Milli Mole; mL - Milli Litre; min – Minutes; mol – Moles; M+- Molecular ion;m/z-mass to charge ratio; N-Normality; NMR - Nuclear Magnetic Resonance; ppm - Parts per million; rt/RT – Room temperature; s – Singlet; d – Doublet, t – Triplet; q – Quartet; m – Multiplet; dd – doublet of doublets; td – triplet of doublets; qd – quartet of doublets; ddd – doublet of doublet of doublets; dt – doublet of triplets; ddt – doublet of doublet of triplets; p-pentate; TLC - Thin Layer Chromatography; THF – Tetrahydrofuran; % - Percentage; µ - Micron; µL-Micro liter and δ - Delta; ±-racemic mixture. GENERAL SCHEME
The general approach for the synthesis of compounds of general formula (I” & II”) is depicted in above scheme. The Compound of formula (B2) can be obtained from compound of formula (B1) coupling with (Ba) in the presence of suitable reagent and base in an appropriate solvent at a suitable temperature. The Compound of formula (B2) can undergo Suzuki coupling reaction with Z’ in the presence of suitable metal catalyst and base in an appropriate solvent at a suitable temperature to obtain compound of formula (B3). Alternatively, compound of formula (B2) can undergo substitution reaction with Z” at higher temperature in appropriate solvent to obtain the compound of formula (B4). Then, compound of formula (B3) or (B4), can be reacted with compound of formula (B5) in the presence of suitable metal catalyst and base in an appropriate solvent at a suitable temperature to obtain compound of formula (Formula II’) which upon demethylation in the presence of suitable acidic condition can yield the compound of formula (I’).
Scheme-II
Another general approach for the synthesis of compound of general formula (I’) is depicted in above scheme. The Compound of formula (A2) can be obtained from compound of formula (A1) coupling with (Aa) in the presence of suitable reagent and base in an appropriate solvent at a suitable temperature. The Compound of formula (A2) can undergo Suzuki coupling with compound of formula (B5) in the presence of suitable metal catalyst and base in an appropriate solvent at a suitable temperature to obtain compound of formula (II’). The compound of formula (II’) can be demethylated with a suitable acid to yield the compound of formula (I’). Scheme-III
Another general approach for the synthesis of compound of general formula (I’) is depicted in above scheme. The Compound of formula (D3) can be obtained from the Suzuki coupling reaction compound of formula (D1) and (D2) in the presence of suitable metal reagent and base in appropriate solvent at a suitable temperature. The Compound of formula (D3) undergone coupling with the compound of formula (Ba) in the presence of suitable reagent and base in appropriate solvent at a suitable temperature to obtained compound of formula (II’). The compound of formula (II’) demethylated with appropriate acid to produce the compound of formula (I’). Example 1: 5-(6-amino-5-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 6-chloro-4-(1H-pyrazol-1-yl)pyridazin-3-amine (3) To a stirred solution of intermediate 1 (0.6 g, 2.87 mmol, 1eq) in MeCN (15 mL) was added K2CO3 (0.79 g, 5.75 mmol, 2 eq) at 0 °C and stirred for 10 min. Then pyrazole (2) (0.215 g, 3.16 mmol, 1.1eq) was added and the reaction mixture was heated at 70 °C for 12 h. Upon completion of the reaction (as confirmed by TLC), the reaction mixture was quenched with water and extracted with DCM (3 X 50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and volatiles were removed under vacuum to provide the crude. It was then purified by combi- flash silica-gel chromatography using 0-60% EtOAc/ hexane as eluent to afford the intermediate 3 (0.41 g, 73%). LC-MS: m/z 196.1 (M+H+). Step 2: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-(1H-pyrazol-1-yl)pyridazin-3-amine (5) To a stirred solution of intermediate 3 (0.4 g, 2.04 mmol) in 1,4-dioxane (6 mL) and water (3 mL), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (0.412 g, 2.25 mmol, 1.1 eq) and K2CO3 (0.56 g, 4.08 mmol, 2 eq) were added. The resultant solution was degassed using Argon balloon for 10 min and then, PddppfCl2.DCM (0.166 g, 0.20 mmol, 0.1 eq) was added. The reaction mixture was further degassed for additional 10 min and then heated at 70 °C for 3h. Upon completion of the reaction (as confirmed by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and volatiles were removed under vacuum to provide the crude. It was then purified by combi-flash
silica-gel chromatography using 0-40% EtOAc/Hexane as eluent to afford intermediate 5. LC-MS: m/z 300.1 (M+H+). Step 3: Synthesis of 5-(6-amino-5-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione (Example 1) The intermediate 5 (0.18 g, 0.6 mmol, 1 eq) was dissolved in 5mL of 1N HCl and the resulting suspension was heated at 60 °C for 5 h and then, stirred at rt for 16 h. Upon completion of the reaction (as confirmed by TLC), the reaction mixture was basified using 1N NaOH and the solid precipitate was filtered off to provide the crude. The crude was then purified by preparative HPLC to afford the compound of Example 1 as a pale yellow solid (0.030 g, 17%). LCMS: m/z 272.05 (M+H+); HPLC: 97.49%; 1H NMR (400 MHz, DMSO-d6): ^ 11.52 (bs, 2H), 8.51 (d, J = 2.8 Hz, 1H), 8.11-8.09 (m, 2H), 7.93 (d, J = 2.8 Hz, 1H), 7.13 (s, 2H), 6.68-6.67 (m, 1H) ppm. Example 2: 5-(6-amino-5-(1H-indazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 6-chloro-4-(1H-indazol-1-yl)pyridazin-3-amine (7) A stirred solution of intermediate 1 (0.5 g, 2.4 mmol), intermediate 6 (0.425 g, 3.56 mmol, 1.5 eq) and Cs2CO3 (1.5 g, 4.79 mmol, 2 eq) in DMSO (6 mL) was degassed with Argon balloon for 5 min. Then, Cu2O (0.034 g, 0.24 mmol, 0.1 eq) was added and the resultant solution was further degassed for 10 min and heated under microwave irradiation at 150 °C for 1.5 h. Upon
completion of the reaction (as confirmed by TLC), the reaction mixture was quenched with ammonium hydroxide solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and volatiles were removed under vacuum to provide the crude. It was then purified by combi-flash silica-gel chromatography using 0-30% EtOAc/Hexane as eluent to afford the intermediate 7 (0.16 g, 27%). LC-MS: m/z 246.1 (M+H+). Step 2: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-(1H-indazol-1-yl)pyridazin-3-amine (8) To a stirred solution of 6-chloro-4-(1H-indazol-1-yl)pyridazin-3-amine (7) (0.16 g, 0.65 mmol, 1 eq) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (0.12 g, 0.65 mmol, 1 eq) in 1,4- dioxane (4 mL) and water (1 mL), then K2CO3 (2 eq) was added to the reaction mixture. The resultant solution was degassed using Argon balloon for 10 min and then, PddppfCl2.DCM (0.1 eq) was added. The reaction mixture was further degassed for additional 10 min and then heated at 70 °C for 3 h. Upon completion of the reaction (as confirmed by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and volatiles were removed under vacuum to provide the crude. It was then purified by combi-flash silica-gel chromatography using EtOAc/Hexane as eluent to afford the intermediate 8 (0.08 g, 35%). LC-MS: m/z 350.1 (M+H+). Step 3: Synthesis of 5-(6-amino-5-(1H-indazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione (Example 2) The intermediate 8 (0.08 g, 0.22 mmol) was dissolved in 5 mL of 1N HCl and the resulting suspension was heated at 60 °C for 5 h and then stirred at RT for 12 h. Upon completion of the reaction (as confirmed by TLC), the reaction mixture was basified using 1N NaOH and the solid precipitate was filtered off to provide the crude. The crude was then purified by preparative HPLC to afford compound Example 2 as a white solid (0.010 g, 20%). LCMS: m/z 322.2 (M+H+); HPLC: 97.36%; 1H NMR (400 MHz, DMSO-d6): ^ 11.44 (s, 1H), 11.36 (s, 1H), 8.55 (s, 1H), 8.21 (s, 1H), 8.16 (d, J = 6 Hz, 1H), 7.97 (d, J = 8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.58-7.56 (m, 1H), 7.36- 7.34 (m, 1H), 6.80 (m, 2H) ppm. Example 3: 5-(6-chloro-4-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 3,6-dichloro-4-(1H-pyrazol-1-yl)pyridazine (10) To a stirred a solution of intermediate 9 (2 g, 2 eq) and K2CO3 (4 eq) in MeCN (15 mL) was added pyrazole (2) (1 eq) to the reaction mixture. Then the reaction mixture was stirred at 90 °C for 12 h. Upon completion of the reaction (as checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, it was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to give the intermediate 10, 1.2 g; 51% yield; LCMS: m/z 215.9 (M+H+) Step 2: Synthesis of 6-chloro-3-(2,4-dimethoxypyrimidin-5-yl)-4-(1H-pyrazol-1- yl)pyridazine (11) The intermediate 10 (0.3 g, 1.395 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4 ) (0.282 g, 1.534 mmol, 1.1 eq), and K2CO3 (0.482 g, 3.48 mmol, 2.5 eq) in dioxane and water (10 mL:2 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0.114 g, 0.13 mmol, 0.1 eq) was added and the reaction mixture was stirred at 90 °C for 1 h. Upon completion of the reaction (as confirmed by TLC), the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude.
The crude was purified by combi flash chromatography to obtain intermediate 11, 100 mg, 22% yield; LCMS: m/z 319 (M+H+) Step 5: Synthesis of 5-(6-chloro-4-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione (Example 3) 4M HCl in dioxane (5 mL) was added to intermediate 11 (0.2 g, 0.628 mmol, 1 eq) in sealed tube and it was stirred at 60 °C for 24 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl to give the crude. The crude was washed with Et2O (3 X 10 mL) to give the desired product compound of Example 3, 20 mg, 10.96% yield; LCMS: m/z 291.4 (M+H+); HPLC: 96.93%;1H NMR (300 MHz, DMSO-d6): ^ 11.38 (1H, d, J = 5.2 Hz), 11.258 (1H, brs), 8.408-8.403 (1H, d, J = 2 Hz ), 8.248 (1H, s), 7.898 (1H, d, J = 6 Hz), 7.822 (1H, s), 6.57 (1H, s) ppm. Example 4: 5-(6-methyl-5-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 6-chloro-3-methyl-4-(1H-pyrazol-1-yl)pyridazine (13) To a stirred solution of intermediate 12 (0.5 g, 3.06 mmol, 1 eq) in MeCN (20 mL) were added intermediate 2 (0.209 g, 3.067 mmol, 1 eq) and K2CO3 (0.848 g, 6.13 mmol, 2 eq) and the reaction mixture was stirred at 85 °C for 12 h. Upon completion of the reaction (checked by TLC),
ice-water was added to the reaction mixture. The resultant precipitate was filtered and washed with EtOAc (2 X 5 mL) to afford the desired product as a white solid. The solid was further purified by combi flash chromatography using EtOAc/Hexane solvent system to give intermediate 13, 0.25 g, 41.88% yield. LC-MS: m/z 195 (M+H). Step 2: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-(1H-pyrazol-1- yl)pyridazine (14) The intermediate 13 (0.34 g, 1.74 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (0.32 g, 1.74 mmol, 1 eq), and K2CO3 (0.64 g, 4.36 mmol, 2.5 eq) in dioxane and water (10mL : 2mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon gas for 0.5 h. Then Pd(dppf)Cl2.DCM (0.1 g, 0.12 mmol, 0.07 eq) was added and the reaction was stirred at 90 °C for 2 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with DCM (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography using DCM/MeOH solvent system to afford the desired intermediate 14, 0.1 g; 19% yield LC-MS: m/z 299 (M+). Step 3: Synthesis of 5-(6-methyl-5-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione A solution of intermediate 14 (0.2 g, 0.67 mmol, 1 eq) in MeOH (5 mL) was taken into sealed tube, 4M HCl in dioxane (5 mL) was added and the reaction was stirred at 60 °C for 8 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl. The crude product was washed with Et2O (2 X 10 mL) and the precipitate formed was filtered and dried to give the desired compound Example 4, 0.05 g, 27% yield. LC-MS: m/z 271.05 (M+H); HPLC: 95.92%; 1H NMR (400 MHz, DMSO-d6): ^ 11.79 (1H, brd), 11.591 (1H, brs), 8.478-8.23 (3H, m), 7.928 (1H, d, J = 2.8 Hz), 6.677-6.662 (1H, brs), 2.79 (3H, s) ppm. Example 5: 5-(6-chloro-4-(cyclopropylamino)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 3,6-dichloro-N-cyclopropylpyridazin-4-amine (16) A solution of intermediate 9 (1.5 g, 8.178 mmol, 1 eq) and intermediate 15 (4.67 g, 81.78 mmol, 10 eq) in THF (15 mL) were taken in a sealed tube and it was stirred at 60 °C for 12 h. Upon completion of the reaction (checked by TLC), the solvent was removed under reduced pressure to give crude. The crude was purified by combi flash chromatography and obtained the intermediate 16, 0.5 g, 29.9% yield. LC-MS: m/z 205.0 (M+H+). Step 2: Synthesis of 6-chloro-N-cyclopropyl-3-(2,4-dimethoxypyrimidin-5-yl)pyridazin-4- amine (17) The intermediate 16 (0.3 g, 1.47 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (0.27 g, 1.47 mmol, 1 eq), and K2CO3 (0.406 g, 2.94 mmol, 2 eq) in dioxane and water (4 mL:1 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0.084 g, 0.1 mmol, 0.07 eq) was added to the reaction mixture and the reaction mixture was stirred at 80 °C for 3 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to give intermediate 17, 200 mg. 44% yield. LC-MS: m/z 308.1 (M+H+). Step 5: Synthesis of 5-(6-chloro-4-(cyclopropylamino)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 5)
1N HCl (10 mL) was added to intermediate 17 (0.25 g, 0.812 mmol, 1 eq) in sealed tube and the reaction mixture was stirred at 60 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and the reaction mixture was quenched with NaHCO3 (5 mL), extracted with EtOAc (3 X 20 mL). The organic layer was washed with brine solution (1 X 10 mL). The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was washed with pentane (2 X 20 mL), diethyl ether (2 X 20 mL) and finally filtered and dried under reduced pressure to give the desired compound Example 5, 100 mg, 44.03% yield. LC-MS: m/z 280.3 (M+H+); HPLC: 97.5%; 1H NMR (400 MHz, DMSO-d6): ^ 11.317 (1H, brs), 11.282 (1H, d, J = 5.6 Hz), 7.604 (1H, d, J = 6 Hz), 7.487 (1H, brs), 7.066 (1H, s), 5.219 (1H, brs), 0.849-0.805 (2H, m), 0.503-0.467 (2H, m) ppm. Example 6: 5-(5-(4-(2-hydroxyethyl)-1H-pyrazol-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole (19) To a stirred solution of intermediate 18 (0.5 g, 1 eq) in DCM (10 mL) was added imidazole (2.5 eq) and the reaction mixture was cooled to 0 °C. Then the TBDMSCl (1.5 eq) was added
dropwise to the reaction mixture and stirred at rt for 12 h. Upon completion of the reaction (checked by TLC), the reation mixture was quenched with water (5 mL) and extracted with EtOAc (2 X 50 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography using EA/DCM solvent system and the product was eluted at 50% EA/Hexane and gave the desired intermediate 19 as a white solid, 0.4 g, 40% yield. LC-MS: m/z 227.2 (M+). Step 2: Synthesis of 4-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-1-yl)-6-(2,4- dimethoxypyra midin-5-yl)-3-methylpyridazine (21) To a stirred solution of intermediate 19 (0.34 g, 1.5 mmol, 2 eq) in MeCN (10 mL) was added Cs2CO3 (0.489 g, 1.5 mmol, 2 eq) and the reaction mixture was purged with Ar for 15 min. Then followed by intermediate 20 (0.5 g, 1.875 mmol, 1 eq) was added to the reaction mixture. The reaction mixture was heated at 80 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2 X 50 mL). Further, the combined organic layer was washed with brine solution, dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography using EA/DCM solvent system to furnish the desired intermediate 21, 400 mg, 46% yield. LC-MS: m/z 457.2 (M+). Step 3: Synthesis of 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine (20) The intermediate 35 (2 g, 12.27 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (2.48 g, 13.5 mmol, 1.1 eq), and Cs2CO3 (6.12 g, 18.77 mmol, 1.53 eq) in dioxane and water (4 mL:1 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0.18 g, 0.24 mmol, 0.02 eq) was added and the reaction mixture was stirred at 90 °C for 16 h. Upon completion of the reaction (checked by TLC), the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the combined organic layer was washed with brine solution. The organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to give the desired intermediate 20, 1.7 g, 52% yield. LC-MS: m/z 267.1 (M+). Step 4: Synthesis of 5-(5-(4-(2-hydroxyethyl)-1H-pyrazol-1-yl)-6-methylpyridazin-3- yl)pyrimidine-2,4(1H,3H)-dione (Example 6)
To a solution of 1N HCl (5 mL) and intermediate 21 (0.1 g, 0.219 mmol, 1 eq) were taken in sealed tube. The reaction mixture was stirred at 60 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl. The crude was washed with EtOAc and the aqueous layer was lyophilised to give the desired compound of Example 6, 25 mg, 36% yield; LC-MS: m/z 315 (M+); HPLC: 93.95%; 1H NMR (300 MHz, DMSO-d6): ^ 11.67 (1H, d, J = 6 Hz), 11.58 (1H, brs), 8.43-8.417 (2H, m), 8.22 (1H, s), 7.79 (1H, s), 3.61-3.57 (2H, t, J = 7.2 Hz), 2.80 (3H, s), 2.667-2.621 (2H, t, J = 7.2 Hz) ppm. Example 7: 5-(6-methyl-5-(pyrrolidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-(pyrrolidin-1- yl)pyridazine (23) To a stirred solution of intermediate 20 (0.25 g, 0.937 mmol, 1 eq) in IPA (8 mL) were added intermediate 22 (0.067 g, 0.937 mmol, 1.1 eq) and DIPEA (0.24 g, 1.870 mmol, 2.5 eq). Then the reaction mixture was stirred at 130 °C for 48 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography and give the intermediate 23, 0.12 g, 43% yield. LC-MS: m/z 302 (M+H). Step 2: Synthesis of 5-(6-methyl-5-(pyrrolidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione (Example 7) To a stirred solution of intermediate 23 (0.123 g, 0.48 mmol, 1 eq) in MeOH (3 mL) were taken in sealed tube was added 1 N HCl (3 mL) and the reaction mixture was stirred at 60 °C for 8h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and gave the crude, which was washed with Et2O (2 X 10 mL) and the precipitate was formed, which was filtered and dried to give the desired compound of Example 7, 0.096 g, 86% yield. LC-MS: m/z 274.3 (M+H); 98.37%; 1H NMR (400
MHz, DMSO-d6): ^ 12.19 (1H, brs), 11.82 (1H, s), 8.411 (1H, s), 7.14 (1H, s), 3.37 (4H, m), 2.77 (3H, s), 1.971 (4H, m) ppm. Example 8: 5-(6-methyl-5-(piperidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 5-(6-methyl-5-(piperidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione (Example 8) To a stirred a solution of intermediate 20 (0.2 g, 0.75 mmol, 1 eq), and intermediate 24 (0.12 g, 1.50 mmol, 2 eq) in IPA:DMF (1:1, 8 mL) was added DIPEA (0.19 g, 1.50 mmol, 2 eq) and the reaction mixture was stirred at 130 °C for 48 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to give the crude compound which was washed with Et2O (2 X 10 mL) and the precipitate formed was filtered and dried to give the desired compound of Example 8, 0.05 g, 25% yield. LC-MS: m/z 288.1 (M+); HPLC: 95.01%; 1H NMR (400 MHz, DMSO-d6): ^ 11.58 (2H, brs), 8.81-8.28 (1H, s) 7.79 (1H, s), 2.98 (4H, s), 2.52 (3H, s), 1.65 (6H, m) ppm. Example 9 and Example 10: (S)-5-(6-chloro-4-(3-fluoropyrrolidin-1-yl)pyridazin-3- yl)pyrimidine-2,4(1H,3H)-dione and (S)-5-(4-(3-fluoropyrrolidin-1-yl)pyridazin-3- yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 3,6-dichloro-4-(3-fluoropyrrolidin-1-yl)pyridazine (27) To a stirred solution of intermediate 25 (0.45 g, 1.97 mmol, 1 eq), intermediate 26 (0.176, 1.975 mmol, 1 eq) in IPA (5 mL) was added DIPEA (0.511, 3.95 mmol, 2 eq) at 0 °C and the reaction mixture was stirred at 70 °C for 6 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with NH4Cl (5 mL) and extracted with ethyl acetate (3 X 50 mL). Further, the combined organic layer was washed with brine solution, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude intermediate 27, 0.442 g, 94.8% yield and this was taken further without any purification. LC-MS: m/z 236.2 (M+). Step 2: Synthesis of (S)-6-chloro-3-(2,4-dimethoxypyrimidin-5-yl)-4-(3-fluoropyrrolidin-1- yl)pyridazine (28) The intermediate 27 (0.42 g, 1.78 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (0.329 g, 1.78 mmol, 1 eq), and K2CO3 (0.494 g, 3.57 mmol, 2 eq) in dioxane and water (20 mL: 4 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 20 min. Then, Pd(dppf)Cl2.DCM (0.073 g, 0.08 mmol, 0.05 eq) was added and the reaction mixture was stirred at 80 °C for 6 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the combined organic layer was washed with brine solution. The washed organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography using EtOAc/Hexane solvent system to afford the desired intermediate 28, 0.311 g, 51.20% yield. LC-MS: m/z 340 (M+). Step 3: Synthesis of (S)-5-(6-chloro-4-(3-fluoropyrrolidin-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 9) To a stirred solution of intermediate 28 (0.3 g, 0.883 mmol, 1 eq) in MeOH (5 mL) in sealed tube was added 1 N HCl (5 mL) and the reaction mixture was stirred at 50 °C for 24 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl to obtain a crude. The crude was washed with pentane (2 X 20 mL), diethyl ether (2 X 20 mL) and finally filtered and dried under reduced pressure to give the desired compound of Example 9, 0.08 g; 29% yield. LC-MS: m/z 311.7 P(M+); HPLC: 96.33%; 1H NMR (400 MHz, DMSO-d6): ^ 11.60 (2H, brs), 8.79 (1H, d), 7.78 (1H, d), 7.18 (1H, d), 3.80-3.62 (2H, brs), 3.19 (1H, s), 2.10-1.72 (4H, m) ppm. Step 4: Synthesis of
(S)-5-(4-(3-fluoropyrrolidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (Example 10) To a stirred solution of 10% palladium on charcoal (20 mg) in MeOH, a solution of Example 9 (0.08 g, 0.25 mmol, 1 eq) in MeOH (5 mL) was added. The resulting suspension was stirred at RT for 4 h under H2 balloon (40 psi). Upon completion of the reaction (as indicated by TLC), the reaction mixture was filtered through celite bed. The celite bed was washed with MeOH (25 ml X 2) and combined organic layer was dried under vacuum to afford the title compound Example 10, (0.010 g, 7.1% yield). LC-MS: m/z 278.1 (M+H+). HPLC: 94.20%; 1H NMR (400 MHz, DMSO-d6): ^ 11.62 (2H, brs), 8.84 (1H, d), 7.82 (1H, d), 7.22 (1H, d), 5.59-5.48 (1H, brd), 4.19-3.80 (4H, m), 2.38-2.20 (2H, m) ppm. Example 11: 5-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of 3-chloro-5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazine (31) To a stirred solution of intermediate 29 (0.1 g, 0.67 mmol, 1 eq), K2CO3 (0.14 g, 1 mmol, 1.5 eq) in MeCN (2.5 mL), was added the intermediate 30 (0.091 g, 0.67 mmol, 1 eq) to the reaction mixture. The reaction mixture was stirred at 70 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was quenched with ice-water. The resultant precipitate was filtered and subsequently washed with EtOAc (2 X 20 mL) and diehtylether (3 X 20 mL) to afford the desired intermediate 31 as a white solid, 0.7 g crude and taken further for the next step without any purification. LC-MS: m/z 249.0 (M+). Step 2: Synthesis of 3-(2,4-dimethoxypyrimidin-5-yl)-5-(4-(trifluoromethyl)-1H-pyrazol-1- yl)pyridazine (32)
The intermediate 31 (0.22 g, 0.88 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid 4 (0.19 g, 1.06 mmol, 1.2 eq), and K2CO3 (0.25 g, 1.77 mmol, 2 eq) in dioxane and water (4 mL:1 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0.02 g, 0.02 mmol, 0.03 eq) was added and the reaction mixture was stirred at 90 °C for 9 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the combined organic layer was washed with brine solution. The washed organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to give the desired inttermediate 32, 0.18 g; 57% yield. LC-MS: m/z 353.1 (M+). Step 3: Synthesis of 5-(5-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 11) To a stirred solution of intermediate 32 (0.2 g, 0.56 mmol, 1 eq) in 1 N HCl (5 mL) in sealed tube, then the reaction mixture was stirred at 60 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and quenched with NaHCO3 (5 mL). Furthermore, the reaction mass was extracted with EtOAc (3 X 20 mL), washed with brine solution (1 X 10 mL). The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was washed with pentane (2 X 20 mL), diethylether (2 X 20 mL) and finally filtered and dried under reduced pressure to give the desired compound Example 11, 0.15 g; 81% yield. LC-MS: m/z 325.1 (M+); HPLC: 98.1%; 1H NMR (400 MHz, DMSO-d6): ^ 11.62 (2H, brs), 9.59 (1H, s), 9.80 (1H, s), 8.92 (1H, s), 8.47 (1H, s), 8.42 (1H, s) ppm. Example 12: (S)-5-(5-(3-fluoropyrrolidin-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of (S)-6-(2,4-dimethoxypyrimidin-5-yl)-4-(3-fluoropyrrolidin-1-yl)-3- methylpyridazine (34) To a stirred a solution of intermediate 20 (0.2 g, 0.74 mmol, 1 eq), intermediate 33 (0.13 g, 1.50 mmol, 2 eq) in IPA:DMF (1:1, 8 mL) was added DIPEA (0.19 g, 1.50 mmol, 2 eq) and the reaction mixture was stirred at 130 °C for 48 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and gave the crude, which was washed with Et2O (2 X 10 mL) and the precipitate formed was filtered and dried to give the desired intermediate 34, 0.1 g, 43% yield. LC-MS: m/z 320 (M+). Step 2: Synthesis of (S)-5-(5-(3-fluoropyrrolidin-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 12) To a stirred solution of intermediate 34 (0.08 g, 0.25 mmol, 1 eq) in MeOH (10 mL) in sealed tube was added 1 N HCl (3 mL) and the reaction mixture was stirred at 60 °C for 8 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and gave the crude, which was washed with Et2O (2 X 10 mL) and the precipitate formed was filtered and dried to give the desired compound Example 12, 0.005 g, 6.84% yield. LC-MS: m/z 292.2 (M+H); HPLC:96.03%; 1H NMR (400 MHz, DMSO-d6): ^ 12.12 (1H, brs), 11.865 (1H, s), 8.41 (1H, s), 7.176 (1H, s), 6.71 (1H, brs), 5.59 (1H, d, 52.4 Hz), 4.147- 3.758 (4H, m), 2.801 (3H, s), 2.370-2.152 (2H, m) ppm. Example 13: 5-(5-(4-fluoro-1H-pyrazol-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-(4-fluoro-1H-pyrazol-1-yl)-3- methylpyridazine (37) To a stirred solution of intermediate 20 (0.3 g, 1.12 mmol, 1 eq), intermediate 36 (0.116 g, 1.35 mmol, 1.2 eq) in DMF (5 mL) was added Cs2CO3 (073 g 225 mmol, 2 eq) at rt. The reaction
mixture was purged with Nitrogen for 15 mins followed by the addition of CuI (0.006 g, 0.03 mmol, 0.03 eq). The reaction mixture was irradiated under microwave conditions at 100 °C for 1 h. Upon completion of the reaction (checked by TLC), the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to give the desired intermediate 37, 200 mg; 56% yield. LC-MS: m/z 317.1 (M+). Step 2: Synthesis of 5-(5-(4-fluoro-1H-pyrazol-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 13) To a stirred solution of intermediate 37 (0.2 g, 0.632 mmol, 1 eq) in 1 N HCl (5 mL) in sealed tube, the reaction mixture was stirred at 60 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and quenched with NaHCO3 (5 mL). Furthermore, the reaction mass was extracted with EtOAc (3 X 20 mL), washed with brine solution (1 X 10 mL). The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was washed with pentane (2 X 20 mL), diethylether (2 X 20 mL) and finally filtered and dried under reduced pressure to give the desired compound Example 13, 0.08 g; 43% yield. LC-MS: m/z 289.3 (M+); HPLC: 99.5%; 1H NMR (400 MHz, DMSO-d6): ^ 11.616-11.587 (2H, brs), 8.637-8.621 (1H, d, J = 4.8 Hz) 8.457-8.420 (2H, m), 8.066 (1H, d, J, 3.9 Hz), 2.786 (3H, s) ppm. Example 14: 5-(6-methyl-5-(4-methylpiperidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione
Step 1: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-(4-methylpiperidin-1- yl)pyridazine (39) To a stirred solution of intermediate 20 (0.15 g, 0.562 mmol, 1 eq), intermediate 38 (0.083 g, 0.84 mmol, 1.5 eq) in DMF (10 mL) was added Cs2CO3 (0.18 g, 1.4 mmol, 2.5 eq) and CuI (0.002 g, 0.010 mmol, 0.03 eq). The reaction mixture was irradiated under microwave conditions at 100 °C for 1 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by Prep-HPLC chromatography and obtained the intermediate 39, 22 mg; 11.88% yield. LC-MS: m/z 330 (M+). Step 2: Synthesis of 5-(6-methyl-5-(4-methylpiperidin-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 14) To a stirred solution of intermediate 39 (0.1 g, 0.30 mmol, 1 eq) in 1N HCl (15 mL) in sealed tube and the reaction mixture was stirred at 60 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and quenched with NaHCO3 (5 mL). Furthermore, the reaction mass was extracted with EtOAc (3 X 20 mL), the separated organic layer was washed with brine solution (1 X 10 mL). The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was washed with pentane (2 X 20 mL), diethyl ether (2 X 20 mL) and finally filtered and dried under reduced pressure to give the crude. The crude was purified by Prep-HPLC chromatography and the compound Example 14 was obtained as 0.010 g; 10% yield; LC-MS: m/z 302.3 (M+); HPLC: 95.13%; ^ 1H NMR (300 MHz, DMSO- d6): ^ 11.92 (1H, brs), 11.78 (1H, brs), 8.396 (1H, d, J = 6 Hz), 7.602 (1H, s), 3.845 (2H, m), 3.110 (2H, m), 2.592 (3H, s), 1.793 (3H, m), 1.305 (2H, m), 0.967 (3H, d, J = 6 Hz) ppm. Example 15: 5-(6-methyl-5-(4-methyl-1H-imidazol-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-(4-methyl-1H-imidazol-1- yl)pyridazine (41) To a stirred a solution of intermediate 20 (0.061 g, 0.375, 1 eq) in DMF (5mL) were added intermediate 40 (0.062 g, 0.75 mmol, 2 eq), CuI (0.002 g, 0.010 mmol, 0.03 eq), and Cs2CO3 (0.244 g, 0.75 mmol, 2 eq) and the reaction mixture was stirred at rt for 18 h. Upon completion of the reaction (checked by TLC), the solvent was evaporated under reduced pressure and quenched with water (10ml) and extracted with EtOAc (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography and give the desired intermediate 41, 0.061 g, 52% yield. LC-MS: m/z 313 (M+H). Step 2: Synthesis of 5-(6-methyl-5-(4-methyl-1H-imidazol-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 15) To a stirred solution of intermediate 41 (0.061 g, 0.195 mmol, 1 eq) in MeOH (3 mL) in sealed tube was added 1 N HCl (1 mL) and the reaction mixture was stirred at 65 °C for 18 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and gave the crude, which was washed with Et2O (2 X 10 mL) and the precipitate formed was filtered and dried to give the desired compound Example 15, 0.005 g, 9% yield. LC-MS: m/z 285.3 (M+H); HPLC: 93.66%; 1H NMR (400 MHz, DMSO-d6): ^ 11.695 (1H, d, J = 6.0 Hz), 11.62 (1H, s), 9.01 (1H, brs), 8.504 (1H, d, J = 6.0 Hz), 8.41 (1H, s), 7.738 (1H, s), 2.65 (3H, s), 2.32 (3H, s) ppm. Example 16: 5-(5-(3,3-dimethylpiperidin-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
To a stirred a solution of intermediate 20 (0.15 g, 0.56 mmol, 1 eq), intermediate 42 (0.19 g, 1.68 mmol, 3 eq) in IPA:DMF (1:1, 6 mL) was added DIPEA (0.21 g, 1.68 mmol, 3 eq) at 0 °C
and the reaction mixture was stirred at 130 °C for 48 h. Upon completion of the reaction (checked by TLC), the reaction mixture was washed with sat. NH4Cl solution and extracted with EtOAc (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was washed with Et2O (2 X 10 mL) and the precipitate formed was filtered and dried to give the desired compound Example 16, 0.05 g, 25% yield. LC-MS: m/z 316.4 (M+); HPLC: 98.13%; 1H NMR (400 MHz, DMSO-d6): ^ 11.437-11.409 (3H, brs), 8.27 (1H, d, J = 2Hz, 6Hz) 7.74 (1H, s), 5.75 (1H, s), 2.943 (2H, m), 2.706 (2H, m), 2.564 (3H, s), 1.710 (2H, m), 1.394 (2H, m), 1.00 (6H, s) ppm. Example 17: 5-(6-methyl-5-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-(4- (trifluoromethyl)piperidin-1-yl)pyridazine (44) To a stirred solution of intermediate 20 (0.05 g, 0.187 mmol, 1 eq) in MeCN (5 mL) was added intermediate 43 (0.029 g, 0.187 mmol, 1 eq) and DIPEA (0.048 g, 0.370 mmol, 2 eq) and the reaction mixture was stirred at 85 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to give the crude intermediate 44. (0.05 g, crude). The crude intermediate 44 was taken further without any purification for the next step. LC-MS: m/z 384 (M+H). Step 2: Synthesis of 5-(6-methyl-5-(4-(trifluoromethyl)piperidin-1-yl)pyridazin-3- yl)pyrimidine-2,4(1H,3H)-dione (Example 17) To a stirred solution of intermediate 44 (0.1 g, 0.261 mmol, 1 eq) in sealed tube was added 1 N HCl (10 mL) and the reaction mixture was stirred at 60 °C for 8 h. Upon completion of the
reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and gave the crude, which was purified by Prep-HPLC chromatography to give the desired compound Example 17, 7 mg, 7.55% yield. LC-MS: m/z 356.6 (M+H); HPLC: 95.8%; 1H NMR (400 MHz, DMSO-d6): ^ 11.59 (2H, brs), 8.319 (1H, d, J = 6.0 Hz), 7.75 (1H, s), 3.59 (2H, m), 2.87 (2H, m), 2.58 (4H, s), 1.98 (2H, m), 1.62 (2H, m) ppm. Example 18: 5-(6-(methylamino)-5-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione
Step 1: Synthesis of 3,6-dichloro-4-(1H-pyrazol-1-yl)pyridazine (10) To a stirred a solution of intermediate 9 (1 g, 5.45 mmol, 1.2 eq) in MeCN (30 mL) was added intermediate 2 (0.371 g, 5.45 mmol, 1 eq) and K2CO3 (1.507 g, 10.9 mmol, 2 eq) and the reaction mixture was stirred at 50 °C for 6 h. Upon completion of the reaction (checked by TLC), the solvent was evaporated under reduced pressure and quenched with water (10ml) and extracted with EtOAc (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography and the desired intermediate 10 was obtained 0.75 g, 64% yield. LC-MS: m/z 216 (M+H). Step 2: Synthesis of 6-chloro-N-methyl-4-(1H-pyrazol-1-yl)pyridazin-3-amine (45) To a stirred solution of intermediate 10 (0.2 g, 0.93 mmol, 1 eq) in MeOH (3 mL) was added methylamine (0.028 g, 0.93, 1 eq) at 0 °C and the reaction mixture was stirred at 100 °C for
2h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to give the crude, which was purified by combi flash chromatography using EtOAc/Hexane solvent system to give the desired intermediate 45, 0.064 g, 32.8% yield. LC-MS: m/z 210 (M+). Step 3: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-N-methyl-4-(1H-pyrazol-1- yl)pyridazin-3-amine (46) The compound intermediate 45 (0.35 g, 1.669 mmol, 1 eq), (2,4-dimethoxypyrimidin-5- yl)boronic acid (4) (0.307 g, 1.669 mmol, 1 eq), and K2CO3 (0.462 g, 3.34 mmol, 2 eq) in dioxane and water (4 mL:1 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0.068g, 0.010 mmol, 0.05 eq) was added and the reaction mixture was stirred at 90 °C for 6 h. Upon completion of the reaction (checked by TLC), the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to give the desired intermediate 46, 0.15 g, 28% yield. LC-MS: m/z 314 (M+). Step 4: Synthesis of 5-(6-(methylamino)-5-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 18) To a stirred solution of intermediate 46 (0.05 g, 0.16 mmol, 1 eq) in MeOH (3 mL) in sealed tube was added 1N HCl (1 mL) and the reaction mixture was stirred at 50 °C for 16 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and gave the crude, which was washed with Et2O (2 X 10 mL) and the precipitate formed was filtered and dried to give the desired compound Example 18, 0.025 g, 54% yield. LC-MS: m/z 286.05 (M+H); HPLC: 93.17%; 1H NMR (400 MHz, DMSO-d6): ^ 11.85 (1H, brs), 11.75 (1H, brs), 8.76-8.75 (1H, d, J = 2 Hz) 8.36 (1H, s), 8.322 (8.307 (1H, d, J = 6 Hz), 8.071 (1H, s), 6.821 (1H, s), 3.086 (3H, s) ppm. Example 19: 5-(6-methyl-5-(3-(trifluoromethyl)pyrrolidin-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of 3,6-dichloro-4-(3-(trifluoromethyl)pyrrolidin-1-yl)pyridazine (48) To a stirred a solution of intermediate 9 (0.35 g, 1.907 mmol, 1 eq), intermediate 47 (0.292, 2.099 mmol, 1.1 eq) in IPA (8 mL) was added DIPEA (0.37, 2.86 mmol, 1.5 eq) and the reaction mixture was stirred at 70 °C for 4 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and the precipitate formed was filtered and dried under reduced pressure to give the desired intermediate 48 (0.39 g, 71.45% yield) and this was taken further without any purification. LCMS: m/z 286.1 (M+H+) Step 2: Synthesis of 6-chloro-3-methyl-4-(3-(trifluoromethyl)pyrrolidin-1-yl)pyridazine (50) The intermediate 48 (0.15 g, 0.526 mmol, 1 eq), 2,4,6-trimethyl-1,3,5,2,4,6- tioxatriborinane (49) (0.079 g, 0.631 mmol, 1.2 eq), and K2CO3 (0.218 g, 1.57 mmol, 3 eq) in dioxane (8 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(PPh3)4 (0.061 g, 0.050 mmol, 0.1 eq) was added and the reaction mixture was stirred at 100 °C for 1 h. Upon completion of the reaction (checked by TLC), the solvent was removed under reduced pressure to give the crude (0.21 g) of intermediate 50 was taken further without any purification. LCMS: m/z 266.2 (M+H+) Step 3: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-(3- (trifluoromethyl)pyrrolidin-1-yl)pyridazine (51)
The intermediate 50 (0.21 g, 0.793 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (0.19 g, 1.03 mmol, 1.3 eq), and K2CO3 (0.219 g, 1.580 mmol, 2 eq) in Dioxane and water (4 mL:1 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(PPh3)4 (0.092 g, 0.080 mmol, 0.1 eq) was added and the reaction mixture was stirred at 100 °C for 1 h. Upon completion of the reaction (checked by TLC), the reaction mixture solvent was removed under reduced pressure to give the crude, and which was purified by combi flash chromatography and the desired intermedaite 51 was obtained (0.090 g, 30% yield). LCMS: m/z 370.1 (M+H+) Step 4: Synthesis of 5-(6-methyl-5-(3-(trifluoromethyl)pyrrolidin-1-yl)pyridazin-3- yl)pyrimidine-2,4(1H,3H)-dione (Example 19) To a stirred solution of 4M HCl in dioxane (5 mL) and intermediate 51 (0.088 g, 0.238 mmol, 1 eq) in sealed tube and the reaction mixture was stirred at 100 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to give the crude. The crude was washed with Pentane (2 X 10 mL), Et2O (2 X 20 mL) and the obtained solid was dried under reduced pressure to give the desired compound Example 19, 0.030, 36% yield. LCMS: m/z 342.1 (M+H+); HPLC: 95.04%; 1H NMR (400 MHz, DMSO-d6): ^ 11.450 (1H, brs), 8.250 (1H, s), 7.453 (1H, s), 3.79-3.75 (1H, m), 3.539 (2H, m), 3.32 (1H, m), 2.693 (3H, s), 2.38 (2H, m), 2.12 (1H, m) ppm. Example 20: 5-(5-(3,5-dimethylpiperidin-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-(3,5-dimethylpiperidin-1-yl)-3- methylpyridazine (53) To a stirred a solution of intermediate 20 (0.2 g, 0.787 mmol, 1 eq) in IPA (3 mL) and DMF (3 mL) was added intermediate 52 (0.134 g, 1.18 mmol, 1.5 eq) and DIPEA (0.2 g, 1.57 mmol, 2 eq) and the reaction mixture was stirred at 130 °C for 48 h. Upon completion of the
reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to give the desired intermediate 53 as 0.15 g; 55% yield. LCMS: m/z 344.1 (M+H+) Step 2: Synthesis of 5-(5-(3,5-dimethylpiperidin-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 20) To a stirred solution of 1N HCl (5 mL) and intermediate 53 (0.12 g, 0.349 mmol, 1 eq) in sealed tube and the reaction mixture was stirred at 60 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl to give the crude. The crude was washed with Et2O (3 X 10 mL) to give the desired compound Example 20, 0.015 g; 13.63% yield. LCMS: m/z 316.1; (M+H+); HPLC: 84%; 1H NMR (400 MHz, DMSO-d6): ^ 11.182 (1H, brs), 8.252 (1H, s), 7.749 (1H, s) , 3.316-3.289 (2H, m), 3.031 (1H, m), 2.702-2.573 (3H, m), 2.322-2.241 (1H, m), 1.846-1.811 (2H, m), 1.255-1.013 (1H, m), 0.918-0.902 (6H, m), 0.803-0.712 (1H, m) ppm. Example 21: 5-(5-(diethylamino)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 6-chloro-N,N-diethylpyridazin-4-amine (55) To a stirred solution of intermediate 29 (0.4 g, 2.685 mmol, 1 eq), intermediate 54 (1.964 g, 26.85 mmol, 10 eq) in IPA was added DIPEA (1.73 g, 13.42 mmol, 5 eq) and the reaction mixture was stirred at 70 °C for 14 h. Upon completion of the reaction (checked by TLC), the solvent was evaporated and the reaction was quenched with ice-water. Subsequently washed with EtOAc (2 X 20 mL) extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography and afford theintermeiate 55, 0.4 g, 80% yield. LCMS: m/z 186.1 (M+H+)
Step 2: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-N,N-diethylpyridazin-4-amine (56) The intermediate 55 (0.4 g, 2.15 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (0.59 g, 3.2 mmol, 1.5 eq), and K2CO3 (0.59 g, 4.3 mmol, 2 eq) in dioxane and water (4 mL:1 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, PddppfCl2.DCM (0.12 g, 0.1 mmol, 0.05 eq) was added and the reaction mixture was stirred at 90 °C for 9 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography and gave the intermediate 56, 0.2 g; 32% yield. LCMS: m/z 290.2 (M+H+) Step 3: Synthesis of 5-(5-(diethylamino)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (Example 21) To a stirred solution of 4M HCl in dioxane (5 mL) and intermediate 56 (0.2 g, 0.69 mmol, 1 eq) in sealed tube and it was stirred at 60 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl. The crude was washed with pentane (2 X 20 mL), diethylether (2 X 20 mL) and finally filtered and dried under reduced pressure to give the desired compound Example 21, 0.1 g; 55% yield. LCMS: m/z 262.2 (M+H+); HPLC: 99.4%; 1H NMR (400 MHz, DMSO-d6): ^ 14.92 (1H, brs), 12.221 (1H, d, J = 4.8 Hz), 11.83 (1H, s), 8.778 )1H, d, J = 1.6 Hz), 8.440 (1H, d, J = 5.6 Hz), 7.427 (1H, d, J = 1.6 Hz), 3.731-3.563 (4H, m), 1.215-1.183 (6H, m) ppm. Example 22: 5-(5-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 3-chloro-5-(4,4-difluoropiperidin-1-yl)pyridazine (58)
To a stirred a solution of intermediate 29 (0.1 g, 0.67 mmol, 1 eq), K2CO3 (0.18 g, 1.34 mmol, 2 eq) in MeCN (10 mL) was added intermediate 57 (0.08 g, 0.671 mmol, 1 eq)at RT. The reaction mixture was stirred at 70 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with ice-water. The resultant precipitate was filtered and subsequently washed with EtOAc (2 X 20 mL) and diehtylether (3 X 20 mL) to afford the desired intermediate 58 as a white solid 0.1 g (crude) and taken further for the next step without any purification. LC- MS: m/z 234.0 (M+) ppm. Step 2: Synthesis of 5-(4,4-difluoropiperidin-1-yl)-3-(2,4-dimethoxypyrimidin-5- yl)pyridazine (59) The intermediate 58 (0.2 g, 0.856 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (0.173 g, 0.942 mmol, 1.1 eq), and K2CO3 (0.237 g, 1.710 mmol, 2 eq) in dioxane and water (10 mL:2 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0.237 g, 1.710 mmol, 0.05 eq) was added and the reaction mixture was stirred at 90 °C for 9 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography and the intermediate 59 was obtained 0.25 g; 86% yield. LC-MS: m/z 338 (M+). Step 3: Synthesis of 5-(5-(4,4-difluoropiperidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione (Example 22) To a stirred solution of intermediate 59 (0.25 g, 0.74 mmol, 1 eq) in MeOH (3 mL) in sealed tube was added 1 N HCl (2 mL) it was stirred at 60 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl. The crude was washed with pentane (2 X 20 mL), diethylether (2 X 20 mL) and finally filtered and dried under reduced pressure to give the desired compound Example 22, 0.030 g; 13% yield. LC-MS: m/z 310.2 (M+); HPLC: 98.7%; 1H NMR (400 MHz, DMSO-d6): ^ 12.18 (1H, brs), 11.86 (1H, brs), 8.988 (1H, d, J = 3.6 Hz), 8.406 (1H, s), 7.63 (1H, d, J = 3.6 Hz)3.876 (4H, m), 2.167 (4H, m) ppm. Example 23 and Example 24: 3-(2,4-dimethoxypyrimidin-5-yl)-5-(1H-pyrazol-1- yl)pyridazine and 5-(5-(1H-pyrazol-1-yl)pyridazin 3 yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 3-chloro-5-(1H-pyrazol-1-yl)pyridazine (60) To a stirred a solution of intermediate 29 (0.5 g, 3.55 mmol, 1 eq), K2CO3 (0.928 g, 6.71 mmol, 2 eq) in MeCN (20 mL) was added intermediate 2 (0.228, 3.355 mmol, 1 eq) and then the reaction mixture was stirred at 60 °C for 6 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with 10% MeOH/DCM solvent system and filtered to remove the undissolved K2CO3. This was further washed with 10% MeOH/DCM solvent system. The combined filtrates were concentrated under reduced pressure to give the crude, which was purified by combi flash chromatography and the product was eluted at 23% MeOH/DCM solvent system and finally obtained the intermediate 60, 0.5 g, 82% yield LC-MS: m/z 181 (M+). Step 2: Synthesis of 3-(2,4-dimethoxypyrimidin-5-yl)-5-(1H-pyrazol-1-yl)pyridazine (Example 23) The intermediate 60 (0.4 g, 2.213 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (0.407 g, 2.213 mmol, 1.1 eq), and K2CO3 (0.612 g, 4.42 mmol, 2 eq) in dioxane and water (10 mL:2 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0.1 g, 0.12 mmol, 0.05 eq) was added and the reaction mixture was stirred at 90 °C for 9h. Upon completion of the reaction (checked by TLC), the reaction was mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to afford the desired compound Example 23, 0.2 g, 31% yield. LC-MS: m/z 285.1 (M+); HPLC: 99.6%; 1H NMR (400 MHz, DMSO-d6): ^ 9.819 (1H, d, J =2.7 Hz), 8.931(1H, s) 8.863 (1H, d, J = 2.7 Hz), 8.439 (1H, d, J = 2.7 Hz), 7.981 (1H, d, 1.5 Hz) 6.739 (1H, t, J = 1.2 Hz), 4.034 (3H, s), 3.995 (3H, s).
Step 3: Synthesis of 5-(5-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (Example 24) To a stirred solution of 1N HCl (10 mL) and Example 23 (0.12 g, 0.422 mmol, 1 eq) in sealed tube, the reaction mixture was stirred at 60 °C for 12h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl. The crude was washed with pentane (2 X 20 mL), diethylether (2 X 20 mL) and finally filtered and dried under reduced pressure to give the crude. The crude was purified by Prep-HPLC chromatography to give the desired compound Example 24, 0.022 g; 20% yield LC-MS: m/z 257.4 (M+); HPLC: 95.7%; 1H NMR (300 MHz, DMSO-d6): ^ 11.62 (1H, d, J = 6.4 Hz), 11.58 (1H, brs), 9.73 (1H, d, J =2.8 Hz), 8.81-8.77 (2H, dd, J = 2Hz, 13.2 Hz ) 8.48-8.46 (1H, d, J = 6.8 Hz ), 7.96 (1H, s), 6.71 (1H, brs) ppm. Example 25: 5-(4-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 3-chloro-4-(1H-pyrazol-1-yl)pyridazine (62) To a stirred a solution of intermediate 61 (0.5 g, 3.355 mmol, 1 eq), K2CO3 (0.928 g, 6.71 mmol, 2 eq) in MeCN (20 mL) was added pyrazole (2) (0.16 g, 2.34 mmol, 0.7 eq) and it was stirred at 80 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to afford the intermediate 62, 0.5 g, 82.5% yield; LC-MS: m/z 181 (M+). Step 2: Synthesis of 3-(2,4-dimethoxypyrimidin-5-yl)-4-(1H-pyrazol-1-yl)pyridazine (63) The intermediate 62 (0.85 g, 4.70 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid 4 (1.03 g, 5.64 mmol, 1.2 eq), and K2CO3 (1.17 g, 8.47 mmol, 1.8 eq) in dioxane and water (20
mL:4 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0.269 g, 0.32 mmol, 0.07 eq) was added and the reaction mixture was stirred at 90 °C for 9 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to give the intermedaite 63, 0.25 g; 18% yield. LC-MS: m/z 285.0 (M+). Step 3: 5-(4-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (Example 25) To a stirred solution of 4M HCl in Dioxane (5mL) and intermediate 63 (0.3 g, 1.05 mmol, 1 eq) in Dioxane (5 mL) in sealed tube and the reaction mixture was stirred at 90 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl to give the crude. The crude was purified by Prep-HPLC column chromatography to give the desired compound Example 25, 0.02 g; 7.40% yield; LC-MS: m/z 257.1 (M+). HPLC 97.3%; 1H NMR (400 MHz, DMSO-d6): ^ 11.35 (1H, d, J = 5.2 Hz), 11.210 (1H, s), 9.314 (1H, d, J =5.6 Hz), 8.307 (1H, d, J = 2.4 Hz) 7.98 (1H, d = J = 5.6 Hz), 7.902 (1H, d = J = 6 Hz), 7.78 (1H, s), 6.529 (1H, s) ppm. Example 26: 5-(6-methyl-5-(2-azaspiro[4.4]nonan-2-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of 4-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazine (20)
The intermediate 35 (0.5 g, 3.06 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid 4 (0.62 g, 3.37 mmol, 1.1 eq), and Cs2CO3 (1.9 g, 6.13 mmol, 2 eq) in dioxane, water (12 mL : 3 mL) were taken in sealed tube. The reaction mixture was purged with argon for 30 min. Then Pd(dppf)Cl2.DCM (0.25 g, 0.3 mmol, 0.1 eq) was added, the reaction mixture was again purged with argon for 10 min and stirred at 70 °C for 5 h. Upon completion of reaction checked by TLC, the reaction mixture was cooled to rt, filtered through celite. The filtrate was then diluted with EtOAc (100 mL), washed with water (50 mL). The combined organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography using 25% EtOAc in Hexane as eluent to obtain desired intermediate 20; 0.45 g; 55.02% yield; LC-MS: m/z 267.1 (M+H+). Step 2: Synthesis of 2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazin-4-yl)-2- azaspiro[4.4]nonane (65) To a stirred solution of intermediate 20 (1 g, 3.75 mmol, 1 eq), intermediate 64 (0.51 g, 4.12 mmol, 1.1 eq) in DMF (15 mL) was added Cs2CO3 (2.4 g, 7.5 mmol, 2 eq) and the reaction mixture was heated at 70 °C for 48 h. Upon completion of the reaction checked by TLC, the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to give the crude. The crude was purified on combi flash chromatography using 4% MeOH in DCM as eluent to obtain desired intermediate 65, 0.8 g as off-white solid; 60% yield; LC-MS: m/z 356.5 (M+H+). Step 3: Synthesis of 5-(6-methyl-5-(2-azaspiro[4.4]nonan-2-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 26) To a solution of intermediate 65 (0.4 g, 1.12 mmol, 1 eq) in MeOH (10 mL) in sealed tube was added conc. HCl (1 mL) and stirred at 70 °C for 5 h. Upon completion of the reaction (as confirmed by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl to obtain a crude, which was purified by prep HPLC (Column: GEMINI (150 ×21.2mm) 5µ) using 0.05% TFA in H2O and Acetonitrile as eluent. The product obtained from prep HPLC was then taken in H2O (2 mL), Acetonitrile (0.3 mL) and basified with aq. Ammonia solution to pH-8. The solid precipitated was filtered, lypholyzed to afford the desired compound Example 26, 0.2 g; 50% yield. LC-MS: m/z 328.10 (M+H+); HPLC: 99.73%; 1H NMR (400 MHz,
DMSO-d6): ^ 11.554 (2H, brs), 8.279 (1H, s), 7.213 (1H, s), 3.692 (2H, t, J = 6.6 Hz), 3.45 (2H, brs), 2.709 (3H, s), 1.849 (2H, t, J = 6.6 Hz), 1.619-1.557 (8H, m) ppm. Example 27: 5-(5-(3,3-difluoroazetidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 3-chloro-5-(3,3-difluoroazetidin-1-yl)pyridazine (67) To a stirred a solution of intermediate 29 (0.05 g, 0.336 mmol, 1 eq), K2CO3 (0.093 g, 0.67 mmol, 2 eq) in MeCN (3 mL) was added intermediate 66 (0.038 g, 0.403 mmol, 1.2 eq), and the reaction mixture was stirred at 70 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, it was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to afford the desired intermediate 67, 0.035 g; 50% yield. LC-MS: m/z 206.0 (M+). Step 2: Synthesis of 5-(3,3-difluoroazetidin-1-yl)-3-(2,4-dimethoxypyrimidin-5- yl)pyridazine (68) The intermediate 67 (0.025 g, 0.122 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (0.027 g, 0.146 mmol, 1.2 eq), and Cs2CO3 (0.080 g, 0.24 mmol, 2 eq) in dioxane and water (2 mL:0.5 mL) were taken in sealed. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0.003 g, 0.03 eq) was added and the reaction mixture was stirred at 90 °C for 2 h. Upon completion of the reaction (checked by TLC), the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to obtain the desired intermediate 68, 0.018, 47% yield; LC-MS: m/z 310.1 (M+).
Step 3: Synthesis of 5-(5-(3,3-difluoroazetidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione (Example 27) To a stirred solution of 4M HCl in dioxane (2 mL) and intermediate 68 (0.1 g, 0.32 mmol, 1 eq) in sealed tube and the reaction mixture was stirred at 90 °C for 4 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and quenched with NaHCO3 (5 mL). Furthermore, the reaction mass was extracted with EtOAc (3 X 20 mL), washed with brine solution (1 X 10 mL). The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to give the desired compound Example 27, 0.045 g; 49% yield. LC-MS: m/z 282.1 (M+); HPLC: 98%; 1H NMR (400 MHz, DMSO-d6): ^ 11.42-11.18 (1H, brs), 8.483 (1H, d, J = 2.7 Hz), 8.327 (1H, s), 7.380 (1H, d, J = 3.3 Hz), 4.534 (4H, t, J = 12.3 Hz) ppm. Example 28: 5-(6-Chloro-5-(pyrrolidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 6-chloro-4-(pyrrolidin-1-yl)pyridazin-3-amine (69) To a stirred a solution of Pyrrolidine.HCl (22) (2.276 g, 21.15 mmol, 7 eq), DIPEA (2.72 g, 21.15 mmol, 7 eq) in IPA (8 mL) was added intermediate 1 (0.63 g, 3.02 mmol, 1 eq) and then
the reaction mixture was stirred at 90 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 70 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude intermediate 69, 0.37 g, 61% yield. The crude was taken further without any purification. LC-MS: m/z 199.1 (M+). Step 2: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-4-(pyrrolidin-1-yl)pyridazin-3-amine (70) The compound intermediate 69 (0.53 g, 2.668 mmol, 1 eq), (2,4-dimethoxypyrimidin-5- yl)boronic acid (4) (0.589 g, 3.201 mmol, 1.2 eq), and Cs2CO3 (1.73 g, 5.33 mmol, 2 eq) in dioxane and water (6 mL:1.5 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0.059 g, 0.080 mmol, 0.03 eq) was added and the reaction mixture was stirred at 90 °C for 2 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to furnish the desired intermediate 70, 0.37 g; 45.87% yield. LC-MS: m/z 302.75 (M+). Step 3: Synthesis of 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-(pyrrolidin-1- yl)pyridazine (71) To a stirred solution of NaNO2 (0.048 g, 0.690 mmol, 2.1 eq) and intermediate 70 (0.1 g, 0.331 mmol, 1 eq) in RBF. Followed by 12 N HCl was added slowly at 0 °C and the reaction mixture was stirred at rt for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography and furnish the desired intermediate 71, 0.080 g, 75% yield; LC-MS: m/z 322.1 (M+). Step 4: Synthesis of 5-(6-chloro-5-(pyrrolidin-1-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione (Example 28) To a stirred solution of 4M HCl in dioxane (2 mL) and intermediate 71 (0.1 g, 0.03 mmol, 1 eq) in sealed tube and it was stirred at 100 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with NaHCO3 solution (5 mL) and extracted with ethyl acetate
(3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography and afforded the desired compound Example 28 in yield of 54.91%, 0.05 g. LC-MS: m/z 294.0 (M+); HPLC: 98.66%; 1H NMR (400 MHz, DMSO-d6): ^ 11.41-11.22 (1H, brs), 8.346 (1H, s), 7.636 (1H, s), 3.553 (4H, m), 1.926 (4H, m) ppm. Example 29: 5-(5-(3-fluoropiperidin-1-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione
To a stirred a solution of intermediate 20 (0.2 g, 0.75 mmol, 1 eq) in IPA (2.5 mL) and DMF (2.5 mL) was added intermediate 72 (0.116 g, 1.125 mmol, 1.5 eq) and DIPEA (0.24 g, 1.87 mmol, 2.5 eq) and the reaction mixture was stirred at 130 °C for 48 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to give the crude. The crude was purified by Prep-HPLC chromatography and afforded directly the compound Example 29 in 7 mg, 3% yield instead of 73; LC-MS: m/z 306.1 (M+); HPLC: 96.24%; 1H NMR (400 MHz, DMSO-d6): ^ 11.997 (1H, brs), 11.802 (1H, s), 8.421 (1H, d, J = 4.4 Hz), 7.679 (1H, s), 5.003-4.884 (1H, d, J = 47.6 Hz), 3.850 (1H, m), 3.633-3.524 (2H, m), 3.352-3.304 (1H, m), 2.623 (3H, s), 1.958-1.909 (3H, m), 1.695-1.684 (1H, m) ppm. Example 30: 5-(6-(dimethylamino)-5-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of 3,6-dichloro-4-(1H-pyrazol-1-yl)pyridazine (10) To a stirred a solution of intermediate 9 (1 g, 5.45 mmol, 1.2 eq) in MeCN (30 mL) was added intermediate 2 (0.371 g, 5.45 mmol, 1 eq) and K2CO3 (1.507 g, 10.9 mmol, 2 eq) and the reaction mixture was stirred at 50 °C for 6 h. Upon completion of the reaction (checked by TLC), the solvent was evaporated under reduced pressure and quenched with water (10ml) and extracted with EtOAc (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography and the desired intermediate 10 was obtained as 0.75 g, 64% yield. LC-MS: m/z 216 (M+H). Step 2: Synthesis of 6-chloro-N,N-dimethyl-4-(1H-pyrazol-1-yl)pyridazin-3-amine (74) To a stirred solution of intermediate 10 (0.1 g, 0.465 mmol, 1 eq) in MeOH (3 mL) was added dimethylamine (0.021 g, 0.460, 1 eq) at 0 °C and the reaction mixture was stirred at 100 °C for 2 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to give the crude compound which was purified by combi flash chromatography using EtOAc/Hexane solvent system to give the desired intermediate 74, 0.08 g, 76% yield. LC-MS: m/z 224 (M+). Step 3: Synthesis of 6-(2,4-dimethoxypyrimidin-5-yl)-N,N-dimethyl-4-(1H-pyrazol-1- yl)pyridazin-3-amine (75) The intermediate 74 (0.075 g, 0.335 mmol, 1 eq), (2,4-dimethoxypyrimidin-5-yl)boronic acid (4) (0.62 g, 0.335 mmol, 1 eq), and K2CO3 (0.093 g, 0.67 mmol, 2 eq) in dioxane and water (4 mL:1 mL) were taken in sealed tube. Followed by the reaction mixture was purged with argon for 30 min. Then, Pd(dppf)Cl2.DCM (0014 g 0010 mmol 005 eq) was added and the reaction
mixture was stirred at 90 °C for 6 h. Upon completion of the reaction (checked by TLC), the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 20 mL). Further, the organic layer was washed with brine solution. The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude. The crude was purified by combi flash chromatography to give the desired intermediate 75, 0.056 g, 51% yield. LC-MS: m/z 328 (M+). Step 4: Synthesis of 5-(6-(dimethylamino)-5-(1H-pyrazol-1-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 30) To a stirred solution of intermediate 75 (0.075 g, 0.229 mmol, 1 eq) in MeOH (4 mL) in sealed tube was added 1 N HCl (3 mL) and it was stirred at 50 °C for 18 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and gave the crude compound which was washed with Et2O (2 X 10 mL) and the precipitate formed was filtered and dried to give the desired compound Example 30, 0.015 g, 21.89% yield. LC-MS: m/z 300.05 (M+H); HPLC: 99%; 1H NMR (400 MHz, DMSO-d6): ^, 8.40 (1H, s) 8.364 (1H, s), 8.272 (1H, d, J = 2 Hz) 7.894 (1H, s), 6.674 (1H, t, 2 Hz), 2.84 (6H, s) ppm. Example - 31: 5-(5-(4-butylpiperidin-1-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione
Step 1: Synthesis of tert-butyl 4-butylidenepiperidine-1-carboxylate (78)
To a stirred solution of intermediate 77 (2.1 g, 5.29 mmol, 1.05 eq) in THF (15 mL) was added n-BuLi (0.35 g, 5.52 mmol, 1.1 eq) at -78 °C and it was stirred at 0 ° for 1 h. Followed by intermediate 76 (1 g, 5.01 mmol, 1 eq) in THF was added dropwise at -78 °C and it was slowly warmed to rt and stirred for 3 h. Upon completion of the reaction (checked by TLC), it was quenched with 10% citric acid solution (10 mL) and extracted with EtOAc (3 X 100 mL), followed by washed with brine solution (1 X 100 mL). The combined organic layer was dried over Na2SO4 and it was filtered. The filtrate was concentrated under reduced pressure to give the crude intermediate 78, 0.4 g; 33% yield. The crude was taken for the next step without any purification. LC-MS: m/z 240.2 (M+H) Step 2: Synthesis of tert-butyl 4-butylpiperidine-1-carboxylate (79) To a stirred solution of alkene intermediate 78 (0.5 g, 2.17 mmol, 1 eq) in EtOH was added 10% palladium on charcoal (1.15 g, 10.86 mmol, 5 eq). The resulting suspension was stirred at RT for 16 h under H2 balloon (45 psi). Upon completion of the reaction (as indicated by TLC), reaction mixture was filtered through celite bed. The celite bed was washed with EtOH (25 ml X 2) and combined organic layer was dried under vacuum to afford the crude, which was purified by combi flash chromatography using EtOAc/Hexane as solvent system and the desired intermediate 79 was obtained 0.3 g, 57% yield. LC-MS: m/z 242.1 (M+H) Step 3: Synthesis of 4-butylpiperidine (80) To a stirred solution of 4M HCl in dioxane (5 mL) and intermediate 79 (0.41 g, 1.69 mmol, 1 eq) in RBF and it was stirred at RT for 2 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl to give the crude. The crude was washed with Et2O (3 X 10 mL) to give the desired intermediate 80, 0.2 g, 83% yield. LC-MS: m/z 141.1 (M+H) Step 4: Synthesis of 4-(4-butylpiperidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3- methylpyridazine (81) To a stirred a solution of intermediate 80 (0.07 g, 0.26 mmol, 1 eq), intermediate 20 (0.04 g, 0.28 mmol, 1.1 eq) in IPA:DMF (1:1, 8 mL) was added DIPEA (0.06, 0.52 mmol, 2 eq) and it was stirred at 130 °C for 24 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to give the crude, which was purified by combi flash chromatography using DCM/MeOH as solvent system and furnish the desired intermediate 81, 0.02 g, 20% yield. LC-MS: m/z 37230 (M+)
Step 5: Synthesis of 5-(5-(4-butylpiperidin-1-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 31) To a stirred solution of intermediate 81 (0.03 g, 0.08 mmol, 1 eq) in MeOH (3 mL) in sealed tube was added 1 N HCl (3 mL) and it was stirred at 70 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl and gave the crude compound which was purified by combi flash chromatography using DCM/MeOH solvent system and obtained the compound Example 31, 0.015 g, 53% yield. LC-MS: m/z 344.2 (M+H); HPLC: 94.65%; 1H NMR (400 MHz, DMSO-d6): ^ 11.765 (1H, s), 11.969 (1H, brs), 8.38 (1H, s), 7.70 (1H, s), 3.846 (2H, m), 3.092 (2H, m), 2.588 (3H, s), 1.83 (2H, m), 1.563 (1H, m), 1.282 (8H, m), 0.899 (3H, m) ppm. Example 32: 5-(5-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-6-methylpyridazin-3- yl)pyrimidine-2,4(1H,3H)-dione
Step 1: Synthesis of 2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazin-4- yl)octahydrocyclopenta[c]pyrrole (83) To a stirred solution of intermediate 20 (0.1 g, 0.37 mmol, 1 eq), intermediate 82 (0.054 g, 0.488 mmol, 1.3 eq) in DMF (5 mL) was added Cs2CO3 (0.35 g, 0.93 mmol, 2.5 eq) and the reaction was heated in a sealed tube at 70 °C for 48 h. Upon completion of the reaction (checked by TLC), the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to give the crude intermediate 83 which was used in the next step without any purification., 50 mg; 45%; LC-MS: m/z 342.2 (M+H+). Step 2: Synthesis of 5-(5-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)-6-methylpyridazin-3- yl)pyrimidine-2,4(1H,3H)-dione (Example 32) To a stirred solution of intermediate 83 (0.05 g, 0.15 mmol, 1 eq) in MeOH (5 mL) in sealed tube was added conc. HCl (0.5 mL) and the reaction mixture was stirred at 70 °C for 5 h. Upon completion of the reaction (as confirmed by TLC), the reaction mixture was concentrated
under reduced pressure to remove excess HCl. The crude was then purified by prep HPLC (Column: LUNA OMEGA PS C18 (250 ×21.2mm) 5µ) using 0.05% TFA in H2O and Acetonitrile as eluent. The product obtained from prep HPLC was then taken in H2O (2 mL), Acetonitrile (0.3 mL) and basified with aq. Ammonia solution to pH-8. The solid precipitated was filtered, lypholyzed to afford the desired compound Example 32, 21 mg; 46% yield. LC-MS: m/z 314.2 (M+H+); HPLC: 98.05%; 1H NMR (400 MHz, DMSO-d6): ^ 10.25 (2H, brs), 8.39 (1H, s), 7.56 (1H, s), 3.48 (2H, m), 3.10 (2H, m), 2.71 (2H, m), 2.61 (3H, s), 1.80 (3H, m), 1.60 (3H, m) ppm. Example 33: 5-(6-methyl-5-(6-azaspiro[2.5]octan-6-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: Synthesis of 6-(6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazin-4-yl)-6- azaspiro[2.5]octane (85) To a stirred solution of intermediate 20 (0.1 g, 0.37 mmol, 1 eq), intermediate 84 (0.054 g, 0.48 mmol, 1.3 eq) in DMF (5 mL) was added Cs2CO3 (0.30 g, 0.93 mmol, 2.5 eq) and the reaction mixture was heated in a sealed tube at 70 °C for 48 h. Upon completion of the reaction (checked by TLC), the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to give the crude intermediate 85 which was used in the next step without any purification.50 mg; 45%; LC-MS: m/z 342.2 (M+H+). Step 2: Synthesis of 5-(6-methyl-5-(6-azaspiro[2.5]octan-6-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 33) To a stirred solution of intermediate 85 (0.05 g, 0.146 mmol, 1 eq) in MeOH (5 mL) in a sealed tube was added conc. HCl (0.5 mL) and was stirred at 70 °C for 5 h. Upon completion of the reaction checked by TLC, the reaction mixture was concentrated under reduced pressure to remove excess HCl. The crude was then purified by prep HPLC (Column: LUNA OMEGA PS C18 (250 ×21.2mm) 5µ) using 0.05% TFA in H2O and Acetonitrile as eluent. The product obtained
from prep HPLC was then taken in H2O (2 mL), Acetonitrile (0.3 mL) and basified with aq. Ammonia solution to pH-8. The solid precipitated was filtered, lypholyzed to afford the desired compound Example 33, 11 mg; 24% yield. LC-MS: m/z 314.1 (M+H+); HPLC: 97.65%; 1H NMR (400 MHz, DMSO-d6): ^ 10.65 (2H, brs), 8.49 (1H, s), 7.92 (1H, s), 3.06 (4H, m), 2.49 (3H, s), 1.52 (4H, m), 0.35 (4H, m) ppm. Example 34: 5-(6-methyl-5-(1-oxa-7-azaspiro[4.4]nonan-7-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step1:7-(6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazin-4-yl)-1-oxa-7- azaspiro[4.4]nonane (87) To a stirred solution of intermediate 20 (0.1 g, 0.375 mmol, 1 eq), intermediate 86 (0.072 g, 0.563 mmol, 1.5 eq) in DMF (5 mL) was added Cs2CO3 (0.3 g, 0.93 mmol, 2.5 eq) and the reaction was heated in a sealed tube at 70 °C for 48 h. Upon completion of the reaction (checked by TLC), the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to give the crude. The crude product 87 was as such taken to the next step without any purification, 90 mg; 45%; LC-MS: m/z 358.2 (M+H+). Step 2: 5-(6-methyl-5-(1-oxa-7-azaspiro[4.4]nonan-7-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione (Example 34) To a stirred solution of intermediate 87 (0.05 g, 0.14 mmol, 1 eq) in MeOH (5 mL) in a sealed tube was added conc. HCl (0.5 mL) and was stirred at 70 °C for 5 h. Upon completion of the reaction (as confirmed by TLC), the reaction mixture was concentrated under reduced pressure to remove excess HCl. The crude was then purified by prep HPLC (Column: LUNA OMEGA PS C18 (250 ×21.2mm) 5µ) using 0.05% TFA in H2O and Acetonitrile as eluent. The product obtained from prep HPLC was then taken in H2O (2 mL), Acetonitrile (0.3 mL) and basified with aq. Ammonia solution to pH-8. The solid precipitated was filtered, lypholyzed to afford the desired
compound Example 34, 15 mg; 32% yield. LC-MS: m/z 330.20 (M+H+); HPLC: 98.09%; 1H NMR (400 MHz, DMSO-d6): ^ 11.36 (2H, brs), 8.23 (1H, s), 7.35 (1H, s), 3.80 (2H, m), 3.60 (4H, m), 2.68 (3H, s), 2.05 (6H, m) ppm. Example 35: 5-(6-methyl-5-(2-azaspiro[3.3]heptan-2-yl)pyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione
Step 1: 2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-methylpyridazin-4-yl)-2-azaspiro[3.3]heptane (88) To a stirred solution of intermediate 20 (0.05 g, 0.187 mmol, 1 eq), intermediate 88 (0.022 g, 0.224 mmol, 1.2 eq) in DMF (2 mL) were added Cu(I)I (0.002 mmol, 0.05 eq) and Cs2CO3 (0.183 g, 0.56 mmol, 3 eq) and the reaction was heated in a sealed tube at 70 °C for 12 h. Upon completion of the reaction (checked by TLC), the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to give the crude. The crude was purified on combi flash chromatography using 4% MeOH in DCM as eluent to obtain desired intermediate 89, 30 mg; 49%; LC-MS: m/z 328.1 (M+H+). Step 2: 5-(6-methyl-5-(2-azaspiro[3.3]heptan-2-yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- dione (Example 35) To a stirred solution of intermediate 89 (0.04 g, 0.029 mmol, 1 eq) in MeOH (5 mL) in a sealed tube was added conc. HCl (0.5 mL) and the reaction mixture was stirred at 70 °C for 5 h. Upon completion of the reaction checked by TLC, the reaction mixture was concentrated under reduced pressure to remove excess HCl. The crude was then purified by combi flash MPLC using 10% MeOH in DCM as eluent to afford the desired compound of Example 35, 15 mg: 54% yield. LC-MS: m/z 300.20 (M+H+); HPLC: 93.56%; 1H NMR (400 MHz, DMSO-d6): ^ 11.55 (2H, brs), 8.27 (1H, s), 7.00 (1H, s), 4.24 (4H, s), 2.20 (4H, t, J = 7.6 Hz), 1.82-1.80 (m, 2H) ppm.
Although the present invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof. For example, the compounds in the Table below which can be prepared by following similar procedure as described in above Schemes/Examples with suitable modifications known to the one ordinary skilled in the art are also included in the scope of the present invention:
CD73 biochemical assay A colorimetric-based method was used for assaying compounds of the invention for CD73 enzyme inhibitory activity. Human CD73 catalyzes the conversion of AMP to adenosine with the release of orthophosphate. A Malachite Green Phosphate Detection kit is used to measure the formation of orthophosphate product. Typically, 40 µL of human-CD73 (Trp27-Lys547, His-tag) in assay buffer (20 mM Tris pH 7.5, 5 mM MgCl2) is added to a 96-well plate containing 20 µl of test compound in final 1% DMSO, serially diluted in 1:2 in an 10-12 point titration. A compound of the present invention and enzyme are incubated for 30 minutes at room temperature. Next, 20 µL of AMP in assay buffer is added to the plate. The final concentration of CD73 and AMP are ~2 nM and 50 µM respectively. Following 30 minutes reaction at room temperature, 20 µL of Malachite reagent is added to all the reaction wells. The formation of green complex formed between Malachite Green, molybdate and free orthophosphate is measured on a plate reader (620 nm). The activity on inhibition of CD73 for the compounds of the present invention is expressed as percent inhibition of internal assay controls and the results are presented in Table-1. Table-1: Percent inhibition data in CD73
Claims
We claim: 1. A compound of formula (I)
or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof; wherein, dotted lines ----- represents a bond or absent; R1 represents hydrogen, alkyl, halogen, haloalkyl, cyano or -NRxRy; R2 represents hydrogen or alkyl; R3 represents cycloalkyl or alkyl; or R2 and R3 combine together with N atom to which they are attached to form ring Q; Q represents 5- to 9-membered heteroaryl, 7- to 10-membered spiroheterocycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo; R4a represents alkoxy or hydroxy; R4b is absent; alternatively, R4a and R4b together represent an oxo group; R4c represents alkoxy or hydroxy; R4d is absent; alternatively, R4c and R4d together represent an oxo group; R4e and R4f independently are hydrogen or absent; and Rx and Ry independently represent hydrogen or alkyl.
2. The compound of claim 1, wherein R2 represents hydrogen or (C1-C6)alkyl.
3. The compound of claim 1, wherein R3 represents (C3-C5)cycloalkyl or (C1-C6)alkyl.
4. The compound of claim 1, wherein R2 represents hydrogen or (C1-C4)alkyl; and R3 represents cyclopropyl or (C1-C4)alkyl.
5. The compound of any one of claims 1 to 4, wherein Q represents 5- to 9-membered heteroaryl selected from 5- to 9-membered heteroaryl selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl (pyridinyl), pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl or purinyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo. 6. The compound of claim 1, wherein Q represents 7- to 10-membered spiroheterocycloalkyl selected from 2-azaspiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl,
6- azaspiro[2.5]octanyl, 5-azaspiro[2.4]heptanyl, 2,7-diazaspiro[4.4]nonanyl, 1,7- diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl or 2-oxa-7- azaspiro[4.4]nonanyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo.
7. The compound of claim 1, wherein Q represents 4- to 8-membered heterocycloalkyl selected from azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl or octahydrocyclopenta[c]pyrrolyl; each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino halo, haloalkyl, hydroxyalkyl and oxo.
8. The compound of claim 1, wherein Q represents pyrrolidinyl, pyrazolyl, piperidinyl, imidazolyl, azetidinyl, indazolyl, 2-azaspiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 6- azaspiro[3.4]octanyl, 6-azaspiro[2.5]octanyl, 5-azaspiro[2.4]heptanyl, 2,7- diazaspiro[4.4]nonanyl, 1,7-diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-6- azaspiro[3.4]octanyl or 2-oxa-7-azaspiro[4.4]nonanyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino halo, haloalkyl, hydroxyalkyl and oxo.
9. The compound of claim 1, wherein R1 represents hydrogen, (C1-C4)alkyl, halogen, -CF3, - CN, -NH2, -NH(CH3) or -N(CH3)2.
10. The compound of claim 1, wherein R4a and R4b together represent an oxo group; and R4c and R4d together represent an oxo group.
12. The compound of claim 11, wherein Q represents azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, imidazolyl, indazolyl, 2-azaspiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 6- azaspiro[3.4]octanyl, 6-azaspiro[2.5]octanyl, 5-azaspiro[2.4]heptanyl, 2,7- diazaspiro[4.4]nonanyl, 1,7-diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-6- azaspiro[3.4]octanyl or 2-oxa-7-azaspiro[4.4]nonanyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from -CH3, -CH2(CH2)2-CH3, gemdimethyl, -F, -Cl, gemdifluoro, -CF3, -(CH2)2OH, amino and oxo.
13. The compound of claim 11, wherein R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy; Q represents 5- to 9-membered heteroaryl, 7- to 10-membered spiroheterocycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo; and Rx and Ry independently represents hydrogen or alkyl.
14. The compound of any one of claims 11 to 13, wherein R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy;
Q represents azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, imidazolyl, indazolyl, 2- azaspiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 6- azaspiro[2.5]octanyl, 5-azaspiro[2.4]heptanyl, 2,7-diazaspiro[4.4]nonanyl, 1,7- diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl or 2-oxa-7- azaspiro[4.4]nonanyl; and each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from -CH3, -CH2(CH2)2-CH3, gemdimethyl, -F, -Cl, gemdifluoro, -CF3, - (CH2)2OH, amino and oxo; and Rx and Ry independently represents hydrogen or -CH3.
16. The compound of claim 15, wherein R1 is hydrogen, (C1-C4)alkyl, halogen, or -NRxRy. Q represents 5- to 9-membered heteroaryl, 7- to 10-membered spiroheterocycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups are unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo; and Rx and Ry independently represents hydrogen or alkyl.
17. The compound of claim 15, wherein R1 is hydrogen, (C1-C4)alkyl, halogen or -NRxRy; Q represents azetidinyl, pyrrolidinyl, pyrazolyl, piperidinyl, imidazolyl, indazolyl, 2- azaspiro[4.4]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 6-azaspiro[3.4]octanyl, 6- azaspiro[2.5]octanyl, 5-azaspiro[2.4]heptanyl, 2,7-diazaspiro[4.4]nonanyl, 1,7- diazaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl or 2-oxa-7-
azaspiro[4.4]nonanyl; wherein each group is unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from -CH3, -CH2(CH2)2-CH3, gemdimethyl, -F, -Cl, gemdifluoro, -CF3, -(CH2)2OH, amino and oxo; and Rx and Ry independently represents hydrogen or -CH3.
19. The compound of claim 18, wherein R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy; Q represents 5- to 9-membered heteroaryl, 7- to 10-membered spiroheterocycloalkyl or 4- to 8-membered heterocycloalkyl, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1, 2 or 3 substituent(s) independently selected from alkyl, amino, halo, haloalkyl, hydroxyalkyl and oxo; and Rx and Ry independently represents hydrogen or alkyl.
21. The compound of claim 20, wherein R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy; ring Z represents (C3-C5) cycloalkyl or 3- to 5-membered heterocycloalkyl containing 1-2 heteroatoms selected from O, N or S; or ring Z is absent; and Rx and Ry independently represents hydrogen or alkyl.
24. The compound of any one of claims 20-23, wherein R1 is hydrogen, (C1-C4)alkyl, halogen, haloalkyl, cyano or -NRxRy; the formula
represents
each group is unsubstituted or substituted with 1 or 2 substituent(s) independently selected from - CH3, -CH2(CH2)2-CH3, gemdimethyl, -F, -Cl, gemdifluoro, -CF3, -(CH2)2OH, amino and oxo; and Rx and Ry independently represents hydrogen or alkyl.
26. A pharmaceutical composition comprising a compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt or stereoisomer or a tautomer thereof, and a pharmaceutically acceptable carrier or excipient.
27. A compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, for use as a medicament.
28. A method of treating a disease or disorder in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof, wherein the disease or disorder is mediated by ecto-5’nucleotidase (CD73).
29. The method of claim 28, wherein the disease or disorder mediated by CD73 is a cancer selected from brain gliomas, glioblastomas, astrocytomas, multiforme, bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, uterine/cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers, testicular cancer and virus-related cancer.
30. Use of a compound according to any one of claims 1 to 25 for the manufacture of a medicament for treating a disease or disorder mediated by ecto-5’nucleotidase (CD73).
31. The use according to claim 30, wherein the disease or disorder mediated by CD73 is a cancer selected from brain gliomas, glioblastomas, astrocytomas, multiforme, bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, uterine/cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers, testicular cancer and virus-related cancer.
32. Compound of any one of claims 1 to 25 for use in the treatment of a disease or disorder mediated by the inhibition of CD73.
33. The compound for use according to claim 32, wherein the disease or disorder is a cancer selected from brain gliomas, glioblastomas, astrocytomas, multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic
neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, uterine/cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers, testicular cancer and virus-related cancer.
34. The pharmaceutical composition according to claim 26 for use in the treatment of a disease or disorder mediated by CD73.
35. The pharmaceutical composition for use according to claim 31, wherein wherein the disease or disorder is a cancer selected from brain gliomas, glioblastomas, astrocytomas, multiforme, bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney, liver, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, uterine/cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers, testicular cancer and virus-related cancer.
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GB2528298A (en) * | 2014-07-16 | 2016-01-20 | Redx Pharma Plc | Compounds |
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WO2019168744A1 (en) * | 2018-03-01 | 2019-09-06 | Eli Lilly And Company | Cd73 inhibitors |
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