Process and compounds for preparing camonsertib and its salts

Abstract

The present invention relates to a process for the preparation of (1R,3r,5S)-3-{6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-3-yl)-1H- pyrazolo[3,4-b]pyridin-4-yl}-8-oxabicyclo[3.2.1]octan-3-ol (camonsertib) and pharmaceutically acceptable salts thereof, which are useful as pharmaceutically active anti-cancer compounds.

Description

[0001] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 PROCESS AND COMPOUNDS FOR PREPARING CAMONSERTIB AND ITS SALTS BACKGROUND The present invention relates to a process for the preparation of (1R,3r,5S)-3-{6-[(3R)-3- methylmorpholin-4-yl]-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl}-8-oxabicyclo[3.2.1]octan- 3-ol (camonsertib), or a pharmaceutically acceptable salt thereof, which are useful pharmaceutically active compounds. The compound of formula (I), (1R,3r,5S)-3-{6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-3- yl)-1H-pyrazolo[3,4-b]pyridin-4-yl}-8-oxabicyclo[3.2.1]octan-3-ol, has shown activities as an ATR inhibitor as described in WO2020087170. A more efficient and scalable synthesis of camonsertib was developed. DNA damage occurs continually in cells as a result of environmental insults including ultraviolet radiation, X-rays, and endogenous stress factors, such as reactive oxygen and hydrolysis of bases. Cancer cells are subject to a higher rate of DNA damage inherently induced by higher rates of DNA replication in these cells. Several DNA damage response (DDR) pathways have evolved in a highly coordinated manner to help repair DNA damage and to act as a cellular checkpoint to stop the replication of cells with damaged DNA, allowing for repair functions to occur before the damaged DNA is passed on to daughter cells. Each of the identified DNA repair pathways sense and repair distinct but overlapping types of DNA damage. One major DDR protein that acts as a key cell cycle checkpoint is the ataxia telangiectasia mutated and rad3-related (ATR) kinase, related to the family of phosphoinositide 3-kinase-related protein kinases (PIKKs). ATR is activated by single stranded (ss) DNA lesions caused by stalled replication forks or during nucleotide excision repair but is also activated by double strand breaks following DNA end resection during homologous recombination. ATR has been identified as an important cancer target since it is essential for dividing cells. Cancer cells that have high levels of replication stress due to oncogenic mutations, dysfunctional G1 / S checkpoint control (e.g., loss of p53 function), defects in other DNA repair pathways (e.g., ATM) or that are subject to the effects of DNA damaging agents, e.g., radiation therapy or chemotherapeutic agents, are therefore more dependent on ATR for DNA repair and survival. Together, these results highlight a rationale for the selective sensitivity of proliferating tumor cells to ATR inhibition and the potential for a therapeutic window over healthy, proliferating cells. There is a need for new anti-cancer therapies and, in particular, for ATR inhibitor-based anti-cancer therapies PATENT ATTORNEY DOCKET NO.: 51246-070WO2 SUMMARY OF THE INVENTION One aspect of the present invention provides a process for the preparation of a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, with a deprotecting agent. In some embodiments, In some embodiments, the deprotecting agent comprises a thiol. In specific embodiments, the deprotecting agent comprises of L-cysteine. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 In some embodiments, the deprotecting agent further comprises an acid. In specific embodiments, the deprotecting agent further comprises trifluoroacetic acid. In specific embodiments, the deprotecting agent comprises L-cysteine and trifluoroacetic acid. Another aspect of the present invention provides a process for the preparation of a compound of formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, which comprises reacting a compound of formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, and R1is selected from the group consisting of chloro, bromo, and iodo, with a compound of formula (III'): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 In some embodiments, R1is iodo. In some embodiments, PG1is selected from the groups in Table 1. In some embodiments, PG1is PMB. In some embodiments, the reaction between the compound of formula (III) and (III’) is a Grignard reaction. Another aspect of the present invention provides a process for the preparation of a compound of formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, and R1is selected from the group consisting of chloro, bromo, and iodo, which comprises reacting a compound of formula (IV):

[0002] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (IV), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups, R1is selected from the group consisting of chloro, bromo, and iodo, and R' is H or absent, in the presence of an acid. In some embodiments, PG2 , wherein R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl, and R5is H or methyl. . In some embodiments, the acid is methanesulphonic acid (MsOH): . Another aspect of the present invention provides a process for the preparation of a compound of formula (IV): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (IV), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups, R1is selected from the group consisting of chloro, bromo, and iodo, and R' is H or absent, the process comprises reacting a compound of formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups, and R' is H or absent, with a compound of formula (VI): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (VI), or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of chloro, bromo, and iodo, and R2is halogen selected from the group consisting of fluoro, chloro, bromo, and iodo. In some embodiments, the compound of formula (IV) is: pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (V) is: pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a process for the preparation of a compound of formula (VI): (VI), or a pharmaceutically acceptable salt thereof, PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein R1is selected from the group consisting of chloro, bromo, and iodo, and R2is a halogen, selected from the group consisting of fluoro, chloro, bromo, and iodo, wherein the process comprising the steps: a. reacting a compound of formula (VII): (VII), or a pharmaceutically acceptable salt thereof, wherein R1and R2are as defined previously, and R3is halogen selected from the group consisting of fluoro, chloro, bromo, and iodo, with (3R)-3-methylmorpholine, or a salt thereof, to form a compound of formula (VIII): (VIII), or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo, and b. formylating the compound of formula (VIII), to form a compound of formula (VI). In some embodiments, the compound of formula (VII) is: . In some embodiments, the compound of formula (VII) is: pharmaceutically acceptable salt thereof. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Another aspect of the present invention provides a process for the preparation of a compound of formula (V): (V), or a pharmaceutically acceptable salt thereof wherein PG1and PG2are protecting groups, and R' is H or absent, the process comprising reacting a compound of formula (V'): (V'), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, with Q, wherein Q is: , wherein R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl. R5is H or methyl, or R4and R5taken together form a C6 cycloalkyl. In specific embodiments, R4is phenyl. In specific embodiments, R5is H. In other embodiments, Q is a ketone. In some embodiments, Q is a ketone selected from the group consisting of acetone, acetophenone, and ethyl methyl ketone. In other embodiments, Q is an aldehyde. In some embodiments, Q is an aldehyde selected from the group consisting of formaldehyde, acetaldehyde, propanal, butanal, 2-methylbutanal, pentanal, benzaldehyde, p- nitrobenzaldehyde, p-methylbenzaldehyde, and p-methoxybenzaldehyde. In specific embodiments, Q is benzaldehyde. In specific embodiments, the compound of formula (V) is: PATENT ATTORNEY DOCKET NO.: 51246-070WO2 pharmaceutically acceptable salt thereof. In specific embodiments, the compound of formula (V) is a hydrochloride salt (e.g., a salt resulting from a reaction with hydrochloric acid). Another aspect of the present invention provides a process for the preparation of a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, which comprises the steps of: a. reacting a compound of formula (V'), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, with Q, wherein, Q is an anhydride, aldehyde, ketone, or a group with the formula L-PG2, to form a compound of formula (V): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (V), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups, and R' is H or absent, b. reacting the compound of formula (V) with a compound of formula (VI): (VI), or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of chloro, bromo, and iodo, and R2is a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo, to form a compound of formula (IV):

[0003] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (IV), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups, R1is selected from the group consisting of chloro, bromo, and iodo, and R' is H or absent, c. reacting the compound of formula (IV), in presence of an acid, to form a compound of formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, and R1is as defined previously, d. reacting the compound of formula (III), with a compound of formula (III'): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 to form compound of formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, and e. reacting the compound of formula (II) to form a compound of formula (I). In some embodiments, PG1is a protecting group selected from Table 1. In specific embodiments, PG1is PMB. In some embodiments, R1is iodo. In some embodiments, R2is fluoro. In some embodiments, PG2is: , wherein R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl, and R5is H or methyl. In specific embodiments, PG2is . PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Another aspect of the present invention provides a process for the preparation of camonsertib sulfuric acid salt, the process comprises (see, e.g., Example 11): . Another aspect of the present invention provides a process for the preparation of camonsertib, the process comprising (see, e.g., Example 10): . Another aspect of the present invention provides a process for the preparation of Int-9, the process comprising (see, e.g., Example 9): . Another aspect of the present invention provides a process for the preparation of Int-7, the process comprising (see, e.g., Example 7): . PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Another aspect of the present invention provides a process for the preparation of Int-6, the process comprising (see, e.g., Example 6): . Another aspect of the present invention provides a process for the preparation of Int-3, the process comprising (see, e.g., Example 3): . Another aspect of the present invention provides a process for the preparation of Int-2, the process comprising (see, e.g., Example 2): . Another aspect of the present invention provides a compound of formula (V'): (V'), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group. In some embodiments, PG1is a group selected from Table 1. In specific embodiments, PG1is PMB. In specific embodiments, the compound of formula (V') is: PATENT ATTORNEY DOCKET NO.: 51246-070WO2 pharmaceutically acceptable salt thereof. In specific embodiments, the compound of formula (V') is a hydrochloride salt. In specific embodiments, the compound of formula (V') is: . Another aspect of the present invention provides a compound of formula (V): or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups, and R' is H or absent. In some embodiments, PG1and PG2are independently selected from the groups in Table 1. In some embodiments, PG1and PG2are independently selected from the group consisting of Boc, PMB, Cbz, and Bn. In specific embodiments, the compound of formula (V) is: pharmaceutically acceptable salt thereof. In specific embodiments, the compound is a hydrochloride salt. In specific embodiments, the compound of formula (V) is: PATENT ATTORNEY DOCKET NO.: 51246-070WO2 . Another aspect of the present invention provides a compound of formula (IV): (IV), or a pharmaceutically acceptable salt thereof wherein PG1and PG2are protecting groups, R1is selected from the group consisting of chloro, bromo, and iodo, and R' is H or absent. In specific embodiments, PG1is a group selected from Table 1. In some embodiments, PG1is PMB. In some embodiments, PG2is: wherein R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl, R5is H or methyl, or R4and R5taken together form a C6 cycloalkyl. In some embodiments, R4is phenyl. In some embodiments, R5is H. In specific embodiments, the compound of formula (IV) is: PATENT ATTORNEY DOCKET NO.: 51246-070WO2 pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a compound of formula (III): (III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, and R1is selected from the group consisting of chloro, bromo, and iodo. In some embodiments, R1is iodo. In some embodiments, PG1is a group selected from Table 1. In some embodiments, PG1is selected from the group consisting of PMB, Boc, Bn, Cbz, and Fmoc. In specific embodiments, PG1is PMB. Another aspect of the present invention provides a compound of formula (II): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (II), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group. In some embodiments, PG1is a group selected from Table 1. In some embodiments, PG1is selected from the group consisting of PMB, Boc, Bn, Cbz, and Fmoc. In specific embodiments, PG1is PMB. Another aspect of the present invention provides a compound of formula (VIII):

[0004] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (VIII), or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of chloro, bromo, and iodo, and R2is a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo. In some embodiments, R1is iodo. In some embodiments, R2is fluoro. Another aspect of the present invention provides a compound of formula (VI): (VI), or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of chloro, bromo, and iodo, and R2is a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo. In some embodiments, R1is iodo. In some embodiments, R2is fluoro. In specific embodiments, the compound of formula (VI) is: , or a pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a compound of formula (Ia): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (Ia), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group. In some embodiments, PG1is a group selected from Table 1. In some embodiments, PG1is selected from the group consisting of PMB, Boc, Bn, Cbz, and Fmoc. In specific embodiments, PG1is PMB. Another aspect of the present invention provides a composition comprising a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (compound of formula (I')), further comprising a compound of formula (II): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (II), wherein PG1is a protecting group, having less than 0.15 % in weight of the compound of formula (II), in particular having between 1 ppb and 100 ppm of the compound of formula (II), more particularly having between 1 ppb and 1 ppm of the compound of formula (II). In some embodiments, PG1is a group selected from Table 1. Another aspect of the present invention provides a composition comprising a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (compound of formula (I')), further comprising a compound of formula (Ia): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (Ia), wherein PG1is a protecting group, having less than 0.55 % in weight of compound of formula (Ia), in particular having between 1 ppb and 100 ppm of the compound of formula (Ia), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ia). In some embodiments, PG1is a group selected from Table 1. Another aspect of the present invention provides a composition comprising a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (compound of formula (I')), further comprising compound of formula (Ib): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (Ib), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, having less than 0.50 % in weight of the compound of formula (Ib), in particular having between 1 ppb and 100 ppm of the compound of formula (Ib), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ib). In some embodiments, PG1is a group selected from Table 1. Another aspect of the present invention provides a pharmaceutical composition comprising compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (compound of formula (I')), further comprising compound of formula (II): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (II), wherein PG1is a protecting group, wherein the composition comprises less than 0.15% in weight of the compound of formula (II), in particular having between 1 ppb and 100 ppm of the compound of formula (II), more particularly having between 1 ppb and 1 ppm of the compound of formula (II). In some embodiments, PG1is a group selected from Table 1. Another aspect of the present invention provides a pharmaceutical composition comprising compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (compound of formula (I')), further comprising a compound of formula (Ia): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (Ia), wherein PG1is a protecting group, wherein the composition comprises less than 0.55% in weight of compound of formula (Ia), in particular having between 1 ppb and 100 ppm of the compound of formula (Ia), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ia). In some embodiments, PG1is a group selected from Table 1. Another aspect of the present invention provides pharmaceutical composition comprising compound of formula (I): formula PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (Ib), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, wherein the composition comprises less than 0.50% in weight of the compound of formula (Ib), in particular having between 1 ppb and 100 ppm of the compound of formula (Ib), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ib). In some embodiments, PG1is a group selected from Table 1. Abbreviations Abbreviations and terms that are commonly used in the fields of organic chemistry, medicinal chemistry, pharmacology, and medicine and are well known to practitioners in these fields are used herein. Representative abbreviations and definitions include: Me is methyl, Et is ethyl, Ac is acetyl, Ph is phenyl, MeOH is methanol, MsOH is methanesulfonic acid, EtOH is ethanol, EtOAc is ethyl acetate, DCM is dichloromethane, DMF is N,N-dimethylformamide, THF is tetrahedrofuran, i-PrOH and IPA are isopropanol, MTBE and TBME are tert-butyl methyl ether, PMB is p- methoxybenzyl, PG is protecting group, LC is liquid chromatography, min is minute, h is hour, rt is room temperature. Definitions In this application, unless otherwise clear from context, (i) the term “a” means “one or more”; (ii) the term "or" is used to mean "and / or" unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or”; (iii) the terms “comprising” and “including” are understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and (iv) where ranges are provided, endpoints are included. As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. "Acid" refers to a compound capable of giving proton as described by Brønsted–Lowry acid- base theory’, dissociating into proton and counter ion in water at 25°C and giving a solution having neutral pH or below. Concrete examples of the acid are phosphoric acid (orthophosphoric acid), sulfuric acid, nitric acid, phosphinic acid, phosphonic acid, diphosphonic acid, hydrochloric acid, pyrophosphoric acid, metaphosphoric acid, and nitrous acid. These acids may be used in the form of metal salts, ammonium salts or the like. In the present invention, hydrochloric acid is preferable. The term “acyl,” as used herein, represents a group –C(=O)–R, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl. Acyl may be optionally substituted as described herein for each respective R group. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 "Aromatic" refers to the conventional idea of aromaticity as defined in the literature, in particular in IUPAC - Compendium of Chemical Terminology, 2ndEdition, A. D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997). The term “aryl,” as used herein, represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings. The aryl group may include from 6 to 10 carbon atoms (C6-10 aryl). All atoms within an unsubstituted carbocyclic aryl group are carbon atoms. Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, etc. The term “aryl alkyl,” as used herein, represents an alkyl group substituted with an aryl group (e.g., C1-6 alkyl C6-10 aryl). The term “alkyl aryl,” as used herein, represents an aryl group substituted with an alkyl group (e.g., C6-10 aryl C1-6 alkyl). The term “alkyl,” as used herein, refers to an acyclic straight or branched chain saturated hydrocarbon group, which, when unsubstituted, has from 1 to 12 carbons, unless otherwise specified. In certain preferred embodiments, unsubstituted alkyl has from 1 to 6 carbons. Alkyl groups are exemplified by methyl; ethyl; n- and iso-propyl; n-, sec-, iso- and tert-butyl; neopentyl, and the like, and may be optionally substituted, valency permitting, with one, two, three, or, in the case of alkyl groups of two carbons or more, four or more substituents independently selected from the group consisting of amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; alkylsulfonyl; alkylsulfinyl; alkylsulfenyl; =O; =S; -SO2R, where R is amino or cycloalkyl; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or, valency permitting, substituted with unsubstituted substituent(s) defined herein for each respective group. "Carbonyl compound" refers to a chemical compound that contains at least one C=O moiety. Examples of carbonyl compounds are aldehydes (–C(=O)–H) and ketones (–C(=O)–R; also referred to as acyl herein). Nonlimiting examples of carbonyl compounds include: benzaldehyde, phenylacetone, acetaldehyde, acetone, MEK, MIBK, cyclohexananone, acetophenone, benzophenone, and the like. The terms, “composition” and “mixture,” as used interchangeably herein, refer to a material made up of at least two different components which can be separated by physical means. The quantities of each component of the composition are as specified herein. "Cycloalkyl" refers to a saturated or partially unsaturated carbocyclic moiety having mono-, bi- (including bridged bicyclic and cycloalkyl spiro moieties) or tricyclic rings and 3 to 10 carbon atoms i.e., (C3-C10)cycloalkyl) in the ring. The cycloalkyl moiety can optionally be substituted with one or more substituents. In particular embodiments cycloalkyl contains from 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other particular embodiments cycloalkyl contains from 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and partially unsaturated (cycloalkenyl) derivatives thereof (e.g. cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, bicyclo[3.1.1]heptenyl and bicyclo[1.1.1]pentane. The cycloalkyl moiety can be attached in a “spiro-cycloalkyl” or “cycloalkyl spiro” fashion such as “spirocyclopropyl”. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 “Compound of formula (I)” refers to: , also known as (1R,3r,5S)-3-{6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4- b]pyridin-4-yl}-8-oxabicyclo[3.2.1]octan-3-ol, or a pharmaceutically acceptable salt thereof. The compound of formula (I) is also known as camonsertib. Herein the compound of formula (I)’s name or reference can be used interchangeably. The compound of formula (I) can also be a salt. Most preferably, a “camonsertib sulfate salt” or “camonsertib sulfuric acid salt”, resulting from the reaction between camonsertib and sulfuric acid (see, e.g., Example 11 and Table 2). "Deprotecting agent" refers to a chemical reagent with the ability to cleave a protecting group from the chemical compound. Examples of deprotecting agents are acidic compounds, basic compounds, compounds able to perform hydrogenation, oxidative compounds, or reductive compounds. Nonlimiting examples of deprotecting agents are HCl, Pd / H2, TFA, NaOH, TBAF, MsOH, and p-TsOH. In some embodiments of the present invention, cysteine is used as a deprotecting agent. "Formylation" refers to refers to any chemical processes in which a compound is functionalized with a formyl group (-CH=O). Some examples of Formylation reactions use DMF and POCl3 to add a formyl group to chemical compound. Other examples of formylation reaction involve the use of phosgene, phtaloyl dichloride, thionyl chloride, diphosgene, triphosgene, or oxalyl chloride to form the Vilsmeier reagent. Additional examples of formylation do not use DMF: such as the Duff reaction, Gattermann-Koch reaction, Gattermann reaction, Reimer-Tiemann reaction, Rieche formylation, and Casiraghi formylation. "Grignard reagent" refers to any compound of formula RMgX, wherein R is an organic group, and X is a halogen. Nonlimiting examples of Grignard reagents are methylmagnesium chloride, isopropylmagnesiumchloride, or butylmagnesiumchloride. "Halo" or “Halogen” as used interchangeably herein, refers to fluoro, chloro, bromo or iodo. The term “heteroalkyl,” as used herein refers to an alkyl, alkenyl, or alkynyl group interrupted once by one or two heteroatoms; twice, each time, independently, by one or two PATENT ATTORNEY DOCKET NO.: 51246-070WO2 heteroatoms; three times, each time, independently, by one or two heteroatoms; or four times, each time, independently, by one or two heteroatoms. Each heteroatom is, independently, O, N, or S. In some embodiments, the heteroatom is O or N. None of the heteroalkyl groups includes two contiguous oxygen or sulfur atoms. The heteroalkyl group may be unsubstituted or substituted (e.g., optionally substituted heteroalkyl). When heteroalkyl is substituted and the substituent is bonded to the heteroatom, the substituent is selected according to the nature and valency of the heteroatom. Thus, the substituent bonded to the heteroatom, valency permitting, is selected from the group consisting of =O, -N(RN2)2, -SO2ORN3, -SO2RN2, -SORN3, -COORN3, an N protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, or cyano, where each RN2is independently H, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl, and each RN3is independently alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl. Each of these substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. When heteroalkyl is substituted and the substituent is bonded to carbon, the substituent is selected from those described for alkyl, provided that the substituent on the carbon atom bonded to the heteroatom is not Cl, Br, or I. It is understood that carbon atoms are found at the termini of a heteroalkyl group. The term “heteroaryl alkyl,” as used herein, represents an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl portions may be optionally substituted as the individual groups described herein. The term “heteroarylene,” as used herein, represents a divalent heteroaryl. An optionally substituted heteroarylene is a heteroarylene that is optionally substituted as described herein for heteroaryl. The term “heteroaryloxy,” as used herein, refers to a structure –OR, in which R is heteroaryl. Heteroaryloxy can be optionally substituted as defined for heterocyclyl. The term “heterocyclyl,” as used herein, represents a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused, bridging, and / or spiro 3-, 4-, 5-, 6-, 7-, or 8-membered rings, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, “heterocyclyl” is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridging 5-, 6-, 7-, or 8- membered rings, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocyclyl can be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclyl has zero or one double bonds, non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds, and non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and / or zero or one carbon-carbon triple bond. Heterocyclyl groups include from 1 to 16 carbon atoms unless otherwise specified. Certain heterocyclyl groups may include up to 9 carbon atoms. Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, etc. If the heterocyclic ring system has at PATENT ATTORNEY DOCKET NO.: 51246-070WO2 least one aromatic resonance structure or at least one aromatic tautomer, such structure is an aromatic heterocyclyl (i.e., heteroaryl). Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl (e.g., 1,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, etc. The term “heterocyclyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and / or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., quinuclidine, tropanes, or diaza- bicyclo[2.2.2]octane. The term “heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring. Examples of fused heterocyclyls include 1,2,3,5,8,8a- hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene. The heterocyclyl group may be unsubstituted or substituted with one, two, three, four or five substituents independently selected from the group consisting of alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silyl; cyano; =O; =S; =NR’, where R’ is H, alkyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) defined herein for each respective group. The term “heterocyclyl alkyl,” as used herein, represents an alkyl group substituted with a heterocyclyl group, each as defined herein. The heterocyclyl and alkyl portions may be optionally substituted as the individual groups described herein. The term “heterocyclylene,” as used herein, represents a divalent heterocyclyl. An optionally substituted heterocyclylene is a heterocyclylene that is optionally substituted as described herein for heterocyclyl. The term “(heterocyclyl)oxy,” as used herein, represents a chemical substituent of formula – OR, where R is a heterocyclyl group, unless otherwise specified. (Heterocyclyl)oxy can be optionally substituted in a manner described for heterocyclyl. The terms “hydroxyl” and “hydroxy,” as used interchangeably herein, represent an -OH group. The term “isomer,” as used herein, means any tautomer, stereoisomer, atropiosmer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention can have one or more chiral centers or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates. Enantiomeric and stereoisomeric mixtures of compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, PATENT ATTORNEY DOCKET NO.: 51246-070WO2 such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, recrystallizing the compound as a chiral salt complex, or recrystallizing the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods. "Organometal compound" refers to chemical compounds having bonds between one or more metal atoms and one or more carbon atoms. Examples of organometal compounds are butyllithium, methylmagnesium chloride, isopropylmagnesiumchloride, or butylmagnesiumchloride. The term organometal compound includes Grignard reagents. "Oxidant" refers to one or more suitable electron acceptors and may be an element, combination of elements, a compound, or combination of compounds including reducible compounds, and is a vapor, solid, or liquid at the process conditions. A nonlimiting example of oxidant is mCPBA (meta-Chloroperoxybenzoic acid). The term “nitro,” as used herein, represents an -NO2 group. The term “oxo,” as used herein, represents a divalent oxygen atom (e.g., the structure of oxo may be shown as =O). "Pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts represent salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1- 19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N- acetylcystein, and the like. Particularly preferable pharmaceutically acceptable salts of the present invention are salts of compounds of formula (I) prepared by reacting compounds of formula (I) with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid. The resulting salts of the present invention are referenced based on the acid used to produce the salt, e.g., salts produced from reactions with hydrochloric acid are referred to herein as “hydrochloric acid salt”, “hydrochloride salt”, or hydrochloric acid is listed after the compound name. When there are multiple free base sites in a compound, the number of salt molecules present is referred to relative to the free base sites with numbers in brackets, e.g., (salts / free base sites). For example, a molecule with two free base sites could react with acid to form one ion pair (1 / 2) or two ion pairs (2 / 2). The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient, and manufactured PATENT ATTORNEY DOCKET NO.: 51246-070WO2 or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein. The term “protecting group,” (PG) as used herein, represents a group intended to protect a hydroxy, an amino, a sulfide (R-S-R), or a carbonyl from participating in one or more undesirable reactions during chemical synthesis. In some embodiments, the protecting group may be removed to yield the final product. In some embodiments, the protecting group may be part of the final product. The term “O-protecting group,” as used herein, represents a group intended to protect a hydroxy or carbonyl group from participating in one or more undesirable reactions during chemical synthesis. The term “N-protecting group,” as used herein, represents a group intended to protect a nitrogen containing (e.g., an amino, amido, heterocyclic N-H, or hydrazine) group from participating in one or more undesirable reactions during chemical synthesis. Commonly used O- and N- protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Exemplary O- and N-protecting groups include alkanoyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ^-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t- butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4’-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4- isopropylpehenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl. Exemplary O-protecting groups for protecting carbonyl containing groups include, but are not limited to: acetals, acylals, 1,3-dithianes, 1,3-dioxanes, 1,3-dioxolanes, and 1,3-dithiolanes. Other O-protecting groups include, but are not limited to: substituted alkyl, aryl, and aryl- alkyl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2,- trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2- (trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p- nitrophenyl, benzyl, p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and diphenymethylsilyl); carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4- dimethoxybenzyl; and nitrobenzyl). Other N-protecting groups include, but are not limited to, chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5 dimethoxybenzyl oxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4 methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5 trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1- PATENT ATTORNEY DOCKET NO.: 51246-070WO2 methylethoxycarbonyl, ^,^-dimethyl-3,5 dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t- butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, aryl-alkyl groups such as benzyl, p- methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, benzyloxymethyl, and the like, silylalkylacetal groups such as [2-(trimethylsilyl)ethoxy]methyl and silyl groups such as trimethylsilyl, and the like. Useful N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, dimethoxybenzyl, [2-(trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), t- butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz). "Silicon protecting groups" refers to a protecting group with at least one Si atom present. These silicon protecting groups are well known to the person skilled in the art. Nonlimiting examples of silicon protecting groups are trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl ether (TBDMS) as well as the diol-protective groups DTBS and TIPDS. "Carboxy protecting group" refers to a protecting group with a -C(O)O- group. These carboxy protecting groups are well known to the person skilled in the art. Examples of carboxy protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or fluorenylmethoxycarbonyl (Fmoc). The term “process,” as used herein, refers to a step or series of steps that uses equipment, systems, and conditions to convert starting materials into products. In some embodiments of the present invention, a process is a chemical reaction (e.g., a process that converts reagents to products by chemical means). The term “stereoisomer,” as used herein, refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers or conformers of the basic molecular structure, including atropisomers. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention. "Substituted" refers to the replacement of at least one of hydrogen atoms of a compound or moiety with a suitable substituent or moiety. Examples of such substituents include, without limitation, halogen, -OH, -CN, oxo, alkoxy, C1-6alkyl, alkylene, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, and heterocycle. For example, the term “haloalkyl” refers to the fact that one or more hydrogen atoms of a C1-6alkyl (as defined below) is replaced by one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.). In one aspect, substituted, as used herein, can refer to replacement of at least one hydrogen atom of a compound or moiety described herein with halogen or C1-6alkyl. The term “optionally substituted X” (e.g., “optionally substituted alkyl”) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein the alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional. As described herein, certain compounds of interest may contain one or more “optionally substituted” moieties. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 "Moiety" and “Substituent” refer to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds thereby forming part of a molecule. When indicating the number of substituents, the term “one or more” refers to the range from one substituent to the highest possible number of substitutions, valency permitting, i.e. replacement of one hydrogen up to replacement of all hydrogens by substituents, in particular wherein “one or more” refers to one, two or three, most particularly “one or more” refers to one or two. Those skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., in which one or more atoms has been substituted with a different isotope of the atom, such as hydrogen substituted for deuterium) forms. Unless otherwise indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in combination. Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. As is known in the art, many chemical entities can adopt a variety of different solid forms such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvate). In some embodiments, compounds of the present invention may be utilized in any such form, including in any solid form. In some embodiments, compounds described or depicted herein may be provided or utilized in hydrate or solvate form. At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-C6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound includes a plurality of positions at which substituents are disclosed in groups or in ranges, unless otherwise indicated, the present disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 DETAILED DESCRIPTION The starting materials, reagents and catalysts, which do not have their synthetic route explicitly disclosed herein, are generally available from commercial sources or are readily prepared using methods known to the person skilled in the art. In general, the nomenclature used in this Application is based on AUTONOMTM2000, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Chemical structures shown herein were prepared using MDL ISIS™ version 2.5 SP2. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Protecting Group As defined herein, a protecting group (PG) represents a group intended to protect a hydroxy, an amino, a sulfide, or a carbonyl from participating in one or more undesirable reactions during chemical synthesis. The protecting group may be removed with a deprotecting agent or may be part of the product. Nonlimiting examples of protecting groups and deprotecting agents used in the present invention are shown in Table 1 below. Particularly preferable protecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), and p-methoxybenzyl (PMB). Further particularly preferable protecting groups are the tert- butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc). A more particularly preferable protecting group is the tert-butoxycarbonyl (Boc). Representative protocols for the protection and deprotection steps of the present invention are in the examples. Table 1. Protecting groups Name Abbreviation Structure Optional Deprotecting Agent treatment with base acyl Ac trifluoro acetyl chloro acetyl acetone aminal treatment with acid tert-butyloxycarbonyl Boc treatment with base Benzoyl Bz hydrogenolysis Benzyl Bn PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Name Abbreviation Structure Optional Deprotecting Agent hydrogenolysis carbobenzyloxy Cbz hydrogenolysis 3,4-Dimethoxybenzyl DMPM treatment with base 9- Fmoc Fluorenylmethyloxycarbonyl hydrogenolysis p-methoxybenzyl carbonyl MeOZ ethoxymethyl methoxymethyl MOM treatment with acid treatment with acid sulfonyl treatment with samarium p-nitrophenylsulfonyl Nosyl iodide, tributyltin hydride hydrogenolysis p-methoxybenzyl PMB treatment with ammonium p-methoxyphenyl PMP cerium(IV) nitrate (CAN) treatment with acid or tert-butyldimethylsilyl TBDMS fluoride ion treatment with acid or tert-butyldiphenylsilyl TBDPS fluoride ion ^ treatment with acid tetrahydropyranyl THP treatment with acid and reducing agents (e.g., p-methylphenylsulfonyl Ts sodium in liquid ammonia or sodium naphthalenide) tert-butyl tBu PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Name Abbreviation Structure Optional Deprotecting Agent treatment with acid and triphenylmethyl Trityl or Tr hydrogenolysis methylene group Synthetic Process, Compounds, and Compositions Some embodiments of the invention include processes described by schemes 1-5, wherein PG1and PG2are protecting groups (e.g., Table 1), and R', R1, and R2are as described below. In some embodiments, R1is chloro In some embodiments, R1is bromo In some embodiments, R1is iodo. In some embodiments, R2is a halogen. In a more particular embodiment, the present invention provides a compound wherein R1is chloro. In a more particular embodiment, the present invention provides a compound wherein R1is bromo. In a more particular embodiment, the present invention provides a compound wherein R1is iodo. In a more particular embodiment, the present invention provides a compound wherein R2is fluoro. In a more particular embodiment, the present invention provides a compound wherein R2is chloro. In a more particular embodiment, the present invention provides a compound wherein R2is bromo. In a more particular embodiment, the present invention provides a compound wherein R2is iodo. In a more particular embodiment, the present invention provides a compound wherein R3is fluoro. In a more particular embodiment, the present invention provides a compound wherein R3is chloro. In a more particular embodiment, the present invention provides a compound wherein R3is bromo. In a more particular embodiment, the present invention provides a compound wherein R3is iodo. In a more particular embodiment, PG1is selected from Table 1. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 In a more particular embodiment, the present invention provides a compound wherein PG1is selected from silicon protecting groups, or carboxy-protective groups. In a more particular embodiment, the present invention provides the compound wherein PG1is selected from tert-butoxycarbonyl (Boc), p-methoxybenzyl (PMB), tetrahydropyranyl ether (THP), ethoxymethyl, acetone aminal, silicon protecting groups (inter alia TBDMS or TBDPS), methoxymethyl ether (MOM), tert-butyl, trityl, benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). In a more particular embodiment, the present invention provides a compound wherein PG1is PMB. In a more particular embodiment, PG2is selected from Table 1. In a more particular embodiment, the present invention provides a compound wherein PG2is , wherein R4is selected from H, C1-10 alkyl, or aryl, in particular, R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl, or R4and R5taken together form a C3-10 cycloalkyl, in particular C6 cycloalkyl, R5is independently selected from H, or methyl, or R4and R5taken together form a C3-10 cycloalkyl, in particular C6 cycloalkyl, and R' is absent. In a more particular embodiment, R4is phenyl. In a more particular embodiment, R5is H. In a more particular embodiment, the present invention provides a compound wherein PG2is Boc, Cbz, Fmoc, acetyl, trifluoroacetyl, chloroacetyl, trityl, benzyl, or sulfonyl, and R' is H. In another embodiment, the present invention provides a compound wherein PG2and R' taken together form a cycle, in particular form a phthaloyl or a 1,8-naphthalyl. In some embodiments, the present invention provides a process as shown in scheme 1, wherein PG1, PG2, R', R1, and R2are as described hereinabove.

[0005] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Scheme 1 In other embodiments, the present invention provides a process as shown in scheme 2, wherein PG1, PG2, R', R1, and R2are as described hereinabove.

[0006] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Scheme 2 In another embodiment, the present invention provides a process as shown in scheme 3, wherein PG1is a protecting group, and compound of formula (II) reacts with a deprotecting agent to form a mixture of a compound of formula (II) and a compound of formula (I). Scheme 3 PATENT ATTORNEY DOCKET NO.: 51246-070WO2 In another embodiment, the present invention provides a process as shown in scheme 4, wherein PG1is a protecting group, and a compound of formula (II) reacts with a deprotecting agent to form a mixture of a compound of formula (I) and a compound of formula (Ia). Scheme 4 In another embodiment, the present invention provides a process as shown in scheme 5, wherein PG1is a protecting group, and a compound of formula (II) reacts with a deprotecting agent to form a mixture of a compound of formula (I) and a compound of formula (Ib). Scheme 5 In a more particular embodiment, the present invention provides the process as described hereinabove, wherein the solvent is ethanol or water, or a combination thereof. In a more particular embodiment, the present invention provides the process as described hereinabove, in the presence of a base, in particular in the presence of potassium tert-butoxide, sodium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium diisopropylamide , lithium tetramethylpiperidide, potassium carbonate, sodium hydroxide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, or potassium hydride, more particular it the presence of potassium tert-butoxide. In a more particular embodiment, the present invention provides the process as described hereinabove, in the presence of an acid, wherein the acid is p-toluenesulfonic acid, methanesulfonic acid, phosphoric acid, nitric acid, triflic acid, hydrochloric acid, or sulfuric acid, in particular the acid is methanesulfonic acid, or p-toluenesulfonic acid. In a more particular embodiment, the present invention provides the process as described hereinabove, in the presence of a organometal compound, lithium, or magnesium, in particular in the presence of an organolithium compound, magnesium, or a Grignard reagent, more particularly in the presence of butyllithium, sec-butyl(isopropyl)magnesium lithium chloride, benzylmagnesium chloride, methoxyphenylmagnesium bromide, methylmagnesium chloride, ethylmagnesium chloride, phenylmagnesium chloride, toluylmagnesium chloride, t-butylmagnesiumchloride, isopropylmagnesium chloride or butylmagnesiumchloride. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 In a more particular embodiment, the present invention provides the process as described hereinabove, in the presence of lanthanide salt, in particular in the presence of a lanthanium or cerium salt, more particularly in the presence of LaCl3•2LiCl, LaCl3, or CeCl3. In a more particular embodiment, the present invention provides the process as described hereinabove, in the presence of an acid, wherein the acid is acetic acid, hydrochloric acid, sulfuric acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, oxalic acid, or trifluoroacetic acid, in particular trifluoroacetic acid. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein the solvent is THF or water, or a combination thereof. In a more particular embodiment, the present invention provides the process as described hereinabove, wherein the formylation is performed with POCl3 and DMF. In one embodiment, the present invention provides a process for the preparation of a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (II):

[0007] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (II), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, with a deprotecting agent (see, e.g., Example 10). In some embodiments, the deprotecting agent is an acid. In specific embodiments, the acid is trifluoroacetic acid. In another embodiment, the present invention provides a process for the preparation of a compound of formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, which comprises of reacting a compound of formula (III): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group; and R1is chloro, bromo, or iodo, with a compound of formula (III'): (see, e.g., Example 9). In another embodiment, the present invention provides a process for the preparation of a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group; and R1is chloro, bromo, or iodo, PATENT ATTORNEY DOCKET NO.: 51246-070WO2 which comprises of reacting a compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups, R1is chloro, bromo, or iodo; and R' is H or absent, with an acid (see, e.g., Example 9). In another embodiment, the present invention provides a process for the preparation of a compound of formula (IV) (see, e.g., Example 7): or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; PATENT ATTORNEY DOCKET NO.: 51246-070WO2 R1is chloro, bromo, or iodo; and R' is H or absent, which comprises reacting a compound of formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; and R' is H or absent, with a compound of formula (VI): or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and R2is halogen, particularly fluoro, chloro, bromo, or iodo. In another embodiment, the present invention provides a process for the preparation of a compound of formula (VI) (see, e.g., Example 6): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (VI), or a pharmaceutically acceptable salt thereof wherein R1is chloro, bromo, or iodo; and R2is halogen, particularly fluoro, chloro, bromo, or iodo, which comprises the steps: a. reacting a compound of formula (VII): (VII), wherein R1is chloro, bromo, or iodo; R2is halogen, particularly fluoro, chloro, bromo, or iodo; and R3is halogen, particularly fluoro, chloro, bromo, or iodo, with (3R)-3-methylmorpholine, or a salt thereof, to form compound of formula (VIII): (VIII), or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and PATENT ATTORNEY DOCKET NO.: 51246-070WO2 R2is halogen, particularly fluoro, chloro, bromo, or iodo, b. formylating the compound of formula (VIII), to form a compound of formula (VI). In another embodiment, the present invention provides a process for the preparation of a compound of formula (V) (see, e.g., Example 3): or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; and R' is H or absent, which comprises reacting a compound of formula (V'): (V'), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, with Q. In some embodiments, Q is an anhydride, aldehyde, ketone, or a group with the formula L- PG2, wherein PG2is a protecting group as described herein and L is a halogen or , wherein RLis an optionally substituted C1-6 alkyl or optionally substituted C6-10 aryl. In some other embodiments, Q is: , wherein R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl. R5is H or methyl, or R4and R5taken together form a C6 cycloalkyl. In a more particular embodiment, R4is phenyl. In a more particular embodiment, R5is H. In a more particular embodiment, Q is benzaldehyde. In another embodiment, the present invention provides a process for the preparation of a compound of formula (I) (see, e.g., Examples 1-10): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (I), or a pharmaceutically acceptable salt thereof, which comprises the steps: a. reacting a compound of formula (V'): or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, with Q, wherein Q is an anhydride, aldehyde, ketone, or a group with the formula L-PG2, to form a compound of formula (V): or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; and R' is H or absent, PATENT ATTORNEY DOCKET NO.: 51246-070WO2 b. reacting the compound of formula (V) with a compound of formula (VI): (VI), or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and R2is halogen, particularly fluoro, chloro, bromo, or iodo, to form compound of formula (IV): (IV), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; R1is chloro, bromo, or iodo; and R' is H or absent, c. reacting the compound of formula (IV), in presence of an acid to form a compound of formula (III): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group; and R1is as defined previously, d. reacting the compound of formula (III), with a compound of formula (III'): (III'), to form a compound of formula (II), (II), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, e. reacting the compound of formula (II) to form a compound of formula (I). PATENT ATTORNEY DOCKET NO.: 51246-070WO2 In a more particular embodiment, the present invention provides the process as described hereinabove, further comprising the preparation of a compound of formula (I'), which comprises reacting a compound of formula (I): or a pharmaceutically acceptable salt thereof, in the presence of sulfuric acid (see, e.g., Example 11). In a more particular embodiment, the present invention provides the process as described hereinabove, which further comprises the preparation of a compound of formula (II) (see, e.g., Example 9): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (II), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, comprising reacting a compound of formula (III), or a pharmaceutically acceptable salt thereof, (III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group; and R1is chloro, bromo, or iodo, with a compound of formula (III'): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (III’). In a more particular embodiment, the present invention provides the process as described hereinabove, which further comprises the preparation of a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group; and R1is chloro, bromo, or iodo, comprising reacting a compound of formula (IV):

[0008] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; R1is chloro, bromo, or iodo; and R' is H or absent, in the presence of an acid. In particular embodiments, a compound of formula (IV) reacts to form a compound of formula (III) in the presence of methansulfonic acid (MsOH). In a more particular embodiment, the present invention provides the process as described hereinabove, which further comprises the preparation of a compound of formula (IV) (see, e.g., Example 7): (IV), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; R1is chloro, bromo, or iodo; and R' is H or absent, which comprises reacting a compound of formula (V): (V), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; and R' is H or absent, with a compound of formula (VI): (VI), or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and R2is halogen, particularly fluoro, chloro, bromo, or iodo. In a more particular embodiment, the present invention provides the process as described hereinabove, further comprising the preparation of a compound of formula (VI) (see, e.g., Example 6): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and R2is halogen, particularly fluoro, chloro, bromo, or iodo, comprising the steps: a. reacting a compound of formula (VII): (VII), wherein R1is chloro, bromo, or iodo; R2is halogen, particularly fluoro, chloro, bromo, or iodo; and R3is halogen, particularly fluoro, chloro, bromo, or iodo, with (3R)-3-methylmorpholine, or a salt thereof, to form a compound of formula (VIII): or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and R2is halogen, particularly fluoro, chloro, bromo, or iodo, b. formylating the compound of formula (VIII) to form a compound of formula (VI). In another embodiment, the present invention provides a compound of formula (V’) (see, e.g., Example 2): or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 In another embodiment, the present invention provides a compound of formula (V) (see, e.g., Example 3): or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups, and R' is H or absent. In another embodiment, the present invention provides a compound of formula (IV) (see, e.g., Example 7): or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups, R1is chloro, bromo, or iodo, and R' is H or absent. In another embodiment, the present invention provides a compound of formula (III), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, and R1is chloro, bromo, or iodo. In another embodiment, the present invention provides a compound of formula (II) (see, e.g., Example 9): or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group. In another embodiment, the present invention provides a compound of formula (VIII), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo. In another embodiment, the present invention provides a compound of formula (VI) (see, e.g., Example 6): or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo. In another embodiment, the present invention provides a compound of formula (Ia):

[0009] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein PG1is a protecting group. In another embodiment, the present invention provides a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (compound of formula (I')), (I), further comprising compound of formula (II): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (II), wherein PG1is a protecting group; having less than 0.15 % in weight of compound of formula (II), in particular having between 1 ppb and 100 ppm of the compound of formula (II), more particularly having between 1 ppb and 1 ppm of the compound of formula (II). In another embodiment, the present invention provides a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (a compound of formula (I')), (I), further comprising a compound of formula (Ia): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (Ia), wherein PG1is a protecting group; having less than 0.55 % in weight of compound of formula (Ia), in particular having between 1 ppb and 100 ppm of the compound of formula (Ia), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ia). In another embodiment, the present invention provides a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (a compound of formula (I')), further comprising a compound of formula (Ib): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (Ib), wherein PG1is a protecting group; having less than 0.50 % in weight of a compound of formula (Ib), in particular having between 1 ppb and 100 ppm of the compound of formula (Ib), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ib). In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (a compound of formula (I')), (I), further comprising a compound of formula (II):

[0010] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (II), wherein PG1is a protecting group; wherein the composition comprises less than 0.15% in weight of a compound of formula (II), in particular having between 1 ppb and 100 ppm of the compound of formula (II), more particularly having between 1 ppb and 1 ppm of the compound of formula (II). In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (a compound of formula (I')), (I), comprising a compound of formula (Ia): PATENT ATTORNEY DOCKET NO.: 51246-070WO2 (Ia), wherein PG1is a protecting group; wherein the composition comprises less than 0.55% in weight of a compound of formula (Ia), in particular having between 1 ppb and 100 ppm of the compound of formula (Ia), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ia). In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), in particular a sulfate salt (a compound of formula (I')), comprising a compound of formula (Ib): wherein PG1is a protecting group; PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein the composition comprises less than 0.50% in weight of a compound of formula (Ib), in particular having between 1 ppb and 100 ppm of the compound of formula (Ib), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ib). EXAMPLES The following examples are provided for the purpose of further illustration and are not intended to limit the scope of the claimed invention. Representative intermediates and products are listed in Table 2. Table 2. Representative compounds of the invention. Compound Name Formula Preparation Structure di-tert-butyl 1-{1-[(4- methoxyphenyl)meth Int-1 yl]-1H-pyrazol-5- Example 1 yl}hydrazine-1,2- dicarboxylate 5-hydrazinyl-1-[(4- methoxyphenyl)meth Int-2 yl]-1H-pyrazole-- (V’) Example 2 hydrogen chloride (1 / 2) 5-[(2E)-2- benzylidenehydrazin yl]-1-[(4- ^ Int-3 methoxyphenyl)meth (V) Example 3 ^^^ ^ ^ ^^^ yl]-1H-pyrazole – ^ ^^ hydrogen chloride (1 / 1) 2,6-Difluoro-4- Int-4 (VII) Example 4 iodopyridine (3R)-3- Int-5 Example 5 methylmorpholine (3R)-3- methylmorpholine 4- Int-5a Example 5 methylbenzenesulfo nate PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Compound Name Formula Preparation Structure 2-fluoro-4-iodo-6- [(3R)-3- Int-6 methylmorpholin-4- (VI) Example 6 yl]pyridine-3- carbaldehyde 2-[(2E)-2- benzylidene-1-{1-[(4- methoxyphenyl)meth yl]-1H-pyrazol-5- Int-7 yl}hydrazinyl]-4-iodo- (IV) Example 7 6-[(3R)-3- methylmorpholin-4- yl]pyridine-3- carbaldehyde rac-(1R,5S)-8- Int-8 oxabicyclo[3.2.1]octa (III’) Example 8 n-3-one (1R,3r,5S)-3-(1-{1- [(4- methoxyphenyl)meth yl]-1H-pyrazol-5-yl}- 6-[(3R)-3- Int-9 (II) Example 9 methylmorpholin-4- yl]-1H-pyrazolo[3,4- b]pyridin-4-yl)-8- oxabicyclo[3.2.1]octa n-3-ol (1R,3r,5S)-3-{6- [(3R)-3- methylmorpholin-4- yl]-1-(1H-pyrazol-3- Camonsertib (I) Example 10 yl)-1H-pyrazolo[3,4- b]pyridin-4-yl}-8- oxabicyclo[3.2.1]octa n-3-ol PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Compound Name Formula Preparation Structure (1R,3r,5S)-3-{6- [(3R)-3- methylmorpholin-4- Camonsertib yl]-1-(1H-pyrazol-3- hydrogen (I’) Example 11 yl)-1H-pyrazolo[3,4- sulfate b]pyridin-4-yl}-8- oxabicyclo[3.2.1]octa n-3-ol Example 1: Synthesis of di-tert-butyl 1-{1-[(4-methoxyphenyl)methyl]-1H-pyrazol-5-yl}hydrazine-1,2- dicarboxylate (Int-1). n-BuLi (2.5 M, 103.4 kg, 1.05 equiv.) was added to a solution of 1-[(4- methoxyphenyl)methyl]-1H-pyrazole (75.5 kg crude, 1.0 equiv.) in THF (882.9 kg, 14 v / w) at -80 °C. The reaction mixture was aged 1 h. A solution of di-tert-butyl (E)-diazene-1,2-dicarboxylate (87.5 kg, 1.05 equiv.) in THF (187.5 kg, 3 v / w) was added to the reaction mass over 6 h at -80°C. The reaction mixture was aged 1 h, quenched with water (136 kg, 2 v / w) and warmed to 0°C. Water (542 kg, 8 V) was added to the reaction mixture and layers separated at 25 °C. The organic layer was concentrated to 4 v / w under vacuum. The aqueous phase was extracted with TBME (603 kg, 12 v / w). The organic layers were combined and washed with water (340 kg, 5 v / w) and aqueous NaCl (24% w / w, 445 kg, 5 v / w). The organic layer was concentrated to 5-6 v / w under reduced pressure. n-Heptane (372.3 kg, 8 v / w) was charged to the residue, which was concentrated to 10-12 v / w under reduced pressure. The suspension was cooled down to 25 °C and aged 30 minutes. The solids were filtered off and washed with n-heptane (169 kg, 3.7 v / w). The wet product was dried at 35 °C under reduced pressure.121.67 kg of product were obtained as white solid, yield=80.5%. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Example 2: (1 / 2) (Int-2). Di-tert-butyl 1-{1-[(4-methoxyphenyl)methyl]-1H-pyrazol-5-yl}hydrazine-1,2-dicarboxylate (122 kg, 1.0 equiv.) was added in aliquots to methanolic HCl (4 M solution, 1009.5 kg) at 30 °C, using methanol (9.8 kg) to rinse. The reaction mixture was aged 20 h. Methanol (305.3 kg) was charged to dissolve product. The solution was polish filtered and concentrated to 5-6 v / w under vacuum at no more than 50 °C. i-PrOH was added, and the mixture was concentrated to 5-6 v / w until methanol content is reduced below 5%. The mixture was cooled to 20 °C and aged 30 minutes. The solids were filtered off and washed with i-PrOH (144 kg, 1.5 v / w). The wet product was dried at 30 °C under reduced pressure.100.15 kg of product (IPA solvate) were obtained as white solid, yield=97.4%. Example 3: 5-Hydrazinyl-1-[(4-methoxyphenyl)methyl]-1H-pyrazole--hydrogen chloride (1 / 2) (60.0 kg, 1.00 equiv.) was dissolved in ethanol (210.0 kg, 3.50 w / w) and water (300.0 kg, 5.00 w / w). The solution was cooled to -3 °C. Benzaldehyde (5.44 kg, 0.091 w / w) was added and ethanol (2.4 kg, 0.04 w / w) used to rinse the transfer lines. Seeds of product (0.06 kg, 0.001 w / w) were added, and the suspension was aged 4 h. Benzaldehyde (9.06 kg, 0.151 w / w) was added in 45 minutes and ethanol (2.4 kg, 0.04 w / w) used to rinse the transfer lines. The reaction mixture was aged 30 minutes. Benzaldehyde (2.50 kg, 0.042 w / w) was added, and ethanol (2.4 kg, 0.04 w / w) used to rinse the transfer lines. The reaction mixture was aged 30 minutes. Water (300.0 kg, 5.00 w / w) was added over 60 minutes and the suspension stirred for 60 minutes. The solids were filtered off and PATENT ATTORNEY DOCKET NO.: 51246-070WO2 washed with water (120.0 kg, 2.00 w / w) and MTBE (120.0 kg, 2.00 w / w). The wet product was dried at 30 °C under reduced pressure, sieved and dried again at 50 °C under reduced pressure.49.07 kg of product were obtained as slightly brown solid, yield=83.8%. In the above preparation of Int-3, the reagent, pyrazole, was from Changzhou Wujin Kangda; the reagent, PMB-chloride, was from Weifang Qianjin Fine Chemical; the reagent, DBAD (diisopropyl azodicarboxylate), was from Suzhou Highfine Biotech. Example 4: Synthesis of 2,6-difluoro-4-iodopyridine (Int-4). 2,6-Difluoro-4-iodopyridine can be prepared following the procedures described in: EurJOC, 2004, 5, 1018-1024. Synthesis of Int-4: In the above preparation of Int-4, the reagent, 2,6-difluoropyridine, was from Fuxin Yuke Chemical Technology; the reagent, n-BuLi in n-hexane, was from Zibo Weiqinag Chemical; the reagent, I2, was from Jiodine Chemical Qingdao.

[0011] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Example 5: Synthesis of (3R)-3-methylmorpholine (Int-5). (3R)-3-methylmorpholine can be prepared following the procedures described in Synthesis, 2015, 47, 712–720 or US20070037794. A mixture of 2,6-difluoro-4-iodopyridine (Int-4) (105.2 kg, 1.0 equiv.), DMF (500 kg, 5.0 v / w) and either (3R)-3-methylmorpholine (Int-5) (52.5 kg, 1.2 equiv.) or salt (Int-5a) was warmed to 80 °C and the reaction mixture was aged 16 h. (3R)-3-methylmorpholine (4.47 kg, 0.1 equiv.) or salt (Int- 5a) was added and the reaction mixture was aged 16 h. POCl3 (215.98 kg, 3.2 equiv.) was added keeping temperature between 45 and 55 °C. The reaction mixture was warmed to 55 °C and aged 26 h. The solution was cooled to 25 °C dosed on water (421 kg, 4.0 v / w) keeping temperature between 20 and 30 °C. The suspension was aged 2 h. The solids were filtered off and washed with water (526 kg, 5.0 v / w). The wet product was dissolved in DMF (500 kg, 5.0 v / w) at 60 °C. Water (421 kg, 4.0 v / w) was added over 2 h. The suspension was aged 2 h, cooled to 25°C, aged 2 h. The solids were filtered off and washed with water (526 kg, 5.0 v / w). The wet product was dried at 55 °C under reduced pressure.131 kg of product were obtained as pale yellow solid, yield=85.7%.

[0012] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Example 7: 5-[(2E)-2-benzylidenehydrazinyl]-1-[(4-methoxyphenyl)methyl]-1H-pyrazole--hydrogen chloride (Int-3) (49.07 kg, 1.00 equiv.) was suspended in THF (176.7 kg, 3.60 w / w) at 20 °C. The suspension was cooled down to 2 °C and t-BuOK (1M solution in THF, 233.6 kg, 1.95 equiv.) was added keeping temperature between 0 and 15 °C, and THF (2.0 kg, 0.04 w / w) used to rinse the transfer lines.2-Fluoro-4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carbaldehyde (Int-6) (45.1 kg, 0.90 equiv.) was added (in 2 portions with 15-20 minutes) keeping temperature between 0 and 15 °C. The reaction mixture was aged at 5 °C for 20 minutes. t-BuOK (1 M solution in THF, 15.7 kg, 0.13 equiv.) was added keeping temperature between 0 and 15 °C, and THF (2.0 kg, 0.04 w / w) used to rinse the transfer lines. The reaction mixture was aged at 5 °C for 20 minutes.2-Fluoro-4-iodo-6- [(3R)-3-methylmorpholin-4-yl]pyridine-3-carbaldehyde (5.0 kg, 0.10 equiv.) was added keeping temperature between 0 and 15 °C. The reaction mixture was aged at 5 °C for 20 minutes. Water (245.4 kg, 5.00 w / w) was added keeping temperature between 0 and 15 °C. The quenched mixture was extracted with TBME (182.0 kg, 3.71 w / w and 92.3 kg, 1.88 w / w) and the combined organic layer was washed with water (122.7 kg, 2.50 w / w) and aqueous NaCl (25 % w / w, 145.2 kg, 2.96 w / w). The organic layer was concentrated to 3- 4 v / w under reduced pressure at 25 °C. n-Heptane (9.8 kg, 0.20 w / w) was added in 10 minutes at 15 °C and the mixture aged 3-4 h. n-Heptane (122.7 kg, 2.50 w / w) was added in 40 minutes and the mixture aged at 5 °C for 3-4 h. The solids were filtered off and washed with n-heptane (2.00 w / w). The wet product was dried at 23 °C under reduced pressure.74.08 kg of product were obtained as slightly yellowish brown solid, yield=81.3%. Example 8: Synthesis of rac-(1R,5S)-8-oxabicyclo[3.2.1]octan-3-one (Int-8). rac-(1R,5S)-8-Oxabicyclo[3.2.1]octan-3-one can be prepared following the procedures described in: Chemische Berichte, 1988, 121(9), 1585-94; Bulletin of the chemical society of Japan, 1983, 56(9), 2661-79. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Example 9: A mixture of 2-MeTHF (318.5 kg, 4.30 w / w), 2-[(2E)-2-benzylidene-1-{1-[(4- methoxyphenyl)methyl]-1H-pyrazol-5-yl}hydrazinyl]-4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyridine- 3-carbaldehyde (Int-7) (74.08 kg, 1.00 equiv.), water (4.2 kg, 0.0566 w / w) and methanesulphonic acid (1.70 kg, 0.023 w / w) was aged at 25 °C. After complete conversion, the reaction mixture was washed with aqueous K2HPO4 (15 % w / w, 217.8 kg, 2.94 w / w), twice with aqueous NaHSO3 solution (16.7%w / w, 2 x 222.2 kg, 2 x 3.00 w / w), with aqueous NaHCO3 solution (8 % w / w, 201.5 kg, 2.72 w / w) and with water (185.2 kg, 2.50 w / w).2-MeTHF was added to the organic layer and the solution of 4-iodo-1-{1-[(4-methoxyphenyl)methyl]-1H-pyrazol-5-yl}-6-[(3R)-3-methylmorpholin-4-yl]-1H- pyrazolo[3,4-b]pyridine was azeotropically dried under atmospheric pressure with an end volume of 10 v / w. The solution was cooled down to -80 °C and i-PrMgCl (2 M in THF, 74.7 kg, 1.21 w / w) was added. The mixture was aged 30 minutes prior addition of a LaCl3•2LiCl / i-PrMgCl THF solution, prepared from LaCl3•2LiCl (0.6 M in THF, 213.5 kg, 3.46 w / w) by azeotropical drying (with THF under atmospheric pressure) and addition of i-PrMgCl (2.0M in THF, 11.3 kg, 0.183 w / w). The mixture was aged 30 minutes and a solution of rac-(1R,5S)-8-oxabicyclo[3.2.1]octan-3-one in 2- MeTHF (44.1 kg, 0.714 w / w) was added. The mixture was aged 15 minutes and warmed to 25 °C. TBME (365.3 kg, 5.92 w / w) and aqueous HCl (3.6%w / w; 273.9 kg, 4.44 w / w) were added. The layers were separated, and the organic layer was washed with water (246.0 kg, 4.00 w / w), aqueous NaHCO3 (8%w / w, 129.6 kg, 2.10 w / w), aqueous NH4Cl solution (25%w / w, 131.4 kg, 2.13 w / w) and water (123.4 kg, 2.00 w / w). The organic layer was concentrated at 45°C under reduced pressure to 10 v / w and the solvent exchange for EtOH (until 2-MeTHF + THF ^ 5.0%). The residue is cooled down to 20 °C and aged 5 h, warmed to 55 °C and aged 5 h, cooled down to 5 °C within 5 h and aged 3 h. The solids were filtered off and washed with MTBE (123.4 kg, 2.00 w / w). The wet product was dried at 43 °C under reduced pressure.49.79 kg of product were obtained as almost white solid, yield=80.7%. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Example 10: Synthesis of camonsertib: (1R,3r,5S)-3-{6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-3-yl)-1H- pyrazolo[3,4-b]pyridin-4-yl}-8-oxabicyclo[3.2.1]octan-3-ol (1R,3r,5S)-3-(1-{1-[(4-methoxyphenyl)methyl]-1H-pyrazol-5-yl}-6-[(3R)-3-methylmorpholin-4- yl]-1H-pyrazolo[3,4-b]pyridin-4-yl)-8-oxabicyclo[3.2.1]octan-3-ol (Int-9) (95 kg, 1.0 equiv.) and L- cysteine (44 kg, 2.0 equiv.) were dissolved in trifluoroacetic acid (705 kg). The mixture was heated to 33 °C and aged at this temperature. After complete conversion, the reaction mixture was cooled to room temperature and added to a mixture of water (4302 kg), NaOH 28% (937 kg) and 2- methyltetrahydrofuran (210 kg) at 50 °C. The suspension formed was cooled to 20 °C. The solids were filtered off and washed with water (2400 kg) and dried at 50 °C under reduced pressure.60.6 kg of product were obtained as a white solid, yield=82%. Example 11: (1R,3r,5S)-3-{6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin- 4-yl}-8-oxabicyclo[3.2.1]octan-3-ol (4.8 kg) was dissolved in a mixture of water (6.36 kg) and THF (144 kg) at 60 °C. The solution was polish filtered, and the filter and transfer lines rinsed with THF (6 kg). The solution was concentrated under normal pressure (to a residual volume of 54 L). The generated suspension was diluted with preheated, and polish filtered THF (45 kg). Additional THF (30 L) was distilled off and the suspension was diluted with THF (21 kg). A polish filtered solution of concentrated sulfuric acid (1.22 kg) in THF (21.8 kg) was added in portions at 40 °C: 3.4 kg of the solution prior seeding, the remaining amount dosed within 4 h after the addition of 40 g seed crystals. The suspension was stirred for 2 h and cooled to 22 °C. The solids were filtered off and washed with THF (17 kg) and dried at 50 °C under reduced pressure.4.04 kg of product were obtained as a white solid, yield=96%. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 Example 12: OTHER EMBODIMENTS Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various PATENT ATTORNEY DOCKET NO.: 51246-070WO2 modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention. Other embodiments are in the claims.

[0013] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 ENUMERATED EMBODIMENTS E1. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the process comprises reacting a compound of formula (II), wherein PG1is a protecting group, in the presence of a deprotecting agent. E2. A process for the preparation of a compound of formula (II), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein PG1is a protecting group, wherein the process comprises reacting a compound of formula (III), wherein PG1is a protecting group, and R1is chloro, bromo, or iodo, with a compound of formula (III') . PATENT ATTORNEY DOCKET NO.: 51246-070WO2 E3. A process for the preparation of a compound of formula (III), wherein PG1is a protecting group, and R1is chloro, bromo, or iodo, wherein the process comprises reacting a compound of formula (IV), wherein PG1and PG2are protecting groups, R1is chloro, bromo, or iodo, and R’ is H or absent, in the presence of an acid. E4. A process for the preparation of a compound of formula (IV), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein PG1and PG2are protecting groups, R1is chloro, bromo, or iodo, and R’ is H or absent, wherein the process comprises reacting a compound of formula (V), wherein PG1and PG2are protecting groups, and R’ is H or absent, with a compound of formula (VI), or a pharmaceutically acceptable salt thereof PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo. E5. A process for the preparation of a compound of formula (VI), wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo, wherein the process comprises: (a) reacting a compound of formula (VII), wherein R1and R2are as defined previously and R3is halogen, particularly fluoro, chloro, bromo, or iodo, with (3R)-3-methylmorpholine to form a compound of formula (VIII), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo, (b) formylating the compound of formula (VIII), to form a compound of formula (VI). E6. A process for the preparation of a compound of formula (V), wherein PG1and PG2are protecting groups, and R’ is H or absent, which comprises reacting a compound of formula (V’), wherein PG1is a protecting group. E7. A process for the preparation of a compound of formula (I) PATENT ATTORNEY DOCKET NO.: 51246-070WO2 which comprises: reacting a compound of formula (V’), wherein PG1is a protecting group, to form a compound of formula (V), wherein PG1and PG2are protecting groups, and R’ is H or absent, reacting the compound of formula (V) with a compound of formula (VI), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo, to form a compound of formula (IV), wherein PG1and PG2are protecting groups, R1is chloro, bromo, or iodo, and R’ is H or absent, reacting the compound of formula (IV) in presence of an acid to form a compound of formula PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein PG1is a protecting group, and R1is as defined previously, reacting the compound of formula (III) with a compound of formula (III') to form a compound of formula (II), wherein PG1is a protecting group, and reacting the compound of formula (II) to form a compound of formula (I). PATENT ATTORNEY DOCKET NO.: 51246-070WO2 E8. The process according to embodiments 1 or 7, further comprising the preparation of a compound of formula (I') reacting a compound of formula (I) in the presence of sulfuric acid. E9. The process according to embodiments 1, which further comprises the preparation of a compound of formula (II), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein PG1is a protecting group, which comprises reacting a compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, and R1is chloro, bromo, or iodo, with a compound of formula (III') . PATENT ATTORNEY DOCKET NO.: 51246-070WO2 E10. The process according to embodiments 3 or 9, which further comprises the preparation of a compound of formula (III), wherein PG1is a protecting group, and R1is chloro, bromo, or iodo, which comprises reacting a compound of formula (IV), wherein PG1and PG2are protecting groups, R1is chloro, bromo, or iodo, and R' is H or absent, in the presence of an acid. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 E11. The process according to embodiments 4 or 10, which further comprises the preparation of a compound of formula (IV), wherein PG1and PG2are protecting groups, R1is chloro, bromo, or iodo, and R' is H or absent, which comprises reacting a compound of formula (V), wherein PG1and PG2are protecting groups, and R’ is H or absent, with a compound of formula (VI), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo. E12. The process according to embodiments 5 or 11, further comprising the preparation of a compound of formula (VI), wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo, which comprises reacting a compound of formula (VII), wherein R1is chloro, bromo, or iodo, R2is halogen, particularly fluoro, chloro, bromo, or iodo, and R3is halogen, particularly fluoro, chloro, bromo, or iodo, with (3R)-3-methylmorpholine to form a compound of formula (VIII), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo, formylating the compound of formula (VIII) to form compound of formula (VI). E13. The process according to any one of embodiments 6 or 9-11, wherein the solvent is ethanol or water, or a combination thereof. E14. The process according to any one of embodiments 4 or 9-11, in the presence of a base, in particular in the presence of potassium tert-butoxide, sodium tert-butoxide, potassium tert-amylate, sodium tert-amylate, lithium diisopropylamide , lithium tetramethylpiperidide, potassium carbonate, sodium hydroxide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, or potassium hydride, more particular it the presence of potassium tert-butoxide. E15. The process according to any one of embodiments 3 or 9-11, in the presence of an acid, wherein the acid is p-toluenesulfonic acid, methanesulfonic acid, phosphoric acid, nitric acid, triflic acid, hydrochloric acid, or sulfuric acid, in particular the acid is methanesulfonic acid, or p- toluenesulfonic acid. E16. The process according to any one of embodiments 2 or 9-11, in the presence of a organometal compound, lithium, or magnesium, in particular in the presence of an organolithium compound, magnesium, or a Grignard reagent, more particularly in the presence of butyllithium, sec- butyl(isopropyl)magnesium lithium chloride, benzylmagnesium chloride, methoxyphenylmagnesium bromide, methylmagnesium chloride, ethylmagnesium chloride, phenylmagnesium chloride, p- toluylmagnesium chloride, t-butylmagnesiumchloride, isopropylmagnesium chloride or butylmagnesiumchloride. E17. The process according to any one of embodiments 2, 9-11 or 16, in the presence of lanthanide salt, in particular in the presence of a lanthanium or cerium salt, more particularly in the presence of LaCl3*2LiCl, LaCl3, or CeCl3. E18. The process according to any one of embodiments 1 or 9-11, in the presence of an acid, wherein the acid is acetic acid, hydrochloric acid, sulfuric acid, formic acid, methanesulfonic acid, p- toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, oxalic acid, or trifluoroacetic acid, in particular trifluoroacetic acid. PATENT ATTORNEY DOCKET NO.: 51246-070WO2 E19. The process according to any one of embodiments 1 or 9-11, wherein the solvent is THF or water, or a combination thereof. E20. The process according to embodiments 5 or 12, wherein the formylation is performed with POCl3 and DMF. E21. A compound of formula (V'), wherein PG1is a protecting group. E22. A compound of formula (V), wherein PG1and PG2are protecting groups, and R' is H or absent. E23. A compound of formula (IV),

[0014] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein PG1and PG2are protecting groups, R1is chloro, bromo, or iodo, and R' is H or absent. E24. A compound of formula (III), wherein PG1is a protecting group, and R1is chloro, bromo, or iodo. E25. A compound of formula (II), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein PG1is a protecting group. E26. A compound of formula (VIII), wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo. E27. A compound of formula (VI), PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein R1is chloro, bromo, or iodo, and R2is halogen, particularly fluoro, chloro, bromo, or iodo. E28. A compound of formula (Ia), wherein PG1is a protecting group. E29. A compound of formula (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (a compound of formula (I'))

[0015] PATENT ATTORNEY DOCKET NO.: 51246-070WO2 comprising a compound of formula (II) wherein PG1is a protecting group; having less than 0.15 % in weight of a compound of formula (II), in particular having between 1 ppb and 100 ppm of the compound of formula (II), more particularly having between 1 ppb and 1 ppm of the compound of formula (II). 30. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (a compound of formula (I')) PATENT ATTORNEY DOCKET NO.: 51246-070WO2 comprising a compound of formula (Ia) wherein PG1is a protecting group; having less than 0.55 % in weight of the compound of formula (Ia), in particular having between 1 ppb and 100 ppm of the compound of formula (Ia), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ia). E31. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (a compound of formula (I')) PATENT ATTORNEY DOCKET NO.: 51246-070WO2 comprising a compound of formula (Ib) wherein PG1is a protecting group; having less than 0.50 % in weight of the compound of formula (Ib), in particular having between 1 ppb and 100 ppm of the compound of formula (Ib), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ib). E32. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (a compound of formula (I’)) PATENT ATTORNEY DOCKET NO.: 51246-070WO2 comprising a compound of formula (II) (II) wherein PG1is a protecting group; wherein the composition comprises less than 0.15% in weight of the compound of formula (II) is, in particular having between 1 ppb and 100 ppm of the compound of formula (II),more particularly having between 1 ppb and 1 ppm of the compound of formula (II). E33. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in particular a sulfate salt (a compound of formula (I’)) comprising a compound of formula (Ia) PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein PG1is a protecting group; wherein the composition comprises less than 0.55% in weight of the compound of formula (Ia), in particular having between 1 ppb and 100 ppm of the compound of formula (Ia), more particularly having between 1 ppb and 1 ppm of the compound of formula (Ia). E34. A pharmaceutical composition comprising a compound of formula (I), in particular a sulfate salt (a compound of formula (I’)) comprising a compound of formula (Ib) PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein PG1is a protecting group; wherein the composition comprises less than 0.50% in weight of the compound of formula (Ib), in particular having between 1 ppb and 100 ppm of the compound of formula (Ib),more particularly having between 1 ppb and 1 ppm of the compound of formula (Ib). E35. The compound of any one of embodiments 4-5, 7, 9-12, 23-24 or 26-27 wherein R1is chloro. E36. The compound of any one of embodiments 4-5, 7, 9-12, 23-24 or 26-27 wherein R1is bromo. E37. The compound of any one of embodiments 4-5, 7, 9-12, 23-24 or 26-27 wherein R1is iodo. E38. The compound of any one of embodiments 4-5, 7, 11-12, 26-27 or 35-38 wherein R2is fluoro. E39. The compound of any one of embodiments 4-5, 7, 11-12, 26-27 or 35-38 wherein R2is chloro. E40. The compound of any one of embodiments 4-5, 7, 11-12, 26-27 or 35-38, wherein R2is bromo. E41. The compound of any one of embodiments 4-5, 7, 11-12, 26-27 or 35-38, wherein R2is iodo. E42. The compound of any one of embodiments 5, 12 or 35-42, wherein R3is fluoro. E43. The compound of any one of embodiments 5, 12 or 35-42, wherein R3is chloro. E44. The compound of any one of embodiments 5, 12 or 35-42, wherein R3is bromo. E45. The compound of any one of embodiments 5, 12 or 35-42, wherein R3is iodo. E46. The compound of any one of embodiments 1-16, 18-19 or 21-25, wherein PG1is selected from silicon protecting groups, or carboxy-protective groups. E47. The compound of any one of embodiments 1-16, 18-19, 21-25 or 47, wherein PG1is selected from tert-butoxycarbonyl (Boc), p-methoxybenzyl (PMB), tetrahydropyranyl ether (THP), ethoxymethyl, acetone aminal, silicon protecting groups (inter alia TBDMS or TBDPS), methoxymethyl ethers (MOM), tert-butyl, trityl, benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). E48. The compound of any one of embodiments 1-16, 18-19, 21-25 or 47-48, wherein PG1is PMB. E49. The compound of any one of embodiments 3, 7, 10-11 or 22-23, wherein PG2is wherein R4is independently selected from C1-10 alkyl, aryl, in particular R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl, or R4and R5taken together form a C3-10 cycloalkyl, in particular C6 cycloalkyl, R5is independently selected from H, or methyl, or R4and R5taken together form a C3-10 cycloalkyl, in particular C6 cycloalkyl, PATENT ATTORNEY DOCKET NO.: 51246-070WO2 and R' is absent. E50. The compound of any one of embodiments 3, 7, 10-11 or 22-23, wherein PG2is Boc, Cbz, Fmoc, acetyl, trifluoroacetyl, chloroacetyl, trityl, benzyl, or sulfonyl, and R' is H.

Claims

PATENT ATTORNEY DOCKET NO.: 51246-070WO2 What is claimed is: CLAIMS 1. A process for the preparation of a compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein the process comprises reacting a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, with a deprotecting agent.

2. The process of claim 1, wherein PG1is PMB.

3. The process of claim 1, wherein the deprotecting agent comprises of L-cysteine.PATENT ATTORNEY DOCKET NO.: 51246-070WO2 4. A process for the preparation of a compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, wherein the process comprises reacting a compound of formula (III):(III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group; and R1is from the group consisting of chloro, bromo, or iodo, with a compound of formula (III'):PATENT ATTORNEY DOCKET NO.: 51246-070WO25. The process of claim 4, wherein R1is iodo.

6. The process of claim 4, wherein PG1is PMB. A process for the preparation of a compound of formula (III):(III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group; and R1is chloro, bromo, or iodo, wherein the process comprises reacting a compound of formula (IV):or a pharmaceutically acceptable salt thereof,PATENT ATTORNEY DOCKET NO.: 51246-070WO2 wherein PG1and PG2are protecting groups; R1is chloro, bromo, or iodo; and R' is H or absent, in the presence of an acid.

8. The process of claim 7, wherein the acid is methanesulfonic acid.

9. The process of claim 8, wherein PG2is:wherein R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl; and R5is H or methyl.

10. The process of claim 8, wherein PG2is.

11. A process for the preparation of a compound of formula (IV):or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; R1is chloro, bromo, or iodo; and R' is H or absent, the process comprises reacting a compound of formula (V):PATENT ATTORNEY DOCKET NO.: 51246-070WO2(V), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; and R' is H or absent, with a compound of formula (VI):(VI), or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and R2is a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo.

12. The process of claim 11, wherein the compound of formula (IV) is:pharmaceutically acceptable salt thereof.

13. The process of claim 11, wherein the compound of formula (V) is:pharmaceutically acceptable salt thereof.PATENT ATTORNEY DOCKET NO.: 51246-070WO2 14. A process for the preparation of a compound of formula (VI):(VI), or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and R2is a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo, wherein the process comprises: (a) reacting a compound of formula (VII):(VII), wherein R1and R2are as defined previously; and R3is a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo, with (3R)-3-methylmorpholine, or a salt thereof, to form compound of formula (VIII):(VIII), or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and R2is a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo; and (b) formylating the compound of formula (VIII), to form a compound of formula (VI).PATENT ATTORNEY DOCKET NO.: 51246-070WO2 15. The process of claim 14, wherein the compound of formula (VII) is:.

16. The process of claim 14, wherein the compound of formula (VI) is:pharmaceutically acceptable salt thereof.

17. A process for the preparation of a compound of formula (V):(V), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; and R' is H or absent, the process comprises reacting a compound of formula (V'):or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, with Q, whereinPATENT ATTORNEY DOCKET NO.: 51246-070WO2 Q is of the formula:,wherein R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl; R5is H or methyl; or R4and R5taken together form a C6 cycloalkyl.

18. The process of claim 17, wherein R5is H.

19. The process of claim 17, wherein R4is phenyl.

20. The process of claim 17, wherein Q is benzaldehyde.

21. The process of claim 17, where the compound of formula (V) is:pharmaceutically acceptable salt thereof.

22. A process for the preparation of a compound of formula (I):which comprises the steps of: (a) reacting a compound of formula (V'):PATENT ATTORNEY DOCKET NO.: 51246-070WO2or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, with Q, wherein Q is of the formula:,wherein R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl; R5is H or methyl; or R4and R5taken together form a C6 cycloalkyl, to form a compound of formula (V):or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; and R' is H or absent, (b) reacting the compound of formula (V) with a compound of formula (VI):PATENT ATTORNEY DOCKET NO.: 51246-070WO2or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and R2is a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo, to form a compound of formula (IV):or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; R1is chloro, bromo, or iodo; and R' is H or absent, (c) reacting the compound of formula (IV) in presence of an acid, to form a compound of formula (III):PATENT ATTORNEY DOCKET NO.: 51246-070WO2(III), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group; and R1is as defined previously, (d) reacting the compound of formula (III) with a compound of formula (III'):(III'), to form a compound of formula (II):PATENT ATTORNEY DOCKET NO.: 51246-070WO2(II), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group, and (e) reacting the compound of formula (II) with a deprotecting agent to form a compound of formula 23. The process of claim 22, wherein the deprotecting agent comprises of L-cysteine.

24. The process of claim 22, wherein PG1is PMB.

25. The process of claim 22, wherein R1is iodo.

26. The process of claim 22, wherein R2is fluoro.

27. The process of claim 22, wherein PG2is.

28. A compound of formula (V'):(V'), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group.PATENT ATTORNEY DOCKET NO.: 51246-070WO2 29. The compound of claim 28, wherein the compound of formula (V') is:pharmaceutically acceptable salt thereof.

30. The compound of claim 29, wherein the compound is a hydrochloride salt.

31. A compound of formula (V):or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; and R' is H or absent.

32. The compound of claim 31, wherein PG1and PG2are independently selected from the group consisting of Boc, PMB, Cbz, and Bn.

33. The compound of claim 31, wherein the compound is:pharmaceutically acceptable salt thereof.

34. The compound of claim 33, wherein the compound is a hydrochloride salt.

35. A compound of formula (IV):PATENT ATTORNEY DOCKET NO.: 51246-070WO2(IV), or a pharmaceutically acceptable salt thereof, wherein PG1and PG2are protecting groups; R1is chloro, bromo, or iodo; and R' is H or absent.

36. The compound of claim 35, wherein PG2is:, wherein R4is H, methyl, ethyl, isobutyl, phenyl, or benzyl; R5is H or methyl; or R4and R5taken together form a C6 cycloalkyl.

37. The compound of claim 36, wherein R5is H.

38. The compound of claim 36, wherein R4is phenyl.

39. The compound of claim 35, wherein the compound of formula (IV) is:PATENT ATTORNEY DOCKET NO.: 51246-070WO2, or a pharmaceutically acceptable salt thereof.

40. A compound of formula (III):or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group; and R1is chloro, bromo, or iodo.

41. The compound of claim 40, wherein R1is iodo.

42. The compound of claim 40, wherein PG1is selected from the group consisting of PMB, Boc, Bn, Cbz, and Fmoc.

43. The compound of claim 42, wherein PG1is PMB.PATENT ATTORNEY DOCKET NO.: 51246-070WO2 44. A compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group.

45. The compound of claim 44, wherein the compound is:, or a pharmaceutically acceptable salt thereof.

46. A compound of formula (VIII):(VIII), or a pharmaceutically acceptable salt thereof, whereinPATENT ATTORNEY DOCKET NO.: 51246-070WO2 R1is chloro, bromo, or iodo; and R2is a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo.

47. The compound of claim 46, wherein R1is iodo.

48. The compound of claim 46, wherein R2is fluoro.

49. A compound of formula (VI):(VI), or a pharmaceutically acceptable salt thereof, wherein R1is chloro, bromo, or iodo; and R2is a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo.

50. The compound of claim 49, wherein the compound is:pharmaceutically acceptable salt thereof.

51. A compound of formula (Ia):PATENT ATTORNEY DOCKET NO.: 51246-070WO2(Ia), or a pharmaceutically acceptable salt thereof, wherein PG1is a protecting group.

52. The compound of claim 51, wherein PG1is PMB.

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