DESC:

FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

NOVEL HETEROARYL COMPOUNDS AS USP1 INHIBITORS

We,
SATYARX PHARMA INNOVATIONS PVT LTD,
having address at 3rd Floor Block B, CDC Towers, Plot No l0/8, Road No. 5, Nacharam Industrial Area, Hyderabad 500 076, India.

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF INVENTION
The present invention relates to novel heteroaryl compounds of formula (I) as USP1 inhibitors, or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, isotopes, prodrugs or deuterated compounds including their isotopes, combinations and use thereof.

(I)

The present invention also relates to a process for the manufacture of novel heteroaryl compounds of formula (I), pharmaceutical compositions containing them, their use in the treatment of cancer and metabolic disorders.

BACKGROUND OF THE INVENTION
Ubiquitination is a reversible, post translational modification essential for various cellular processes particularly protein turnover (J Biochem 2010 Jun;147(6):793-8). Ubiquitinated proteins are usually marked for degradation and are directed towards proteasome for recycling of amino acids (Proc Natl Acad Sci U S A. 1998 Mar 17; 95(6): 2727–2730). Ubiquitin is a 76 amino acid small protein tag that gets attached to a protein and marks it for degradation. Depending on the number of Ubiquitin molecules attached per molecule of the protein, the modification is named as mono-ubiquitination or poly-ubiquitination. Tight regulation and balance of ubiquitination and de-ubiquitination processes is essential for proper execution of cellular processes and reprogramming (Stem Cells International Volume 2016, Article ID 6705927). USP1 (Ubiquitin specific protease 1) is one of the most well characterized deubiquitinase involved in DNA repair (Biochimica et Biophysica Acta 1823 (2012) 2014–2021). It is a 785 amino acid of cysteine protease belonging to a family of deubiquitinating enzymes called USPs (Mol Cell 2007;28:786–97). USP1 forms a heterodimer with UAF, deubiquitinates mono-ubiquitinated PCNA and plays pivotal role in translesion synthesis, especially in BRCA1 mutant cancer cells (Mol Cell 2005;17:331–9; Nature 2002;419:135–41). USP1 is thus crucial for cancer cell survival via DNA synthesis, and safe and effective USP1 inhibitors will be useful in treating cancer patients as single agents and in combination with other DNA damaging agents or players in DNA repair pathways (Mol Cancer Ther; 22(2) February 2023).

OBJECTIVE OF THE INVENTION
An objective of the present invention is to provide novel heteroaryl compounds of formula (I) as USP1 inhibitors, or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, isotopes, prodrugs or deuterated compounds including their isotopes, combinations and use thereof.

Another objective of the present invention is to provide a process for the manufacture of novel heteroaryl compounds of formula (I), pharmaceutical compositions containing them.

Yet another objective of the present invention is to provide novel heteroaryl compounds of formula (I) for use in the treatment of cancer and metabolic disorders.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel heteroaryl compounds as shown below:

A compound of formula (I)

(I)

wherein X1 and X2 are independently selected from -N or -CR6;
ring A is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl;
ring B is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- carbocycle, and substituted- or unsubstituted- heterocycle;
R1 and R2 are independently selected from halogen, nitro, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, - NR7bC(=O)R7a, -OR7b, -C(=O)OR7b, -C(=O)N(R7b)2, and -N(R7b)2;
R3 is selected from halogen, nitro, cyano, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, substituted- or unsubstituted- 5-6 membered aryl, substituted- or unsubstituted- heteroaryl, - NR7bC(=O)R7a, and -C(=O)N(R7b)2;
R4 and R5 are independently selected from hydrogen, halogen, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, or R4 and R5 together can form a substituted- or unsubstituted- 3-8 membered carbocycle, substituted- or unsubstituted- 4-8 membered heterocycle;
R6 is selected from hydrogen, halogen, nitro, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, -NR7bC(=O)R7a, -OR7b, -C(=O)OR7b, -C(=O)N(R7b)2, and -N(R7b)2;
R7a is selected from substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocycle;
R7b is selected from hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocycle;
m is an integer selected from 0-3;
n is an integer selected from 0-2;
o is an integer selected from 1-3;or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, isotopes, prodrugs or deuterated compounds including their isotopes, combinations and use thereof.

The compounds of formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, isotopes, prodrugs or deuterated compounds including their isotopes, combinations and use thereof, wherein the compounds are selected from the group comprising of:
Example # IUPAC name
I 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoro methyl)-1H-imidazol-2-yl)benzyl)quinazoline
II 2-(1-isopropyl-1H-pyrazol-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)quinazoline
III N-(4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl) phenyl)-3-(trifluoromethyl)benzamide
IV 4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide
V N-cyclopropyl-4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)benzamide
VI 5-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)-N-(3-(trifluoromethyl)phenyl)picolinamide
VII 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)quinazoline
VIII N-(4-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)phenyl)-3-(trifluoromethyl)picolinamide
IX 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)quinazoline
X 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline
XI 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline
XII 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline
XIII 2-(1-Isopropyl-1H-pyrazol-5-yl)-8-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline

Further, the présent invention also provides a process for preparing compounds of Formula (I) as below:

A process for preparation of novel heteroaryl compounds of formula (I)

(I)
wherein,
X1 and X2 are independently selected from -N or -CR6;
ring A is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl;
ring B is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- carbocycle, and substituted- or unsubstituted- heterocycle;
R1 and R2 are independently selected from halogen, nitro, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, - NR7bC(=O)R7a, -OR7b, -C(=O)OR7b, -C(=O)N(R7b)2, and -N(R7b)2;
R3 is selected from halogen, nitro, cyano, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, substituted- or unsubstituted- 5-6 membered aryl, substituted- or unsubstituted- heteroaryl, - NR7bC(=O)R7a, and -C(=O)N(R7b)2;
R4 and R5 are independently selected from hydrogen, halogen, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, or R4 and R5 together can form a substituted- or unsubstituted- 3-8 membered carbocycle, substituted- or unsubstituted- 4-8 membered heterocycle;
R6 is selected from hydrogen, halogen, nitro, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, -NR7bC(=O)R7a, -OR7b, -C(=O)OR7b, -C(=O)N(R7b)2, and -N(R7b)2;
R7a is selected from substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocycle;
R7b is selected from hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocycle;
m is an integer selected from 0-3;
n is an integer selected from 0-2;
o is an integer selected from 1-3;

or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, isotopes, prodrugs or deuterated compounds including their isotopes thereof, comprising the steps of:
i) converting compounds of Formula (1)

wherein X1, X2, R2 and “m” as defined above
to give boronate ester compounds of Formula (2);

wherein X1, X2, R2 and “n” as defined above

ii) coupling boronate ester compounds of Formula (2) with bromo compounds of Formula (3)

wherein Ring B, R3 , R4, R5 and “o” as defined above

to give compounds of Formula (4);

wherein X1, X2, Ring B, R2, R3, R4, R5, “n” and “o” as defined above

iii) coupling compounds of Formula (4) with boronic acid or boronate ester compounds of Formula (5);

wherein Ring A, R, R1 and “m” as defined above
to give compounds of Formula (I).

The present invention also provides pharmaceutical composition comprising at least one or more compounds of Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including isotopes thereof, and a pharmaceutically acceptable excipients or carriers.

The present invention also provides the use of a compound of Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including isotopes thereof for manufacturing of medicament for a treatment of a cancer and metabolic disorders associated with USP1 protein.

The present invention also provides the use of a compound of Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including isotopes thereof for a treatment of a cancer and metabolic disorders associated with USP1 protein.

The present invention also provides a method of treating cancer and metabolic disorders by administering to a subject therapeutically effective amount of a pharmaceutical composition comprising at least one or more of the compound of Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including isotopes thereof, wherein the subject has cancer. The said cancer and metabolic disorders are associated with USP1 protein.

Further, the cancer is a solid tumor or hematopoietic tumor:
wherein the solid tumor is selected from but not limited to breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer, rhabdomyosarcoma, fibrosarcoma, thyroid follicular cancer or Kaposi's sarcoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoactanthoma or uterine cancer;

wherein the hematopoietic tumor is selected from but not limited to the group comprising:
(a) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-20 lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma or Burkett's lymphoma; and
(b) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukemias, myelodysplastic syndrome or promyelocytic leukemia.

DETAILED DESCRIPTION OF THE INVENTION
Embodiments described herein can be understood more readily by reference to the following detailed description, examples, and tables. Numerous modifications and adaptations will be readily apparent to those skilled in the art without departing from the spirit and scope of the invention.

Disclosed herein is the detailed description of the present invention pertaining to novel heteroaryl compounds of formula (I), or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, isotopes, prodrugs or deuterated compounds including their isotopes, combinations and use thereof.

General terms used in formula can be defined as follows; however, the meaning stated should not be interpreted as limiting the scope of the term per se.

The term “halogen” or “halo” means fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (I).

The term ‘alkyl’ refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has carbon atoms from one to six, i.e. C1-6, preferably carbon atoms from one to four, i.e. C1-4, 10 and is attached to the remainder of the molecule by a single bond. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.

When ‘alkyl’ is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, -CN, perhaloalkyl, cycloalkyl, heterocycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, -OR8b, -SO2R8a, -C(=O)OR8b, -OC(=O)R8a, -OC(=O)OR8a, -C(=O)N(H)R8, -C(=O)N(alkyl)R8, -N(H)C(=O)R8a, -N(H)R8, and -N(alkyl)R8.

The term ‘carbocycle’ or ‘cycloalkyl’ refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, i.e. C3-12, preferably carbon atoms from 3 to 6. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
When ‘carbocycle’ or ‘cycloalkyl’ is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, -CN, alkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, -OR8b, -SO2R8a, -C(=O)OR8b, -OC(=O)R8a, -OC(=O)OR8a, -C(=O)N(H)R8, -C(=O)N(alkyl)R8, -N(H)C(=O)R8a, -N(H)R8, and -N(alkyl)R8.

The term ‘heterocycle’, unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered monocyclic /bicyclic / tricyclic ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S and unless stated otherwise specifically in the specification, the heterocycle may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include spiro or fused or bridged ring system.

When ‘heterocycle’ is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, -CN, alkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, -OR8b, -SO2R8a, -C(=O)OR8b, -C(=O)R8b, -OC(=O)R8a, -OC(=O)OR8a, -C(=O)N(H)R8, -C(=O)N(alkyl)R8, -N(H)C(=O)R8a, -N(H)R8, and -N(alkyl)R8.

The term ‘aryl’, as used herein, refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system. Unless set forth or recited to the contrary, all aryl ring system described or claimed herein may be substituted or unsubstituted.

When the ‘aryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, -CN, alkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, -O-alkyl, -O-perhaloalkyl, -O-C(=O)-aryl, -N(alkyl)alkyl, -N(H)alkyl, -NH2, -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -C(=O)OH, -C(=O)-alkyl, and -C(=O)O-alkyl.

The term ‘heteroaryl’, as used herein, refers to a 5-14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated).

When the ‘heteroaryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, -CN, alkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, -O-alkyl, O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -NH2, -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -C(=O)OH, -C(=O)-alkyl, and -C(=O)O-alkyl.

each R8 is independently selected from hydrogen, alkyl, and cycloalkyl;
each R8a is independently selected from alkyl, alkenyl, perhaloalkyl and cycloalkyl;
each R8b is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl.

According to one embodiment the present invention provides a compound of Formula (I):

(I)

wherein X1 and X2 are independently selected from -N or -CR6;
ring A is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl;
ring B is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- carbocycle, and substituted- or unsubstituted- heterocycle;
R1 and R2 are independently selected from halogen, nitro, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, - NR7bC(=O)R7a, -OR7b, -C(=O)OR7b, -C(=O)N(R7b)2, and -N(R7b)2;
R3 is selected from halogen, nitro, cyano, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, substituted- or unsubstituted- 5-6 membered aryl, substituted- or unsubstituted- heteroaryl, - NR7bC(=O)R7a, and -C(=O)N(R7b)2;
R4 and R5 are independently selected from hydrogen, halogen, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, or R4 and R5 together can form a substituted- or unsubstituted- 3-8 membered carbocycle, substituted- or unsubstituted- 4-8 membered heterocycle;
R6 is selected from hydrogen, halogen, nitro, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, -NR7bC(=O)R7a, -OR7b, -C(=O)OR7b, -C(=O)N(R7b)2, and -N(R7b)2;
R7a is selected from substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocycle;
R7b is selected from hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocycle;
m is an integer selected from 0-3;
n is an integer selected from 0-2;
o is an integer selected from 1-3;or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, isotopes, prodrugs or deuterated compounds including their isotopes, combinations and use thereof.

The particular compounds obtained from compound of Formula (I) without departing from the scope of the definitions given under compounds of Formula (I) are summarized herein below in Table 1 encompassing the entirety of the scope of compounds within compound of Formula (I).

Table 1: List of compounds of Formula (I) with structures
Example # Structure and IUPAC name
I
2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoro methyl)-1H-imidazol-2-yl)benzyl)quinazoline
II
2-(1-isopropyl-1H-pyrazol-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)quinazoline
III
N-(4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl) phenyl)-3-(trifluoromethyl)benzamide
IV
4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide
V
N-cyclopropyl-4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)benzamide
VI
5-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)-N-(3-(trifluoromethyl)phenyl)picolinamide
VII
2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)quinazoline
VIII
N-(4-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)phenyl)-3-(trifluoromethyl)picolinamide
IX
2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)quinazoline
X
2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline
XI
2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline
XII
2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline
XIII
2-(1-Isopropyl-1H-pyrazol-5-yl)-8-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline

In another embodiment, the present invention provides the use of the compounds of Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including isotopes thereof.

Unless specifically indicated, the general Formula (I) shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates and hydrates of the free compound or solvates and hydrates of a salt of the compound.

Compounds disclosed herein and their tautomeric forms, atropisomers, stereoisomers, prodrugs may be prepared, for example, by techniques well known in the organic synthesis and familiar to a practitioner ordinarily skilled in art of this invention. In addition, the processes described herein may enable the synthesis of the compounds of the present invention. However, these may not be the only means by which the compounds described in the invention may be synthesized. Further, the various synthetic steps described herein may be performed in alternate sequences to furnish the desired compounds.

All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include but are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2H (“D”), 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I and 125I.

The term “pharmaceutically acceptable salt” is taken to mean an active ingredient, which comprises a compound of the Formula (I) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active ingredient compared with the free form of the active ingredient or any other salt form of the active ingredient used earlier. The pharmaceutically acceptable salt form of the active ingredient can also provide this active ingredient for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active ingredient with respect to its therapeutic efficacy in the body. Compounds having basic amine groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

The term “tautomer” or “tautomers” refers to the compounds of Formula (I) of the present invention wherein any hydrogen atom is replaced by a hydroxyl group on a carbon with a double bond. The present invention includes all possible tautomeric forms.

The term “prodrugs” refers to a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like, by solvolysis or under physiological conditions. Examples of the group for forming a prodrug include groups as described in Prog. Med., 5, 2157-2161 (1985).

Pharmaceutical compositions
The present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compounds described in the aspect of the present invention or their tautomers, endogenous Racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or it’s pharmaceutically acceptable salts thereof.

The present invention further provides a pharmaceutical composition comprising at one or more compound according to Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including isotopes thereof, and a pharmaceutically acceptable excipient or carrier.

"Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions, alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.

The pharmaceutical preparation of the present invention may be in various oral dosage forms include, but are not limited to tablets, pills, dragees (containing the active ingredient in powder or pellet form), troches, lozenges, ointments, capsules (soft or hard gelatin), syrups, suppositories, pessaries, emulsions, or in parenteral dosage forms such as injections for intramuscular, intravenous, or subcutaneous administration.

All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include but are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2H (“D”), 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I and 125I.

Methods of Treatment
Disclosed herein are methods of treating a disease modulated at least in part by USP1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.

A "subject" is a mammal, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).

Disclosed herein is a method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.

The present invention provides a compound described in the above aspect of the present invention or its tautomer, meso, racemate, enantiomer, and diastereomer, or the use of mixture forms thereof, or it’s pharmaceutically acceptable salts thereof, for the preparation of medicaments for the prevention and/or treatment of USP1-mediated related diseases.

The related disease mediated by USP1 is a cancer selected from the group consisting of but not limited to (a) a solid or hematologically derived tumor selected from cancer of the bladder, endometrial, lung squamous cell, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall-bladder, brain, head and neck, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, (b) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-20 lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma, (c) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia (d) a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma, (e) a tumor of the central and peripheral nervous system selected from astrocytoma, neuroblastoma, glioma and schwannoma, or (f) a melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoactanthoma, thyroid follicular cancer or Kaposi's sarcoma.

Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

Pharmaceutical formulations can be adapted for administration via any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).

Pharmaceutical formulations adapted for oral administration can be administered as separate units, such as, for example, capsules, tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

For example, in the case of oral administration as tablet or capsule, the active-ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a pharmaceutical excipient comminuted in a similar manner, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol. A flavor, preservative, dispersant and dye may likewise be present.

Capsules are produced by preparing a powder mixture as described above and filling shaped gelatine shells therewith. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling operation. A disintegrant or solubilizer, such as, for example, agar-agar, calcium carbonate or sodium carbonate, may likewise be added in order to improve the availability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants and disintegrants as well as dyes can likewise be incorporated into the mixture. Suitable binders include starch, gelatine, natural sugars, such as, for example, glucose or beta-lactose, sweeteners made from maize, natural and synthetic rubber, such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like. The tablets are formulated by, for example, preparing a powder mixture, granulating or dry pressing the mixture, adding a lubricant and a disintegrant and pressing the entire mixture to give tablets. A powder mixture is prepared by mixing the compound comminuted in a suitable manner with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone, a dissolution retardant, such as, for example, paraffin, an absorption accelerator, such as, for example, a quaternary salt, and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder, such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulose or polymer materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tableting machine, giving lumps of non-uniform shape which are broken up to form granules. The granules can be lubricated by addition of stearic acid, a stearate salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds. The lubricated mixture is then pressed to give tablets. The active ingredients can also be combined with a free-flowing inert excipient and then pressed directly to give tablets without carrying out the granulation or dry-pressing steps. A transparent or opaque protective layer consisting of a shellac sealing layer, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can be prepared in the form of dosage units so that a given quantity comprises a pre-specified amount of the compounds. Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable flavour, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspension can be formulated by dispersion of the compounds in a non-toxic vehicle. Solubilisers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavour additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners and the like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, be encapsulated in microcapsules. The formulation can also be prepared in such a way that the release is extended or retarded, such as, for example, by coating or embedding particulate material in polymers, wax and the like.

Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

Pharmaceutical formulations adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouth encompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprising a coarse powder having a particle size, for example, in the range 20-500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a container containing the powder held close to the nose. Suitable formulations for administration as nasal spray or nose drops with a liquid as carrier substance encompass active-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalation encompass finely particulate dusts or mists, which can be generated by various types of pressurized dispensers with aerosols, nebulizers or inhalers. Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspension media and thickeners. The formulations can be administered in single-dose or multidose containers, for example sealed ampoules and vials, and stored in freeze-dried (lyophilized) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary.

Injection solutions and suspensions prepared in accordance with the recipe can be prepared from sterile powders, granules and tablets.

In addition to the above particularly mentioned constituents, the formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, formulations which are suitable for oral administration may comprise flavors.

A therapeutically effective amount of a compound of the Formula (I) and of the other active ingredients depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of administration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.

In further aspect, the present invention provides a process of preparing novel compounds of Formula (I).

The novel heteroaryl compounds of Formula (I) may be prepared using the following general method and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. Moreover, by utilizing the procedures described in detail, one of the ordinary skills in art can prepare additional compounds of the present invention claimed herein. All temperatures are in degrees Celsius (°C) unless otherwise noted.

The processes described herein may enable the synthesis of the compounds of the present invention. However, these may not be the only means by which the compounds described in the invention may be synthesized. Further, the various synthetic steps described herein may be performed in alternate sequences to furnish the desired compounds.

In one embodiment the present invention provides a process for preparing the compounds of Formula (I) depicted in the Schemes given hereunder. One skilled-in-the-art will recognize that any of the Schemes can be adapted to produce the compounds of Formula (I) and pharmaceutically acceptable salts of compounds of Formula (I) according to the present invention. All symbols/variables are as defined hereunder unless otherwise stated.

General Method of Preparation:
General Scheme:

Compounds of Formula (1) can be converted to Boronate ester of formula (2). Boronate ester compounds of formula (2) can be coupled with Bromo compounds of formula (3) to get compounds of formula (4). Compounds of formula (4) can be coupled with compounds of formula (5) (Boronic acid or Boronate ester) to get the Compound of Formula (I). Following this sequence below intermediates and Examples were synthesized.

In one embodiment, the present invention provides process for preparing compound of Formula (I) and compound of Formula (II) as shown in Scheme 1 comprising the steps of:

Scheme 1

Scheme 1 shows a method of preparation of Compound I and II from intermediate 1. intermediate 2 was prepared from intermediate 1. intermediate 3 was prepared as reported in WO2021247606. intermediate 2 and intermediate 3 were coupled together to get intermediate 4. intermediate 4 was coupled with intermediate 5 to get Example I. intermediate 4 coupled with intermediate 6 to get Example II.

In another embodiment, the present invention provides process for preparing compound of Formula (III) as shown in Scheme 2 comprising the steps of:

Scheme 2

Scheme 2 shows a method of preparation of Compound III from intermediate 1. intermediate 2 was prepared from intermediate 1. intermediate 2 and intermediate 7 were coupled together to get intermediate 8. intermediate 8 was coupled with intermediate 5 to get intermediate 9. intermediate 9 was reduced to intermediate 10. intermediate 10 was coupled with acid intermediate 11 to get Example III.

In one embodiment, the present invention provides process for preparing compound of Formula (IV) and compound of Formula (V) as shown in Scheme 3 comprising the steps of:

Scheme 3:0150141275

Scheme 3 shows a method of preparation of Compound IV and Compound V from intermediate 1. intermediate 2 was prepared from intermediate 1. intermediate 2 and intermediate 12 were coupled together to get intermediate 13. intermediate 13 was coupled with intermediate 5 to get intermediate 14. intermediate 14 was hydrolyzed to intermediate 15. intermediate 15 was coupled with Amine intermediate 16 to get Example IV. intermediate 15 was coupled with Amine intermediate 17 to get Example V.

In another embodiment, the present invention provides process for preparing compound of Formula (VI) as shown in Scheme 4 comprising the steps of:

Scheme 4:

Scheme 4 shows a method of preparation of Compound V intermediate 1. intermediate 2 was prepared from intermediate 1. intermediate 2 and methyl 5-(bromomethyl)picolinate were coupled together to get intermediate 16. Intermediate 16 was coupled with intermediate 5 to get intermediate 17. intermediate 17 was hydrolyzed to intermediate 18. Intermediate 18 was coupled with 3-(Trifluoromethyl)aniline to get Example VI.

In another embodiment, the present invention provides process for preparing compound of Formula (VII) as shown in Scheme 5 comprising the steps of:

Scheme 5:

Scheme 5 shows a method of preparation of Compound VII from commercially available intermediates methyl 5-formylpicolinate and 3,3-dibromo-1,1,1-trifluoropropan-2-one. Intermediate 19 was prepared from methyl 5-formylpicolinate and 3,3-dibromo-1,1,1-trifluoropropan-2-one. Intermediate 19 was treated with 2-Iodopropane to obtain intermediate 20. Intermediate 20 was reduced with LiAlH4 to obtain intermediate 21. Intermediate 21 was converted to intermediate 22. Intermediate 22 coupled with Intermediate 2 to obtain intermediate 23. Intermediate 23 was coupled with Intermediate 5 to obtain compound VII.

In another embodiment, the present invention provides process for preparing compound of Formula (IX) as shown in Scheme 6 comprising the steps of:

Scheme 6:

Scheme 6 shows a method of preparation of Compound IX and II from intermediate 1. intermediate 2 was prepared from intermediate 1. Intermediate 24 was prepared as reported in CN118084900. Intermediate 24 and intermediate 2 were coupled together to get intermediate 25. Intermediate 25 was coupled with intermediate 5 to get Example IX.

In another embodiment, the present invention provides process for preparing compound of Formula (X) as shown in Scheme 7 comprising the steps of:

Scheme 7:

Scheme 7 shows a method of preparation of Compound X from intermediate 1. Intermediate 2 was prepared from intermediate 1. Intermediate 27 was prepared as reported in WO2021247606. intermediate 27 and intermediate 2 were coupled together to get intermediate 28. Intermediate 28 was coupled with intermediate 5 to get Example X.

In another embodiment, the present invention provides process for preparing compound of Formula (XI) and compound of Formula (XIII) as shown in Scheme 8 comprising the steps of:

Scheme 8:

Scheme 8 shows a method of preparation of Compound XI and XIII from intermediate 1. Intermediate 2 was prepared from intermediate 1. Intermediate 28 was prepared as reported in WO2021247606. Intermediate 28 and intermediate 2 were coupled together to get intermediate 29. Intermediate 29 was coupled with intermediate 5 to get Example XI. Intermediate 29 was coupled with intermediate 6 to get Example XIII.

In another embodiment, the present invention provides process for preparing compound of Formula (XII) as shown in Scheme 9 comprising the steps of:

Scheme 9:

Scheme 9 shows a method of preparation of Compound XII from intermediate 1. Intermediate 2 was prepared from intermediate 1. Intermediate 30 was prepared as reported in WO2021247606. Intermediate 30 and intermediate 2 were coupled together to get intermediate 31. Intermediate 31 was coupled with intermediate 5 to get Example XII.

EXAMPLES
Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

Intermediates:
Intermediate-2: 2-Chloro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline

Commercially available intermediate 1 (300 mg, 1.23 mmol), KOAc (243 mg, 2.46 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane (313 mg, 1.23 mmol) were suspended in Dioxane and degassed with N2 for 20 mins. After 20 mins Pd(dppf)Cl2.CH2Cl2 (80 mg, 0.09 mmol) was added to above reaction mixture and degassed reaction mixture with N2 for 20 mins. Reaction mixture was refluxed for 3 h. After 3h, reaction mixture was cooled to rt. Reaction mixture was diluted with water and extracted with EtOAc. EtOAc layer was dried on anhydrous Na2SO4. EtOAc layer was distilled on rotavapour to obtain the titled compound, which was used in the next step without further purification.
LCMS m/z = 292.10 (M+H).

Intermediate 3: 2-(4-(bromomethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole

Intermediate 3 was prepared as per procedure reported in WO2021247606.

Intermediate 4: 2-Chloro-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)quinazoline

Intermediate 2 (200 mg, 0.58 mmol), Intermediate 3 (140 mg, 0.48 mmol), Sodium carbonate (244 mg, 2.3 mmol), dioxane (10 ml) and water (1 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(PPh3)4 (22 mg, 0.027 mmol)was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by column chromatography on 100-200 mesh silica gel using EtOAc and Hexane (4:6) as eluent. Combined pure fractions were distilled to obtain the titled compound as a pale-brown solid.
LCMS m/z =431.20 (M+ H).

Intermediate 8: 2-chloro-8-(4-nitrobenzyl)quinazoline

Intermediate 2 (300 mg, 1.0 mmol), Commercially available Intermediate 7 (194 mg, 1.0 mmol), Sodium carbonate (424 mg, 4 mmol), dioxane (10 ml) and water (2 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(PPh3)4 (65 m, 0.07 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by column chromatography on 100-200 mesh silica gel using EtOAc and Hexane (3:7) as eluent. Combined pure fractions were distilled to obtain the titled compound as a pale-brown solid.

Intermediate 9: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-nitrobenzyl) quinazoline

Intermediate 8 (300 mg, 1.0 mmol), Commercially available Intermediate 5 (194 mg, 1.0 mmol), Sodium carbonate (424 mg, 4 mmol), dioxane (10 ml) and water (2 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(PPh3)4 (65 mg, 0.07 mmol)was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by column chromatography on 100-200 mesh silica gel using EtOAc and Hexane (4:6) as eluent. Combined pure fractions were distilled to obtain the titled compound as a pale-brown solid. LCMS m/z = 414.20 (M+H).

Intermediate 10: 4-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl) methyl)aniline

Intermediate 9 (120 mg, 0.3 mmol) was dissolved in EtOH (10 ml) and Water (2 ml) mixture. To this mixture added NH4Cl (154 mg, 2.8 mmol) and Iron Powder (32 mg, 0.6 mmol). This reaction mixture was refluxed for 3 h. After 3 h, the reaction mixture was cooled to rt and filtered on celite bed. celite bed was washed with EtOH. Combined filtrate was distilled on rotavapour to obtain a residue. The residue was diluted with water and extracted with EtOAc. The organic layer was dried on Na2SO4 and distilled on rotavapour to obtain the titled compound which was used in the next step without further purification. LCMS m/z = 384.20 (M+H)

Intermediate 13: Ethyl 4-((2-chloroquinazolin-8-yl)methyl)benzoate

Intermediate 2 (500 mg, 1.72 mmol), Commercially available Intermediate 12 (394 mg, 1.72 mmol), Potassium phosphate (1.4 g, 6.6 mmol), dioxane (10 ml) and water (2 ml) were mixed, and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf).CH2Cl2 (112 mg, 0.13 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, the reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by column chromatography on 100-200 mesh silica gel using EtOAc and Hexane (4:7) as eluent. Combined pure fractions were distilled to obtain the titled compound as a pale-brown solid. LCMS m/z = 327.00 (M+H)

Intermediate 14: Ethyl 4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)benzoate

Intermediate 13 (250 mg, 0.8 mmol), Commercially available Intermediate 5 (158 mg, 0.8 mmol), Potassium phosphate (679 mg, 3.2 mmol), dioxane (10 ml) and water (1 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(PPh3)4 (52 mg, 0.064 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, the reaction mixture was refluxed for 3 h. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by column chromatography on 100-200 mesh silica gel using EtOAc and Hexane (3:7) as eluent. Combined pure fractions were distilled to obtain the titled compound as a pale-brown solid. LCMS m/z = 545.20 (M+H).

Intermediate 15: 4-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl) methyl)benzoic acid

Intermediate 12 (200 mg, 4.8 mmol) was suspended in a mixture of THF (2 ml), MeOH (2 ml) and Water (1 ml). To this mixture LiOH (200 mg, 4.8 mmol) was added. This reaction mixture was stirred at rt for 4 h. After 4 h, reaction mixture was acidified to pH ~ 2 using 6 N HCl to obtain a solid. Solid was filtered and dried to obtain the titled compound as a pale brown solid.

Intermediate 16: Methyl 5-((2-chloroquinazolin-8-yl)methyl)picolinate

Intermediate 2 (400 mg, 1.0 mmol), Commercially available methyl 5-(bromomethyl)picolinate (380 mg, 1.2 mmol), Cesium carbonate (1.35mg, 4.13 mmol), dioxane (5 ml) and water 12 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf)Cl2.CH2Cl2 (70 mg, 0.07 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by column chromatography on 100-200 mesh silica gel using EtOAc and Hexane (3:7) as eluent. Combined pure fractions were distilled to obtain the titled compound as a pale-brown solid.

Intermediate 17: Methyl 5-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)picolinate

Intermediate 16 (200 mg, 0.64 mmol), Commercially available Intermediate 5 (148 mg, 0.76 mmol), Cesium carbonate (621 mg, 1.9 mmol), dioxane (2.4 ml) and water (0.6 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf)Cl2.CH2Cl2 (24 mg, 0.032 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, the reaction mixture was refluxed for 3 h. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by column chromatography on 100-200 mesh silica gel using EtOAc and Hexane (4:6) as eluent. Combined pure fractions were distilled to obtain the titled compound as a pale-brown solid.

Intermediate 18: 5-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)picolinic acid

Intermediate 17 (70 mg, 0.16 mmol) was suspended in a mixture of THF (1 ml), MeOH (1 ml) and Water (1 ml). To this mixture LiOH (47 mg, 0.9 mmol) was added. This reaction mixture was stirred at rt for 4 h. After 4 h, reaction mixture was acidified to pH ~ 2 using 6 N HCl to obtain a solid. Solid was filtered and dried to obtain the titled compound as a pale brown solid (35 mg).

Intermediate 19: Methyl 5-(4-(trifluoromethyl)-1H-imidazol-2-yl)picolinate

Intermediate 19 was prepared as per procedure reported in CN116496252.

Intermediate 20: Methyl 5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)picolinate

Intermediate 19 (1.4 g, 5 mmol) and Cesium carbonate (5 g, 16.3 mmol)was dissolved in acetonitrile (20 ml). This mixture was stirred at rt for 30 mins. After 30 mins, 2-Iodopropane was added and stirred the mixture at 80°C for 1 h. After 1 h, reaction mixture was cooled to rt and diluted with water. Aqueous layer was extracted with DCM. DCM layer was dried on anhydrous Na2SO4. DCM layer was evaporated on rotavapour to obtain crude. Crude was purified by combi-flash using DCM and MeOH (98:2) as eluent. Combined pure fractions were distilled to obtain titled compound (1.1 g). LCMS m/z = 314.00 (M+H).

Intermediate 21: (5-(1-Isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methanol

Intermediate 20 (1.1 g, 3.5 mmol) was dissolved in THF (15 ml). This mixture was cooled to 0°C and Lithiumaluminium hydride (630 mg, 15 mmol) was added and stirred at rt for 1 h. Progress of the reaction was monitored by TLC. After 1h, reaction mixture was quenched with aq NH4Cl and reaction mixture diluted with DCM. Reaction mixture filtered through cealite bed. Filtrate was distilled to obtain the titled compound (600 mg). LCMS m/z = 286.00 (M+H).

Intermediate 22: 2-(Bromomethyl)-5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

Intermediate 21 (600 mg, 2.08 mmol), triphenyl phosphine (544 mg, 2.08 mmol) and Sodium bicarbonate (350 mg, 4.16 mmol) was dissolved in DCM (6 ml) and cooled to 0°C. Carbon tetrabromide (688 mg, 2.08 mmol) was added to the above mixture and stirred at rt for 1 h. After 1 h reaction mixture diluted with DCM and water. Separated the DCM layer and dried on anhydrous Na2SO4. DCM layer was distilled on rotavapour to obtain crude. Crude was purified by combi-flash using DCM as eluent. Combined pure fractions were distilled under vacuum to obtain the titled compound (135 mg). LCMS m/z = 348.00 (M+H).

Intermediate 23: 2-Chloro-8-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)quinazoline

Intermediate 2 (100 mg, 0.34 mmol), Intermediate 22 (143 mg, 0.42 mmol), cesium carbonate (340 mg, 1.03 mmol), dioxane (1.6 ml) and water (0.4 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf)2Cl2.CH2Cl2 (20 mg, 0.017 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by combi-flash using MeOH and DCM (1:99) as eluent. Combined pure fractions were distilled to obtain the titled compound (50 mg) as a pale-brown solid. LCMS m/z =432.00 (M+H).

Intermediate 24: 5-(bromomethyl)-2-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridine

Intermediate 24 was prepared as per procedure reported in CN118084900.

Intermediate 25: 2-Chloro-8-((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)quinazoline

Intermediate 2 (100 mg, 0.34 mmol), Intermediate 22 (143 mg, 0.42 mmol), cesium carbonate (340 mg, 1.03 mmol), dioxane (1.6 ml) and water (0.4 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf)2Cl2.CH2Cl2 (20 mg, 0.017 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by combi-flash using MeOH and DCM (1:99) as eluent. Combined pure fractions were distilled to obtain the titled compound (100 mg) as a pale-brown solid.

Intermediate 26: 1-(4-(Bromomethyl)phenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole

Intermediate 26 was prepared as per procedure reported in WO2021247606.

Intermediate 27: 2-Chloro-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline

Intermediate 2 (410 mg, 1.41 mmol), Intermediate 26 (450 mg, 1.41 mmol), potassium carbonate (583 mg, 4.23 mmol), dioxane (10 ml) and water (1 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins, Pd(dppf)2Cl2.CH2Cl2 (115 mg, 0.14 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by combi-flash using EtOAc and Hexane (3:7) as eluent. Combined pure fractions were distilled to obtain the titled compound (450 mg) as a yellow viscous liquid. LCMS m/z =403.00 (M+H).

Intermediate 28: 1-(4-(Bromomethyl)phenyl)-5-methoxy-3-(trifluoromethyl)-1H-pyrazole (SP-0308-083)

Intermediate 28 was prepared as per procedure reported in WO2021247606.

Intermediate 29: 2-Chloro-8-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline

Intermediate 2 (220 mg, 0.7 mmol), Intermediate 28 (250 mg, 0.7 mmol), potassium carbonate (412 mg, 2.98 mmol), dioxane (10 ml) and water 21 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins, Pd(dppf)2Cl2.CH2Cl2 (61 mg, 0.07 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by combi-flash using EtOAc and Hexane (3:7) as eluent. Combined pure fractions were distilled to obtain the titled compound (70 mg) as a yellow viscous liquid. LCMS m/z =419.10 (M+H).

Intermediate 30: 1-(4-(bromomethyl)-2-fluorophenyl)-5-methyl-3-(trifluoromethyl)-1H-pyrazole

Intermediate 30 was prepared as per procedure reported in WO2021247606.

Intermediate 31: 2-Chloro-8-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline

Intermediate 2 (220 mg, 0.7 mmol), Intermediate 30 (250 mg, 0.7 mmol), potassium carbonate (412 mg, 2.98 mmol), dioxane (10 ml) and water 21 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins, Pd(dppf)2Cl2.CH2Cl2 (61 mg, 0.07 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by combi-flash using EtOAc and Hexane (3:7) as eluent. Combined pure fractions were distilled to obtain the titled compound (100 mg) as a pale-brown viscous liquid. LCMS m/z =421.00 (M+H).

EXAMPLES
Example-I: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)quinazoline

Intermediate 4 (50 mg, 0.12 mmols), Commercially available Intermediate 5 (22 mg, 0.12 mmol), Sodium carbonate (49 mg, 0.48 mmol), dioxane (10 ml) and water (2 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(PPh3)4 (12 mg, 0.01 mmol)was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, the reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by column chromatography on 100-200 mesh using EtOAc and Hexane (3:7) as eluent to obtain the titled compound as a pale-brown solid. LCMS m/z = 545.20 (M+H).1H NMR (400MHz, DMSO-d6) ?: 9.54 (s, 1H), 8.70 (s, 1H), 7.90 (d, 1H, J = 8 Hz), 7.72 (d, 1H, J = 6.8 Hz), 7.63 (t,1H, J = 8 Hz), 7.46-7.38 (m, 5H), 4.68 (s, 2H), 4.54 (Septet, 1H, J = 6.8 Hz), 3.95 (s, 3H), 1.75-1.82 (m, 1H), 1.43 (d, 6H, J = 6.8 Hz), 0.90-0.80 (m, 4H).

Example-II: 2-(1-Isopropyl-1H-pyrazol-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)quinazoline

Intermediate 4 (50 mg, 0.12 mmol), Commercially available Intermediate 6 (16 mg, 0.12 mmol), Sodium carbonate (49 mg, 0.48 mmol), dioxane (10 ml) and water (2 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(PPh3)4 (12 mg, 0.01 mmol)was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by preparative HPLC to obtain the titled compound as a pale-brown solid. LCMS m/z = 505.10 (M+H).1H NMR (400MHz, DMSO-d6) ?: 9.45 (s, 1H), 7.85 (d, 1H, J = 8 Hz), 7.71 (d, 1H, J = 6.4 Hz), 7.63 (d, 1H, J = 1.6 Hz), 7.59 (t, J = 7.6 Hz, 1H), 7.47 (d, 2H, J = 7.6 Hz), 7.39 (s, 1H), 7.33 (d, 2H, J = 7.6 Hz), 7.19 (d, 1H, J = 1.6 Hz), 6.05 (septet, 1H, J = 6.8 Hz), 4.68 (s, 2H), 4.53 (septet, 1H, J = 6.4), 1.53 (d, 6H, J = 6.8 Hz), 1.43 (d, 6H, J = 6.4 Hz).

Example-III: N-(4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)phenyl)-3-(trifluoromethyl)benzamide

Intermediate 10 (60 mg, 0.16 mmol), Commercially available Intermediate 11 (36 mg, 0.19 mmol), HATU (71 mg, 0.19 mmol) and DMF (2 ml) were mixed. DIPEA (80 mg, 0.62 mmol) was added drop-wise to this mixture and stirred for 1 h. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. Organic layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by column chromatography on 100-200 mesh silica gel using EtOAc and Hexane (3:7) as eluent to obtain the titled compound as a pale-brown solid. LCMS m/z = 556.10 (M+H).1H NMR (400MHz, DMSO-d6) ?: 9.54 (s, 1H), 8.73 (s, 1H), 8.11 (s, 1H), 8.04 (d, 1H, J = 8 Hz), 7.89 (d, 1H, J = 8 Hz), 7.83-7.75 (m, 3H), 7.60-7.52 (m, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.33 (d, 2H, J = 8.4 Hz), 4.61 (s, 2H), 3.97 (s, 3H), 1.84-1.78 (m, 1H), 1.28-1.21 (m, 2H), 0.90-0.82 (m, 2H).

Example-IV: 4-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide

Intermediate 15 (50 mg, 0.12 mmol), Commercially available Intermediate 16 (23 mg, 0.14 mmol), HATU (55 mg, 0.14 mmol) and DMF (2 ml) were mixed. DIPEA (63 mg, 0.48 mmol) was added drop-wise to this mixture and stirred for 1 h. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. Organic layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by preparative HPLC to obtain the titled compound as a pale-brown solid. LCMS m/z = 556.10 (M+H).1H NMR (400MHz, DMSO-d6) ?: 9.54 (s, 1H), 8.70 (s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.92 (d, 1H, J = 7.6 Hz), 7.86 (d, J = 7.6 Hz, 2H), 7.78 (t, 2H, J = 8.4 Hz), 7.67 (t, J = 7.6, 1 H), 7.52 (s, 1H), 7.50-7.43 (m, 2H), 7.39 (d, 2H, J = 8 Hz), 4.69 (s, 2H), 3.96 (s, 3H), 1.80-1.70 (m, 1H), 1.28-1.21 (m, 2H), 0.90-0.80 (m, 2H).

Example-V: N-Cyclopropyl-4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin -8-yl)methyl)benzamide

Intermediate 15 (56 mg, 0.135 mmol), Commercially available Intermediate 17 (0.012 ml, 0.16 mmol), HATU (62 mg, 0.16 mmol) and DMF (3 ml) were mixed. DIPEA (70 mg, 0.54 mmol) was added drop-wise to this mixture and stirred for 1 h. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. Organic layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by preparative HPLC to obtain the titled compound as a pale-brown solid. LCMS m/z = 451.53 (M+H).1H NMR (400MHz, DMSO-d6) ?: 9.73 (s, 1H), 8.72 (s, 1H), 8.30 (d, 1H, J = 4 Hz), 8.11 (d, 1H, J = 8 Hz), 7.97 (d, 1H, J = 6.8 Hz), 7.76 (t, 1H, J = 7.6 Hz), 7.67 (d, 2H, J = 8.0 Hz), 7.34 (d, 2H, J = 8.0 Hz), 4.55 (s, 2H), 3.85 (s, 3H), 2.82-2.76 (m, 1H), 1.69-1.60 (m, 1H), 1.10-1.03 (m, 2H), 0.86-0.78 (m, 2H), 0.69-0.61 (m, 2H), 0.55-0.49 (m, 2H).

Example-VI: 5-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)-N-(3-(trifluoromethyl)phenyl)picolinamide

Intermediate 18 (35 mg, 0.085 mmol), Commercially available 3-(trifluoromethyl)aniline (17 mg, 0.10 mmol), HATU (40 mg, 0.10 mmol) and DMF (1 ml) were mixed. DIPEA (0.06 ml, 0.34 mmol) was added drop-wise to this mixture and stirred for 30 min. After 30 min, the reaction mixture was diluted with water and extracted with EtOAc. Organic layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by preparative HPLC to obtain the titled compound as a pale-brown solid. LCMS m/z = 557.20 (M+H).1H NMR (400MHz, DMSO-d6) ?: 10.92 (s, 1H), 9.76 (s, 1H), 8.74 (d, J 8.4 Hz, 2H), 8.40 (s, 1H), 8.40-8.00 (m, 4H), 7.91-7.79 (m, 2H), 7.62-7.55 (m, 1H), 7.50-7.43 (m, 1H), 4.66 (s, 2H), 3.84 (s, 3H), 1.66-1.59 (m, 1H), 1.10-1.00 (m, 2H), 0.85-0.75 (m, 2H).

Example-VII: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)quinazoline

Intermediate 23 (50 mg, 0.12 mmols), Commercially available Intermediate 5 (27 mg, 0.14 mmol), Cesium carbonate (113 mg, 0.35 mmol), dioxane (1.8 ml) and water (0.4 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf)2Cl2.CH2Cl2 (6 mg, 0.016 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, the reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by preparative HPLC to obtain titled compound as a pale-brown solid (4 mg). LCMS m/z = 546.10 (M+H).

Example-VIII: N-(4-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)phenyl)-3-(trifluoromethyl)picolinamide

Intermediate 10 (80 mg, 0.21 mmol), 3-(trifluoromethyl)picolinic acid (49 mg, 0.25 mmol), HATU (95.2 mg, 0.19 mmol) and DMF (5 ml) were mixed. DIPEA (0.15 ml, 0.83 mmol) was added drop-wise to this mixture and stirred for 1 h. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. Organic layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by combi-flash using EtOAc and Hexane (3:7) as eluent to obtain the titled compound as a pale-brown solid. LCMS m/z = 557.10 (M+H).

Example-IX: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)quinazoline

Intermediate 25 (80 mg, 0.19 mmols), Commercially available Intermediate 5 (44 mg, 0.22 mmol), potassium carbonate (103 mg, 0.74 mmol), dioxane (7 ml) and water (1.5 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf)2Cl2.CH2Cl2 (16 mg, 0.019 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, the reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by combi-flash using EtOAc and Hexane (2:8) as eluent to obtain titled compound as a pale-brown solid (13 mg). LCMS m/z = 546.20 (M+H).1H NMR (400MHz, DMSO-d6) ?: 9.54 (s, 1H), 8.71 (s, 1H), 8.62 (d, J 1.6, 1H), 8.04 (d, J 8 Hz, 1H), 7.91 (d, J 8.4 Hz, 1H), 7.80 (d, J 6.8 Hz, 1H), 7.72 (dd, J 8, 1.6 Hz, 1H), 7.66 (t, J 8, 1H), 7.44 (s, 1H), 5.85 (septet, J 6.8 Hz, 1H), 4.64 (s, 2H), 3.94 (s, 3H), 1.80-1.72 (m, 1H), 1.45 (d, J 6.8 Hz, 6H), 1.28-1.22 (m, 2H), 0.91-0.81 (m, 2H).

Example-X: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline

Intermediate 27 (200 mg, 0.5 mmols), Commercially available Intermediate 5 (115 mg, 0.6 mmol), potassium carbonate (274 mg, 1.0 mmol), dioxane (5 ml) and water (1 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf)2Cl2.CH2Cl2 (406 mg, 0.05 mmol)was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, the reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by combi-flash using EtOAc and Hexane (1:1) as eluent to obtain the titled compound as an off-white solid (80 mg). LCMS m/z = 517.10 (M+H).1H NMR (400MHz, DMSO-d6) ?: 9.75 (s, 1H), 8.73 (s, 1H), 8.14 (d, J 8 Hz, 1H), 8.04 (d, J 7.6 Hz, 1H), 7.80 (t, J 7.6 Hz, 1H), 7.47 (d, J 8.8 Hz, 2H), 7.43 (d, J 8.8 Hz, 2H), 6.72 (s, 1H), 4.61 (s, 2H), 3.86 (s, 3H), 2.33 (s, 3H), 1.72-1.65 (m, 1H), 1.08-1.03 (m, 2H), 0.87-0.80 (m, 2H).

Example-XI: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline

Intermediate 29 (70 mg, 0.16 mmols), Commercially available Intermediate 5 (39 mg, 0.2 mmol), potassium carbonate (93 mg, 0.7 mmol), dioxane (10 ml) and water (2 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf)2Cl2.CH2Cl2 (13.6 mg, 0.016 mmol) was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, the reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by preparative HPLC to obtain the titled compound as an off-white solid (24 mg). LCMS m/z = 533.20. (M+H).1H NMR (400MHz, DMSO-d6) ?: 9.74 (s, 1H), 8.72 (s, 1H), 8.13 (dd, J 8, 1.2 Hz, 1H), 8.01 (d, J 7.6 Hz, 1H), 7.79 (t, J 8, 1H), 7.48 (d, J 8.4 Hz, 2H), 7.42 (d, J 8.4 Hz, 2H), 6.43 (s, 1H), 4.57 (s, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 1.70-1.62 (m, 1H), 1.09-1.04 (m, 2H), 0.85-0.77 (m, 2H).

Example-XII: 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline

Intermediate 31 (100 mg, 0.24 mmols), Commercially available Intermediate 5 (55 mg, 0.28 mmol), potassium carbonate (131 mg, 0.95 mmol), dioxane (10 ml) and water (2 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf)2Cl2.CH2Cl2 (19.5 mg, 0.024 mmol)was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, the reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by preparative HPLC to obtain the titled compound as an off-white solid (20 mg). LCMS m/z = 533.20. LCMS m/z = 535.10 (M+H).1H NMR (400MHz, DMSO-d6) ?: 9.76 (s, 1H), 8.73 (s, 1H), 8.15 (dd, J 8, 1.2 Hz, 1H), 8.09 (d, J 6.4 Hz, 1H), 7.81 (t, J 7.6 Hz, 1H), 7.53-7.44 (m, 2H), 7.32 (d, J 8 Hz, 1H), 6.74 (s, 1H), 4.62 (s, 2H), 3.84 (s, 3H), 2.14 (s, 3H), 1.70-1.64 (m, 1H), 1.44-1.20 (m, 2H), 0.86-0.80 (m, 2H).

Example-XIII: 2-(1-Isopropyl-1H-pyrazol-5-yl)-8-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline

Intermediate 29 (130 mg, 0.31 mmols), Commercially available Intermediate 6 (57.45 mg, 0.37 mmol), potassium carbonate (172 mg, 1.24 mmol), dioxane (3 ml) and water (1 ml) were mixed and this mixture was degassed with N2 for 20 mins. After 20 mins Pd(dppf)2Cl2.CH2Cl2 (25.39 mg, 0.03 mmol)was added to the above mixture and degassed with N2 for 20 mins. After 20 mins, the reaction mixture was refluxed for overnight. Reaction mixture diluted with water and extracted with EtOAc. EtOAc layer was washed with water and dried on anhydrous Na2SO4. Organic layer was distilled on rotavapour to obtain crude. Crude was purified by preparative HPLC to obtain the titled compound as an off-white solid (54 mg). LCMS m/z = 493.20 (M+H).1H NMR (400MHz, DMSO-d6) ?: 9.70 (s, 1H), 8.10 (d, J 7.6 Hz, 1H), 7.96 (d, J 7.6 Hz, 1H), 7.75 (t, J 7.6 Hz, 1H), 7.60 (d, J 2 Hz, 1H), 7.53 (d, J 8.4 Hz, 1H), 7.33 (d, J 8.8 Hz, 1H), 7.12 (d, J 2 Hz, 1H), 6.43 (s, 1H), 5.91 (septet, J 6.8 Hz, 1H), 4.64 (s, 2H), 3.94 (s, 3H), 1.38 (d, J 6.8 Hz, 6H).

Abbreviations
°C = degree Celsius
DMSO = Dimethyl sulphoxide
DIPEA = Diisopropylethyl amine
DMF = Dimethylformamide
EtOAc = Ethyl acetate
h = hour
HATU = N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
1H NMR = Proton nuclear magnetic resonance
LCMS = Liquid chromatography-mass spectrometry
m/z = mass to charge ratio
mg = milligram
ml = milliliter
Na2SO4 = Sodium sulphate
PdCl2dppf .CH2Cl2 = [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane
Pd(PPh3)4 = Palladium-tetrakis(triphenylphosphine)
DIPEA = Diisopropylethyl amine
EtOAc = Ethyl acetate

PHARMACOLOGICAL ACTIVITY:
USP1 biochemical assay
Compounds were screened for inhibition of USP-1 using fluorogenic assay kit (BPS biosciences # 78831). 1 µl of 10X compound was prepared in an assay buffer and added to the corresponding wells in 384 well plate. Next, USP-1/UAF1enzyme mix was diluted in assay buffer to a working concentration of 1 ng/µl and 5 µl added to each well. The plate was then incubated for 30 minutes at room temperature with gentle shaking. Post incubation, Ub-AMC was diluted to 1X from 400X (supplied in kit) using assay buffer. 4 µl of 1X Ub-AMC substrate was added to corresponding wells. The plate was further incubated for 30 minutes at room temperature protected from light. The fluorescence was measured in a plate reader with excitation at 350 nm and emission at 460 nm. “Blank” value was subtracted from all other values. % inhibition was calculated using the formula 100-(fluorescence value of treatment*100/Fluorescence value of DMSO control). Blank well contains only ub-AMC probe and buffer.

% inhibition @ 1000 nM: > 70% = ***; > 50% = **; < 50% = *

Example # % inhibition @ 1000 nM
I ***
II ***
III ***
IV ***
V ***
VI **
VII **
VIII ***
IX ***
X ***
XI ***
XII ***
XIII ***

,CLAIMS:We claim:
1. A compound of formula (I)

(I)

wherein X1 and X2 are independently selected from -N or -CR6;
ring A is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl;
ring B is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- carbocycle, and substituted- or unsubstituted- heterocycle;
R1 and R2 are independently selected from halogen, nitro, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, - NR7bC(=O)R7a, -OR7b, -C(=O)OR7b, -C(=O)N(R7b)2, and -N(R7b)2;
R3 is selected from halogen, nitro, cyano, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, substituted- or unsubstituted- 5-6 membered aryl, substituted- or unsubstituted- heteroaryl, - NR7bC(=O)R7a, and -C(=O)N(R7b)2;
R4 and R5 are independently selected from hydrogen, halogen, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, or R4 and R5 together can form a substituted- or unsubstituted- 3-8 membered carbocycle, substituted- or unsubstituted- 4-8 membered heterocycle;
R6 is selected from hydrogen, halogen, nitro, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, -NR7bC(=O)R7a, -OR7b, -C(=O)OR7b, -C(=O)N(R7b)2, and -N(R7b)2;
R7a is selected from substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocycle;
R7b is selected from hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocycle;
m is an integer selected from 0-3;
n is an integer selected from 0-2;
o is an integer selected from 1-3;
or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, isotopes, prodrugs or deuterated compounds including their isotopes, combinations and use thereof.

2. The compounds of Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, isotopes, prodrugs or deuterated compounds including their isotopes, combinations and use thereof as claimed in claim 1, wherein the compounds are selected from the group comprising of:
I 2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(1-isopropyl-4-(trifluoro methyl)-1H-imidazol-2-yl)benzyl)quinazoline
II 2-(1-isopropyl-1H-pyrazol-5-yl)-8-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)quinazoline
III N-(4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl) phenyl)-3-(trifluoromethyl)benzamide
IV 4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)-N-(3-(trifluoromethyl)phenyl)benzamide
V N-cyclopropyl-4-((2-(4-cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)benzamide
VI 5-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)-N-(3-(trifluoromethyl)phenyl)picolinamide
VII 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-2-yl)methyl)quinazoline
VIII N-(4-((2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)quinazolin-8-yl)methyl)phenyl)-3-(trifluoromethyl)picolinamide
IX 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-((6-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-3-yl)methyl)quinazoline
X 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline
XI 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline
XII 2-(4-Cyclopropyl-6-methoxypyrimidin-5-yl)-8-(3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline
XIII 2-(1-Isopropyl-1H-pyrazol-5-yl)-8-(4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzyl)quinazoline
3. A process for preparation of novel heteroaryl compounds of formula (I)

(I)
wherein,
X1 and X2 are independently selected from -N or -CR6;
ring A is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl;
ring B is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- carbocycle, and substituted- or unsubstituted- heterocycle;
R1 and R2 are independently selected from halogen, nitro, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, - NR7bC(=O)R7a, -OR7b, -C(=O)OR7b, -C(=O)N(R7b)2, and -N(R7b)2;
R3 is selected from halogen, nitro, cyano, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, substituted- or unsubstituted- 5-6 membered aryl, substituted- or unsubstituted- heteroaryl, - NR7bC(=O)R7a, and -C(=O)N(R7b)2;
R4 and R5 are independently selected from hydrogen, halogen, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, or R4 and R5 together can form a substituted- or unsubstituted- 3-8 membered carbocycle, substituted- or unsubstituted- 4-8 membered heterocycle;
R6 is selected from hydrogen, halogen, nitro, cyano, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, -NR7bC(=O)R7a, -OR7b, -C(=O)OR7b, -C(=O)N(R7b)2, and -N(R7b)2;
R7a is selected from substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocycle;
R7b is selected from hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocycle;
m is an integer selected from 0-3;
n is an integer selected from 0-2;
o is an integer selected from 1-3;

or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, isotopes, prodrugs or deuterated compounds including their isotopes thereof, comprising the steps of:

i) converting compounds of Formula (1)

wherein X1, X2, R2 and “m” as defined above
to give boronate ester compounds of Formula (2);

wherein X1, X2, R2 and “n” as defined above

(ii) coupling boronate ester compounds of Formula (2) with bromo compounds of Formula (3)

wherein Ring B, R3 , R4, R5 and “o” as defined above

to give compounds of Formula (4);

wherein X1, X2, Ring B, R2, R3, R4, R5, “n” and “o” as defined above

iii) coupling compounds of Formula (4) with boronic acid or boronate ester compounds of Formula (5);

wherein Ring A, R, R1 and “m” as defined above, to give compounds of Formula (I).

4. A pharmaceutical composition comprising at least one or more compounds of Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including isotopes thereof, and a pharmaceutically acceptable excipient or carrier.

5. Use of a compound of Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including isotopes thereof for manufacturing of medicament for a treatment of a cancer and metabolic disorders associated with USP1 protein.

6. Use of a compound of Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including isotopes thereof for a treatment of a cancer and metabolic disorders associated with USP1 protein.

7. A method of treating cancer and metabolic disorders by administering to a subject therapeutically effective amount of a pharmaceutical composition comprising at least one or more of the compound of Formula (I) or it’s pharmaceutically acceptable salts, solvates, polymorphs, tautomers, atropisomers, optical and geometric isomers, prodrugs, or deuterated compounds including isotopes thereof.

8. The method as claimed in claim 7, wherein the cancer and metabolic disorders are associated with USP1 protein.

9. The method as claimed in any one of claims 7 and 8, wherein the cancer is a solid tumor or hematopoietic tumor.

10. The method as claimed in claim 9, wherein the solid tumor is selected from breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, glioblastoma, hepatocellular carcinoma, lung cancer, neuroblastoma, ovarian cancer, prostate cancer, stomach cancer, rhabdomyosarcoma, fibrosarcoma, thyroid follicular cancer or Kaposi's sarcoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoactanthoma or uterine cancer.

11. The method as claimed in claim 10, wherein the hematopoietic tumor is selected from the group comprising:
(a) a hematopoietic tumor of lymphoid lineage selected from leukemia, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-20 lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma or Burkett's lymphoma; and
(b) a hematopoietic tumor of myeloid lineage selected from acute and chronic myelogenous leukaemia’s, myelodysplastic syndrome or promyelocytic leukemia.

Dated this Eleventh (11th) day of February, 2025

Your Sincerely,

Sathyanarayana Murthy Chavali,
CEO,
Satyarx Pharma Innovations Pvt Ltd