This application is a continuation of Ser. No. 18/308,441, filed Apr. 27, 2023, which is a continuation of International Application No. PCT/US2022/028594, filed May 10, 2022, which claims the benefit of U.S. Provisional Application Ser. No. 63/187,049, filed May 11, 2021; U.S. Provisional Application Ser. No. 63/249,809, filed Sep. 29, 2021; U.S. Provisional Application Ser. No. 63/317,174, filed Mar. 7, 2022, and U.S. Provisional Application Ser. No. 63/337,445, filed May 2, 2022, which are hereby incorporated by reference in their entirety.

›BACKGROUND OF THE INVENTION

The Polo-like kinases (PLKs) are a family of serine/threonine kinases that play a critical role in cell cycle regulation and cellular responses under stress (Helmke et al. 2016; Zitouni et al. 2014). Mammalian cells express five PLK family members (PLK1-5). All PLKs share a similar structure, with an N-terminal kinase catalytic domain and C-terminal Polo-box domains (PBDs) (Archambault et al. 2015). Polo-like kinase 4 (PLK4), also known as SAK, is a regulator of centriole duplication (Habedanck et al. 2005; Kleylein-Sohn et al. 2007). In proliferating tissues, PLK4 is expressed as a low-abundance enzyme under normal conditions and is required for centriole biogenesis via phosphorylation and interaction with centriolar proteins (Habedanck et al. 2005; Maniswami et al. 2018). Overexpression of PLK4 results in centriole amplification and further genomic instability and tumorigenesis (Holland et al. 2010). Aberrant PLK4 expression has been reported to be involved in several common human cancers (Marina and Saavedra 2014; Shinmura et al. 2014). Thus, strong evidence supports the critical role of PLK4 in carcinogenesis and therapeutic invention. Thus, there is a need for compounds that inhibit PLK4 in subjects having cancer for the treatment of those cancers.

›SUMMARY OF THE INVENTION · 1 of 2

Provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring A is C 6 -C 10 aryl, heteroaryl, C 3 -C 10 cycloalkyl, or heterocycloalkyl;

each R 1 is independently deuterium, halogen, —CN, oxo, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —P(O)(R a ) 2 , —P(O) 2 (R a ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a ;

or two R 1 on adjacent atoms are taken together to form a C 3 -C 10 cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1b ;

each R 1a is independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl;

or two R 1a on the same atom are taken together to form an oxo;

each R 1b is independently deuterium, halogen, —CN, —NO 2 . —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl;

or two R 1b on the same atom are taken together to form an oxo;

n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

each of R 4a , R 4b , and R 4c is independently hydrogen, deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —NR c R d , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;

R 5 is hydrogen, deuterium, halogen, —CN, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;

each R 6 is independently hydrogen, deuterium, halogen, —CN, —OH, —OR a , —NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;

R 7 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;

each of R 8a , R 8b , R 8c , and R 8d is independently hydrogen, deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl;

each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;

each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; and

each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O)NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;

›SUMMARY OF THE INVENTION · 2 of 2

or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.

In some embodiments of a compound of Formula (I), Ring A is C 6 -C 10 aryl or heteroaryl.

In some embodiments of a compound of Formula (I), Ring A is C 1 -C 10 aryl.

In some embodiments of a compound of Formula (I), Ring A is heteroaryl.

In some embodiments of a compound of Formula (I), Ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl.

In some embodiments of a compound of Formula (I), each R 1 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; wherein each of the C 1 -C 6 alkyl, C 1 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a .

In some embodiments of a compound of Formula (I), n is 1, 2, or 3.

In some embodiments of a compound of Formula (I), R 2 is hydrogen.

In some embodiments of a compound of Formula (I), R 3 is hydrogen.

In some embodiments of a compound of Formula (I), R 4a , R 4b , and R 4c are hydrogen.

In some embodiments of a compound of Formula (I), R 5 is hydrogen.

In some embodiments of a compound of Formula (I), each R 6 is hydrogen.

In some embodiments of a compound of Formula (I), R 7 is hydrogen or C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), each of R 8a , R 8b , and R 8d are hydrogen and R 8c is hydrogen, halogen, or —OR a .

In some embodiments of a compound of Formula (I), R 8c is halogen or —OR a .

In some embodiments of a compound of Formula (I), R 8c is —OR a .

In some embodiments of a compound of Formula (I), R a is C 1 -C 6 alkyl.

In some embodiments of a compound of Formula (I), R a is —CH 3 .

Also disclosed herein is a pharmaceutical composition comprising an amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

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

›INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 34

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

“Administering” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering”, when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a subject by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.

The term “C 2 -C 6 alkenyl” as used herein, means an alkyl moiety comprising 2 to 6 carbon atoms having at least one carbon-carbon double bond. The carbon-carbon double bond in such a group may be anywhere along the 2 to 6 carbon atom chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl. The alkenyl may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples of alkenyls include, but are not limited to ethenyl (—CH═CH 2 ), 1-propenyl (—CH 2 CH═CH 2 ), isopropenyl [—C(CH 3 )═CH 2 ], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C 2 -C 6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.

The term “C 1 -C 6 alkyl,” as used herein, refers to a straight or branched chain hydrocarbon monoradical, which may be fully saturated or unsaturated, having from one to about ten carbon atoms, or from one to six carbon atoms. Examples of saturated hydrocarbon monoradical include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C 1 -C 6 alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.

The term “C 2 -C 6 alkynyl,” as used herein, means an alkyl moiety comprising from 2 to 6 carbon atoms and having at least one carbon-carbon triple bond. The carbon-carbon triple bond in such a group may be anywhere along the 2 to 6 carbon chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, and 3-hexyne, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C 2 -C 6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.

The term “C 6 -C 10 aryl,” as used herein, refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 10 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl.

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 34

The term “C 1 -C 6 aminoalkyl,” as used herein, refers to a C 1 -C 6 alkyl radical, as defined above, that is substituted with one or more amino groups. The amino groups in such C 1 -C 6 aminoalkyl groups may be unsubstituted, mono-substituted, or disubstituted. Examples of C 1 -C 6 aminoalkyl groups include, but are not limited to, —CH 2 NH 2 , —CH 2 N(H)CH 3 , —CH 2 N(CH 3 ) 2 , and the like.

The term “C 3 -C 10 cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring comprising from 3 to 10 carbon atoms, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl

The term “C 1 -C 6 deuteroalkyl,” as used herein, means a C 1 -C 6 alkyl group as defined herein wherein one or more hydrogen atoms in the C 1 -C 6 alkyl group is replaced with a deuterium atom.

The term “C 1 -C 6 haloalkyl,” as used herein, refers to a C 1 -C 6 alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

The term “C 1 -C 6 hydroxyalkyl,” as used herein, refers to a C 1 -C 6 alkyl radical, as defined above, that is substituted with one or more hydroxy groups.

The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals. As used herein, the terms “subject.” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the subject is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In further instances, the human is under the age of 12 years. In certain instances, the human is elderly. In other instances, the human is 60 years of age or older. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology.

The term “Aurora kinase A,” or “AurA,” as used herein, means the human protein known to those of ordinary skill in the art as Aurora kinase A, and that is encoded by the AURKA gene.

The term “Aurora kinase B,” or “AurB,” as used herein, means the human protein known to those of ordinary skill in the art as Aurora kinase B, and that is encoded by the AURKB gene.

A “cyano” group refers to a —CN group.

The term “halo” or “halogen,” as used herein, refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

The term “heterocycloalkyl,” as used herein, refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from boron, nitrogen, oxygen, phosphorous, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenrofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).

The term “C 1 -C 6 heteroalkyl,” as used herein, means an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., boron, oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 34

The term “heteroaryl,” as used herein refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from boron, nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxoyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, I-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).

By “pharmaceutically acceptable,” as used herein, is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term “pharmaceutical composition” means a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

The term “pharmaceutically acceptable salt,” as used herein, means a salt of a compound of the present invention that retains the biological effectiveness of the free acids and bases of the specified derivative and that is not biologically or otherwise undesirable.

The term “PLK4,” as used herein, means the human protein known to those of ordinary skill in the art as polo-like kinase 4, and that is encoded by the PLK4 gene

The term “oxo,” as used herein, refers to a carbonyl moiety such that alkyl substituted by oxo refers to a ketone group.

The term “solvate,” as used herein, means a molecular complex between compounds of the present invention and solvent molecules. Examples of solvates include, but are not limited to, compounds of the invention in combination water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term “hydrate” can be used when said solvent is water. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that in the present invention less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate. Furthermore, solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds.

Where a compound of the invention contains an alkenyl group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism (‘tautomerism’) can occur. Examples of tautomerism include keto and enol tautomers. A single compound may exhibit more than one type of isomerism. Included within the scope of the invention are all stereoisomers, geometric isomers, and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

The term “stereoisomers” refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space. In particular, the term “enantiomers” refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. The terms “racemic” or “racemic mixture,” as used herein, refer to a 1:1 mixture of enantiomers of a particular compound. A mixture of racemates in which one racemate is present in a greater amount than the other racemate in such mixture may be described as “enantiomerically enriched.” The term “diastereomers”, on the other hand, refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another. Designations that are conventional in the art may be used to describe stereoisomers of compounds, or the stereochemistry of a particular asymmetric carbon atom, of the compounds disclosed herein, or mixtures thereof. For example, a single racemate or stereocenter of a compound, may be described as of the (+), the (−), the (R)-, or the (S) configuration. A mixture of racemates may be described by use of the (±) symbol.

›DETAILED DESCRIPTION OF THE INVENTION · 4 of 34

The compounds of the present invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the present invention may be depicted herein using a solid line ( ), a solid wedge ( ) or a dotted wedge ( ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of the present invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

The term “substituted,” as used herein, means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. The term “optionally substituted” means that the specified group is unsubstituted or substituted by one or more substituents. It is to be understood that in the compounds of the present invention when a group is said to be “unsubstituted,” or is “substituted” with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen. For example, if a C 6 aryl group, also called “phenyl” herein, is substituted with one additional substituent, one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the C 6 aryl group (6 initial positions, minus one to which the remainder of the compound of the present invention is bonded, minus an additional substituent, to leave 4). In such cases, the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies. Similarly, if a C 6 aryl group in the present compounds is said to be “disubstituted,” one of ordinary skill in the art would understand it to mean that the C 6 aryl group has 3 carbon atoms remaining that are unsubstituted. Those three unsubstituted carbon atoms are each bound to one hydrogen atom to fill their valencies.

In accordance with a convention used in the art, the symbol

is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. In accordance with another convention, in some structural formulae herein the carbon atoms and their bound hydrogen atoms are not explicitly depicted, e.g.,

represents a methyl group,

represents an ethyl group, and

represents a cyclopentyl group, etc.

If a group, as for example, (R 1 ) n is depicted as “floating” Ring A in the formula:

then, unless otherwise defined, the substituent R 1 may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed. A ring system A may be, for example, but not limited to aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, spirocyclyl or a fused ring system.

If a group “R” is depicted as “floating” on a ring system A as shown above, and Ring A contains saturated carbons, then “n” can be more than one, assuming each replaces a currently depicted, implied, or expressly defined hydrogen the ring A; then, unless otherwise defined, where the resulting structure is stable, two R 1 groups may reside on the same carbon. For example, when R 1 is a methyl group, there can exist a germinal dimethyl on a carbon of the ring A. In another example, two R 1 groups on the same carbon, including that carbon, may form a ring, thus creating a spirocyclic ring (a “spirocyclyl group”). It is to be understood that in the compounds of Formulae (I), (Ia), (Ib), (II), and (III) if n is less than the number of substitutable atoms on Ring A, the other substitutable positions on Ring A are bonded to a hydrogen atom.

As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a subject.

›DETAILED DESCRIPTION OF THE INVENTION · 5 of 34

A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).

The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease, amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition. As used herein, “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments.

The term “TRIM37,” as used herein, means the human protein known those of ordinary skill in the art as tripartite motif-containing protein 37, an E3 ubiquitin ligase that is encoded by the TRIM37 gene.

The term “CFI-400495” means the compound having the Chemical Abstract Service Registry No. 1338806-73-7, and the structure shown below. The preparation of the compound is described in PCT Application Publication No. WO 2011/123946 and is commercially available for purchase.

PLK4 Inhibitor Compounds

Provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring A is C 6 -C 10 aryl, heteroaryl, C 3 -C 10 cycloalkyl, or heterocycloalkyl;

or two R 1 on adjacent atoms are taken together to form a C 3 -C 10 cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1b ;

or two R 1a on the same atom are taken together to form an oxo;

each R 1b is independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl;

or two R 1b on the same atom are taken together to form an oxo;

n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

›DETAILED DESCRIPTION OF THE INVENTION · 6 of 34

R 7 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;

each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;

or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)?N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ), —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.

Provided herein are compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring A is C 6 -C 10 aryl, heteroaryl, C 3 -C 10 cycloalkyl, or heterocycloalkyl;

each R 1 is independently deuterium, halogen, —CN, oxo, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a ;

or two R 1 on adjacent atoms are taken together to form a C 3 -C 10 cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1b ;

each R 1a is independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R 3 , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl;

or two R 1a on the same atom are taken together to form an oxo;

›DETAILED DESCRIPTION OF THE INVENTION · 7 of 34

or two R 1b on the same atom are taken together to form an oxo;

n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 7 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;

each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;

or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O)CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)?N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ), —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.

In other embodiments are provided compounds of Formula (Ia), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring A is C 6 -C 10 aryl, heteroaryl, C 3 -C 10 cycloalkyl, or heterocycloalkyl;

each R 1 is independently deuterium, halogen, —CN, oxo, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O)R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a ;

or two R 1 on adjacent atoms are taken together to form a C 3 -C 10 cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1b ;

›DETAILED DESCRIPTION OF THE INVENTION · 8 of 34

or two R 1a on the same atom are taken together to form an oxo;

or two R 1b on the same atom are taken together to form an oxo;

n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 7 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;

each R a is independently C 1 -C 6 alkyl. C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;

or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O)CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O)?N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ), —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.

›DETAILED DESCRIPTION OF THE INVENTION · 9 of 34

In other embodiments are provided compounds of Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring A is C 6 -C 10 aryl, heteroaryl, C 3 -C 10 cycloalkyl, or heterocycloalkyl;

each R 1 is independently deuterium, halogen, —CN, oxo, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a ;

or two R 1 on adjacent atoms are taken together to form a C 3 -C 10 cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R 1b ;

each R 1a is independently deuterium, halogen, —CN, —NO 2 , —OH, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SH, —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR a , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl. C 6 -C 10 aryl, or heteroaryl;

or two R 1a on the same atom are taken together to form an oxo;

or two R 1b on the same atom are taken together to form an oxo;

n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuteroalkyl;

R 7 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 aminoalkyl;

›DETAILED DESCRIPTION OF THE INVENTION · 10 of 34

Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is C 6 -C 10 aryl or heteroaryl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is C 6 -C 10 aryl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is phenyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is heteroaryl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 1-pyrazolyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyrazolyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyrazolyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrazolyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyridinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyridinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyridinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyridinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyridinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, or 6-pyrazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyrazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyrazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrimidinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrimidinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyrimidinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrimidinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyrimidinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyridazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyridazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyridazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyridazinyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is C 3 -C 10 cycloalkyl or heterocycloalkyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is C 3 -C 10 cycloalkyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is heterocycloalkyl.

›DETAILED DESCRIPTION OF THE INVENTION · 11 of 34

Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, —OC 1 -C 6 haloalkyl, —CF 3 , C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently fluoro, chloro, bromo, iodo, —CN, —OH, —OR a , C 1 -C 6 alkyl, —OC 1 -C 6 haloalkyl, —CF 3 , C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently fluoro, chloro, bromo, —CN, —OH, —OC 1 -C 6 alkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 alkyl, —CF 3 , C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently fluoro, chloro, —CN, —OH, —OCH 3 , —OCH 2 CH 3 , —C 1 -C 6 alkyl(OR 1a ), —CH 3 , —CH 2 CH 3 , iso-propyl, n-propyl, n-butyl, i-butyl, t-butyl, —OCHF 2 , —OC 1 -C 6 hydroxyalkyl, —CF 3 , cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, or thiazinyl; wherein each of the azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiazinyl, and 1,4-oxazepanyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —CN, —OH, —OCH 3 , —OCH 2 CH 3 , —CH 3 , iso-propyl, —OCHF 2 , —CF 3 , cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, or 1,4-oxazepanyl; wherein each of the azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, and 1,4-oxazepanyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —CN, —OCH 3 —CH 3 , iso-propyl, —OCHF 2 , —CF 3 , cyclopropyl, azetidinyl, piperidinyl, piperazinyl, or morpholinyl; wherein each of the azetidinyl, piperidinyl, piperazinyl, and morpholinyl, is optionally and independently substituted with one or more R a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —CN, —OCH 3 —CH 3 , iso-propyl, —OCHF 2 , —CF 3 , cyclopropyl, azetidinyl, piperidinyl, piperazinyl, or morpholinyl; wherein each of the azetidinyl, piperidinyl, piperazinyl, and morpholinyl, is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —CN, —OCH 3 —CH 3 , iso-propyl, —OCHF 2 , —CF 3 , cyclopropyl, piperidinyl, piperazinyl, or morpholinyl; wherein piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more R 1a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —CN, —OCH 3 —CH 3 , iso-propyl, —OCHF 2 , —CF 3 , cyclopropyl, piperidinyl, piperazinyl, or morpholinyl; wherein piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OH, and —OCH 3 . In some embodiments are provided compounds of Formula (I). Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —CN, —OCH 3 —CH 3 , —OCHF 2 , cyclopropyl, piperidinyl, piperazinyl, or morpholinyl; wherein piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OH, and —OCH 3 . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —CN, —OCH 3 —CH 3 , —OCHF 2 , cyclopropyl, or morpholinyl; wherein morpholinyl is optionally substituted with one or more —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OH, and —OCH 3 . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —OCH 3 —CH 3 , —OCHF 2 , cyclopropyl, or morpholinyl; wherein morpholinyl is optionally substituted with one or more —CH 3 .

›DETAILED DESCRIPTION OF THE INVENTION · 12 of 34

Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1, 2, or 3. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 3.

Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 2 is hydrogen. Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3 is hydrogen.

Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a , R 4b , and R 4c are independently hydrogen or halogen. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a is halogen and R 4b , and R 4c are hydrogen. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4c are hydrogen and R 4b is halogen. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4b are hydrogen and R 4c is halogen. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4b are halogen and R 4c is hydrogen. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4b are halogen and R 4c is hydrogen. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a , R 4b and R 4c are halogen. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a , R 4b , and R 4c are hydrogen. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 5 is hydrogen.

Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 6 is hydrogen.

Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is hydrogen or C 1 -C 6 alkyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is hydrogen. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is C 1 -C 6 alkyl.

Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of R 8a , R 8b , R 8c , and R 8d is independently hydrogen, halogen, or —OR a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of R 8a , R 8b , and R 8c are hydrogen and R 8c is hydrogen, halogen, or —OR a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is halogen or —OR a . In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is halogen. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is fluoro, chloro, bromo, or iodo. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is —OR a .

Further provided herein are compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R a is C 1 -C 6 alkyl. In some embodiments are provided compounds of Formula (I), Formula (Ia), and Formula (Ib), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R a is —CH 3 .

Further provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring A is C 6 -C 10 aryl or heteroaryl, C 3 -C 10 cycloalkyl, and heterocycloalkyl;

each R 1 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 1 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; wherein each of the C 1 -C 6 alkyl, C 3 -C 1 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a ;

›DETAILED DESCRIPTION OF THE INVENTION · 13 of 34

n is 1, 2, 3, 4, 5, 6, 7, or 8;

R 2 is hydrogen or C 1 -C 6 alkyl;

R 3 is hydrogen or C 1 -C 6 alkyl;

R 4a , R 4b , and R 4c are each independently hydrogen, deuterium, or halogen;

R 7 is hydrogen or C 1 -C 6 alkyl;

each of R 8a , R 8b , R 8c , and R 8d is independently hydrogen, deuterium, halogen, or —OR a ;

Further provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is C 6 -C 10 aryl or heteroaryl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is C 6 -C 10 aryl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is phenyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is heteroaryl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is furanyl, pyrrolyl, thiophenyl, oxazolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, or pyrimidinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 1-pyrazolyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyrazolyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyrazolyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrazolyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyridinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyridinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyridinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyridinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyridinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, or 6-pyrazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyrazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyrazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrimidinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrimidinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyrimidinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrimidinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyrimidinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyridazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyridazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyridazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyridazinyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is C 3 -C 10 cycloalkyl or heterocycloalkyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is C 3 -C 10 cycloalkyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is heterocycloalkyl.

›DETAILED DESCRIPTION OF THE INVENTION · 14 of 34

Further provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, OC 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently fluoro, chloro, bromo, iodo, —CN, —OH, —OR a , C 1 -C 6 alkyl, —CF 3 , —OC 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently fluoro, chloro, bromo, —CN, —OH, —OR a , C 1 -C 6 alkyl, —CF 3 , —OC 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently fluoro, chloro, —CN, —OH, —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, —CF 3 , —OC 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the —OC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently fluoro, chloro, —CN, —OH, —OCH 3 , —OCH 2 CH 3 , —C 1 -C 6 alkyl(OR 1a ), —CH 3 , —CH 2 CH 3 , iso-propyl, n-propyl, n-butyl, i-butyl, t-butyl, —OC 1 -C 6 hydroxyalkyl, —CF 3 , —OCHF 2 , cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, or thiazinyl; wherein each of the azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiazinyl, and 1,4-oxazepanyl is optionally and independently substituted with one or more R a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —CN, —OH, —OCH 3 , —OCH 2 CH 3 , —CH 3 , iso-propyl, —CF 3 , —OCHF 2 , cyclopropyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, or 1,4-oxazepanyl; wherein each of the azetidinyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, and 1,4-oxazepanyl is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —CN, —OCH 3 , —CH 3 , iso-propyl, —CF 3 , —OCHF 2 , cyclopropyl, azetidinyl, piperidinyl, piperazinyl, or morpholinyl; wherein each of the azetidinyl, piperidinyl, piperazinyl, and morpholinyl, is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —CN, —OCH 3 , —CH 3 , iso-propyl, —CF 3 , —OCHF 2 , cyclopropyl, piperidinyl, piperazinyl, or morpholinyl; wherein each of the cyclopropyl, piperidinyl, piperazinyl, and morpholinyl, is optionally and independently substituted with one or more R 1a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —OCH 3 , —CH 3 , iso-propyl, —CF 3 , —OCHF 2 , cyclopropyl, piperidinyl, piperazinyl, or morpholinyl; wherein piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more R 1a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —OCH 3 , —CH 3 , iso-propyl, —CF 3 , —OCHF 2 , cyclopropyl, piperidinyl, piperazinyl, or morpholinyl; wherein piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OH, and —OCH 3 . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —OCH 3 , —CH 3 , —OCHF 2 , cyclopropyl, piperidinyl, piperazinyl, or morpholinyl; wherein piperidinyl, piperazinyl, and morpholinyl are optionally substituted with one or more —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OH, and —OCH 3 . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —OCH 3 —CH 3 , —OCHF 2 , cyclopropyl, or morpholinyl; wherein morpholinyl is optionally substituted with one or more —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OH, and —OCH 3 . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 1 is independently chloro, —OCH 3 . —CH 3 , cyclopropyl, or morpholinyl; wherein morpholinyl is optionally substituted with one or more —CH 3 .

›DETAILED DESCRIPTION OF THE INVENTION · 15 of 34

Further provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1, 2, or 3. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 3.

Further provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 2 is hydrogen.

Further provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 3 is hydrogen.

Further provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a , R 4b , and R 4c are independently hydrogen or halogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a is halogen and R 4b , and R 4c are hydrogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4c are hydrogen and R 4b is halogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4b are hydrogen and R 4c is halogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4b are halogen and R 4c is hydrogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a and R 4c are halogen and R 4b is hydrogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a is halogen and R 4b and R 4c are hydrogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a , R 4b , and R 4c are hydrogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a , R 4b , and R 4c are halogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 4a , R 4b , and R 4c are fluoro.

Further provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is hydrogen or C 1 -C 6 alkyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 1 is hydrogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 7 is C 1 -C 6 alkyl.

Further provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of R 8a , R 8b , R 8c , and R 8d is independently hydrogen, deuterium, halogen, or —OR a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each of R 8a , R 8b and R 8c are hydrogen and R 8d is hydrogen, halogen, or —OR a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is halogen or —OR a . In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is halogen. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is fluoro, chloro, bromo, or iodo. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 8c is —OR a .

Further provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R a is C 1 -C 6 alkyl. In some embodiments are provided compounds of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R a is —CH 3 .

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

wherein:

Ring A is heteroaryl;

each R 1 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a ;

each R 1a is independently deuterium, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl;

n is 1, 2, 3, 4, 5, 6, 7, or 8;

R 7 is hydrogen or C 1 -C 6 alkyl;

R 8c is halogen or —OR a ; and

each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl. C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.

›DETAILED DESCRIPTION OF THE INVENTION · 16 of 34

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazolyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 1-pyrazolyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyrazolyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyrazolyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrazolyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyridinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyridinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyridinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyridinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyridinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, or 6-pyrazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyrazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyrazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyrimidinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 2-pyrimidinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyrimidinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyrimidinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyrimidinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyridazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, or 6-pyridazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 3-pyridazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-pyridazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-pyridazinyl. In some embodiments are provided compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-pyridazinyl.

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl; each R 1 is independently halogen, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a ; each R 1a is independently —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; n is 1, 2, or 3; R 7 is hydrogen; R 8c is —OR a ; and each R a is C 1 -C 6 alkyl. In some embodiments. Ring A is pyrimidinyl. In other embodiments, Ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. Instill further embodiments, Ring A is 2-pyrimidinyl. Further embodiments provide Ring A is 4-pyrimidinyl. In other embodiments, Ring A is 5-pyrimidinyl. In yet other embodiments, Ring A is 6-pyrimidinyl.

›DETAILED DESCRIPTION OF THE INVENTION · 17 of 34

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is pyridinyl or pyrimidinyl; each R 1 is independently fluoro, chloro, —CN, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a ; each R 1a is independently —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; n is 1, 2, or 3; R 7 is hydrogen; R 8c is —OCH 3 ; and each R a is C 1 -C 6 alkyl. In some embodiments, Ring A is pyridinyl. In other embodiments, Ring A is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 5-pyridinyl, or 6-pyridinyl. In still further embodiments, Ring A is 2-pyridinyl. In some embodiments, Ring A is 3-pyridinyl. In some embodiments, Ring A is 4-pyridinyl. In some embodiments, Ring A is 5-pyridinyl. In some embodiments, Ring A is 6-pyridinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, or 6-pyrimidinyl. In some embodiments, Ring A is 2-pyrimidinyl. In some embodiments, Ring A is 4-pyrimidinyl. In some embodiments, Ring A is 5-pyrimidinyl. In some embodiments, Ring A is 6-pyrimidinyl.

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is pyridinyl or pyrimidinyl; each R 1 is independently chloro, —CN, —OH, —OCH 3 , —OCH 2 CH 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —OCHF 2 , cyclopropyl, morpholinyl, piperidinyl, piperazinyl, azetidinyl, 1,1-dioxidothiomorpholinyl, or oxetanyl; wherein morpholinyl, piperidinyl, piperazinyl, azetidinyl, 1,1-dioxidothiomorpholinyl, and oxetanyl are each optionally and independently substituted with one or more R 1a ; each R 1a is independently —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 heteroalkyl; n is 1, 2, or 3; R 7 is hydrogen; R 8c is —OCH 3 ; and each R a is C 1 -C 6 alkyl.

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is heteroaryl; each R 1 is independently halogen, —CN, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R a a; each R 1a is independently deuterium, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; n is 1, 2, or 3; R 7 is hydrogen or C 1 -C 6 alkyl; R 8c is halogen or —OR a ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; and each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O)CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 . —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl. In some embodiments, Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl.

›DETAILED DESCRIPTION OF THE INVENTION · 18 of 34

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is heteroaryl; each R 1 is independently halogen, —OR a , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R 1a ; each R 1a is independently deuterium, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; n is 1, 2, or 3; R 7 is hydrogen or C 1 -C 6 alkyl; R 1 is halogen or —OR a ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; and each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O)CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl. In some embodiments, Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments. Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is heteroaryl; each R 1 is independently halogen, —OR a , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a . —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, or heterocycloalkyl; wherein each of the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, and heterocycloalkyl is optionally and independently substituted with one or more R a ; each R 1a is independently deuterium, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 2 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; n is 1, 2, or 3; R 7 is hydrogen or C 1 -C 6 alkyl; R 8c is halogen or —OR a ; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 2 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; and each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 . —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl. In some embodiments, Ring A is pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl.

›DETAILED DESCRIPTION OF THE INVENTION · 19 of 34

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl; each R 1 is independently halogen, —S(═O) 2 (C 1 -C 6 alkyl), —S(═O) 2 N(C 1 -C 6 alkyl) 2 , —OC 1 -C 6 alkyl, —C(═O)N(C 1 -C 6 alkyl) 2 , —C(═O)N(H)(C 1 -C 6 alkyl), —OC 1 -C 6 haloalkyl, C 1 -C 6 alkyl, —S(C 1 -C 6 alkyl), heterocycloalkyl, or —C(═O)(heterocycloalkyl); n is 1, 2, or 3; R 7 is hydrogen; and R 8c is hydrogen, halogen, CH 3 , or —OCH 3 . In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH 3 . In some embodiments, R 8c is or —OCH 3 .

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl; each R 1 is independently halogen, —CF 3 , —CN, —S(═O) 2 (CH 3 ), —S(═O) 2 (CH 2 CH 3 )—S(═O) 2 N(CH 3 ) 2 , —OCH 3 , —CH 2 CHF 2 , —C(═O)N(CH 3 ) 2 , —C(═O)N(H)(CH 3 ), —OC 1 -C 6 haloalkyl, —CH 3 , —CH 2 CH 3 , iso-propyl, n-propyl, —SCH 3 , azetidinyl, pyrrolidinyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidothiomorpholinyl, —C(═O)(morpholinyl), —C(═O)(azetidinyl), —C(═O)(difluoroazetidinyl), or —C(═O)difluoropiperidinyl; n is 1, 2, or 3; R 7 is hydrogen; and R 8c is hydrogen, halogen, CH 3 , or —OCH 3 . In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments. R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH 3 . In some embodiments, R 8c is or —OCH 3 .

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl; each R 1 is independently halogen, —CF 3 , —CN, —S(═O) 2 (CH 3 ), —S(═O) 2 (CH 2 CH 3 ), —S(═O) 2 (i-Pr), —S(═O) 2 (cyclopropyl), —S(═O) 2 (C 1 -C 6 haloalkyl), —S(═O) 2 N(CH 3 ) 2 , —S(═O) 2 NH 2 , —S(═O) 2 N(CH 3 )(H), —OCH 3 , —OCH 3 , —OCH 2 CH 3 , —CH 2 CHF 2 , —C(O)N(CH 3 ) 2 , —C(═O)N(H)(CH 3 ), —OC 1 -C 6 haloalkyl, —CH 3 , —CH 2 CH 3 , iso-propyl, n-propyl, —SCH 3 , azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidothiomorpholinyl, —C(═O)(morpholinyl), —C(═O)(azetidinyl), —C(═O)(difluoroazetidinyl), or —C(═O)difluoropiperidinyl; n is 1, 2, or 3; R 7 is hydrogen; and R 8c is hydrogen, halogen, CH 3 , or —OCH 3 . In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH. In some embodiments, R 8c is or —OCH 3 .

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl; each R 1 is independently halogen, —CF 3 , —CN, —S(═O) 2 (C 1 -C 6 alkyl), —S(═O) 2 (C 3 -C 10 cycloalkyl), —S(═O) 2 N(C 1 -C 6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 N(C 1 -C 6 alkyl)(H), —OC 1 -C 6 alkyl, —CH 2 CHF 2 , —C(═O)N(C 1 -C 6 alkyl) 2 , —C(═O)N(H)(C 1 -C 6 alkyl), —OC 1 -C 6 haloalkyl, —C 1 -C 6 alkyl, —SC 1 -C 6 alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidothiomorpholinyl, —C(═O)(morpholinyl), —C(═O)(azetidinyl), —C(═O)(difluoroazetidinyl), or —C(═O)difluoropiperidinyl; n is 1, 2, or 3; R 7 is hydrogen; and R 8c is hydrogen, halogen, CH 3 , or —OCH 3 . In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH 3 . In some embodiments, R 8c is or —OCH 3 .

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is phenyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl; each R 1 is independently halogen, —CF 3 , —CN, —S(═O) 2 (C 1 -C 6 alkyl), —S(═O) 2 (C 3 -C 10 cycloalkyl), —S(═O)N(C 1 -C 6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 N(C 1 -C 6 alkyl)(H), —OC 1 -C 6 alkyl, —CH 2 CHF 2 , —C(═O)N(C 1 -C 6 alkyl) 2 , —C(═O)N(H(C 1 -C 6 alkyl), —OC 1 -C 6 haloalkyl, —C 1 -C 6 alkyl, —SC 1 -C 6 alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidothiomorpholinyl, —C(═O(morpholinyl), —C(═O)(azetidinyl), —C(═O)(difluoroazetidinyl), or —C(═O)difluoropiperidinyl, and wherein at least one of R 1 is —S(═O) 2 (C 1 -C 6 alkyl), —S(═O) 2 (C 3 -C 10 cycloalkyl), —S(═O) 2 N(C 1 -C 6 alkyl) 2 , —S(═O) 2 NH 2 , or —S(═O) 2 N(C 1 -C 6 alkyl)(H); n is 1, 2, or 3; R 7 is hydrogen; and R 8c is hydrogen, halogen, CH 3 , or —OCH 3 . In some embodiments, Ring A is phenyl. In some embodiments, Ring A is pyrazolyl. In some embodiments, Ring A is pyridinyl. In some embodiments, Ring A is pyrazinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is pyridazinyl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8b is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH 3 . In some embodiments, R 8c is or —OCH 3 .

›DETAILED DESCRIPTION OF THE INVENTION · 20 of 34

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is heterocycloalkyl; each R 1 is independently halogen, —CF 3 , —CN, —S(═O) 2 (C 1 -C 6 alkyl), —S(═O) 2 (C 3 -C 10 cycloalkyl), —S(═O) 2 N(C 1 -C 6 alkyl) 2 , —S(═O) 2 NH 2 , —S(═O) 2 N(C 1 -C 6 alkyl)(H), —OC 1 -C 6 alkyl, —CH 2 CHF 2 , —C(═O)N(C 1 -C 6 alkyl) 2 , —C(═O)N(H)(C 1 -C 6 alkyl), —OC 1 -C 6 haloalkyl, —C 1 -C 6 alkyl, —SC 1 -C 6 alkyl, azetidinyl, pyrrolidinyl, oxazolyl, fluoropyrrolidinyl, difluoropiperidinyl, difluoroazetidinyl, fluoroazetidinyl, morpholinyl, dioxidothiomorpholinyl, —C(═O)(morpholinyl), —C(═O(azetidinyl), —C(═O)(difluoroazetidinyl), or —C(═O)difluoropiperidinyl; n is 1, 2, or 3; R 7 is hydrogen; and R 8c is hydrogen, halogen, CH 3 , or —OCH 3 . In some embodiments, Ring A is dihydropyridazinyl. In some embodiments, Ring A is 1,6-dihydropyridin-3-yl. In some embodiments, R 8c is hydrogen. In some embodiments, R 8c is halogen. In some embodiments, R 8c is fluoro, chloro, bromo, or iodo. In some embodiments, R 8c is fluoro. In some embodiments, R 8c is CH 3 . In some embodiments, R 8c is or —OCH 3 .

Further provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

Ring A is aryl; each R 1 is independently halogen, —CN, —OR a , —OC(═O)R a , —OC(═O)OR b , —OC(═O)NR c R d , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR c R d , —NR c R d , —NR b C(═O)NR c R d , —NR b C(═O)R a , —NR b C(═O)OR a , —NR b S(═O) 2 R a , —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OC 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is optionally and independently substituted with one or more R 1a ; each R 1a is independently deuterium, —OH, —OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, or heteroaryl; n is 1, 2, or 3; R 7 is hydrogen or C 1 -C 6 alkyl; R 8c is hydrogen, C 1 -C 6 alkyl, halogen or —OR a ; each R 8c is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl. C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; and each R c and R d are independently hydrogen, C 1 -C 6 alkyl. C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, heteroaryl, C 1 -C 6 alkyl(C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl(heterocycloalkyl), C 1 -C 6 alkyl(C 6 -C 10 aryl), or C 1 -C 6 alkyl(heteroaryl); wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocycloalkyl, C 6 -C 10 aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 . —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH 3 , —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O) 2 NH 2 , —S(═O) 2 NHCH 3 , —S(═O) 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 3 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.

Further provided herein are compounds of Formula (I) selected from (1R,2S)-5′-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(5-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-ethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-cyclopropylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1S,2R)-5′-methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(2-chloro-5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-6-(piperidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(3-methoxypyrazin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(6-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(3-methoxypyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(4-methoxypyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(3-methoxypyridin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(1,3,5-trimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-(trifluoromethyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-chloro-2-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(2-methoxypyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(3-hydroxy-2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[(3S)-3-hydroxy-2,3-dihydro-1-benzofuran-7-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[(3R)-3-hydroxy-2,3-dihydro-1-benzofuran-7-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(2,3-dihydropyrazolo[5,1-b][1,3]oxazol-7-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(3-oxo-2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(2,3-dihydrofuro[2,3-c]pyridin-7-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[(3S)-3-(hydroxymethyl)-2,3-dihydrofuro[2,3-c]pyridin-7-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[(3R)-3-(hydroxymethyl)-2,3-dihydrofuro[2,3-c]pyridin-7-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-((6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′-one; (1R,2S)-2-(3-{[6-(2-hydroxyethoxy)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one); (1R,2S)-5′-methoxy-2-(3-{[6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-methyl-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(azetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-6-(3-hydoxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[4-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[1-(2-hydroxyethyl)-3-methoxy-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-cyclopropyl-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxypyrimidin-4-yl}amino)-1H-indazol-6-yl]-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-((5-chloro-6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one; (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)-5-methoxypyrimidin-4-yl)amino)-H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′-one; (1R,2S)-2-(3-{[5-(2-hydroxyethyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(2-hydroxyethyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)-5-methoxy-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one; (1R,2S)-2-(3-((5-chloro-6-(1,1-dioxidothiomorpholino)-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one; (1R,2S)-2-(3-((2-cyclopropyl-6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one; (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one; 5-methoxy-4-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-6-(morpholin-4-yl)pyrimidine-2-carbonitrile; 4-(1,1-dioxidothiomorpholino)-5-methoxy-6-((6-((1R,2S)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazol-3-yl)amino)pyrimidine-2-carbonitrile; (1R,2S)-2-{3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 4-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-1-methyl-1H-pyrazole-3-carbonitrile; (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxy-2-methylpyrimidin-4-yl}amino)-1H-indazol-6-yl]-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-(2-hydroxyethyl)-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-((2-cyclopropyl-6-(1,1-dioxidothiomorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one; (1R,2S)-2-(3-((5-chloro-2-cyclopropyl-6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′-one; (1R,2S)-5′-methoxy-2-{3-[(3-methoxy-6-methylpyrazin-2-yl}amino]-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-5-methoxy-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(1,3-dimethyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(4-methoxy-1-methyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-2-cyclopropyl-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-[3-({2-cyclopropyl-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxypyrimidin-4-yl}amino)-1H-indazol-6-yl]-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-((5-chloro-6-(1,1-dioxidothiomorpholino)-2-isopropylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one; (1R,2S)-5′-methoxy-2-{3-[(4-methoxy-1-methyl-1H-pyrazol-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(6-cyclopropyl-3-methoxypyrazin-2-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-cyclopropyl-6-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(3,6-dimethylpyrazin-2-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-6-(propan-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)-2-isopropyl-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(5-methoxy-2-methylpyridin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(3-methoxy-6-methylpyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(2-methoxy-5-methylpyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(4-methoxypyridazin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(3-cyclopropyl-1-ethyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-(2-hydroxy-2-methylpropyl)-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-5-(morpholin-4-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-2-(morpholin-4-yl)pyridin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-chloro-2-methylpyridin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-chloro-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-6-(morpholin-4-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-6-(oxetan-3-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-6-(propan-2-yl)pyridazin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[6-(morpholin-4-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(3-hydroxyazetidin-1-yl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methyl-6-(propan-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[6-(propan-2-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxy-1′-methylspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-1′-ethyl-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(difluoromethoxy)-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(azetidin-3-yl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; and (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 21 of 34

Further provided herein are compounds of Formula (I) selected from (1R,2S)-2-(3-{[1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-5-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-1′-methylspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[6-(oxetan-3-yl)pyrazin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-2-(oxetan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-(oxetan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-2-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-1′-methylspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2R)-2-{7-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1H)-one; (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methylspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1S,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methylspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-4′-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1S,2S)-4′-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-6′-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-chloro-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-fluoro-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-ethoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-[3-({2-methyl-5-[(propan-2-yl)oxy]pyrimidin-4-yl}amino)-1H-indazol-6-yl]spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-(trifluoromethyl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-(trifluoromethoxy)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1S,2S)-2-{3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-(trifluoromethoxy)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-cyclopropyl-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(difluoromethoxy)-2-(oxetan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2R)-5′-fluoro-2-{7-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; and (1R,2R)-2-(3-{[5-(difluoromethoxy)-2-methylpyrimidin-4-yl]amino}-7-fluoro-1H-indazol-6-yl)-5′-fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Further provided herein are compounds of Formula (I) selected from (1R,2R)-2-{5-fluoro-3-[(5-methoxy-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(3-methoxy-6-methylpyridazin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(cyclopropylmethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(2,2-difluoroethoxy)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-[3-(2-methoxy-5-methylanilino)-1H-indazol-6-yl]spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[2-methyl-5-(2,2,2-trifluoroethoxy)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(2-methoxy-6-methylpyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[2-methyl-6-(propan-2-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(5-ethyl-2-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(2-methyl-6,7-dihydrofuro[3,2-d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-(oxan-4-yl)pyrimidin-4-yl]amino}-H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(2,5-dimethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-5-(trifluoromethyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(2-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(2-ethyl-5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(7-methoxyquinolin-6-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[2-methyl-5-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(3-methoxyquinolin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(2,5-dimethoxypyridin-3-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(2-chlorofuro[3,2-d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-(pyrrolidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(methanesulfonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-[3-({2-[(3R)-3-fluoropyrrolidin-1-yl]-5-methoxypyrimidin-4-yl}amino)-1H-indazol-6-yl]-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-(3,3-difluoropyrrolidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 5-methoxy-4-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyrimidine-2-carbonitrile; (1R,2S)-2-(3-{[2-(3,3-difluoroazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-(3-fluoroazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[5-(ethanesulfonyl-2-methoxyanilino]-1H-indazol-6-yl-}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 4-methoxy-3-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylbenzamide; 4-methoxy-3-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N-methylbenzamide; (1R,2S)-5′-methoxy-2-{3-[2-methoxy-5-(propane-2-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 4-methoxy-3-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylbenzene-1-sulfonamide; (1R,2S)-5′-methoxy-2-{3-[2-methoxy-5-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide; (1R,2S)-2-(3-{[2-(dimethylamino)-5-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[2-methoxy-6-(morpholine-4-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(3,3-difluoroazetidine-1-carbonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(4,4-difluoropiperidine-1-carbonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(4-fluoro-3-{[5-methoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(2-methoxy-5-methylpyrimidin-4-yl)amino]-H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[2-methoxy-6-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-(4,4-difluoropiperidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 4-[5-methoxy-4-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyrimidin-2-yl]-1)-1λ6-thiomorpholine-1,1-dione; 6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N-methylpyridine-2-carboxamide; (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(methanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N-methyl-N-(propan-2-yl)pyridine-2-carboxamide; (1R,2S)-2-(3-{[5-ethoxy-2-(methylsulfanyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(methanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 5-methoxy-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide; 5-methoxy-4-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide; (1R,2S)-5′-methoxy-2-{3-[2-methoxy-4-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; Diastereomer 1: (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-(oxolan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; Diastereomer 2: (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-(oxolan-3-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[2-ethoxy-6-(methanesulfonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 5-ethoxy-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-carboxamide; 5-methoxy-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-3-sulfonamide; (1R,2S)-2-(3-{[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 2-fluoro-5-methoxy-4-((6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl)amino)-N,N-dimethylbenzamide; (1R,2S)-2-{3-[5-fluoro-2-methoxy-4-(morpholine-4-carbonyl)anilino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; and (1R,2S)-2-(3-{[3-ethoxy-5-(methanesulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one, or a pharmaceutically acceptable salt thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 22 of 34

Further provided herein are compounds of Formula (I) selected from (1R,2S)-2-(3-{[6-(ethanesulfonyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 5-methoxy-4-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,2-dimethylbenzene-1-sulfonamide; (1R,2S)-2-{3-[(2,5-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 2,5-dimethoxy-4-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)benzene-1-sulfonamide; (1R,2S)-2-(3-{[2-(dimethylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 6-ethoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide; (1R,2S)-5′-methoxy-2-(3-{[2-methoxy-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[2-methoxy-5-(morpholine-4-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(3-methoxy-1,5-naphthyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; N,6-dimethoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-H-indazol-3-yl}amino)-N-methylpyridine-2-carboxamide; 6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N′-(propan-2-yl)pyridine-2-carbohydrazide; (1R,2S)-5′-methoxy-2-(3-{[2-methoxy-5-(2-oxopyrrolidin-1-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[2-methoxy-5-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-sulfonamide; 6-ethoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-sulfonamide; (1R,2S)-5′-methoxy-2-{3-[2-methoxy-5-(oxane-4-sulfonyl)anilino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(dimethylphosphoryl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(2-hydroxypropan-2-yl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (0R,2S)-2-(3-{[6-(methanesulfonyl)-2-methoxy-5-methylpyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(ethanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; N-(cyclopropylmethyl)-6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide; 6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N-(propan-2-yl)pyridine-2-carboxamide; (1R,2S)-5′-methoxy-2-(3-{[2-methoxy-6-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[2-methoxy-5-(1,3-oxazol-2-yl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-5-(3-methoxyazetidine-1-carbonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-H-indazol-3-yl}amino)-N,N-dimethylpyrazine-2-carboxamide; 6-ethoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyrazine-2-carboxamide; 6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N,3-trimethylpyridine-2-carboxamide; (1R,2S)-2-(3-{[6-(methanesulfinyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(methanesulfinyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(methanesulfonyl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(methanesulfonyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; N,N-dicyclopropyl-6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide; N-(2,2-difluoroethyl)-6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide; (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylpiperidine-1-carbonyl]-2-methoxypyridin-3-yl}amino)-1H-indazol-6-yl]-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[2-methoxy-6-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[3-chloro-5-(methanesulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-5-(propane-2-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(dimethylphosphoryl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; N-(1,3-difluoropropan-2-yl)-6-methoxy-5-{6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carboxamide; 6-chloro-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide; (1R,2S)-2-{3-[(5-chloro-2-methyl-1,3-benzoxazol-6-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 4-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N,N-dimethylpyridine-2-carboxamide; 3-[6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyrazin-2-yl]-1)-1λ6-thietane-1,1-dione; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-5-(morpholine-4-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-5-(8-oxa-3-azabicyclo[3.2.1]octane-3-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(diethylphosphoryl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(cyclopropanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-5-(oxane-4-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 6-methoxy-5-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyridine-2-carbonitrile; (1R,2S)-2-{3-[5-(diethylphosphoryl)-2-methoxyanilino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(ethanesulfonyl)-4-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(azetidine-1-carbonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(6-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-{3-[(4-methoxy-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-5′-methoxy-2-(3-{[3-methoxy-5-(1,2-oxazolidine-2-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(azetidine-1-sulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 5-methoxy-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N-(3-methyloxetan-3-yl)pyridine-3-sulfonamide; 5-methoxy-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N-methyl-N-(3-methyloxetan-3-yl)pyridine-3-sulfonamide; (1R,2S)-2-(3-{[5-(1-hydroxyethyl)-2-methoxypyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[2-ethoxy-4-(methanesulfonyl)anilino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[3-ethoxy-5-(4-methylpiperazine-1-sulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[5-(ethanesulfonyl)-3-ethoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; 5-ethoxy-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-N-methylpyridine-3-sulfonamide; (1R,2S)-5′-chloro-2-(3-{[3-ethoxy-5-(methanesulfonyl)pyridin-2-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-{3-[(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[6-(2-hydroxypropan-2-yl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; (1R,2S)-2-(3-{[4-ethoxy-6-(methanesulfonyl)pyridin-3-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one; and (1R,2S)-2-(3-{[5-(difluoromethanesulfonyl)-3-methoxypyridin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one, or a pharmaceutically acceptable salt thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 23 of 34

Further provided herein are compounds of Formula (I) selected from those set forth in Table 1A.

Further provided herein are pharmaceutical compositions comprising an amount of a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

Methods of Treatment

Further provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein comprising a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Provided herein are such methods of treating cancer in a subject, wherein the cancer in the subject is a solid tumor. In some embodiments, the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or pituitary adenoma. In some embodiments, the cancer in the subject expresses polo-like kinase 4 (PLK4). In some embodiments, the cancer in the subject has been determined to express polo-like kinase 4 (PLK4) prior to administering to the subject a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer in the subject exhibits an overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments, the cancer in the subject exhibits an overexpression of the gene that encodes the tripartite motif-containing protein 37 (TRIM37). In some embodiments, the cancer in the subject exhibits an amplification of the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

Further provided herein are methods of treating cancer in a subject in need thereof, wherein the cancer in the subject has been determined to overexpress the gene that encodes the tripartite motif-containing protein 37 (TRIM37), comprising administering to the subject a therapeutically effective amount of compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Further provided herein are methods of treating cancer in a subject, comprising:

a. obtaining a biological sample of the cancer from the subject; b. determining whether the biological sample of the cancer overexpresses the gene that encodes the tripartite motif-containing protein 37 (TRIM37); and c. administering to the subject a therapeutically effective amount of a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, if the biological sample of the cancer is determined to overexpress the gene that encodes the tripartite motif-containing protein 37 (TRIM37).

Further provided herein are methods of treating cancer in a subject described herein, wherein the cancer is neuroblastoma or breast cancer. Also provided herein are methods of treating cancer in a subject described herein, wherein the cancer is neuroblastoma. Also provided herein are methods of treating cancer in a subject described herein, wherein the cancer is breast cancer.

Further provided herein are methods of treating cancer in a subject described herein, wherein a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to the subject with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is selected from one or more mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and/or serine/threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, and immuno-oncology agents.

Further provided herein are methods of inhibiting polo-like kinase 4 (PLK4) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

›DETAILED DESCRIPTION OF THE INVENTION · 24 of 34

Further provided herein are methods of inhibiting polo-like kinase 4 (PLK4) in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition comprising a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the cancer in the subject has been determined to express polo-like kinase 4 (PLK4) prior to administering the compound or the pharmaceutical composition to the subject.

Further provided herein are compounds of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or pharmaceutical compositions comprising a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in methods of treating cancer in a subject in need thereof. In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer in the subject is a solid tumor. In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or pituitary adenoma. In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer in the subject expresses polo-like kinase 4 (PLK4). In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer in the subject has been determined to express polo-like kinase 4 (PLK4) prior to administering the compound or the pharmaceutical composition to the subject. In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer in the subject exhibits an overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer in the subject exhibits an overexpression of the gene that encodes the tripartite motif-containing protein 37 (TRIM37). In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer in the subject exhibits an amplification of the gene that encodes the tripartite motif-containing protein 37 (TRIM37). In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer in the subject has been determined to overexpress the gene that encodes the tripartite motif-containing protein 37 (TRIM37) prior to administration of the compound or the pharmaceutical composition to the subject. In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer is neuroblastoma or breast cancer. In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer is neuroblastoma. In some embodiments are provided such compounds or pharmaceutical compositions for such use, wherein the cancer is breast cancer.

›DETAILED DESCRIPTION OF THE INVENTION · 25 of 34

Further provided herein are uses of a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof. In some embodiments are provided such uses, wherein the cancer is neuroblastoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, or pituitary adenoma. In some embodiments the cancer in the subject expresses polo-like kinase 4 (PLK4). In some embodiments the cancer in the subject has been determined to express polo-like kinase 4 (PLK4) prior to administering the compound to the subject. In some embodiments the cancer in the subject exhibits an overexpression of the E3 ubiquitin-protein ligase (TRIM37) protein. In some embodiments the cancer in the subject exhibits an overexpression of the gene that encodes the tripartite motif-containing protein 37 (TRIM37). In some embodiments the cancer in the subject exhibits an amplification of the gene that encodes the tripartite motif-containing protein 37 (TRIM37). In some embodiments the cancer in the subject has been determined to overexpress the gene that encodes the tripartite motif-containing protein 37 (TRIM37) prior to administration of the compound to the subject. In some embodiments the cancer is neuroblastoma or breast cancer. In some embodiments the cancer is neuroblastoma. In some embodiments the cancer is breast cancer.

In some embodiments, compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is used in combination with one or more additional anti-cancer agents. In some embodiments, the anti-cancer agent is mitoxantrone, estramustine, etoposide, vinblastine, carboplatin, vinorelbine, paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In some embodiments, the anti-cancer agent is paclitaxel, daunomycin, darubicin, epirubicin, docetaxel, cabazitaxel, or doxorubicin. In certain embodiments, the anti-cancer agent is docetaxel.

In some embodiments, one or more additional anti-cancer agents may include, without limitations, surgery, radiation, or chemotherapy. The chemotherapy may be an androgen receptor antagonist, a mitotic inhibitor, an antimetabolite, a platinum-based agent. Examples of androgen receptor antagonist include, without limitations, apalutamide, flutamide, nilutamide, bicalutamide, or enzalutamide. Examples of mitotic inhibitors include, without limitations, a taxane (e.g. paclitaxel, docetaxel, paclitaxel, docetaxel, cabazitaxel, tesetaxel, or nab-paclitaxel.

or nab-paclitaxel) or a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, or vinorelbine). Examples of antimetabolites include, without limitations, 5-Fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxycarbamide, methotrexate, pemetrexed, or phototrexate. Examples of platinum-based agents include, without limitations, cisplatin, carboplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, or triplatin tetranitrate. The additional anti-cancer therapy may comprise an anti-PDL1 agent, an anti-PD1 agent or an anti CTLA-4 agent. The anti-PD-L1 agent may comprise atezolizumab, avelumab, durvalumab, MPDL3280A (RG7446), MDX-1105 (BMS-936559) or BMS-935559, MSB0010718C, and MEDI4736. The anti-PD1 agent may comprise pembrolizumab, nivolumab, cemiplimab, partalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, or AMP-514 (MEDI0680). The anti-CTLA agent may comprise ipilimumab, or tremelimumab.

›DETAILED DESCRIPTION OF THE INVENTION · 26 of 34

Methods of Treatment in Conjunction with Biomarkers

Disclosed herein, in some embodiments, are methods of detecting the presence, absence, or level, of a biomarker. Such biomarkers may comprise genetic alterations in the gene encoding for certain proteins such as tripartite motif-containing protein 37 (TRIM37). The presence, absence, or level, of such biomarkers may be measured in a biological sample obtained from a subject, such as a sample of a solid tumor, such as a prostate cancer, or from a sample of a relevant biological fluid, such as a blood sample. In some instances, the methods of detection disclosed herein are useful for predicting a therapeutic response to a therapy described herein (e.g., a PLK4 inhibitor) in, monitor the treatment using the therapy of, and treating with the therapy, a proliferative disease or condition described herein in a subject. In some embodiments, the presence, or an absence, and/or a level of expression of the one or more biomarkers is detected in the sample obtained from a subject by analyzing the genetic material in the sample. In some embodiments, the genetic material is obtained from blood, serum, plasma, sweat, hair, tears, urine, and other techniques known by one of skill in the art. In some embodiments the sample comprises circulating tumor RNA (ctRNA). In some embodiments the sample comprises peripheral blood mononuclear cells (PBMCs). In some cases, the genetic material is obtained from a tumor biopsy or liquid biopsy. In some embodiments, a tumor biopsy comprises a formalin-fixed paraffin embedded biopsy, a fresh frozen biopsy, a fresh biopsy, or a frozen biopsy. In some embodiments, a liquid biopsy comprises PBMCs, circulating tumor RNA, plasma cell-free RNA, or circulating tumor cells (CTCs). Tumor biopsies can undergo additional analytic processing for sample dissociation, cell sorting, and enrichment of cell populations of interest.

In some embodiments, methods of detecting a presence, absence, or level of a biomarker in the sample obtained from the subject involve detecting a nucleic acid sequence. In some cases, the nucleic acid sequence comprises deoxyribonucleic acid (DNA), such as in the case of detecting complementary DNA (cDNA) of an mRNA transcript. In some instances, the nucleic acid sequence comprises a denatured DNA molecule or fragment thereof. In some instances, the nucleic acid sequence comprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some instances, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denaturing double-stranded DNA, synthetic DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In some instances, the nucleic acid sequence comprises ribonucleic acid (RNA). In some instances, the nucleic acid sequence comprises fragmented RNA. In some instances, the nucleic acid sequence comprises partially degraded RNA. In some instances, the nucleic acid sequence comprises a microRNA or portion thereof. In some instances, the nucleic acid sequence comprises an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA, a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circular RNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), a pre-tRNA, a long non-coding RNA (lncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell-free RNA, an exosomal RNA, a vector-expressed RNA, an RNA transcript, a synthetic RNA, and combinations thereof.

Disclosed herein, in some embodiments, the biomarker is detected by subjecting a sample obtained from the subject to a nucleic acid-based detection assay. In some instances, the nucleic acid-based detection assay comprises quantitative polymerase chain reaction (qPCR), gel electrophoresis (including for e.g., Northern or Southern blot), immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), cytochemistry, microarray, or sequencing. In some embodiments, the sequencing technique comprises next generation sequencing. In some embodiments, the methods involve a hybridization assay such as fluorogenic qPCR (e.g., TaqMan™, SYBR green, SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin), which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acid probes comprising a detectable moiety or molecule that is specific to a target nucleic acid sequence. In some instances, a number of amplification cycles for detecting a target nucleic acid in a qPCR assay is about 5 to about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles. For TaqMan™ methods, the probe may be a hydrolysable probe comprising a fluorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid. In some cases, the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles. In some instances, hybridization may occur at standard hybridization temperatures, e.g., between about 35° C. and about 65° C. in a standard PCR buffer.

An additional exemplary nucleic acid-based detection assay comprises the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence. In some instances, the nucleic acid probe is specific to one or more gene products described herein. In some instances, the nucleic acid probe specific to a biomarker comprises a nucleic acid probe sequence sufficiently complementary to the polynucleotide sequence of the biomarker. In some instances, the biomarker comprises a transcribed polynucleotide sequence (e.g., RNA, cDNA). In some embodiments, the nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least about 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 nucleotides in length and sufficient to specifically hybridize under standard hybridization conditions to the target nucleic acid sequence. In some embodiments, the target nucleic acid sequence is immobilized on a solid surface and contacted with a probe, for example by running the isolated target nucleic acid sequence on an agarose gel and transferring the target nucleic acid sequence from the gel to a membrane, such as nitrocellulose. In some embodiments, the probe(s) are immobilized on a solid surface, for example, in an Affymetrix gene chip array, and the probe(s) are contacted with the target nucleic acid sequence.

›DETAILED DESCRIPTION OF THE INVENTION · 27 of 34

In some embodiments, the term “probe” with regards to nucleic acids, refers to any nucleic acid molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence. In some instances, probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art. In some instances, the fluorescent label comprises a fluorophore. In some instances, the fluorophore is an aromatic or heteroaromatic compound. In some instances, the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin. Exemplary xanthene dyes include, e.g., fluorescein and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2′7′-dimethoxy-4′5′-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N′-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position. For example, naphthylamino compounds include 1-dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalene sulfonate, and 2-p-toluidinyl-6-naphthalene sulfonate, 5-(2′-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS). Exemplary coumarins include, e.g., 3-phenyl-7-isocyanatocoumarin; acridines, such as 9-isothiocyanatoacridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g., indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3′-ethyl-5,5′-dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H-Xantheno[2,3, 4-ij: 5,6, 7-i′j′]diquinolizin-18-ium, 9-[2 (or 4)-[[[6-[2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4 (or 2)-sulfophenyl]-2,3, 6,7, 12,13, 16,17-octahydro-inner salt (TR or Texas Red); or BODIPY™ dyes. In some cases, the probe comprises FAM as the dye label.

In some embodiments, detecting the one or more biomarkers, such as gene products in a predictive response signature (PRS), comprises sequencing genetic material obtained from a sample from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include next-generation sequencing, e.g., modern sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.

In some instances, a number of nucleotides that are sequenced are at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides. In some instances, the number of nucleotides sequenced is in a range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 1000M nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about 20 to about 100000 nucleotides, about 20 to about 10000 nucleotides, about 20 to about 1000 nucleotides, about 20 to about 500 nucleotides, about 20 to about 300 nucleotides, about 20 to about 200 nucleotides, about 20 to about 100 nucleotides, about 30 to about 100000 nucleotides, about 30 to about 10000 nucleotides, about 30 to about 1000 nucleotides, about 30 to about 500 nucleotides, about 30 to about 300 nucleotides, about 30 to about 200 nucleotides, about 30 to about 100 nucleotides, about 50 to about 100000 nucleotides, about 50 to about 10000 nucleotides, about 50 to about 1000 nucleotides, about 50 to about 500 nucleotides, about 50 to about 300 nucleotides, about 50 to about 200 nucleotides, or about 50 to about 100 nucleotides.

Disclosed herein are methods comprising: (a) providing a sample obtained from a subject with a proliferative disease or condition (e.g., cancer); (b) assaying to detect in the sample obtained from the subject a presence or absence of the relevant biomarker; and (c) detecting the presence or absence of the biomarker in the sample using the methods described herein. In some cases, a hybridization assay, such as those described herein, is used to detect the biomarker in the sample. Exemplary probe sequences that are hybridizable to a target nucleic acid sequence (e.g., one or more genes in the biomarker, such as the PRS) comprise at least 10, but no more than 100 contiguous nucleotides comprising the relevant sequence. In some cases, RNA sequencing (RNAseq) is used to detect the one or more biomarkers.

Detection of the relevant biomarker, in some cases, involves amplification of the subject's nucleic acid by the polymerase chain reaction (PCR). In some embodiments, the PCR assay involves use of a pair of primers capable of amplifying at least about 10 contiguous nucleobases within a nucleic acid sequence, thereby amplifying the one or more gene products in the biomarker. In fluorogenic quantitative PCR, quantitation is based on amount of fluorescence signals (TaqMan and SYBR green). In some embodiments, the nucleic acid probe is conjugated to a detectable molecule. The detectable molecule may be a fluorophore. The nucleic acid probe may also be conjugated to a quencher.

›DETAILED DESCRIPTION OF THE INVENTION · 28 of 34

In some embodiments, the assay for detecting the presence or absence of a relevant biomarker comprises reverse-transcribing the relevant mRNA molecule to produce a corresponding complementary DNA (cDNA) molecule). In some embodiments, the assay further comprises contacting the cDNA molecule with a nucleic acid probe comprising a nucleic acid sequence that is complementary to a nucleic acid sequence of the cDNA molecule. In some embodiments, the assay comprises detecting a double-stranded hybridization product between the nucleic acid probe and the cDNA molecule. In some embodiments, the hybridization product is further amplified using a pair of primers. In some embodiments, the primers comprises a first primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a relevant nucleic acid sequence that binds to a top strand of the double-stranded hybridization product; and a second primer with a nucleic acid sequence comprising at least 10 but not more than 50 contiguous nucleic acids within a nucleic acid sequence that is reverse complement to the relevant nucleic acid sequence that binds to a bottom strand of the double-stranded hybridization product.

Disclosed herein, in some embodiments, are methods comprising preparing a complementary DNA (cDNA) library. In some embodiments, the cDNA library is sequenced using suitable sequence methodologies disclosed herein. In some embodiments, the cDNA library is labeled, a plurality of nucleic acid probes is generated, and fixed to an immobile surface (such as a microarray). In some embodiments, the plurality of nucleic acid probes is capable of hybridizing to at least about 10 contiguous nucleotides of the two or more genes in a sample obtained from the subject. In some embodiments, detecting the presence of or absence of a biomarker includes detecting a high or a low level of expression of the two or more genes as compared to a reference level.

Disclosed herein, in some embodiments, genetic material is extracted from a sample obtained from a subject, e.g., a sample of blood or serum. In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification. In certain embodiments, RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol/guanidine isothiocyanate extraction (RNAzol B: Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix, Switzerland).

Circulating Tumor DNA (ctDNA) and RNA (ctRNA)

In some aspects, circulating tumor DNA (ctDNA) is used to assess the presence of certain DNA molecules and circulating tumor RNA (ctRNA) is used to assess the expression levels of RNA molecules, shed by the tumor into the blood stream.

In some embodiments, detection of ctDNA or ctRNA is useful, for example, for detecting and diagnosing a tumor. Because tumor DNA and RNA has acquired multiple genetic mutations, leading to tumor development, ctDNA and ctRNA are not an exact match to the individual's DNA and RNA, respectively. Finding DNA and RNA with genetic differences aids in tumor detection. Diagnosing the type of tumor using ctDNA or ctRNA can reduce the need for getting a sample of the tumor tissue (tumor biopsy), which can be challenging when a tumor is difficult to access, such as a tumor in the brain or lung.

In some embodiments, a decrease in the quantity of ctDNA or ctRNA suggests the solid tumor is shrinking and treatment with a compound of Formulae (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof is effective. In some embodiments, a lack of ctDNA or ctRNA in the bloodstream indicates that the cancer has not returned after treatment with a compound of Formulae (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof.

Described herein are methods of assessing genetic alterations by ctDNA or ctRNA genomic profiling. In some embodiments, the genomic profiling is performed after each treatment cycle with a compound of Formulae (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the gene mutations indicate that the cancer is becoming resistant to the treatment with a compound of Formulae (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof. In some embodiments, the lack of gene mutations indicate that the cancer is not becoming resistant to the treatment with a compound of Formulae (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt thereof.

The compounds of Formulae (I), (Ia), (Ib), (II), and (III) may be administered as prodrugs. Thus certain derivatives of the compounds, which may have little or no pharmacological activity themselves can, when administered to a mammal, be converted into a compound having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs.” Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compound of Formulae (I), (Ia), (Ib), (II), and (III) with certain moieties known to those skilled in the art. See, e.g. “Pro-drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and “Bioreversible Carriers in Drug Design”. Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties. Some examples of such prodrugs include: an ester moiety in the place of a carboxylic acid functional group; an ether moiety or an amide moiety in place of an alcohol functional group: and an amide moiety in place of a primary or secondary amino functional group. Examples of replacement groups are known to those of skill in the art. See, e.g. “Design of Prodrugs” by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

›DETAILED DESCRIPTION OF THE INVENTION · 29 of 34

Salts of the present invention can be prepared according to methods known to those of skill in the art. Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edisylate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, .gamma.-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methane-sulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phosphate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.

The compounds of Formulae (I), (Ia), (Ib), (II), and (III) that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

The compounds of Formulae (I), (Ia), (Ib), (II), and (III) that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.

If the compound of Formulae (I), (Ia), (Ib), (II), and (III) is a base, the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the compound of Formulae (I), (Ia), (Ib), (II), and (III) is an acid, the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

If the compound of Formulae (I), (Ia), (Ib), (II), and (III) is a solid, it is understood by those skilled in the art that the compounds or salts thereof may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.

Also provided herein are isotopically-labeled compounds of Formulae (I), (Ia), (Ib), (II), and (III), wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3 H, and carbon-14, 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

›DETAILED DESCRIPTION OF THE INVENTION · 30 of 34

Isotopically-labeled compounds of Formulae (I), (Ia), (Ib), (II), and (III) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

In one aspect, the compositions of compounds of Formulae (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, described herein are used for the treatment of cancer in a subject. In one embodiment, such compositions are in the form of suitable dosage forms. Suitable dosage forms include, for example, liquids, suspensions, powders for reconstitution, tablets, pills, sachets, or capsules of hard or soft gelatin (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

The compounds of Formulae (I), (Ia), (Ib), (II), and (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable. Pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of the present invention and an inert, pharmaceutically acceptable carrier or diluent.

The pharmaceutical carriers employed may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, tale, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water, and the like. Similarly, the inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties. For example, a bioavailability enhancer, such as Labrasol®, Gelucire™ or the like, or formulator, such as CMC (carboxymethylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added. Gelucire™, a semi-solid vehicle that protects active ingredients from light, moisture, and oxidation, may be added, e.g., when preparing a capsule formulation.

If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations. The inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.

To obtain a stable water-soluble dose form, a salt of a compound of the present invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable co-solvent or combinations of co-solvents. Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume. In an exemplary embodiment, a compound of the present invention is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.

Proper formulation is dependent upon the route of administration selected. For injection, the agents of the compounds of the present invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.

Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as tale or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

›DETAILED DESCRIPTION OF THE INVENTION · 31 of 34

For administration intranasally or by inhalation, the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

In addition to the formulations described above, the compounds of the present invention may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. A pharmaceutical carrier for hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1:1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. The proportions of a co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity non-polar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide (DMSO) also may be employed, although usually at the cost of greater toxicity due to the toxic nature of DMSO. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Furthermore, additives or excipients such as Gelucire™, Capryol™, Labrafil™, Labrasol™, Lauroglycol™, Plurol™, Peceol™, Transcutol™ and the like may be used.

Further, the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.

It will be appreciated that the actual dosages of the agents of this invention will vary according to the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. Those skilled in the art using conventional dosage-determination tests in view of the experimental data for a given compound may ascertain optimal dosages for a given set of conditions. For oral administration, an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.

Furthermore, the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a salt or solvate thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 to about 500 mg, or from about 100 mg to about 500 mg.

›DETAILED DESCRIPTION OF THE INVENTION · 32 of 34

Additionally, the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a salt or solvate thereof, in an amount from about 0.5 w/w % to about 95 w/w %, or from about 1 w/w % to about 95 w/w %, or from about 1 w/w % to about 75 w/w %, or from about 5 w/w % to about 75 w/w %, or from about 10 w/w % to about 75 w/w %, or from about 10 w/w % to about 50 w/w %.

The compounds of the present invention, or salts or solvates thereof, may be administered to a mammal suffering from abnormal cell growth, such as a human, either alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, or four times a day, or even more frequently.

Those of ordinary skill in the art will understand that with respect to the compounds Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the particular pharmaceutical formulation, the dosage, and the number of doses given per day to a mammal requiring such treatment, are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.

Dosages of compositions described herein can be determined by any suitable method. Maximum tolerated doses (MTD) and maximum response doses (MRD) for the compounds of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can be determined via established animal and human experimental protocols as well as in the examples described herein. For example, toxicity and therapeutic efficacy of the compounds of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via the protocols.

In some embodiments, the amount of the compounds of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, comprising a formulation that corresponds to such an amount varies depending upon factors such as the particular salt or form, disease condition and its severity, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, but can nevertheless be determined according to the particular circumstances surrounding the case, including. e.g., the specific agent being administered, the liquid formulation type, the condition being treated, and the subject or host being treated.

In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount between about 10 mg to 500 mg per day. In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof) is administered in an amount between about 100 mg to about 400 mg per day. In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered in an amount between about 150 mg to about 350 mg per day. In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered in an amount between about 150 mg to about 30) mg per day. In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount between about 160 mg to about 300 mg per day. In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 160 mg per day. In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 200 mg per day. In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 240 mg per day. In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 280 mg per day. In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in an amount of about 320 mg per day.

In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the subject. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the subject.

›DETAILED DESCRIPTION OF THE INVENTION · 33 of 34

In certain embodiments wherein the subject's condition does not improve, upon the doctor's discretion the administration of a composition described herein are administered chronically, that is, for an extended period of time, including throughout the duration of the subject's life in order to ameliorate or otherwise control or limit the symptoms of the subject's disease. In other embodiments, administration of a composition continues until complete or partial response of a disease.

In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject in need thereof once a day. In some embodiments, a compound of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered to a subject in need thereof twice a day. In some embodiments, a compound of Formulae (I), (Ia), (Ib). (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is administered to a subject in need thereof three times a day.

In some instances, the methods described herein comprise administering the compositions and formulations comprising the compounds of Formulae (I), (Ia), (Ib), (II), (III) in combination with one or more additional therapeutic agents, to the subject or subject in need thereof in multiple cycles repeated on a regular schedule with periods of rest in between each cycle. For example, in some instances, treatment given for one week followed by three weeks of rest is one treatment cycle.

The length of a treatment cycle depends on the treatment being given. In some embodiments, the length of a treatment cycle ranges from two to six weeks. In some embodiments, the length of a treatment cycle ranges from three to six weeks. In some embodiments, the length of a treatment cycle ranges from three to four weeks. In some embodiments, the length of a treatment cycle is three weeks (or 21 days). In some embodiments, the length of a treatment cycle is four weeks (28 days). In some embodiments, the length of a treatment cycle is 56 days. In some embodiments, a treatment cycle lasts one, two, three, or four weeks. In some embodiments, a treatment cycle lasts three weeks. In some embodiments, a treatment cycle lasts four weeks. The number of treatment doses scheduled within each cycle also varies depending on the drugs being given.

Kits and Articles of Manufacture

Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one or more methods and compositions described herein. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

A kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded, or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Methods of Preparation

Compounds of Formulae (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, may be prepared using the reaction routes and synthetic schemes described below, employing the techniques available in the art using starting materials that are readily available. The preparation of certain embodiments of the present invention is described in detail in the following examples, but those of ordinary skill in the art will recognize that the preparations described may be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplified compounds according to the invention may be performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions referred to herein or known in the art will be recognized as having adaptability for preparing other compounds of the invention.

The compounds of Formula (I) may be prepared from Compounds of Formula (IV), wherein R 2 , R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , and R 8d are as defined herein, by allowing the compounds to react with compounds of Formula (V), wherein A, R a , and n are as defined herein, and wherein LG is a leaving group. LG that may be used include halogens, such as chloro, bromo, and iodo. The reaction of the compounds of Formula (IV) with compounds of Formula (V) may be conducted using methods known to those of ordinary skill in the art. For example, the reaction of the compounds of Formula (IV) with compounds of Formula (V) may be conducted in aprotic solvents, such as acetonitrile, DMF, and the like, protic solvents, such as water or alcohols, mixtures of protic and aprotic solvents, such as mixtures of acetonitrile and water, at temperatures in the range from 25° C. to 200° C., and in the presence of an acid or a base. Compounds of Formula (V) may be prepared by methods disclosed herein and/or by methods known to those of ordinary skill in the art.

›DETAILED DESCRIPTION OF THE INVENTION · 34 of 34

Alternatively, compounds of Formula (I) may be prepared by allowing compounds of Formula (VI), wherein R 3 , R 4a , R 4b , R 4c , R 5 , R 6 , R 7 , R 8a , R 8b , R 8c , and R 8d are as defined herein, and Hal is a halogen, such as bromo or iodo, by allowing the compounds to react with compounds of Formula (VII), wherein A, R 1 , R 2 , and n are as defined herein. Such reactions may be performed in the presence of a catalytic amount of a palladium-containing compound, such as palladium(0) bis(dibenzylideneacetone) (also known as Pd(dba) 2 ), a phosphate ligand, such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (also known as Xantphos), a base, and in an aprotic solvent. The base may be selected from an organic base, such as a tertiary amine, for example triethyl amine, or an inorganic base, for example cesium carbonate. The aprotic solvent may be, for example, toluene. The reactions of the compounds of Formula (VI) with the compounds of Formula (VII) may be conducted at temperatures in the range from 25° C. to 200° C., for example such reactions may be conducted in toluene at a temperature of 100° C. The compounds of Formula (VII) are commercially available, or may be prepared by methods known to those having ordinary skill in the art, or by methods similar to those set forth herein.

Compounds of Formula (VI) may be prepared by methods known to those having ordinary skill in the art. For example, the compound of Formula (IV) (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one may be prepared according to the scheme set forth below. Other compounds of Formula (VI) may be prepared by methods known to those of skill in the art by modifications apparent to those skilled in the art, e.g. by using different starting materials, appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.

Similarly, (1R,2S)-2-(3-Iodo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one may be prepared by allowing (1R,2S)-2-(1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one to react with iodine in DMF and methanol in the presence of potassium carbonate as set forth below.

Compounds of Formula (IV) may be prepared from compounds of Formula (VI) by methods known to those having ordinary skill in the art. For example, tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate may be prepared from (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′-one as set forth below.

Compounds such as tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate may be allowed to react with compounds of Formula (V) as described herein, followed by deprotection of the Boc groups using an acid, such as trifluoroacetic acid, to provide compounds of Formula (I). For example, tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate may be allowed to react with 4-chloro-5-methoxypyrimidine to afford (1R,2S)-5′-methoxy-2-(3-((5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one.

In the following Preparations and Examples, “Ac” means acetyl, “ACN” and “MeCN” mean acetonitrile, “Me” means methyl, “Et” means ethyl, “Ph” means phenyl, “BOC”, “Boc” or “boc” means N-tert-butoxycarbonyl, “DCM” (CH 2 Cl 2 ) means methylene chloride, “DIPEA” or “DIEA” means diisopropyl ethyl amine, “DMA” means N,N-dimethylacetamide, “DMF” means N—N-dimethyl formamide, “DMSO” means dimethylsulfoxide, “DPPP” means 1,3-bis(diphenylphosphino)propane, “HOAc” means acetic acid, “IPA” means isopropyl alcohol, “min” means minute, “NMP” means 1-methyl 2-pyrrolidinone, “TEA” means triethyl amine, “TFA” means trifluoroacetic acid, “DCM” means dichloromethane, “EtOAc” and “EA” mean ethyl acetate, “MgSO 4 ” means magnesium sulphate, “Na 2 SO 4 ” means sodium sulphate, “MeOH” means methanol, “Et 2 O” means diethyl ether, “EtOH” means ethanol, “H 2 O” means water, “HCl” means hydrochloric acid, “K 2 CO 3 ” means potassium carbonate, “THF” means tetrahydrofuran, “DBU” means 1,8-diazabicyclo[5.4.0]undec-7-ene, “LiHMDS” or “LHMDS” means lithium hexamethyldisilazide, “TBME” or “MTBE” means tert-butyl methyl ether, “LDA” means lithium diisopropylamide, “N” means Normal, “M” means molar, “mL” means milliliter, “mmol” means millimoles, “μmol” means micromoles, “eq.” means equivalent, “C.” means degrees Celsius, “Pa” means pascals, “rt” or “RT” means room temperature, “h” means hours, “satd.” means saturated, “aq” means aqueous, “anhyd.” or “anh.” means anhydrous, “MBTE” means methyl tert-butyl ether, “PE” means petroleum ether, and “TBSCl” means tert-butyldimethylsily chloride.

›EXAMPLES

Intermediate 1. (1R,2S)-2-(3-Amino-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

›Step A. (E)-3-(3-Fluoro-4-isocyanobenzylidene)-5-methoxyindolin-2-one

A round bottom flask was charged with 5-methoxyoxindole (5.00 g, 30.6 mmol), 4-cyano-3-fluorobenzaldehyde (4.57 g, 30.6 mmol), piperidine (835 μL, 8.40 mmol) and ethanol (120 mL). The reaction was refluxed for 4 h and was stirred for 16 h at rt. The reaction was cooled to 0° C. and the resulting precipitate was collected by filtration and dried to give the title compound (5.10 g, 57%) as a dark red solid. m/z (ESI, +ve ion)=295.0 [M+H] + .

Step B. racemic-2-Fluoro-4-((1R,2S)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)benzonitrile

To a solution of trimethylsulfoxonium iodide (4.20 g, 19.1 mmol) in anhydrous DMF (173 mL) under nitrogen was added sodium hydride (60% dispersion in oil) (81.5 mg, 2.04 mmol) at 0° C. The mixture was stirred for 15 minutes after which (E)-3-(3-fluoro-4-isocyanobenzylidene)-5-methoxyindolin-2-one (5.10 g, 17.3 mmol) was added to the solution and the reaction was stirred for 1 h at rt. The solution was quench with satd. aq. ammonium chloride solution and extracted with EtOAc. The organic layer was then washed with brine, dried with anhyd. Na 2 SO 4 , filtered and concentrated under vacuum. The crude mixture was purified by column chromatography (10% to 65% EtOAc/heptanes, gradient elution), affording the title compound (1.50 g, 28%) as an orange solid. NOESY NMR experiment confirmed relative stereochemistry. m/z (ESI, +ve ion)=309.0 [M+H] + . 1H NMR (400 MHz, CDCl 3 ) δ 8.14 (s, 1H), 7.63-7.54 (m, 1H), 7.13-7.08 (m, 2H), 6.85 (d, J=8.5 Hz, 1H), 6.67 (dd, J=8.5, 2.5 Hz, 1H), 5.55 (d, J=2.4 Hz, 1H), 3.55 (s, 3H), 3.29 (t, J=8.5 Hz, 1H), 2.26 (dd, J=9.0, 5.0 Hz, 1H), 1.94 (dd, J=8.0, 5.0 Hz, 1H). The corresponding diastereoisomer was found to be less polar and was first to elute in the given conditions. m/z (ESI, +ve ion)=309.0 [M+H] + . 1H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.52 (dd, J=7.8, 6.9 Hz, 1H), 7.21 (s, 1H), 7.19 (s, 1H), 6.78 (d, J=1.5 Hz, 2H), 6.54 (s, 1H), 3.81 (s, 3H), 3.07 (t, J=8.7 Hz, 1H), 2.34 (dd, J=8.5, 5.3 Hz, 1H), 2.12 (dd, J=8.9, 5.3 Hz, 1H).

›Step C. (1R,2S)-2-(3-Amino-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

In a 20 mL vial was dissolved 2-fluoro-4-((1R,2S)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)benzonitrile (20.0 mg, 64.9 μmol) in tert-amyl alcohol (10.0 mL) and hydrazine hydrate solution (50.0 μL, 1.58 mmol) was subsequently added. The reaction was reflux for 16 h. The reaction was cooled to it and silica was directly added to the mixture and concentrated. The product was purified by column chromatography (0 to 20% MeOH/DCM, gradient elution), affording the title compound (60.0 mg, 58%) as colorless oil. m/z (ESI, +ve ion)=321.1 [M+H] + .

Intermediate 2. (1R,2S)-2-(1H-Indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

›Step A. 1-Benzyl-5-methoxyindoline-2,3-dione

Benzyl bromide (9.65 mL, 79.7 mmol) was added to a mixture of 5-methoxyisatin (12.0 g, 66.4 mmol) and potassium carbonate (27.5 g, 199 mmol) in acetonitrile (250 mL). The mixture was stirred for 15 h at 80° C. then cooled to rt. The mixture was filtered and the filtrate concentrated. It was diluted with water (300 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine, then dried (Na 2 SO 4 ), filtered and concentrated. The resulting solid was triturated with heptane, filtered, and washed with heptane, affording the title compound (18.2 g, quantitative yield) as a solid. m/z (ESI, +ve ion)=268.1 [M+H] + . 1H NMR (400 MHz, CDCl 3 ) δ 7.38-7.27 (m, 5H), 7.15 (d, J=2.7 Hz, 1H), 7.02 (dd, J=8.6, 2.7 Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 4.90 (s, 2H), 3.77 (s, 3H).

›Step B. 1-Benzyl-5-methoxyindolin-2-one

Hydrazine monohydrate (8.64 mL, 107 mmol) was added to a mixture of 1-benzyl-5-methoxyindoline-2,3-dione (18.2 g, 68.1 mmol) in DMSO (44.1 mL). The mixture was stirred for 5 h at 140° C. then cooled to rt. The mixture was diluted with water (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with 1 M H 2 SO 4 , brine (twice), then dried (Na 2 SO 4 ), filtered and concentrated, affording the title compound (14.0 g, 81%) as a dark oil. m/z (ESI, +ve ion)=254.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.38-7.22 (m, 5H), 6.90-6.86 (m, 1H), 6.68 (dd, J=8.5, 2.6 Hz, 1H), 6.60 (d, J=8.5 Hz, 1H), 4.89 (s, 2H), 3.75 (s, 3H), 3.61 (s, 2H).

›Step C. 1-Benzyl-6-bromo-1H-indazole

Potassium tert-butoxide (20.5 g, 179 mmol) was added to a mixture of 6-bromo-1H-indazole (30.0 g, 152 mmol) in DMSO (149 mL). The mixture was stirred for 10 min then benzyl chloride (20.8 mL, 179 mmol) was slowly added at 0° C. The mixture was stirred at rt for 3 h then diluted with saturated aqueous NH 4 Cl (400 mL) and extracted with MTBE (3×200 mL). The combined organic layers were washed with brine twice, then dried (Na 2 SO 4 ), filtered and concentrated to give crude material as a mixture of 1-benzyl-6-bromo-1H-indazole and 2-benzyl-6-bromo-2H-indazole. Benzyl bromide (37.7 mL, 311 mmol) was added to a mixture of 1-benzyl-6-bromo-1H-indazole and 2-benzyl-6-bromo-2H-indazole (31 g, 108 mmol). The mixture was stirred neat at 150° C. After 6 h, benzyl bromide was removed by distillation under high vacuum (vacuum pump) at 130° C. The residue was triturated in heptanes, then filtered and washed with heptanes. The crude material was put on the high vacuum overnight, affording the tittle compound (20.6 g, 67%) as a solid. m/z (ESI, +ve ion)=287.0 [M+H] + .

›Step D. 1-Benzyl-6-vinyl-1H-indazole

A mixture of 1-benzyl-6-bromo-1H-indazole (6.33 g, 22.0 mmol) and potassium carbonate (9.14 g, 66.1 mmol) in previously degassed (nitrogen bubbled through) DME/water (3:1) (70.0 mL) was purged with nitrogen and nitrogen was further bubbled through the reaction mixture. Vinylboronic acid pinacol ester (4.82 mL, 27.6 mmol) was added, followed by dichlorobis(triphenylphosphine)palladium (II) (774 mg, 1.10 mmol) and the mixture was heated to 80° C. overnight. The mixture was diluted with heptanes and washed with water (3×) and brine. The organic phase was dried with Na 2 SO 4 , filtered and concentrated. The crude product was purified by column chromatography (0 to 10% EtOAc/hexanes, gradient elution) to afford the title compound 4D (3.80 g, 74%). m/z (ESI, +ve ion)=235.4 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=0.9 Hz, 1H), 7.73-7.64 (m, 1H), 7.36-7.23 (m, 5H), 7.23-7.16 (m, 2H), 6.80 (dd, J=17.6, 10.9 Hz, 1H), 5.80 (dd, J=17.5, 0.7 Hz, 1H), 5.60 (s, 2H), 5.30 (dd, J=10.9, 0.6 Hz, 1H).

›Step E. (S)-1-(1-Benzyl-1H-indazol-1-yl)ethane-1,2-diol

To a 500 mL flask was added AD-mix-alpha (83.7 g, 59.8 mmol) and t-BuOH/water (1:1) (598 mL) forming a clear biphasic mixture on stirring. The reaction mixture was cooled with an ice bath to 0° C. before adding 1-benzyl-6-vinyl-1H-indazole (14.0 g, 59.8 mmol). The resulting mixture was vigorously stirred at 0° C. and let warm to room temperature with the ice bath slowly warming up. The reaction mixture was stirred for 9 h. The reaction was quench by the portion-wise addition of 92 g of sodium sulfite. The reaction mixture was stirred overnight. The reaction mixture was diluted with brine and DCM and filtered through a pad of Celite. The filtrate was extracted with DCM (4×) and the combined organic layers were dried over MgSO 4 , filtered and concentrated. The crude product was recrystallized from toluene (80 mL) to afford the title compound (12.2 g, 76%) as a white solid. m/z (ESI, +ve ion)=269.2 [M+H] + . 99.1% ee.

›Step F. (S)-1-(1-Benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate

A solution of (S)-1-(1-Benzyl-1H-indazol-6-yl)ethane-1,2-diol (12.2 g, 45.5 mmol) and triethylamine (16.0 mL, 114 mmol) in DCM (227 mL) was cooled in an ice bath and treated by slow addition of methanesulfonyl chloride (7.77 mL, 100 mmol) over 15 minutes. The internal temperature increased to a maximum of 11° C. The resulting mixture was stirred at 0° C. After 6 h, LCMS showed 10% mono mesylated product. 0.400 mL of methanesulfonyl chloride and 0.600 mL of triethylamine were added. The mixture was stirred 1 h and upon completion, diluted with DCM (500 mL) and 1 M aqueous HCl (200 mL) at 0° C. The layers were separated and the organic layer was washed with saturated aqueous NaHCO 3 (2×200 mL), brine (200 mL), then dried (Na 2 SO 4 ), filtered and concentrated. The crude material was passed through a small pad of Celite eluting with a mixture of DCM/Et 2 O (1:1). Removal of the solvents gave a white solid. The solid was triturated in Et 2 O (40 mL) and the precipitate was collected by filtration, affording the title compound (17.5 g, 91%) as white crystalline solid. m/z (ESI, +ve ion)=425.0 [M+H] + . 1H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.41 (s, 1H), 7.35-7.27 (m, 3H), 7.18 (dd, J=17.3, 7.5 Hz, 3H), 5.89 (dd, J=8.6, 3.2 Hz, 1H), 5.66 (d, J=15.8 Hz, 1H), 5.60 (d, J=15.8 Hz, 1H), 4.53 (dd, J=11.9, 8.6 Hz, 1H), 4.40 (dd, J=11.9, 3.3 Hz, 1H), 3.05 (s, 3H), 2.75 (s, 3H).

Step G. (1R,2S)-1′-Benzyl-2-(1-benzyl-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

A solution of (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (2.03 g, 8.01 mmol) in dry THF (80 mL) under nitrogen was cooled in an ice bath. Sodium hydride (673 mg, 16.8 mmol) was added portion-wise and the mixture was stirred at 0° C. for 15 min. A solution of 1-benzyl-5-methoxyindolin-2-one (3.40 g, 8.01 mmol) in dry THF (50 mL) was added dropwise with an addition funnel. The reaction mixture was stirred for 3 h at 0° C. The reaction was quench with satd. NH 4 Cl solution, diluted with water, and extracted with EtOAc (3×). The organic layer was dried with anhyd. MgSO 4 and concentrated to a crude product. The crude product was triturated with 3:1 hexanes/EtOAc, affording the title compound (2.10 g, 54%) as an orange solid. m/z (ESI, +ve ion)=486.2 [M+H] + .

›Step H. (1R,2S)-2-(1H-Indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one · 1 of 2

To a round-bottom flask charged with a stir bar was added (1R,2S)-1′-Benzyl-2-(1-benzyl-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2-one (4.00 g, 8.24 mmol) in THF (118 mL). The solution was cooled to 0° C. and potassium tert-butoxide (23.0 mL, 165 mmol) was added portion wise over 20 min and then DMSO (10.7 mL) was added. Oxygen was bubbled through the solution at 0° C. for 1 h. The reaction was quenched with satd. aqueous NH 4 Cl at 0° C. and diluted with EtOAc (50 mL). The mixture was washed with satd. aqueous NH 4 Cl (1×) and extracted with EtOAc (2×). The organic phase was dried over Na 2 SO 4 , filtered, and concentrated under vacuum. The crude was triturated in Et 2 O and recrystallized from ethanol, affording the title compound (2.56 g, 56%). m/z (ESI, +ve ion)=306.4 [M+H] + .

Intermediate 3: (1R,2S)-2-(3-Bromo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

In a flask, (1R,2S)-2-(1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (4.49 g, 12.5 mmol) was dissolved in DMF (16.7 mL) and NBS (2.70 g 15.0 mmol) dissolved in DMF (8.33 mL) was added dropwise at 0° C. The reaction was stirred for 2 h at rt. The reaction was quenched with an aqueous solution of Na 2 S 2 O 3 and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated. The crude was purified by column chromatography (40 to 100% EtOAc/hexanes, gradient elution), affording the title compound (3.12 g, 65%). m/z (ESI, +ve ion)=384.0, 386.0 [M+H] + .

Intermediate 4: Tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate

4-Dimethylaminopyridine (79.8 mg, 640 μmol) was added to a solution of triethylamine (3.61 mL, 25.6 mmol), di-tert-butyl dicarbonate (4.0 mL, 17.3 mmol) and (1R,2S)-2-(3-bromo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (2.46 g, 6.40 mmol) in DCM (24 mL). The solution was stirred at room temperature for 16 h. LCMS showed incomplete conversion. Di-tert-butyl dicarbonate (0.75 mL, 3.2 mmol, 0.5 equiv.) was added and the reaction was stirred another hour. The crude product was purified by column chromatography (0 to 20% EtOAc/heptanes, gradient elution), affording the title compound (3.06 g, 82%) as a yellow foamy solid. m/z (ESI, +ve ion)=384.0, 386.0 [M+H−boc] + .

Intermediate 5: Tert-butyl 3-amino-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate

Step A. Tert-butyl 6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-3-((diphenylmethylene)amino)-1H-indazole-1-carboxylate

A microwave vial was charged with tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indol]-2-yl)-1H-indazole-1-carboxylate (1.00 g, 1.71 mmol), cesium carbonate (1.14 g, 3.42 mmol), Pd 2 (dba) 3 (157 mg, 171 μmol) and XantPhos (101 mg, 171 μmol). Dry dioxane (17.1 mL) followed by benzophenone imine (310 μL, 1.83 mmol) were added and nitrogen was bubbled through the reaction mixture for 5 min. The vial was scaled, and the reaction mixture was heated to 90° C. for 2 h in an oil bath. A satd. aqueous solution of NaHCO 3 was added and the reaction mixture was extracted with EtOAc (3×). The combined extracts were then washed with brine, dried with anhyd. Na 2 SO 4 , filtered and concentrated under vacuum. The crude product was purified by column chromatography (0 to 30% EtOAc/heptanes, gradient elution), affording the title compound (1.03 g, 88%) as yellow oil. m/z (ESI, +ve ion)=685.4 [M+H] + .

Step B. Tert-butyl 3-amino-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate

Hydroxylamine hydrochloride (101 mg, 1.46 mmol) and sodium acetate (120 mg, 1.46 mmol) were added to tert-butyl 6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-3-((diphenylmethylene)amino)-1H-indazole-1-carboxylate (1.00 g, 1.46 mmol) in dry MeOH (14.6 mL) at room temperature and the reaction was stirred for 16 h. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (0 to 60% EtOAc/heptanes, gradient elution), affording the title compound (640 mg, 84%) as yellow solid. m/z (ESI, +ve ion)=521.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ8.06 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.66 (dd, J=8.9, 2.6 Hz, 1H), 5.55 (d, J=2.3 Hz, 1H), 4.44 (s, 2H), 3.49 (t, J=8.6 Hz, 1H), 3.37 (s, 3H), 2.34 (dd, J=9.2, 4.8 Hz, 1H), 2.14-2.06 (m, 1H), 1.67 (d, J=2.4 Hz, 18H).

Example 1. racemic-5′-Methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

In a 4 mL vial was dissolved (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2-one (54.0 mg, 169 μmol) and 4-chloro-5-methoxypyrimidine (29.8 mg, 202 μmol) in acetic acid/water (1:1) (1.00 mL). The reaction was heated to 100° C. for 1 h. The reaction mixture was poured into 5 mL of a solution of aq. NaOH 2 M. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhyd. sodium sulfate and concentrated. The product was purified by column chromatography (0 to 10% MeOH/DCM, gradient elution), affording Example 1 (22.9 mg, 32%) as white solid after lyophilization. m/z (ESI, +ve ion)=429.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 10.42 (s, 1H), 9.12 (s, 1H), 8.04 (d, J=3.0 Hz, 2H), 7.40 (d, J=7.9 Hz, 2H), 6.89 (d, J=9.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.5, 2.6 Hz, 1H), 5.72 (d, J=2.5 Hz, 1H), 3.94 (s, 3H), 3.33 (s, 3H under water peak), 3.18 (t, J=8.5 Hz, 1H), 2.33 (dd, J=7.8, 4.7 Hz, 1H), 1.98 (dd, J=9.0, 4.7 Hz, 1H).

Example 2. racemic-5′-Methoxy-2-{3-[(5-methylpyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Example 2 was prepared using the procedure described in Example 1 from (1R,2S)-2-(3-amino-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (60.0 mg, 187 μmol) and 4-chloro-5-methylpyrimidine (27 mg, 206 μmol). The product was purified by column chromatography (0 to 10% MeOH/DCM, gradient elution), concentrated, and then lyophilized from MeCN and water to afford Example 2 (7.7 mg, 10%) as white solid. m/z (ESI, +ve ion)=413.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.69 (s, 1H), 10.43 (s, 1H), 9.02 (s, 1H), 8.24 (s, 1H), 8.13 (s, 1H), 7.41 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 6.89 (dd, J=8.5, 1.0 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.5, 2.6 Hz, 1H), 5.71 (d, J=2.6 Hz, 1H), 3.33 (s, 3H, under water peak), 3.18 (t, J=8.4 Hz, 1H), 2.33 (dd, J=7.9, 4.7 Hz, 1H), 2.21 (s, 3H), 1.98 (dd, J=9.0, 4.7 Hz, 1H).

›Step H. (1R,2S)-2-(1H-Indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one · 2 of 2

Example 3. racemic-2-{3-[(5-Chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Example 3 was prepared using the procedure described in Example 1 from (1R,2S)-2-(3-Amino-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (60.0 mg, 187 μmol) and 4,5-dichloropyrimidine (31.3 mg, 206 μmol). The product was purified by C18 column chromatography (5 to 40% MeCN/aq. ammonium formate buffer, gradient elution), affording Example 3 (4.8 mg, 6%) as white solid after lyophilization. m/z (ESI, +ve ion)=433.1 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 10.43 (s, 1H), 9.58 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.44 (s, 1H), 7.37 (d, J=8.3 Hz, 1H), 6.95-6.87 (m, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.5, 2.6 Hz, 1H), 5.70 (d, J=2.5 Hz, 1H), 3.33 (s, 3H), 3.19 (t, J=8.4 Hz, 1H), 2.34 (dd, J=8.0, 4.7 Hz, 1H), 1.98 (dd, J=9.0, 4.6 Hz, 1H).

Example 4. (1R,2S)-5′-Methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

This compound was prepared using the procedure described in Example 1, from tert-butyl 3-amino-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (108 mg, 207 μmol) and 4-chloro-5-methoxypyrimidine (36.7 mg, 249 μmol). The Boc groups are cleaved in situ during the reaction conditions. The product was purified by C18 column chromatography (10% to 30% MeCN/aq. ammonium formate buffer, gradient elution), affording Example 4 (9.6 mg, 11%) as white solid after lyophilization. m/z (ESI, +ve ion)=429.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 10.43 (s, 1H), 9.12 (s, 1H), 8.04 (d, J=3.1 Hz, 2H), 7.44-7.35 (m, 2H), 6.89 (d, J=9.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.5, 2.6 Hz, 1H), 5.72 (d, J=2.5 Hz, 1H), 3.94 (s, 3H), 3.33 (s, 3H under water peak), 3.18 (t, J=8.6 Hz, 1H), 2.33 (dd, J=7.9, 4.7 Hz, 1H), 1.98 (dd, J=9.0, 4.6 Hz, 1H).

Example 5. (1R,2S)-5′-Methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. (1R,2S)-2-(3-Iodo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one · 1 of 2

To an oven-dried flask was added (1R,2S)-2-(1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (4.00 g, 13.1 mmol) followed by DMF (8 mL and Methanol (8 mL. To this suspension was added K 2 CO 3 (3.62 g, 26.2 mmol). Finally, molecular iodine (4.32 g, 17.0 mmol) dissolved in DMF (8 mL) and was added dropwise and allowed to stir at rt. After 4 h, the reaction was complete. The mixture was quenched with Na 2 S 2 O 3 in water and stirred for 2 h. Solid was collected by filtration and washed with water. Wet solid was frozen and lyophilized, affording the title compound (4.4 g, 78% yield.

Step B. Tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To an oven-dried flask was added 4-dimethylaminopyridine (9.0 mg, 0.07 mmol) followed by (1R,2S)-2-(3-iodo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one (637 mg, 1.48 mmol), N-ethyl-N-isopropyl-propan-2-amine (1.0 mL, 5.9 mmol) and MeCN (5.0 mL). The mixture was stirred at room temperature and di-tert-butyl dicarbonate (967 mg, 4.43 mmol) was added, resulted in light yellow homogeneous solution. After 2 h, the reaction mixture was concentrated and the resulting residue was purified by column chromatography (0% to 25%, EtOAc/hexanes, gradient elution) to afford the product as a white foam (5B) (822 mg, 88%).

Step C. Tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-ethoxypyrimidin-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To a 50 ml round bottom flask were added cesium carbonate (41.3 mg, 0.130 mmol), 5-ethoxypyrimidin-4-amine (9.3 mg, 0.070 mmol), Pd 2 (dba) 3 (5.8 mg, 0.010 mmol), tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (40.0 mg, 0.0600 mmol), XantPhos (3.7 mg, 0.010 mmol) and dry toluene (4.2 mL). The reaction mixture was stirred and purged with argon (in balloon) for 10 min to form a green suspension, and then heated to 120° C., resulting in a yellow suspension. The reaction was monitored by LCMS and TLC until the full conversion of the starting materials (approx. 70 min), cooled down to rt, diluted with EtOAc, washed with sat. aq. NaHCO 3 and dried over Na 2 SO 4 . The residue was purified by column chromatography (0% to 90% ethyl acetate/hexane, gradient elution) to provide the title compound (24.0 mg, 59%) as a yellow oil.

Step D. (1R,2S)-2-[3-[(5-ethoxypyrimidin-4-yl)amino]-1H-indazol-6-yl]-5′-methoxy-spiro[cyclopropane-1,3′-indoline]-2′-one

To a 50 ml round bottom flask containing tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-ethoxypyrimidin-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (24.0 mg, 0.0400 mmol) in DCM (1.9 mL) was added trifluoroacetic acid (0.15 mL, 1.9 mmol). The reaction mixture was stirred and monitored by LCMS until the full conversion of the starting materials (approx. 3 hrs), diluted with acetonitrile. The resulting brown solution was purified by Prep. HPLC (Gemini C18, 30 to 80% (0.1% TFA in water)/(0.1% TFA in Acetonitrile)) to provide the desired product Example 5 (12.4 mg, 75%) as a yellow film. m/z (ESI, +ve ion) 443.2 (M+H) + . 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 1.58 (t, J=6.94 Hz, 3H) 2.10-2.32 (m, 2H) 3.26-3.30 (m, 3H) 3.32-3.39 (m, 1H) 4.27-4.44 (m, 2H) 5.50-5.61 (m, 1H) 6.55-6.67 (m, 1H) 6.76-6.89 (m, 1H) 6.91-7.04 (m, 1H) 7.44-7.62 (m, 2H) 8.03-8.18 (m, 1H) 8.36-8.49 (m, 1H).

Example 6. (1R,2S)-2-{3-[(5-cyclopropylpyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. Tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-cyclopropylpyrimidin-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate

This compound was prepared using the procedure described in Example 5 from tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (40.0 mg, 0.0600 mmol) and 5-cyclopropylpyrimidin-4-amine (9.0 mg, 0.070 mmol). The residue was purified by column chromatography (ethyl acetate/hexane=0˜90%) to provide the title compound (17.0 mg, 42%) as a yellow oil.

Step B. (1R,2S)-2-[3-[(5-Cyclopropylpyrimidin-4-yl)amino]-1H-indazol-6-yl]-5′-methoxy-spiro[cyclopropane-1,3′-indoline]-2′-one

This compound was prepared using the procedure described in Example 5 from tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[(5-cyclopropylpyrimidin-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (17.0 mg, 0.0400 mmol) and trifluoroacetic acid (0.10 mL, 1.3 mmol). The resulting brown solution was purified by Prep. HPLC (Gemini C18, 10 to 90% (0.1% TFA in water)/(0.1% TFA in Acetonitrile)) to provide the desired product Example 6 (6.2 mg, 53%) as a colorless film. m/z (ESI, +ve ion) 439.2 (M+H)+. 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 0.85-0.97 (m, 2H) 1.16-1.31 (m, 2H) 1.87-2.04 (m, 1H) 2.16-2.32 (m, 2H) 5.53-5.63 (m, 1H) 6.58-6.69 (m, 1H) 6.79-6.90 (m, 1H) 6.96-7.06 (m, 1H) 7.48-7.63 (m, 2H) 8.15-8.30 (m, 1H) 8.52-8.63 (m, 1H).

Example 7. (1R,2S)-2-{3-[(5-Chloropyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. Tert-butyl 6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-3-((5-chloropyrimidin-4-yl)amino)-1H-indazole-1-carboxylate

This compound was prepared using the procedure described in Example 5 from tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (110 mg, 188 μmol) and 4-amino-5-chloropyrimidine (29.3 mg, 215 μmol). The product was purified by column chromatography (20 to 100% EtOAc/heptanes, gradient elution), affording the title compound (18.0 mg, 15%). m/z (ESI, +ve ion)=633.3 [M+H] + .

Step B. (1R,2S)-2-(3-((5-Chloropyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

›Step A. (1R,2S)-2-(3-Iodo-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one · 2 of 2

This compound was prepared using the procedure described in Example 5 from tert-butyl 6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indol]-2-yl)-3-((5-chloropyrimidin-4-yl)amino)-1H-indazole-1-carboxylate (18 mg, 28.4 μmol). The product was purified by C18 column chromatography (10 to 40% MeCN in aq. ammonium formate buffer), affording Example 7 (3.0 mg, 24%) as white solid after lyophilization. m/z (ESI, +ve ion)=433.1 [M+H] + . 1H NMR (400 MHz, DMSO) δ12.85 (s, 1H), 10.43 (s, 1H), 9.58 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 7.44 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.4, 2.4 Hz, 1H), 5.70 (d, J=2.3 Hz, 1H), 3.33 under water (s, 3H), 3.19 (t, J=8.4 Hz, 1H), 2.34 (dd, J=7.9, 4.6 Hz, 1H), 1.98 (dd, J=9.0, 4.6 Hz, 1H).

Example 8. (1S,2R)-5′-Methoxy-2-{3-[(5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. (1S,2R)-5′-methoxy-2-(3-((5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (8A)

A vial containing Example 1 (17.0 mg, 39.7 μmol) was submitted to chiral HPLC separation. Separation conditions are: Column: AS-H, 10×250 mm 5 um. Mode: Isocratic, Mobile phase: 60% MeOH-0.1% ammonium hydroxide, 40% supercritical CO 2 , Flow rate: 10 mL/min, Back pressure: 120 bar, Column Temperature: 40° C., Run time (min): 16). The second peak to elute corresponds to title product while the first peak is the corresponding enantiomer (1R,2S). The solution is concentrated and lyophilized from MeCN and water, affording the title compound (15a) (6.7 mg, 39%) as white solid. m/z (ESI, +ve ion)=429.3 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 10.41 (s, 1H), 9.10 (s, 1H), 8.04 (d, J=2.1 Hz, 2H), 7.42-7.37 (m, 2H), 6.89 (d, J=9.5 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.5, 2.6 Hz, 1H), 5.72 (d, J=2.5 Hz, 1H), 3.94 (s, 3H), 3.18 (t, J=8.5 Hz, 1H), 2.32 (dd, J=7.9, 4.6 Hz, 1H), 1.98 (dd, J=9.0, 4.7 Hz, 1H).

Example 9. (1R,2S)-2-(3-{[5-Chloro-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 5-Chloro-6-morpholinopyrimidin-4-amine (9A)

A reaction vial was charged with 4-amino-5,6-dichloropyrimidine (300 mg, 1.83 mmol) and morpholine (145 μL, 1.65 mmol) in DMSO (3.66 mL). The reaction mixture was heated to 60° C. for 16 h. The reaction mixture was partially concentrated and directly purified by column chromatography (40% to 100% EtOAc/heptanes, gradient elution), affording the title compound (9A) (318 mg, 81%) as white crystals. m/z (ESI, +ve ion)=215.0 [M+H] + .

Step B. tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((5-chloro-6-morpholinopyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate

›Step C

In a flask, tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((5-chloro-6-morpholinopyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (49.5 mg, 60.7 μmol) was dissolved in DCM (4.40 mL) and trifluoroacetic acid (440 μL, 5.69 mmol) was added. The reaction was stirred at rt for 5 h and then concentrated to dryness. The crude residue was directly purified by C18 column chromatography (10 to 40% MeCN/aq. ammonium formate buffer, gradient elution). The desired fractions were combined and lyophilized, affording Example 9 (12.3 mg, 39%) as white solid. m/z (ESI, +ve ion)=518.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.72 (s, 1H), 10.43 (s, 1H), 9.16 (s, 1H), 7.98 (s, 1H), 7.41 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 6.94-6.83 (m, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.5, 2.5 Hz, 1H), 5.71 (d, J=2.6 Hz, 1H), 3.74-3.67 (m, 4H), 3.51-3.44 (m, 4H), 3.33 (with water peak) (s, 3H), 3.18 (t, J=8.4 Hz, 1H), 2.33 (dd, J=8.0, 4.8 Hz, 1H), 1.98 (dd, J=9.0, 4.7 Hz, 1H).

Example 10. (1R,2S)-2-{3-[(2-Chloro-5-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

A microwave vial was charged with tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (75.0 mg, 128 μmol), 2-chloro-5-methoxypyrimidin-4-amine (22.6 mg, 137 μmol), cesium carbonate (85.3 mg, 257 μmol). Pd 2 (dba) 3 (11.8 mg, 12.8 μmol) and XantPhos (7.6 mg, 12.8 μmol) and was purged with nitrogen. Previously degassed toluene (2.6 mL) was added, and nitrogen was bubbled through the reaction mixture for 2 min. The vial was scaled, and the reaction mixture was heated to 100° C. for 2 h in an oil bath. The reaction mixture was then filtered on a pad of Celite using EtOAc and the crude product was concentrated. The residue was dissolved in DCM (5.00 mL) and trifluoroacetic acid (1.00 mL, 13.0 mmol) was added. The reaction was stirred at rt for 1.5 h. A saturated aqueous solution of sodium bicarbonate was slowly added, and the reaction mixture was transferred to an extraction funnel. The layers were separated, and the aqueous layer was extracted with DCM (3×10 mL). The organic layer was dried with anhyd. Na 2 SO 4 , filtered and concentrated under vacuum. The product was purified by C18 column chromatography (10% to 40% MeCN/aq. ammonium formate buffer, gradient elution). The desired fractions were combined and lyophilized, affording Example 10 (4.8 mg, 8.0%) as white solid. m/z (ESI, +ve ion)=463.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 10.43 (s, 1H), 9.61 (br s, 1H), 7.94 (s, 1H), 7.46-7.40 (m, 2H), 6.97-6.91 (m, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.57 (dd, J=8.5, 2.6 Hz, 1H), 5.70 (d, J=2.5 Hz, 1H), 3.94 (s, 3H), 3.30 (s, 3H), 3.19 (t, J=8.3 Hz, 1H), 2.33 (dd, J=7.9, 4.6 Hz, 1H), 1.98 (dd, J=9.1, 4.7 Hz, 1H).

Example 11. (1R,2S)-5′-Methoxy-2-(3-{[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

A microwave vial was charged with tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (75.0 mg, 128 μmol), 5-chloro-6-morpholinopyrimidin-4-amine (29.7 mg, 141 μmol), cesium carbonate (85.3 mg, 257 μmol), Pd 2 (dba) 3 (11.8 mg, 12.8 μmol) and XantPhos (7.6 mg, 12.8 μmol) and was purged with nitrogen. Previously degassed toluene (2.57 mL) was added and nitrogen was bubbled through the reaction mixture for 2 min. The vial was sealed and the reaction mixture was heated to 100° C. for 2 h in an oil bath. The reaction mixture was filtered on a pad of Celite using EtOAc and the crude product was concentrated. The residue was then dissolved in DCM (5.00 mL) and trifluoroacetic acid (1.00 mL, 13.0 mmol) was added. The reaction was stirred at rt for 1.5 h. A saturated aqueous solution of sodium bicarbonate was slowly added and the reaction mixture was transferred to an extraction funnel. The layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The combined extracts were dried with anhyd. Na 2 SO 4 , filtered and concentrated under vacuum. The crude was purified by C18 column chromatography (10% to 40% MeCN/aq. ammonium formate buffer, gradient elution). The desired fractions were combined and lyophilized, affording Example 11 (23.2 mg, 35%) as white solid. m/z (ESI, +ve ion)=514.3 [M+H]+. 1H NMR (400 MHz, DMSO) δ 12.58 (s, 1H), 10.42 (s, 1H), 8.88 (s, 1H), 7.80 (s, 1H), 7.47-7.32 (m, 2H), 6.87 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.4, 2.3 Hz, 1H), 5.72 (d, J=2.2 Hz, 1H), 379-3.68 (m, 4H), 3.67 (s, 3H), 3.62-3.53 (m, 4H), 3.33 (s, 3H), 3.18 (t, J=8.4 Hz, 1H), 2.32 (dd, J=7.7, 4.7 Hz, 1H), 1.98 (dd, J=8.9, 4.6 Hz, 1H).

Example 12. (1R,2S)-5′-Methoxy-2-(3-{[5-methoxy-6-(piperidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 5-Methoxy-6-(piperidin-1-yl)pyrimidin-4-amine (12A) · 1 of 2

A reaction vial was charged with 4-amino-6-chloro-5-methoxypyrimidine (100 mg, 595 μmol) and piperidine (120 μL, 1.19 mmol) in toluene (1.2 mL). The reaction mixture was heated to 105° C. for 16 h. The solution was then concentrated to dryness. The product was purified by column chromatography (50% to 100% EtOAc/heptanes, gradient elution), affording the title compound (87.8 mg, 71%) as white crystals. m/z (ESI, +ve ion)=209.0 [M+H] + .

Step B. (1R,2S)-5′-methoxy-2-(3-((5-methoxy-6-(piperidin-1-yl)pyrimidin-4-yl)amino)-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one

A microwave vial was charged with tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (75.0 mg, 128 μmol), 5-methoxy-6-(piperidin-1-yl)pyrimidin-4-amine (29.4 mg, 141 μmol), cesium carbonate (85.3 mg, 257 μmol), Pd 2 (dba) 3 (11.8 mg, 12.8 μmol) and XantPhos (7.6 mg, 12.8 μmol) and was purged with nitrogen. Previously degassed toluene (2.57 mL) was added and nitrogen was bubbled through the reaction mixture for 2 min. The vial was sealed and the reaction mixture was heated to 100° C. for 2 h in an oil bath. The reaction mixture was filtered on a pad of Celite using EtOAc and the crude product was concentrated. The residue was dissolved in DCM (5.00 mL) and trifluoroacetic acid (1.00 mL, 13.0 mmol) was added. The reaction was stirred at rt for 1.5 h. A satd. aq. solution of bicarbonate was added and the reaction mixture was transferred to an extraction funnel. The layers were separated, and the aqueous layer was extracted with DCM (3×10 mL). The combined organic extracts were dried with anhyd. Na 2 SO 4 , filtered and concentrated under vacuum. The product was purified by C18 column chromatography (20 to 40% MeCN in aq. ammonium formate buffer). The desired fractions were combined and lyophilized, affording the title compound (23.2 mg, 35%) as white solid. m/z (ESI, +ve ion)=512.3 [M+H]+. 1H NMR (400 MHz, DMSO) δ 12.53 (s, 1H), 10.41 (s, 1H), 8.76 (, 1Hs), 7.76 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.4, 2.4 Hz, 1H), 5.72 (d, J=2.3 Hz, 1H), 3.65 (s, 3H), 3.62-3.53 (m, 4H), 3.33 (s, 3H under water peak), 3.17 (t, J=8.5 Hz, 1H), 2.31 (dd, J=7.8, 4.7 Hz, 1H), 1.97 (dd, J=8.9, 4.6 Hz, 1H), 1.67-1.54 (m, 6H).

Example 13. (1R,2S)-5′-methoxy-2-{3-[(3-methoxypyrazin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

This compound was prepared using the procedure described in Example 5, from tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (50.0 mg, 85.5 μmol) and 3-methoxypyrazine-2-amine (18.6 mg, 145 μmol). The product was purified by C18 column chromatography (0 to 50% MeCN in water), affording the title compound (13) (9.3 mg, 20%) as yellow solid after lyophilization. m/z (ESI, +ve ion)=429.4 [M+H]+. 1H NMR (500 MHz, DMSO) δ 12.56 (s, 1H), 10.40 (s, 1H), 8.80 (s, 1H), 7.48 (d, J=3.0 Hz, 1H), 7.46 (d, J=3.0 Hz, 1H), 7.42-7.37 (m, 2H), 6.87 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.4, 2.6 Hz, 1H), 5.72 (d, J=2.5 Hz, 1H), 3.98 (s, 3H), 3.33 (s, J=0.9 Hz, 3H), 3.17 (t, J=8.5 Hz, 1H), 2.31 (dd, J=7.9, 4.7 Hz, 1H), 1.98 (dd, J=9.0, 4.7 Hz, 1H).

Example 14. (1R,2S)-5′-methoxy-2-{3-[(6-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

This compound was prepared according to the procedure described in Example 5, from tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (50.0 mg, 85.5 μmol) and 6-methoxypyrimidine-4-amine (16.4 mg, 128 μmol). The product was purified by C18 column chromatography (0 to 50% MeCN in aq. ammonium formate buffer), affording the title compound (19.6 mg, 43%) as white solid after lyophilization. m/z (ESI, +ve ion)=429.3 [M+H]+. 1H NMR (500 MHz, DMSO) δ12.43 (s, 1H), 10.41 (s, 1H), 10.17 (s, 1H), 8.38 (d, J=0.9 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.20 (s, 1H), 6.91 (dd, J=8.5, 1.0 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.5, 2.6 Hz, 1H), 5.68 (d, J=2.6 Hz, 1H), 3.87 (s, 3H), 3.31 (s, 3H), 3.17 (t, J=8.4 Hz, 1H), 2.32 (dd, J=7.9, 4.7 Hz, 1H), 1.97 (dd, J=9.0, 4.7 Hz, 1H).

Example 15. (1R,2S)-2-{3-[(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[5H,6H,7H-cyclopenta[d]pyrimidin-4-ylamino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (240.00 mg, 0.380 mmol, 1.00 equiv) and 5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (61.65 mg, 0.456 mmol, 1.2 equiv) in dry toluene (20.00 mL) were added Cs 2 CO 3 (247.67 mg, 0.760 mmol, 2.00 equiv), Pd 2 (dba) 3 (34.80 mg, 0.038 mmol, 0.10 equiv) and XantPhos (21.99 mg, 0.038 mmol, 0.10 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h. The solvent was filtered and washed with EtOAc (10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in PE to give the title compound (80 mg, 31.31%) as light yellow oil. m/z (ESI, +ve ion)=639.35 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.12 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.72-6.69 (m, 1H), 5.62 (d, J=2.8 Hz, 1H), 4.17-4.12 (m, 1H), 3.53 (t, J=8.4 Hz, 1H), 3.42 (s, 3H), 3.12 (t, J=8.0 Hz, 2H), 2.94 (t, =7.6 Hz, 2H), 2.41-2.37 (m, 1H), 2.28-2.21 (m, 2H), 2.13-2.10 (m, 1H), 1.70 (s, 18H).

Step B. (1R,2S)-2-(3-[5H,6H,7H-cyclopenta[d]pyrimidin-4-ylamino]-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

To a mixture of the compound from Step A (60.00 mg, 0.094 mmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (0.20 mL). The mixture was stirred at 25° C. for 12 h, then diluted with DCM (20 mL) and washed with saturated NaHCO 3 (20 mL). The aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue (two batches combined, total 0.125 mmol) was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min: Gradient: 13% B to 40% B in 8 min; 254/220 nm; RT1: 7.35 min to give Example 15 (30 mg, 72.10%) as a white solid. m/z (ESI+ve ion)=439.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.65 (s, 1H), 10.42 (s, 1H), 9.22 (s, 1H), 8.24 (s, 1H), 7.43-7.41 (m, 2H), 6.92-6.89 (m, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.60-6.58 (m, 1H), 5.72 (d, J=2.4 Hz, 1H), 3.35 (s, 3H), 3.19 (t, J=8.4 Hz, 1H), 2.80 (t, J=7.6 Hz, 2H), 2.73-2.68 (m, 2H), 2.35-2.32 (m, 1H), 2.04-1.96 (m, 3H).

›Step A. 5-Methoxy-6-(piperidin-1-yl)pyrimidin-4-amine (12A) · 2 of 2

Example 16. (1R,2S)-2-{3-[(2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-(2,3-dihydro-1-benzofuran-7-ylamino)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (200.00 mg, 0.317 mmol, 1.00 equiv) and 2,3-dihydro-1-benzofuran-7-amine (51.37 mg, 0.380 mmol, 1.20 equiv) in dry toluene (5.0 mL) were added Cs 2 CO 3 (206.39 mg, 0.634 mmol, 2.00 equiv), Pd 2 (dba) 3 (29.00 mg, 0.032 mmol, 0.10 equiv) and XantPhos (18.33 mg, 0.032 mmol, 0.10 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h. The solvent was removed under reduced pressure. The residue was purified by prep-TLC (rinsed with PE/EA=2/1) to give the title compound (200 mg, 97.88%) as yellow oil. m/z (ESI+ve ion)=639.20 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.16 (d, J=8.0 Hz, 1H), 7.82-7.80 (m, 1H), 7.56-7.52 (m, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.96-6.88 (m, 2H), 6.70-6.66 (m, 2H), 5.57 (d, J=2.8 Hz, 1H), 4.69-4.65 (m, 2H), 3.56-3.50 (m, 1H), 3.38 (s, 3H), 3.31 (t, J=8.4 Hz, 2H), 2.39-2.36 (m, 1H), 2.14-2.10 (m, 1H), 1.71 (d, J=5.6 Hz, 18H).

Step B. (1R,2S)-2-[3-(2,3-dihydro-1-benzofuran-7-ylamino)-1H-indazol-6-yl]-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

To the mixture of the compound from Step A (215 mg, 0.336 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at 25° C. for 12 h, then diluted with DCM (20 mL) and washed with saturated NaHCO 3 (20 mL) and brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 19×250 mm, 10 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1% NH 3 ·H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 42% B to 52% B in 8 min; 254 nm; RT1: 7.15 min to give Example 2 (80 mg, 54%) as a white solid. m/z (ESI +ve ion)=439.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 10.41 (s, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.82 (t, J=4.4 Hz, 1H), 7.28 (s, 1H), 6.86-6.83 (m, 1H), 6.76-6.74 (m, 3H), 6.60-6.57 (m, 1H), 5.71 (d, J=2.4 Hz, 1H), 4.60 (t, J=8.8 Hz, 2H), 3.33 (s, 3H), 3.33-3.15 (m, 3H), 2.33-2.30 (m, 1H), 1.99-1.97 (m, 1H).

Example 17. (1R,2S)-5′-methoxy-2-{3-[(3-methoxypyridin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

This compound was prepared using the procedure described in Example 5, from tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (75.0 mg, 128 μmol) and 3-methoxypyridin-2-amine (17.9 mg, 141 μmol). The product was purified by C18 column chromatography (10 to 30% MeCN in aq. ammonium formate buffer), affording the title compound (16.1 mg, 29%) as white solid after lyophilization. m/z (ESI, +ve ion)=428.3 [M+H]+. 1H NMR (400 MHz, DMSO) δ 12.42 (s, 1H), 10.42 (s, 1H), 8.16 (s, 1H), 7.51 (dd, J=5.0, 1.3 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.19 (dd, J=7.9, 1.3 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 6.76-6.66 (m, 2H), 6.58 (dd, J=8.5, 2.6 Hz, 1H), 5.74 (d, J=2.6 Hz, 1H), 3.87 (s, 3H), 3.30 (s, 3H, peak under water), 3.17 (t, J=8.4 Hz, 1H), 2.35-2.29 (m, 1H), 1.97 (dd, J=9.0, 4.6 Hz, 1H).

Example 18. (1R,2S)-5′-methoxy-2-{3-[(4-methoxypyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

This compound was prepared using the procedure described in Example 5, from tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (75.0 mg, 128 μmol) and 4-methoxypyridin-3-amine (18.4 mg, 141 μmol). The product was purified by C18 column chromatography (10 to 401% MeCN in aq. ammonium formate buffer), affording the title compound (9.5 mg, 17%) as white solid after lyophilization. m/z (ESI, +ve ion)=428.2 [M+H]+. 1H NMR (400 MHz, DMSO) δ 12.13 (s, 1H), 10.43 (s, 1H), 9.18 (s, 1H), 8.02 (d, J=5.3 Hz, 1H), 7.90-7.81 (m, 21H), 7.31 (s, 1H), 7.03 (d, J=5.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 11H), 6.74 (d, J=8.4 Hz, 11H), 6.58 (dd, J=8.4, 2.5 Hz, 1H), 5.70 (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 3.32 (s, 3H), 3.17 (t, J=8.5 Hz, 1H), 2.32 (dd, J=7.8, 4.8 Hz, 1H), 1.97 (dd, J=9.0, 4.7 Hz, 1H).

Example 19. (1R,2S)-5′-methoxy-2-{3-[(3-methoxypyridin-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

This compound was prepared according to the procedure described in Example 5, from tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (50.0 mg, 85.5 μmol) and 3-methoxypyridin-4-amine (16.1 mg, 126 μmol). The product was purified by C18 column chromatography (0 to 30% MeCN in water), affording the title compound (6.5 mg, 14%) as white solid after lyophilization. m/z (ESI, +ve ion)=428.3 [M+H]+. 1H NMR (500 MHz, DMSO) δ 12.95 (s, 1H), 10.43 (s, 1H), 9.97 (s, 1H), 8.28 (s, 1H), 8.20 (d, J=6.6 Hz, 1H), 7.82 (d, J=6.6 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.59 (dd, J=8.5, 2.6 Hz, 1H), 5.70 (d, J=2.6 Hz, 1H), 4.07 (s, 3H), 3.20 (t, J=8.4 Hz, 1H), 2.35 (dd, J=8.0, 4.9 Hz, 1H), 2.00 (dd, J=9.1, 4.7 Hz, 1H).

Example 20. (1R,2S)-2-(3-{[5-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 4,5-dichloro-6-(4-methylpiperazin-1-yl)pyrimidine

1-Methylpiperazine (200 μL, 1.77 mmol) was added to a mixture of 4,5,6-trichloropyrimidine (336 mg, 1.77 mmol) and N,N-diisopropylethylamine (930 μL, 5.32 mmol) in NMP (7.0 mL). The reaction was stirred at 80° C. for 15 h. EtOAc and water were added and the reaction mixture was transferred to an extraction funnel. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were then washed with brine, dried with anh. Na 2 SO 4 , filtered and concentrated under vacuum. The product was purified by column chromatography (0 to 5% MeOH in DCM), affording the title compound (312 mg, 71%) as red oil. m/z (ESI, +ve ion)=247.0 [M+H]+.

Step B. (1R,2S)-2-(3-((5-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

A microwave vial was charged with tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (75.0 mg, 144 μmol), 4,5-dichloro-6-(4-methylpiperazin-1-yl)pyrimidine (39.2 mg, 158 μmol), cesium carbonate (95.8 mg, 288 μmol), Pd 2 (dba) 3 (13.2 mg, 14.4 μmol) and XantPhos (8.5 mg, 14.4 μmol) and was purged with nitrogen. Previously degassed toluene (3.0 mL) was added and nitrogen was bubbled through the reaction mixture for 2 min. The vial was sealed and the reaction mixture was heated to 100° C. for 1.5 h in an oil bath. The reaction mixture was filtered on a pad of Celite using EtOAc and the crude product was concentrated. The residue was dissolved in DCM (5.00 mL) and trifluoroacetic acid (1.00 mL, 13.0 mmol) was added. The reaction was stirred at rt for 1.5 h. A satd. aqueous solution of sodium bicarbonate was added and the reaction mixture was transferred to an extraction funnel. The layers were separated and the aqueous layer was extracted with DCM (3×10 mL). The combined extracts were dried with anhyd. Na 2 SO 4 , filtered and concentrated under vacuum. The product was purified by C18 column chromatography (5 to 30% MeCN in aq. ammonium formate buffer). The desired fraction were combined and lyophilized, affording the title compound (37.1 mg, 55%) as yellow solid identified as a formate salt. m/z (ESI, +ve ion)=531.3 [M+H]+. 1H NMR (400 MHz, DMSO) δ 12.71 (s, 1H), 10.43 (s, 1H), 9.11 (s, 1H), 7.95 (s, 1H), 7.41 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.4, 2.2 Hz, 1H), 5.71 (d, J=2.0 Hz, 1H), 3.54-3.45 (m, 4H), 3.33 (s, 3H under water), 3.18 (t, J=8.4 Hz, 1H), 2.47-2.39 (m, 4H), 2.33 (dd, J=7.5, 4.9 Hz, 1H), 2.22 (s, 3H), 1.98 (dd, J=8.9, 4.6 Hz, 1H).

Example 21. (1R,2S)-5′-methoxy-2-{3-[(1,3,5-trimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

This compound was prepared according to the procedure described in Example 5, from tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (50.0 mg, 85.5 μmol) and 1,3,5-trimethyl-1H-pyrazol-4-amine (7.3 mg, 58.2 μmol). The product was purified by C18 column chromatography (0 to 30% MeCN in aq. ammonium formate buffer), affording the title compound (8.2 mg, 33%) as white solid after lyophilization. m/z (ESI, +ve ion)=429.1 [M+H]+. 1H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 10.39 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 6.75 (s, 1H), 6.73 (s, 1H), 6.58 (dd, J=8.5, 2.6 Hz, 1H), 5.67 (d, J=2.6 Hz, 1H), 3.64 (s, 3H), 3.12 (t, J=8.5 Hz, 1H), 2.25 (dd, J=7.9, 4.6 Hz, 1H), 2.06 (d, J=5.9 Hz, 3H), 1.98-1.89 (m, 4H).

Example 22. (1R,2S)-5′-methoxy-2-(3-{[5-(trifluoromethyl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

This compound was prepared according to the procedure described in Example 1, from tert-butyl 3-amino-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indol]-2-yl)-1H-indazole-1-carboxylate (30.9 mg, 59.4 μmol) and 4-chloro-5-(trifluoromethyl)pyrimidine (11.9 mg, 65.3 μmol). The product was purified by C18 column chromatography (15 to 40% MeCN in aq. ammonium formate buffer), affording the title compound (6.9 mg, 25%) as yellow solid after lyophilization. m/z (ESI, +ve ion)=467.1 [M+H]+. 1H NMR (500 MHz, DMSO) δ 12.89 (s, 1H), 10.42 (s, 1H), 8.68 (s, 1H), 8.54 (s, 1H), 7.46 (s, 1H), 7.32 (d, J=8.4 Hz, 1H), 6.92 (dd, J=8.4, 1.0 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.5, 2.6 Hz, 1H), 5.69 (d, J=2.6 Hz, 1H), 3.19 (t, J=8.4 Hz, 1H), 2.33 (dd, J=8.0, 4.7 Hz, 1H), 1.99 (dd, J=9.0, 4.7 Hz, 1H). CH3O signal is in water peak.

Example 23. (1R,2S)-2-{3-[(5-chloro-2-methoxypyrimidin-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 5-chloro-2-methoxypyrimidin-4-amine

In a flask was dissolved 2,5-dichloropyrimidin-4-amine (300 mg, 1.74 mmol) in MeOH (8.7 mL) to which was added a sodium methoxide solution (30 wt. % in MeOH, 150 μL, 2.09 mmol) and the solution was heated at 70° C. for 2 h (reflux) and cooled back to rt. Some conversion was observed by LCMS but reaction was not complete. Another 0.5 equiv of sodium methoxide solution (60 μL, 869 μmol) was added and the reaction was stirred further at reflux for another 2 h, when it was then quenched with water and extracted with EtOAc. The organic layer was washed with water, dried (Na 2 SO 4 ) and concentrated. Crude white solid material (6a) was used such as in next step. m/z (ESI, +ve ion)=159.7 [M+H]+. 1H NMR (500 MHz, DMSO) δ 8.19 (s, 1H), 8.13-7.38 (m, 2H), 3.86 (s, 3H).

Step B. (1R,2S)-2-(3-((5-chloro-2-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

In a vial were added tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indol]-2-yl)-1H-indazole-1-carboxylate (50.0 mg, 85.5 μmol), cesium carbonate (70.4 mg, 216 μmol), Pd 2 (dba) 3 (9.8 mg, 10.7 μmol), XantPhos (6.31 mg, 10.9 μmol), 5-chloro-2-methoxypyrimidin-4-amine (41.0 mg, 128 μmol) and toluene (2.50 mL) and the vial degassed (nitrogen bubbled through solvent for 5 min), and sealed and stirred at 100° C. for 2 h in an oil bath. The reaction was then transferred to a flask and concentrated to dryness. The residue was dissolved in DCM (2.50 mL) and trifluoroacetic acid (1.7 mL) and stirred at rt for 1 h when it was subsequently concentrated to dryness. The product was purified by C18 column chromatography (15 to 40% MeCN in aq. ammonium formate buffer). The desired fraction were combined and lyophilized, affording the title compound (9.0 mg, 18%) as white solid. m/z (ESI, +ve ion)=463.1 [M+H]+. 1H NMR (500 MHz, DMSO) δ 12.81 (s, 1H), 10.41 (s, 1H), 9.57 (s, 1H), 8.23 (s, 1H), 7.44-7.40 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.5, 2.6 Hz, 1H), 5.65 (d, J=2.6 Hz, 1H), 3.48 (s, 3H), 3.19 (t, J=8.5 Hz, 1H), 2.32 (dd, J=8.0, 4.7 Hz, 1H), 1.98 (dd, J=9.0, 4.7 Hz, 1H); (Extra MeO signal unseparated from water peak).

Example 24. (1R,2S)-5′-methoxy-2-{3-[(2-methoxypyridin-3-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

This compound was prepared using the procedure described in Example 5, from tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (75.0 mg, 128 μmol) and 2-methoxypyridin-3-amine (18.6 mg, 145 μmol). The product was purified by C18 column chromatography (10 to 50% MeCN in aq. ammonium formate buffer), affording the title compound (28.0 mg, 51%) as white solid after lyophilization. m/z (ESI, +ve ion)=428.2 [M+H]+. 1H NMR (400 MHz, DMSO) δ 12.16 (s, 1H), 10.43 (s, 1H), 8.37 (dd, J=7.8, 1.4 Hz, 1H), 8.02 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.61 (dd, J=4.9, 1.4 Hz, 1H), 7.31 (s, 1H), 6.97-6.85 (m, 2H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (dd, J=8.4, 2.5 Hz, 1H), 5.70 (d, J=2.3 Hz, 1H), 3.98 (s, 3H), 3.32 (s, 3H), 3.17 (t, J=8.4 Hz, 1H), 2.32 (dd, J=7.7, 4.8 Hz, 1H), 1.97 (dd, J=8.9, 4.6 Hz, 1H).

Example 25. (1R,2S)-5′-methoxy-2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

This compound was prepared according to the procedure described in Example 5, from tert-butyl 3-bromo-6-((1R,2S)-1′-(tert-butoxycarbonyl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazole-1-carboxylate (50.0 mg, 85.5 μmol) and 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (15.4 mg, 94.1 μmol). The product was purified by C18 column chromatography (20 to 40% MeCN in aq. ammonium formate buffer), affording the title compound (7.4 mg, 20%) as white solid after lyophilization. m/z (ESI, +ve ion)=431.4 [M+H]+. 1H NMR (500 MHz, DMSO) δ 11.54 (s, 1H), 10.39 (s, 1H), 7.88 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 7.17 (s, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.57 (dd, J=8.5, 2.6 Hz, 1H), 5.68 (d, J=2.5 Hz, 1H), 3.84 (s, 3H), 3.66 (s, 3H), 3.33 (s, 3H), 3.14 (t, J=8.5 Hz, 1H), 2.27 (dd, J=8.0, 4.6 Hz, 1H), 1.95 (dd, J=9.0, 4.7 Hz, 1H).

Example 26. (1R,2S)-2-{3-[(1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 7-bromo-2,3-dihydro-1-benzofuran-3-ol

NaBH 4 (23.09 mg, 0.610 mmol, 1.3 equiv) was added to a mixture of 7-bromo-2H-1-benzofuran-3-one (100.00 mg, 0.469 mmol, 1.00 equiv) in MeOH (1.00 mL) at 0° C. The mixture was stirred at 0° C. for 1 h. The solvent was concentrated in vacuo. The residue was diluted with water (20 mL), extracted with EA (3×10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated in vacuo to give the title compound (100 mg, 97%) as a light yellow solid. The product showed no signal in LCMS. 1 H NMR (400 MHz, Chloroform-d) δ7.48-7.38 (m, 2H), 6.90-6.86 (m, 1H), 5.50-5.48 (m, 1H), 4.70-4.67 (m, 1H), 4.59-4.56 (m, 1H).

›Step B: [(7-bromo-2,3-dihydro-1-benzofuran-3-yl)oxy](tert-butyl)diphenylsilane · 1 of 2

To the mixture of 7-bromo-2,3-dihydro-1-benzofuran-3-ol (100.00 mg, 0.465 mmol, 1.00 equiv) and imidazole (63.31 mg, 0.930 mmol, 2 equiv) in DMF (1.00 mL) was added TBDPS-Cl (153.38 mg, 0.558 mmol, 1.2 equiv) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 3 h. The reaction was diluted with water (10 mL) and extracted with EA (3×10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column eluted with 0-10% EA in PE to give the title compound (150 mg, 70.43%) as a colorless oil. The product showed no signal in LCMS. 1 H NMR (400 MHz, Chloroform-d) δ 7.72-7.66 (m, 4H), 7.52-7.35 (m, 7H), 6.88 (d, J=7.6 Hz, 1H), 6.70 (t, J=8.0 Hz, 1H), 5.54-5.52 (m, 1H), 4.52-4.48 (m, 1H), 4.40-4.36 (m, 1H), 1.08 (s, 9H).

Step C. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-([3-[(tert-butyldiphenylsilyl)oxy]-2,3-dihydro-1-benzofuran-7-yl]amino)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (130.00 mg, 0.250 mmol, 1.00 equiv) and [(7-bromo-2,3-dihydro-1-benzofuran-3-yl)oxy](tert-butyl)diphenylsilane (147.21 mg, 0.325 mmol, 1.30 equiv) in dry Dioxane (4 mL) were added K 3 PO 4 (106.01 mg, 0.499 mmol, 2 equiv), Pd 2 (dba) 3 (22.87 mg, 0.025 mmol, 0.1 equiv) and XantPhos (14.45 mg, 0.025 mmol, 0.1 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h. The solvent was removed under reduced pressure. The residue was purified by prep-TLC (rinsed with PE/EA=3/1) to give the title compound (120 mg, 51.11%) as yellow solid. m/z (ESI, +ve ion)=893.25 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J=8.0 Hz, 1H), 8.13-8.10 (m, 1H), 7.83-7.80 (m, 1H), 7.73-7.68 (m, 4H), 7.53-7.40 (m, 6H), 7.06 (d, J=8.0 Hz, 1H), 6.92-6.88 (m, 1H), 6.71-6.66 (m, 3H), 5.57-5.52 (m, 2H), 4.51-4.47 (m, 1H), 4.38-4.34 (m, 1H), 3.53 (t, J=8.4 Hz, 1H), 3.38 (d, J=6.8 Hz, 3H), 2.40-2.36 (m, 1H), 2.12 (s, 1H), 1.73-1.70 (m, 18H), 1.09 (s, 9H)

Step D. (1R,2S)-2-[3-([3-[(tert-butyldiphenylsilyl)oxy]-2,3-dihydro-1-benzofuran-7-yl]amino)-1H-indazol-6-yl]-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

The mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-([3-[(tert-butyldiphenylsilyl)oxy]-2,3-dihydro-1-benzofuran-7-yl]amino)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (68.00 mg, 0.076 mmol, 1.00 equiv) in bis(2-aminoethyl)amine (0.50 mL) was stirred at 25° C. for 16 h. The resulting mixture was diluted with EA (20 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (rinsed with EA/PE=2/1) to give the title compound (50 mg, 90.04%) as a yellow solid. m/z (ESI, +ve ion)=693.15 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.81-7.79 (m, 1H), 7.75-7.66 (m, 5H), 7.56-7.54 (m, 1H), 7.49-7.40 (m, 8H), 6.95-6.80 (m, 2H), 6.70-6.61 (m, 1H), 5.58-5.52 (m, 2H), 4.49-4.45 (m, 1H), 4.38-4.32 (m, 1H), 3.47-3.42 (m, 1H), 3.37 (d, J=1.6 Hz, 3H), 2.30-2.26 (m, 1H), 2.06-2.04 (m, 1H), 1.10-1.09 (m, 9H).

Step E. (1R,2S)-2-[3-(1-benzofuran-7-ylamino)-1H-indazol-6-yl]-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

To the mixture of (1R,2S)-2-[3-([3-[(tert-butyldiphenylsilyl)oxy]-2,3-dihydro-1-benzofuran-7-yl]amino)-1H-indazol-6-yl]-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one (9.00 mg, 0.010 mmol, 1.00 equiv) in DCM (0.50 mL, 0.006 mmol, 0.58 equiv) was added TFA (0.05 mL). The mixture was stirred at 25° C. for 12 h. The mixture was diluted with DCM (20 ml) and washed with sat. aq. NaHCO 3 (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 +0.1% NH 3 ·H 2 O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 8 min: 254 nm; RT1: 6.73 min. The product-containing fractions were concentrated to give the title compound as a white solid (2.2 mg, 49.52%). m/z (ESI, +ve ion)=437.15 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ7.76 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.57-7.55 (m, 1H), 7.37 (s, 1H), 7.16-7.10 (m, 2H), 6.91-6.87 (m, 1H), 6.85-6.83 (m, 2H), 6.65-6.62 (m, 1H), 5.63 (d, J=2.4 Hz, 1H), 3.39-3.37 (m, 1H), 3.32 (s, 3H), 2.26-2.23 (m, 1H), 2.20-2.17 (m, 1H).

Example 27. 2-{3-[(3-hydroxy-2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one (mixture of diastereomers)

To the mixture of (1R,2S)-2-[3-([3-[(tert-butyldiphenylsilyl)oxy]-2,3-dihydro-1-benzofuran-7-yl]amino)-1H-indazol-6-yl]-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one (50.00 mg, 0.069 mmol, 1.00 equiv) in tetraethylene glycol (1.00 mL) was added KF (5.97 mg, 0.104 mmol, 1.50 equiv). The resulting mixture was stirred at 80° C. for 12 h. The mixture was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 38% B in 8 min; 254/220 nm; RT1: 7.63 min. The product-containing fractions were concentrated to give the title compound (15 mg, 45.7%) as a white solid. m/z (ESI, +ve ion)=455.10 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.66-7.64 (m, 2H), 7.34 (s, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.89-6.83 (m, 3H), 6.64-6.61 (m, 1H), 5.61 (s, 1H), 5.39-5.38 (m, 1H), 4.65-4.60 (m, 1H), 4.47-4.44 (m, 1H), 3.38-3.35 (m, 1H), 3.30 (s, 3H), 2.25-2.21 (m, 1H), 2.20-2.16 (m, 1H).

Example 28. (1R,2S)-2-(3-{[(3S)-3-hydroxy-2,3-dihydro-1-benzofuran-7-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step B: [(7-bromo-2,3-dihydro-1-benzofuran-3-yl)oxy](tert-butyl)diphenylsilane · 2 of 2

Example 29. (1R,2S)-2-(3-{[(3R)-3-hydroxy-2,3-dihydro-1-benzofuran-7-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

The racemic mixture was separated by PREP-Chiral-HPLC with the following conditions: CHIRALPAK IF, 2×25 cm, 5 μm; Mobile Phase A: HEX:DCM=3:1 (0.1% DEA)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 15.5 min: 220/254 nm; RT1: 9.797 min; RT2: 13.157 min. The first product-containing fractions were collected and roto-evaporated in vacuo and lyophilized overnight to give Example 4 (5 mg) as a white solid. m/z (ESI, +ve ion)=455.35 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.66-7.64 (m, 2H), 7.34 (s, 1H), 6.99 (d, J=6.8 Hz, 1H), 6.89-6.83 (m, 3H), 6.64-6.61 (m, 1H), 5.61 (d, J=2.4 Hz, 1H), 5.40-5.38 (m, 1H), 4.64-4.60 (m, 1H), 4.48-4.44 (m, 1H), 3.35-3.33 (m, 1H), 3.30 (s, 3H), 2.25-2.22 (m, 1H), 2.20-2.16 (m, 1H). The second product-containing fractions were collected and roto-evaporated in vacuo and lyophilized overnight to give Example 5 (3.9 mg) as a white solid. m/z (ESI, +ve ion)=455.30 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 7.67-7.65 (m, 2H), 7.34 (s, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.89-6.83 (m, 3H), 6.64-6.61 (m, 1H), 5.61 (d, J=2.4 Hz, 1H), 5.40-5.38 (m, 1H), 4.65-4.61 (m, 1H), 4.48-4.44 (m, 1H), 3.35-3.33 (m, 1H), 3.30 (s, 3H), 2.24-2.22 (m, 1H), 2.20-2.17 (m, 1H).

Example 30. (1R,2S)-2-{3-[(2,3-dihydropyrazolo[5,1-b][1,3]oxazol-7-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. benzyl (2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)carbamate

To an oven-dried flask was added 2,3-dihydropyrazolo[5,1-b]oxazole-7-carboxylic acid (250 mg, 1.62 mmol) followed by 1,4-dioxane (7.0 mL). diisopropylethylamine (0.57 mL, 3.2 mmol), benzyl alcohol (0.84 mL, 8.1 mmol) and diphenyl phosphorazidate (0.42 mL, 1.9 mmol). The mixture was heated at 90° C. overnight during which time the solution turned dark brown. The mixture was concentrated purified by column chromatography (20% to 30% acetone/hexanes, gradient elution) to afford the title compound (220 mg, 52%) as an off-white solid. m/z (ESI, +ve ion)=260.2 [M+H] + .

›Step B. 2,3-dihydropyrazolo[5,1-b]oxazol-7-amine

To a suspension of benzyl (2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)carbamate (220 mg, 0.849 mmol) in ethanol (9.0 mL) was added 10% Pd/C (44 mg). The atmosphere was replaced with argon and then replaced with hydrogen. The reaction mixture was stirred at under a hydrogen atmosphere for 2.5 h. The catalyst was removed by filtering over a pad of celite and rinsed with ethanol. The filtrate was concentrated and purified by column chromatography (0% to 10% methanol/DCM, gradient elution) to afford the title compound (90 mg, 85%) as a red purple solid. m/z (ESI, +ve ion)=126.3 [M+H] + .

Step C. tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To an oven-dried flask was added tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (63.1 mg, 0.100 mmol), 2,3-dihydropyrazolo[5,1-b]oxazol-7-amine (13.8 mg, 0.110 mmol), xantphos (5.8 mg, 0.010 mmol), Pd 2 dba 3 (9.2 mg, 0.010 mmol), and toluene (2.0 mL). The mixture was degassed with bubbling argon for 10 min. At this time, Cs 2 CO 3 (65.2 mg, 0.200 mmol) was added and the reaction mixture was heated to 100° C. for 2 h. The reaction mixture was cooled was cooled to room temperature and diluted with EtOAc and washed with sat. aqueous NaHCO 3 . The aqueous layer was extracted an additional three times with EtOAc. Combined organic layers were washed with brine, dried with MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (0.5% to 7% methanol/DCM, a gradient elution) to provide the title compound (10 mg, 16%) as a yellow foam. m/z (ESI, +ve ion)=629.2 [M+H] + .

›Step D

To an oven-dried flask was added tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (10 mg, 0.016 mmol) followed DCM (0.4 mL) and trifluoroacetic acid (0.12 mL, 1.5 mmol). The reaction mixture was stirred at room temperature for 2.5 h. At this time, the mixture was concentrated and purified by prep HPLC (15% to 45% ACN/H 2 O, 0.1% TFA modifier, gradient elution) to afford the Example 30 (5.7 mg, 66%) as a white amorphous solid after lyophilization. m/z (ESI, +ve ion)=429.1 [M+H] + . 1 H NMR (400 MHz, MeOD) δ=7.81 (d, J=8.6 Hz, 1H), 7.52 (s, 1H), 7.38 (d, J=0.8 Hz, 1H), 7.06 (dd, J=1.0, 8.6 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 6.67 (dd, J=2.5, 8.6 Hz, 1H), 5.65 (d, J=2.5 Hz, 1H), 5.23-5.17 (m, 2H), 4.38 (t, J=8.0 Hz, 2H), 3.41 (s, 3H), 3.35-3.34 (m, 1H), 2.29-2.16 (m, 2H). Did not observe exchangeable protons.

Example 31. (1R,2S)-5′-methoxy-2-{3-[(3-oxo-2,3-dihydro-1-benzofuran-7-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(3-hydroxy-2,3-dihydro-1-benzofuran-7-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((3-((tert-butyldiphenylsilyl)oxy)-2,3-dihydrobenzofuran-7-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (300.00 mg, 0.336 mmol, 1.00 equiv) in THF (5.00 mL) was added TBAF (131.74 mg, 0.504 mmol, 1.50 equiv). After stirred at 25° C. for 2 h. the solvent was removed under reduced pressure. The residue was purified by prep-TLC (rinsed with EA/PE=1/1) to give the title compound (7a) (200 mg, 90.94%) as a light yellow solid. m/z (ESI, +ve ion)=655.30 [M+H]+.

Step B. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(3-oxo-2H-1-benzofuran-7-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(3-hydroxy-2,3-dihydro-1-benzofuran-7-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (50.00 mg, 0.076 mmol, 1.00 equiv) in DMSO (1.00 mL) was added IBX (42.77 mg, 0.152 mmol, 2.0) equiv). The resulting mixture was stirred at 25° C. for 12 h. The mixture was diluted with EA (50 mL) and washed with brine (30 mL×3). The organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by prep-TLC (rinsed with EA/PE=1/1) to give the title compound (35 mg, 66.71%) as a light yellow solid. m/z (ESI, +ve ion)=653.30 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J=8.0 Hz, 1H), 8.11 (s, 1H), 7.84-7.82 (m, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.33-7.31 (m, 1H), 7.22-7.19 (m, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.86 (s, 1H), 6.71-6.68 (m, 1H), 5.58 (d, J=2.8 Hz, 1H), 4.77 (s, 2H), 3.59-3.52 (m, 1H), 3.41 (s, 3H), 2.41-2.38 (m, 1H), 2.12 (s, 1H), 1.72 (d, J=9.2 Hz, 18H).

Step C. (1R,2S)-5′-methoxy-2-[3-[(3-oxo-2H-1-benzofuran-7-yl)amino]-1H-indazol-6-yl]-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

The mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(3-oxo-2H-1-benzofuran-7-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (25.00 mg, 0.038 mmol, 1.00 equiv) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1.00 mL) was stirred at 50° C. for 12 h. The solvent was removed under reduced pressure and the residue was purified with the following conditions: Column: XBridge Prep OBD C18 Column, 30 Å, 150 mm 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 28% B to 42% B in 8 min; Detector: 254/220 nm; RT1: 7.27 min. The product-containing fractions was concentrated in vacuo to give Example 31 (3.3 mg, 18.85%) as a light yellow solid. m/z (ESI, +ve ion)=453.30 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.16-8.14 (m, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.38 (s, 1H), 7.16-7.14 (m, 1H), 7.08-7.04 (m, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 6.64-6.62 (m, 1H), 5.62 (d, J=2.4 Hz, 1H), 4.82 (s, 2H), 3.39-3.37 (m, 1H), 3.31 (s, 3H), 2.26-2.23 (m, 1H), 2.20-2.17 (m, 1H).

Example 32. (1R,2S)-2-{3-[(2,3-dihydrofuro[2,3-c]pyridin-7-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 2H,3H-furo[2,3-c]pyridin-7-amine

To a mixture of furo[2,3-c]pyridin-7-amine (400.00 mg, 2.982 mmol, 1.00 equiv) in AcOH (8 mL) was added 10% Pd/C (400.00 mg, 0.376 mmol, 0.13 equiv). The reaction mixture was stirred for 16 h at 1 atm H 2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved with EA (50 mL) and washed with saturated NaHCO 3 (3×20 mL). The organic layers were dried over anhydrous Na 2 SO 4 , filtered. The filtrate was concentrated under reduced pressure to give the title compound (400 mg, 98.52%) as a yellow oil. m/z (ESI, +ve ion)=137.00 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ7.46 (d, J=5.2 Hz, 1H), 6.53 (d, J=5.2 Hz, 1H), 5.53 (s, 2H), 4.50 (t, J=8.8 Hz, 2H), 3.18-3.08 (m, 2H).

Step B. tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl)-3-[2H,3H-furo[2,3-c] pyridin-7-ylamino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (190.00 mg, 0.301 mmol, 1.00 equiv), 2H,3H-furo[2,3-c]pyridin-7-amine (49.16 mg, 0.361 mmol, 1.2 equiv) and Cs 2 CO 3 (196.07 mg, 0.602 mmol, 2.00 equiv) in toluene (6.00 mL) were added Pd 2 (dba) 3 (27.55 mg, 0.030 mmol, 0.1 equiv) and XantPhos (17.41 mg, 0.030 mmol, 0.10 equiv) under N 2 atmosphere. The resulting mixture was stirred for 2 h at 90° C. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluted with 7% MeOH in DCM to afford the title compound (160 mg, 83.13%) as a yellow oil. m/z (ESI, +ve ion)=640.40 [M+H] + .

Step C. (1R,2S)-2-(3-[2H,3H-furo[2,3-c]pyridin-7-ylamino]-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

To a mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[2H,3H-furo[2,3-c] pyridin-7-ylamino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (160.00 mg, 0.250 mmol, 1.0) equiv) in DCM (5.00 mL) was added TFA (0.50 mL, 6.732 mmol, 26.91 equiv). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by RP flash, eluted with 45% ACN in water (10 mM NH 4 HCO 3 ) to afford Example 32 (40 mg, 36.39%) as an off-white solid. m/z (ESI, +ve ion)=440.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.32 (s, 1H), 10.42 (s, 1H), 8.42 (s, 1H), 7.52 (d, J=5.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.34 (s, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.77-6.73 (m, 2H), 6.59 (dd, J=8.5, 2.6 Hz, 1H), 5.74 (d, J=2.6 Hz, 1H), 4.59 (t, J=8.9 Hz, 2H), 3.3 (s, 3H), 3.22 (t, J=8.9 Hz, 2H), 3.17 (t, J=8.4 Hz, 1H), 2.32 (dd, J=8.0, 4.7 Hz. 1H), 1.98 (dd, J=9.1, 4.6 Hz, 1H).

Example 33. (1R,2S)-2-(3-{[(3S)-3-(hydroxymethyl)-2,3-dihydrofuro[2,3-c]pyridin-7-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Example 34. (1R,2S)-2-(3-{[(3R)-3-(hydroxymethyl)-2,3-dihydrofuro[2,3-c]pyridin-7-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 3-[[(tert-butyldimethylsilyl)oxy]methyl]-7-chloro-2H,3H-furo[2,3-c] pyridine

To a stirred mixture of [7-chloro-2H,3H-furo[2,3-c]pyridin-3-yl]methanol (500.00 mg, 2.694 mmol, 1.0) equiv) and Imidazole (220.07 mg, 3.233 mmol, 1.20 equiv) in DMF (4.00 mL, 0.055 mmol) were added t-butyldimethylchlorosilane (487.22 mg, 3.233 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (3×40 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford the crude title product (1.0 g). m/z (ESI, +ve ion)=300.15 [M+H] + .

Step B. N-(3-[[(tert-butyldimethylsilyl)oxy]methyl]-2H,3H-furo[2,3-c]pyridin-7-yl)-1,1-diphenylmethanimine

To a stirred mixture of 3-[[(tert-butyldimethylsilyl)oxy]methyl]-7-chloro-2H,3H-furo[2,3-c] pyridine (300.00 mg, 1.000 mmol, 1.00 equiv). diphenylmethanimine (36.26 mg, 0.200 mmol, 1.20 equiv) in toluene (5.00 mL, 4.699 mmol, 28.18 equiv) were added t-BuONa (134.60 mg, 1.400 mmol, 1.40 equiv), BINAP (12.46 mg, 0.020 mmol, 0.12 equiv) and Pd 3 (dba) (36.64 mg, 0.040 mmol, 0.04 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90° C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give 400 mg crude title compound. m/z (ESI, +ve ion)=445.15 [M+H] + .

›Step C. 3-[[(tert-butyldimethylsilyl)oxy]methyl]-2H,3H-furo[2,3-c]pyridin-7-amine

A mixture of N-(3-[[(tert-butyldimethylsilyl)oxy]methyl]-2H,3H-furo[2,3-c]pyridin-7-yl)-1,1-diphenylmethanimine (400.00 mg, 0.900 mmol, 1.00 equiv) and NH 2 OH (50% in water, 0.50 mL) in MeOH (0.50 mL) and H 2 O (0.50 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the title compound (177 mg, 70.16%) as a white solid. m/z (ESI, +ve ion)=281.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.47 (d, J=4.8 Hz, 1H), 6.56 (d, J=5.2 Hz, 1H), 5.55 (s, 2H), 4.61-4.51 (m, 1H), 4.35-4.26 (m, 1H), 3.81-3.73 (m, 1H), 3.72-3.64 (m, 11H), 3.63-3.52 (m, 1H), 0.84 (s, 9H), 0 (s, 6H).

Step D. tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(3-[[(tert-butyldimethylsilyl)oxy]methyl]-2H,3H-furo[2,3-c]pyridin-7-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate (150.00 mg, 0.238 mmol, 1.00 equiv) and 3-[[(tert-butyldimethylsilyl)oxy]methyl]-2H,3H-furo[2,3-c]pyridin-7-amine (79.94 mg, 0.286 mmol, 1.20 equiv) in toluene (2.30 mL) were added Cs 2 CO 3 (154.79 mg, 0.476 mmol, 2.00 equiv), XantPhos (13.74 mg, 0.024 mmol, 0.10 equiv) and Pd 2 (dba) 3 ·CHCl 3 (24.59 mg, 0.024 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 85° C. under nitrogen atmosphere then concentrated under vacuum. The resulting mixture was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give 100 mg of the crude title compound. The crude resulting mixture was used for the next step directly without further purification. m/z (ESI, +ve ion)=784.50 [M+H] + .

Step E. (1R,2S)-2-(3-[[3-(hydroxymethyl)-2H,3H-furo[2,3-c]pyridin-7-yl] amino]-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

To a stirred mixture of the crude tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(3-[[(tert-butyldimethylsilyl)oxy]methyl]-2H,3H-furo[2,3-c]pyridin-7-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100.00 mg, 1 equiv) were added DCM (3.00 mL) and TFA (1.50 mL) at room temperature. The resulting mixture was stirred for 6 h at room temperature, then concentrated wider vacuum. The residue was purified by prep-HPLC with the following conditions: Column: Sunfire prep C18 column, 30×150, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 40% B in 8 min 220 nm; RT1: 7.12 min to afford the title compound (55 mg, 91.84%) as a white solid. m/z (ESI, +ve ion)=470.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.53 (s, 1H), 10.42 (s, 1H), 8.91 (s, 1H), 7.66-7.46 (m, 2H), 7.36 (s, 1H), 6.94-6.79 (m, 2H), 6.75 (d, J=8.4 Hz, 1H), 6.61-6.54 (m, 1H), 5.73 (d, J=2.6 Hz, 1H), 5.04 (s, 1H), 4.77-4.65 (m, 1H), 4.55-4.42 (m, 1H), 3.74-3.53 (m, 3H), 3.22-3.13 (m, 1H), 2.51 (s, 3H), 2.38-2.26 (m, 1H), 2.04-1.92 (m, 1H).

Step F: (1R,2S)-2-(3-[[(3S)-3-(hydroxymethyl)-2H,3H-furo[2,3-c] pyridin-7-yl]amino]-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one and (1R,2S)-2-(3-[[(3R)-3-(hydroxymethyl)-2H,3H-furo[2,3-c]pyridin-7-yl]amino]-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

Racemic (1R,2S)-2-(3-[[3-(hydroxymethyl)-2H,3H-furo[2,3-c]pyridin-7-yl] amino]-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one was separated by prep-Chiral-HPLC with the following conditions: Column: Column: CHIRALPAK IG, 2×25 cm, 5 μm; Mobile Phase A: Hex (0.2% DEA)-HPLC, Mobile Phase B: EtOH:DCM=1:1-HPLC; Flow rate: 20 mL/min; Gradient: 60% B to 60% B in 12 min; Wavelength: 220/254 nm; RT1 (min): 6.603: RT2 (min): 8.571 to afford (first peak) Example 34 (13.9 mg) as a white solid. m/z (ESI, +ve ion)=470.15 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.63 (d, J=8.4 Hz, 2H), 7.40 (s, 1H), 6.92 (d, J=7.6 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 5.66 (d, J=2.4 Hz, 1H), 4.89 (s, 3H), 4.82-4.78 (m, 1H), 4.65-4.63 (m, 1H), 3.85-3.71 (m, 3H), 3.36-3.34 (s, 1H), 2.26-2.22 (m, 1H), 2.19-2.16 (m, 1H). And to afford second peak, the other diastereomer (11.3 mg) as a white solid. m/z (ESI, +ve ion)=470.15 [M+H]+. 1H NMR (400 MHz, Methanol-d 4 ) δ 7.63 (d, J=8.4 Hz, 2H), 7.40 (s, 1H), 6.92 (d, J=7.6 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 5.66 (d, J=2.4 Hz, 1H), 4.89 (s, 3H), 4.82-4.78 (m, 1H), 4.65-4.63 (m, 1H), 3.85-3.71 (m, 3H), 3.36-3.34 (s, 1H), 2.26-2.22 (m, 1H), 2.19-2.16 (m, 1H).

Example 35. (1R,2S)-5′-methoxy-2-(3-{[6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 6-(3-methoxyazetidin-1-yl)pyrimidin-4-amine)

To a mixture of 6-chloropyrimidin-4-amine (516.00 mg, 3.983 mmol, 1.00 equiv) and 3-methoxyazetidine hydrochloride (590.67 mg, 4.800 mmol, 1.20 equiv) in THF (20.00 mL) was added TEA (806.08 mg, 7.966 mmol, 2.00 equiv). The resulting mixture was stirred for 16 h at 60° C. The reaction was concentrated under reduced pressure. The residue was purified by RP flash, eluted with 10% ACN in water (10 mM NH 4 HCO 3 ) to afford the title compound (200 mg, 27.86%) as a white solid. m/z (ESI, +ve ion)=181.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.91 (d, J=1.0 Hz, 1H), 6.23 (s, 2H), 5.23 (d, J=1.0 Hz, 1H), 4.30-4.26 (m, 1H), 4.08-4.04 (m, 2H), 3.69-3.66 (m, 2H), 3.23 (s, 3H).

Step B. tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl)-3-[[6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of 6-(3-methoxyazetidin-1-yl)pyrimidin-4-amine) (35.00 mg, 0.194 mmol, 1.00 equiv) and tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (134.91 mg, 0.214 mmol, 1.1 equiv) in toluene (3.00 mL) were added Cs 2 CO 3 (126.56 mg, 0.388 mmol, 2 equiv). Pd 2 (dba) 3 (17.78 mg, 0.019 mmol, 0.1 equiv) and XantPhos (11.24 mg, 0.019 mmol, 0.1 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h. The mixture was filtered and washed with EA (3×10 mL). The filtrate was removed under reduced pressure and the residue was purified by prep-TLC (rinsed with EA/PE=1/1) to give the title compound (88 mg, 62.95%) as a yellow solid. m/z (ESI, +ve ion)=684.45 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.29 (d, J=1.2 Hz, 1H), 8.13 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.75-7.73 (m, 1H), 7.56-7.54 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.70-6.67 (m, 1H), 5.55 (d, J=2.4 Hz, 1H), 4.41-4.38 (m, 3H), 4.11 (d, J=8.0 Hz, 2H), 3.52 (t, J=8.8 Hz, 1H), 3.40 (d, J=8.8 Hz, 6H), 2.39-2.36 (m, 1H), 2.12 (s, 1H), 1.71 (d, J=4.4 Hz, 18H).

Step C. (1R,2S)-5′-methoxy-2-(3-[[6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl] amino]-1H-indazol-6-yl)-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

The mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[[6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100 mg, 0.146 mmol, 1.00 equiv) in TFA (0.50 mL) and DCM (5.00 mL) was stirred at 25° C. for 2 h. The mixture was quenched with saturated aqueous of NaHCO 2 (20 mL) and extracted with EA (3×20 mL). The combined organic was dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The product was purified with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ). Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 35% B in 8 min; Detector: 254 and 220 nm; RT1: 7.43 min. The product-containing fractions were combined and concentrated to give Example 35 (32.3 mg, 45.7%) as a white solid. m/z (ESI, +ve ion)=484.20 [M+H] + . 1 H NMR (400 MHz, DMSO-4) δ 12.37 (s, 1H), 10.42 (s, 1H), 9.82 (s, 1H), 8.15 (d, J=0.8 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 6.90-6.88 (m, 1H), 6.78-6.74 (m, 2H), 6.60-6.57 (m, 1H), 5.69 (d, J=2.8 Hz, 1H), 4.37-4.31 (m, 1H), 4.19-4.15 (m, 2H), 3.80-3.76 (m, 2H), 3.33 (s, 3H), 3.26 (s, 3H), 3.17 (t, J=8.4 Hz, 1H), 2.35-2.32 (m, 1H), 1.99-1.95 (m, 1H).

Example 36. (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 3-[(tert-butyldimethylsilyl)oxy]azetidine

To a stirred solution of azetidin-3-ol (1.09 g, 14.912 mmol, 1.00 equiv) and t-butyldimethylchlorosilane (2.25 g, 14.912 mmol, 1.00 equiv) in DCM (10.00 mL) was added DIEA (4.82 g, 37.280 mmol, 2.50 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere, then concentrated under vacuum. The residue was neutralized to pH 8 with saturated NaHCO 3 . The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (3×40 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to give the title compound (12a) (1.5 g, 53.69%) as a yellow oil. 1 H NMR (400 MHz, Chloroform-d) δ 4.50-4.53 (m, 1H), 3.47-3.44 (m, 2H), 2.50-2.52 (s, 2H), 0.85-0.87 (m, 9H), 0.02-0.04 (m, 6H).

›Step B. 6-[3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl]pyrimidin-4-amine

To a stirred mixture of 3-[(tert-butyldimethylsilyl)oxy]azetidine (299.37 mg, 1.598 mmol, 1.50 equiv) and 6-chloropyrimidin-4-amine (138.00 mg, 1.065 mmol, 1.00 equiv) in THF (0.50 mL) was added TEA (161.40 mg, 1.598 mmol, 1.50 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 60° C., then cooled down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3/1) to afford the title compound (256 mg, 85.69%) as a yellow solid. m/z (ESI, +ve ion)=281.20 [M+H] + .

Step C. (1R,2S)-5′-methoxy-2-(3-[[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl](methyl)amino]-1H-indazol-6-yl)-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

To the mixture of 6-[3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl]pyrimidin-4-amine (60.00 mg, 0.214 mmol, 1.00 equiv) and tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (135.10 mg, 0.214 mmol, 1 equiv) in toluene (2.50 mL) were added Cs 2 CO 3 (139.41 mg, 0.428 mmol, 2 equiv), Pd 2 (dba) 3 (19.59 mg, 0.021 mmol, 0.1 equiv) and XantPhos (12.38 mg, 0.021 mmol, 0.1 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h. The mixture was filtered and washed with EA (3×10 mL). The filtrate was removed under reduced pressure and the residue was purified by silica gel column eluted with EA/PE=1/1 to give the title compound (100 mg, 56.64%) as an off-white solid. m/z (ESI, +ve ion)=784.25 [M+H] + . 1 H NMR (400 MHz, DMSO-4) δ 10.45 (s, 1H), 8.28-8.24 (m, 2H), 8.04 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.36-7.34 (m, 1H), 7.26 (d, J=1.2 Hz, 1H), 6.74-6.71 (m, 1H), 5.71 (d, J=2.8 Hz, 1H), 4.85-4.80 (m, 1H), 4.31-4.28 (m, 2H), 3.80-3.74 (m, 2H), 3.44-3.40 (m, 1H), 3.35 (s, 3H), 2.48-2.45 (m, 1H), 2.21-2.17 (m, 1H), 1.60 (d, J=6.4 Hz, 18H), 0.88 (s, 9H), 0.08 (s, 6H).

Step D. (1R,2S)-2-(3-[[6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino]-1H-indazol-6-yl-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

The mixture of (1R,2S)-5′-methoxy-2-(3-[[5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl](methyl)amino]-1H-indazol-6-yl)-1′H-spiro[cyclopropane-1,3′-indol]-2′-one (100.00 mg, 0.128 mmol, 1.00 equiv) in TFA (0.50 mL) and DCM (2.50 mL) was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure. The residue was further purified with the following conditions: Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 40% B in 7 min; Detector: 254 & 220 nm; RT1: 7.27 min. The product-containing fractions were combined and concentrated to give Example 36 (33.4 mg, 58.12%) as a white solid. m/z (ESI, +ve ion)=470.35 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.38 (s, 1H), 10.43 (s, 1H), 9.81 (s, 1H), 8.14 (d, J=0.8 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 6.90-6.87 (m, 1H), 6.77-6.73 (m, 2H), 6.59-6.56 (m, 1H), 5.75 (d, J=6.8 Hz, 1H), 5.68 (d, J=2.4 Hz, 1H), 4.58 (s, 1H), 4.20-4.16 (m, 2H), 3.72-3.69 (m, 2H), 3.32 (s, 3H), 3.17 (t, J=8.4 Hz, 1H), 2.35-2.32 (m, 1H), 1.98-1.95 (m, 1H).

Example 37. (1R,2S)-2-(3-((6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

›Step A. 5-(6-chloro-5-methoxy-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.2]octane

To a 50 ml round bottom flask containing 4,6-Dichloro-5-methoxypyrimidine (200.0 mg, 1.120 mmol) in DMSO (3.7 mL) were added (1R,5S)-3-Oxa-8-azabicyclo[3.2.1]octane hydrochloride (1:1) (167.2 mg, 1.120 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.50 mL, 2.8 mmol). The reaction mixture was heated to 60° C. and stirred, monitored by LCMS until the full conversion of the starting materials (approx. 80 min). Then the reaction mixture was cooled down to rt, diluted with EtOAc and water, extracted with EtOAc for 3 times. The organic layer was then dried over Na 2 SO 4 . The residue was purified by column chromatography (ethyl acetate/hexane=0˜50%) to provide the title compound (228.0 mg, 80%) as a white solid.

Step B. tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[[5-methoxy-6-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To a 50 ml round bottom flask were added cesium carbonate (37.6 mg, 0.115 mmol), tert-butyl (1R,2S)-2-(3-amino-1-tert-butoxycarbonyl-indazol-6-yl)-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (30.0 mg, 0.0600 mmol), Tris(dibenzylideneacetone)dipalladium(0) (5.3 mg, 0.010 mmol), 5-(6-chloro-5-methoxy-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.2]octane (15.4 mg, 0.0605 mmol), Xantphos (3.3 mg, 0.010 mmol) and dry toluene (2.9 mL). The reaction mixture was stirred and purged with argon (in balloon) for 10 min to form a green suspension, and then heated to 120° C., resulting in a yellow suspension. The reaction was monitored by LCMS and TLC until the full conversion of the starting materials (approx. 5 hrs), cooled down to rt, diluted with EtOAc, washed with sat. aq. NaHCO 3 and dried over Na 2 SO 4 . The residue was purified by column chromatography (ethyl acetate/hexane=0˜50%) to provide the title compound (16.0 mg, 38%) as a yellow oil.

›Step C

This compound was prepared from tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[[5-methoxy-6-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1-carboxylate (16.0 mg, 0.0200 mmol) and trifluoroacetic acid (0.17 mL, 2.2 mmol). The resulting brown solution was purified by Prep. HPLC (Gemini C18, 10 to 90% (0.1% TFA in water)/(0.1% TFA in Acetonitrile)) to provide Example 37 (7.8 mg, 67%) as a colorless film. 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 2.08-2.14 (m, 2H) 2.15-2.27 (m, 5H) 3.34-3.36 (m, 3H) 3.70-3.75 (m, 2H) 3.79-3.84 (m, 5H) 4.98-5.03 (m, 2H) 5.61 (d, J=2.27 Hz, 1H) 6.62 (dd, J=8.59, 2.53 Hz, 1H) 6.83 (d, J=8.84 Hz, 1H) 7.03 (dd, J=8.46, 0.88 Hz, 1H) 7.48-7.51 (m, 1H) 7.87-7.91 (m, 1H) 8.22 (s, 1H); m/z (ESI, +ve ion) 540.2 (M+H)+.

Example 38. (1R,2S)-2-(3-{[6-(2-hydroxyethoxy)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 6-[2-[(tert-butyldimethylsilyl)oxy]ethoxy] pyrimidin-4-amine

To a stirred mixture of 6-chloropyrimidin-4-amine (600.00 mg, 4.631 mmol, 1.00 equiv) and 2-[(tert-butyldimethylsilyl)oxy]ethanol (1224.99 mg, 0.000 mmol, 1.50 equiv) in THF (15.00 mL) was added NaH (222.29 mg, 9.262 mmol, 2.00 equiv. 60% in mineral oil) in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100° C. under nitrogen atmosphere, then cooled down to room temperature. The reaction was quenched with sat. NH 4 Cl (30 mL) at room temperature. The resulting mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column. C18 silica gel; mobile phase. ACN in water, 30% to 70% gradient in 60 min; detector, UV 254 nm to give the title compound (164 mg, 13.14%) as a pink solid. m/z (ESI, +ve ion)=270.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (d, J=1.0 Hz, 1H), 6.60 (s, 2H), 5.68 (d, J=1.1 Hz, 1H), 4.58-4.07 (m, 2H), 3.86 (m, 2H), 0.86 (d, J=1.4 Hz, 9H), 0.12-0.03 (m, 6H).

Step B. tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(6-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyrimidin-4-yl)amino]indazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate

To a stirred solution of 6-[2-[(tert-butyldimethylsilyl)oxy]ethoxy] pyrimidin-4-amine (51.15 mg, 1.2 equiv) and tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate (100 mg, 1.00 equiv) in toluene (3 mL) were added Pd 2 (dba) 3 (14.50 mg, 0.1 equiv), XantPhos (9.16 mg, 0.1 equiv) and Cs 2 CO 3 (103.26 mg, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The resulting mixture was cooled down and filtered, the filter cake was washed with MeOH (2×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (2/1) to afford the title compound (110 mg, 89.86%) as a yellow solid. m/z [ESI +ve ion]=773.35 [M+H] + .

Step C. (1R,2S)-2-(3-[[6-(2-hydroxyethoxy)pyrimidin-4-yl]amino]-1H-indazol-6-yl)-5-methoxy-1H-spiro[cyclopropane-1,3-indol]-2-one

A mixture of tert-butyl(1R,2S)-2-[1-tert-butoxycarbonyl)-3-[(6-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyrimidin-4-yl)amino]indazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate (130.00 mg, 0.168 mmol, 1.00 equiv) and TFA (2.00 mL, 0.018 mmol, 0.10 equiv) in DCM (10.00 mL) was stirred for 4 h at room temperature. The mixture was neutralized to pH 7 with saturated NaHCO 3 . The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC with the following conditions Column: YMC-Actus Triart C18 ExRS, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ). Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 30% B in 10 min, 30% B; Wavelength: 254 nm; RT1: 8.5 min to afford Example 38 (8.2 mg, 25.94%) as a white solid. m/z (ESI +ve ion)=459.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.42 (s, 1H), 10.42 (s, 1H), 10.19 (s, 1H), 8.36 (d, J=0.8 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.24 (s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.59 (m, 1H), 5.69 (d, J=2.4 Hz, 1H), 4.88 (s, 1H), 4.30 (t, J=4.8 Hz, 2H), 3.70 (d, J=4.4 Hz, 2H), 3.30 (s, 3H), 3.20 (s, 1H), 2.33 (s, 1H), 1.98 (m, 1H).

Example 39. (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

›Step A. 4-(6-aminopyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione

Into a 20 mL vial were added 6-chloropyrimidin-4-amine (300.00 mg, 2.316 mmol, 1.00 equiv) and 1lambda 6-thiomorpholine-1,1-dione (939.11 mg, 6.947 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred overnight at 80° C. under nitrogen atmosphere. After cooled down to room temperature, the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3/1) to afford the title compound (110 mg, 19.21%) as a yellow solid. m/z (ESI, +ve ion)=229.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.01 (d, J=0.9 Hz, 1H), 6.34 (s, 2H), 5.75 (d, J=1.1 Hz, 1H), 4.00-3.88 (m, 4H), 3.15-3.06 (m, 4H).

Step B. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[[6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate (100.00 mg, 0.158 mmol, 1.00 equiv) and 4-(6-aminopyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione (43.38 mg, 0.190 mmol, 1.20 equiv) in toluene (1.00 mL) were added Cs 2 CO 3 (103.19 mg, 0.316 mmol, 2.00 equiv), Pd 2 (dba) 3 (14.50 mg, 0.016 mmol, 0.10 equiv) and XantPhos (9.16 mg, 0.016 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere and then cooled down to room temperature. The resulting mixture was diluted with water (20 mL), extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA(1/1) to afford the title compound (100 mg, 86.29%) as an off-white solid. m/z (ESI, +ve ion)=732.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.57 (s, 1H), 8.36 (d, J=0.9 Hz, 1H), 8.27 (d, J=8.3 Hz, 1H), 8.05 (d, J=14.3 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.40-7.33 (m, 1H), 6.74-6.69 (m, 1H), 5.70 (d, J=2.7 Hz, 1H), 4.20-3.99 (m, 4H), 3.27-3.08 (m, 8H), 1.60 (d, J=5.2 Hz, 18H), 1.23 (s, 2H).

Step C. 4-[6-([6-[(1R,2S)-5′-methoxy-2′-oxo-1′H-spiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl]amino)pyrimidin-4-yl]-1lambda6-thiomorpholine-1,1-dione

A mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[[6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100.00 mg) in DCM (0.80 mL) and TFA (0.20 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 32% B in 8 min, 254/220 nm; RT1: 7.05 min to afford Example 39 (15.1 mg) as a white solid m/z (ESI, +ve ion)=532.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.41 (s, 1H), 10.42 (s, 1H), 9.93 (s, 1H), 8.26 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.34 (s, 1H), 7.27 (s, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.60-6.57 (m, 1H), 5.69 (d, J=2.8 Hz, 1H), 4.04 (s, 4H), 3.33 (s, 3H), 3.19-3.16 (m, 5H), 2.35-2.32 (m, 1H), 1.99-1.96 (m, 1H).

Example 40. (1R,2S)-5′-methoxy-2-(3-{[6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 6-(1,4-oxazepan-4-yl)pyrimidin-4-amine

A mixture of 6-chloropyrimidin-4-amine (516.00 mg, 1 equiv) in 1,4-oxazepane (3.00 mL) was stirred for 16 h at 60° C. The mixture was purified with RP flash, eluted with RP flash, eluted with 10% ACN in water (10 mM NH 4 HCO 3 ) to afford the title compound (300 mg, 38.78%) as a white solid. m/z (ESI+ve ion)=195.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.92 (d, J=1.0 Hz, 1H), 6.12 (s, 2H), 5.50 (d, J=1.0 Hz, 1H), 3.66 (s, 4H), 3.63-3.55 (m, 4H), 1.88-1.78 (m, 2H).

Step B. tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl)-3-[[6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (200.00 mg, 0.317 mmol, 1.00 equiv) and 6-(1,4-oxazepan-4-yl)pyrimidin-4-amine (73.82 mg, 0.380 mmol, 1.2 equiv) in toluene (5.00 mL) were added Cs 2 CO 3 (206.39 mg, 0.633 mmol, 2 equiv), Pd 2 (dba) 3 (29.00 mg, 0.032 mmol, 0.1 equiv) and XantPhos (18.33 mg, 0.032 mmol, 0.1 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h. The mixture was filtered and washed with EA (3×10 mL). The filtrate was removed under reduced pressure and the residue was purified by silica gel column eluted with EA/PE=1/1 to give the title compound (80 mg, 34.39%) as a yellow solid. m/z (ESI, +ve ion)=698.50 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.31-8.27 (m, 2H), 8.04 (s, 1H), 7.72-7.68 (m, 1H), 7.60 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 6.73 (d, J=9.6 Hz, 1H), 5.71 (s, 1H), 3.89-3.71 (m, 6H), 3.66-3.62 (m, 2H), 3.45-3.43 (m, 1H), 3.35 (s, 3H), 2.34 (s, 1H), 2.22-2.18 (m, 1H), 1.92 (s, 2H), 1.60 (s, 18H).

Step C. (1R,2S)-5′-methoxy-2-(3-[[6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino]-1H-indazol-6-yl)-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

A mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[[6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (80.00 mg, 0.115 mmol, 1.00 equiv) in TFA (0.50 mL) and DCM (5.00 mL) was stirred at 25° C. for 2 h. The mixture was quenched with saturated aqueous of NaHCO 3 (20 mL) and extracted with EA (3×20 mL). The combined organics were dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The product was purified with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN: Flow rate: 60 mL/min: Gradient: 20% B to 45% B in 8 min; Detector: 254&220 nm; RT1: 5.73 min. The product-containing fractions were combined and concentrated to give Example 40 (19.3 mg, 33.50%) as a white solid. m/z (ESI, +ve ion)=498.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.37 (s, 1H), 10.43 (s, 1H), 9.75 (s, 1H), 8.17 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.12 (s, 1H), 6.90-6.88 (m, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.60-6.57 (m, 1H), 5.69 (d, J=2.4 Hz, 1H), 3.78-3.68 (m, 6H), 3.63 (t, J=5.6 Hz, 2H), 3.33 (s, 3H), 3.18 (t, J=8.0 Hz, 1H), 2.35-2.32 (m, 1H), 1.99-1.96 (m, 1H), 1.90-1.88 (m, 2H).

Example 41. (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-2-methyl-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 6-Hydroxy-5-methoxy-2-methylpyrimidin-4(3H)-one

To an oven-dried flask containing methanol (100 mL) at 0° C. was added sodium tert-butoxide (12.2 g, 127 mmol) in four-portions over 20 minutes. To this solution was added acetimidamide hydrochloride (4.5 g, 50.9 mmol) and dimethyl methoxymalonate (7.0 mL, 51 mmol). The mixture was heated to reflux for 2 h and then cooled to 0° C. The reaction mixture was made acidic with concentrated HCl and the resulting solid was collected by vacuum filtration. The wet material was frozen and lyophilized to afford the title compound (2.4 g, 30%) as a beige solid. m/z (ESI, +ve ion)=157.1 [M+H] + .

›Step B. 4,6-Dichloro-5-methoxy-2-methylpyrimidine

To a microwave tube was added 6-hydroxy-5-methoxy-2-methylpyrimidin-4(3H)-one (2.40 g, 15.4 mmol), N,N-dimethylaniline (1.94 mL, 15.4 mmol), and phosphoryl chloride (12.7 mL, 135 mmol) and the mixture was heated to 100° C. in a microwave reactor for 1 h. The reaction mixture was filtered and concentrated. The resulting material was purified by column chromatography (0% to 25% EtOAc/hexanes, gradient elution) to afford the title compound (2.6 g, 87%) as a white solid.

›Step C. 4-(6-Chloro-5-methoxy-2-methylpyrimidin-4-yl)morpholine

To an oven-dried flask was added 4,6-Dichloro-5-methoxy-2-methylpyrimidine (1.0 g, 5.18 mmol) followed by ethanol (30 mL). The mixture was cooled to 0° C. morpholine (0.54 mL, 6.2 mmol) was added followed by TEA (1.0 mL, 7.3 mmol), dropwise. The reaction mixture was stirred at room temperature for 1 h and concentrated. The residue was purified by column chromatography (0% to 30% EtOAc/hexanes, gradient elution) to provide the title compound (909 mg, 72%) as a white crystalline solid. m/z (ESI, +ve ion)=244.1 [M+H] + .

Step D. Tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((5-methoxy-2-methyl-6-morpholinopyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To an oven-dried flask was added 4-(6-Chloro-5-methoxy-2-methylpyrimidin-4-yl)morpholine (28.1 mg, 0.115 mmol), tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (30.0 mg, 0.0576 mmol), Xantphos Pd G4 (5.6 mg, 0.0058 mmol), and 1,4-dioxane (0.6 mL). The mixture was degassed with bubbling argon for 10 min. At this time, Cs 2 CO 3 (37.6 mg, 0.115 mmol) was added and the reaction mixture was heated to 100° C. for 2 h. The reaction mixture was cooled was cooled to room temperature and diluted with EtOAc and washed with sat. aqueous NaHCO 3 . The aqueous layer was extracted an additional three times with EtOAc. Combined organic layers were washed with brine, dried with MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (0% to 50% acetone/hexanes, a gradient elution) to provide the title compound (25 mg, 59%) as a white foam. m/z (ESI, +ve ion)=728.3 [M+H] + .

›Step E

To an oven-dried flask was added tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((5-methoxy-2-methyl-6-morpholinopyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (25 mg, 0.034 mmol) followed DCM (1.7 mL) and trifluoroacetic acid (0.13 mL, 1.7 mmol). The reaction mixture was stirred at room temperature for 2 h. At this time, the mixture was concentrated and purified by prep HPLC (20% to 40% ACN/H 2 O, 0.1% TFA modifier, gradient elution) to afford Example 41 (8.1 mg, 45%) as a white amorphous solid after lyophilization. m/z (ESI, +ve ion)=528.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ=12.88 (br s, 1H), 10.45 (s, 1H), 9.90 (br s, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 6.97 (d, J=8.6 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 6.59 (dd, J=2.7, 8.5 Hz, 1H), 5.74 (d, J=2.5 Hz, 1H), 3.81-3.70 (m, 8H), 3.67 (s, 3H), 3.35 (s, 3H), 3.19 (t, J=8.5 Hz, 1H), 2.35 (dd, J=4.7, 8.0 Hz, 1H), 2.27 (s, 3H), 1.99 (dd, J=4.7, 9.0 Hz, 1H).

Example 42. (1R,2S)-2-(3-{[6-(azetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 5-(6-chloro-5-methoxy-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.2]octane

This compound was prepared from 4,6-dichloro-5-methoxypyrimidine (200.0 mg, 1.120 mmol) and azetidine (63.4 mg, 0.08 mL, 1.12 mmol). The residue was purified by column chromatography (ethyl acetate/hexane=0˜50%) to provide the title compound (179.0 mg, 80%) as a white solid.

Step B. tert-butyl (1R,2S)-2-[3-[[6-(azetidin-1-yl)-5-methoxy-pyrimidin-4-yl]amino]-1-tert-butoxycarbonyl-indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate

This compound was prepared using the procedure described in Example 5 from tert-butyl (1R,2S)-2-(3-amino-1-tert-butoxycarbonyl-indazol-6-yl)-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (30.0 mg, 0.0600 mmol) and 5-(6-chloro-5-methoxy-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.2]octane (12.1 mg, 0.0605 mmol). The residue was purified by column chromatography (ethyl acetate/hexane=0˜80%) to provide the title compound (3.0 mg, 7.6%) as a yellow oil.

Step C. (1R,2S)-2-[3-[[6-(azetidin-1-yl)-5-methoxy-pyrimidin-4-yl]amino]-1H-indazol-6-yl]-5′-methoxy-spiro[cyclopropane-1,3′-indoline]-2′-one

This compound was prepared using the procedure described in Example 5 from tert-butyl (1R,2S)-2-[3-[[6-(azetidin-1-yl)-5-methoxy-pyrimidin-4-yl]amino]-1-tert-butoxycarbonyl-indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (3.0 mg, 0.0044 mmol) and trifluoroacetic acid (0.03 mL, 0.4 mmol). The resulting brown solution was purified by Prep. HPLC (Gemini C18, 10 to 90% (0.1% TFA in water)/(0.1% TFA in Acetonitrile)) to provide the desired product Example 42 (1.7 mg, 81%) as a colorless film. 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 2.15-2.22 (m, 1H) 2.24 (dd, J=7.83, 4.80 Hz, 1H) 2.53 (quin, J=7.71 Hz, 2H) 3.33 (s, 3H) 3.33-3.38 (m, 1H) 3.83 (s, 3H) 4.42-4.59 (m, 4H) 5.55-5.63 (m, 1H) 6.58-6.66 (m, 1H) 6.78-6.89 (m, 1H) 6.96-7.08 (m, 1H) 7.42-7.50 (m, 1H) 7.80-7.91 (m, 1H) 8.11-8.19 (m, 1H); m/z (ESI, +ve ion) 484.3 (M+H)+.

Example 43. (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-5-methoxypyrimidin-4-yl]amino}-1H-indazol-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 1-(6-chloro-5-methoxy-pyrimidin-4-yl)azetidin-3-ol

This compound was prepared using 4,6-dichloro-5-methoxypyrimidine (200.0 mg, 1.120 mmol) and azetidin-3-ol Hydrochloride (122.4 mg, 1.120 mmol). The residue was purified by column chromatography (ethyl acetate/hexane=0˜100%) to provide the title compound (216.0 mg, 90%) as a white solid.

›Step B. tert-butyl-[1-(6-chloro-5-methoxy-pyrimidin-4-yl)azetidin-3-yl]oxy-dimethyl-silane

To a 50 ml round bottom flask containing 1-(6-chloro-5-methoxy-pyrimidin-4-yl)azetidin-3-ol (143.0 mg, 0.6600 mmol) in DCM (3.3 mL) were added tert-butylchlorodimethylsilane (119.9 mg, 0.8000 mmol) and Imidazole (112.9 mg, 1.660 mmol). The reaction mixture was stirred at rt and monitored by LCMS until the full conversion of the starting materials (approx. 80 min), cooled down to rt, diluted with EtOAc and water, extracted with EtOAc for 3 times. The organic layer was then dried over Na 2 SO 4 . The residue was purified by column chromatography (ethyl acetate/hexane=0˜50%) to provide the title compound (180.0 mg, 82%) as a colorless oil.

Step C. tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[[6-[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]-5-methoxy-pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (5c)

This compound was prepared using the procedure described in Example 5 from tert-butyl (1R,2S)-2-(3-amino-1-tert-butoxycarbonyl-indazol-6-yl)-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (30.0 mg, 0.0600 mmol) and tert-butyl-[1-(6-chloro-5-methoxy-pyrimidin-4-yl)azetidin-3-yl]oxy-dimethyl-silane (20.9 mg, 0.0605 mmol). The residue was purified by column chromatography (ethyl acetate/hexane=0˜50%) to provide the title compound (6.0 mg, 13%) as a yellow oil.

Step D. (1R,2S)-2-[3-[[6-(3-hydroxyazetidin-1-yl)-5-methoxy-pyrimidin-4-yl]amino]-1H-indazol-6-yl]-5′-methoxy-spiro[cyclopropane-1,3′-indoline]-2′-one

This compound was prepared using the procedure described in Example 5 from tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[[6-[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]-5-methoxy-pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (6.0 mg, 0.010 mmol) and trifluoroacetic acid (0.06 mL, 0.7 mmol). The resulting brown solution was purified by Prep. HPLC (Gemini C18, 20 to 40% (0.1% TFA in water)/(0.1% TFA in Acetonitrile)) to provide the desired product Example 43 (2.3 mg, 62%) as a colorless film. 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 2.16-2.21 (m, 1H) 2.25 (dd, J=7.96, 4.93 Hz, 1H) 3.33 (s, 3H) 3.33-3.38 (m, 1H) 3.83 (s, 3H) 4.16-4.27 (m, 2H) 4.61-4.86 (m, 3H) 5.60 (d, J=2.27 Hz, 1H) 6.62 (dd, J=8.59, 2.53 Hz, 1H) 6.83 (d, J=8.08 Hz, 1H) 7.03 (dd, J=8.59, 1.01 Hz, 1H) 7.48 (d, J=1.01 Hz, 1H) 7.87 (d, J=8.34 Hz, 1H) 8.17 (s, 1H); m/z (ESI, +ve ion) 500.1 (M+H)+.

Example 44. (1R,2S)-5′-methoxy-2-(3-{[5-methoxy-6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 4-(6-chloro-5-methoxy-pyrimidin-4-yl)-1,4-oxazepane

This compound was prepared using 4,6-Dichloro-5-methoxypyrimidine (200.0 mg, 1.120 mmol) and 1,4-Oxazepane (113.0 mg, 1.120 mmol). The residue was purified by column chromatography (ethyl acetate/hexane=0˜50%) to provide the title compound (203.0 mg, 75%) as a colorless oil.

Step B. tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[[5-methoxy-6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate

This compound was prepared using the procedure described in Example 5 from tert-butyl (1R,2S)-2-(3-amino-1-tert-butoxycarbonyl-indazol-6-yl)-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (30.0 mg, 0.0600 mmol) and 4-(6-chloro-5-methoxy-pyrimidin-4-yl)-1,4-oxazepane (14.7 mg, 0.0605 mmol). The residue was purified by column chromatography (ethyl acetate/hexane=0˜60%) to provide the title compound (13.0 mg, 31%) as a yellow oil.

Step C. (1R,2S)-5′-methoxy-2-[3-[[5-methoxy-6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino]-1H-indazol-6-yl]spiro[cyclopropane-1,3′-indoline]-2′-one

This compound was prepared using the procedure described in Example 5 from tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl-3-[[5-methoxy-6-(1,4-oxazepan-4-yl)pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (13.0 mg, 0.0179 mmol) and trifluoroacetic acid (0.14 mL, 1.8 mmol). The resulting brown solution was purified by Prep. HPLC (Gemini C18, 10 to 90% (0.1% TFA in water)/(0.1% TFA in Acetonitrile)) to provide Example 44 (6.8 mg, 72%) as a colorless film. 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 1.98-2.05 (m, 2H) 2.16-2.21 (m, 1H) 2.25 (dd, J=7.96, 4.93 Hz, 1H) 3.33 (s, 3H) 3.34-3.38 (m, 1H) 3.77-3.81 (m, 2H) 3.82 (s, 3H) 3.87 (t, J=5.31 Hz, 2H) 4.04-4.17 (m, 4H) 5.60 (d, J=2.53 Hz, 1H) 6.62 (dd, J=8.59, 2.53 Hz, 1H) 6.83 (d, J=8.34 Hz, 1H) 7.04 (dd, J=8.59, 1.01 Hz, 1H) 7.50 (d, J=1.01 Hz, 1H) 7.91 (dd, J=8.59, 0.76 Hz, 1H) 8.24 (s, 1H); m/z (ESI, +ve ion) 528.2 (M+H)+.

Example 45. (1R,2S)-2-(3-{[6-(azetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 4-(azetidin-1-yl)-6-chloro-pyrimidine

This compound was prepared from 4,6-dichloropyrimidine (200.0 mg, 1.340 mmol) and azetidine (76.6 mg, 0.09 mL, 1.34 mmol). The residue was purified by column chromatography (ethyl acetate/hexane=050%) to provide the title compound (148.0 mg, 65%) as a white solid.

Step B. tert-butyl (1R,2S)-2-[3-[[6-(azetidin-1-yl)pyrimidin-4-yl]amino]-1-tert-butoxycarbonyl-indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate

This compound was prepared using the procedure described in Example 5 from tert-butyl (1R,2S)-2-(3-amino-1-tert-butoxycarbonyl-indazol-6-yl)-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (36.0 mg, 0.0700 mmol) and 4-(azetidin-1-yl)-6-chloro-pyrimidine (12.3 mg, 0.0700 mmol). The residue was purified by column chromatography (ethyl acetate/hexane=0˜90%) to provide the title compound (5.0 mg, 11%) as a yellow oil.

Step C. (1R,2S)-2-[3-[[6-(azetidin-1-yl)pyrimidin-4-yl]amino]-1H-indazol-6-yl]-5′-methoxy-spiro[cyclopropane-1,3′-indoline]-2′-one

This compound was prepared using the procedure described in Example 5 from tert-butyl (1R,2S)-2-[3-[[6-(azetidin-1-yl)pyrimidin-4-yl]amino]-1-tert-butoxycarbonyl-indazol-6-yl]-5′-methoxy-2′-oxo-spiro[cyclopropane-1,3′-indoline]-1′-carboxylate (5.0 mg, 0.0044 mmol) and trifluoroacetic acid (0.06 mL, 0.8 mmol). The resulting brown solution was purified by Prep. HPLC (Gemini C18, 10 to 90% (0.1% TFA in water)/(0.1% TFA in Acetonitrile)) to provide the desired product Example 45 (1.4 mg, 40%) as a colorless film. 1 H NMR (400 MHz, METHANOL-d 4 ) δ ppm 2.15-2.20 (m, 1H) 2.24 (dd, J=7.96, 4.93 Hz, 1H) 2.49-2.59 (m, 2H) 3.32 (s, 3H) 3.33-3.37 (m, 1H) 4.16-4.44 (m, 4H) 5.58 (d, J=2.53 Hz, 1H) 5.82-6.34 (m, 1H) 6.62 (dd, J=8.59, 2.53 Hz, 1H) 6.83 (d, J=8.34 Hz, 1H) 7.01 (dd, J=8.72, 0.88 Hz, 1H) 7.45 (d, J=0.76 Hz, 1H) 7.77 (d, J=8.59 Hz, 1H) 8.35 (s, 1H); m/z (ESI, +ve ion) 454.3 (M+H)+.

Example 46. (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 6-[3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl]-5-chloropyrimidin-4-amine

A mixture of 6-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)pyrimidin-4-amine (110.00 mg, 0.392 mmol, 1.00 equiv) and NCS (62.85 mg, 0.470 mmol, 1.20 equiv) in AcOH (0.60 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the title compound (70 mg, 56.68%) as a yellow solid. m/z (ESI, +ve ion)=315.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.91 (d, J=1.0 Hz, 1H), 6.22 (s, 2H), 4.72-4.77 (m, 1H), 4.11-4.15 (m, 2H), 3.58-3.61 (m, 2H), 0.88 (s, 9H), 0.08 (s, 6H).

›Step B

To a stirred mixture of 6-[3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl]-5-chloropyrimidin-4-amine (47.77 mg, 0.152 mmol, 1.20 equiv) and tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate (80.00 mg, 0.127 mmol, 1.00 equiv) in toluene (5.00 mL) were added XantPhos (7.34 mg, 0.013 mmol, 0.10 equiv), Pd 2 (dba) 3 (11.61 mg, 0.013 mmol, 0.1 equiv) and Cs 2 CO 3 (82.62 mg, 0.254 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90° C. under nitrogen atmosphere. The product was diluted by water (10 mL), extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×5 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the title compound (15 mg, 14.96%) as a white solid. m/z (ESI, +ve ion)=818.45 [M+H] + .

Step C. (1R,2S)-2-(3-[[5-chloro-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl] amino]-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

A mixture of the compound from Step B (80.00 mg, 0.098 mmol, 1.00 equiv) and TFA (0.20 mL) in DCM (1 mL) was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (5 mM, NH 4 HCO 3 ). gradient: 10% to 50% in 60 min to afford Example 46 (5.03 mg, 10%) as a white solid. m/z (ESI, +ve ion)=504.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.68 (s, 1H), 10.43 (s, 1H), 8.91 (s, 1H), 7.83 (d, J=4 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.59-6.57 (m, 1H), 5.72-5.68 (m, 2H), 4.52-4.43 (m, 3H), 3.99-3.96 (m, 2H), 3.18-3.16 (m, 1H), 3.34 (s, 3H), 2.53-2.50 (m, 1H), 1.99-1.95 (m, 1H).

Example 47. (1R,2S)-2-(3-{[5-chloro-6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 5-chloro-6-(3-methoxyazetidin-1-yl) pyrimidin-4-amine

A mixture of 6-(3-methoxyazetidin-1-yl)pyrimidin-4-amine (200.00 mg, 1.110 mmol, 1.00 equiv) and NCS (177.84 mg, 1.332 mmol, 1.2 equiv) in ACN (10.00 mL) was stirred for 16 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of Water (10 mL) at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to the title compound (220 mg, 92.35%) as a white solid. m/z (ESI +ve ion)=215.10 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 5.08 (s, 2H), 4.52 (d, J=5.7 Hz, 1H), 4.35-4.17 (m, 4H), 3.35 (s, 3H).

Step B. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[[5-chloro-6-(3-methoxyazetidin-1-yl) pyrimidin-4-yl] amino] indazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate

To a stirred mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate (100.00 mg, 0.158 mmol, 1.00 equiv) and 5-chloro-6-(3-methoxyazetidin-1-yl) pyrimidin-4-amine (40.79 mg, 0.190 mmol, 1.2 equiv) in toluene (2.50 mL) were added Pd 2 (dba) 3 (14.50 mg, 0.016 mmol, 0.1 equiv) and XantPhos (9.16 mg, 0.016 mmol, 0.1 equiv) and Cs 2 CO 3 (103.19 mg, 0.317 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched by the addition of Water (10 mL). The resulting mixture was extracted with DCM (3×15 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10/1) to afford the title compound (62 mg, 54.51%) as a yellow solid. m/z=718.25 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J=11.5 Hz, 1H), 7.87-7.70 (m, 2H), 7.62 (s, 1H), 7.55 (m, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.70 (m, 1H), 5.62 (d, J=2.7 Hz, 1H), 4.63-4.58 (m, 1H), 4.37-4.26 (m, 3H), 3.52 (t, J=8.7 Hz, 1H), 3.38 (d, J=10.9 Hz, 4H), 3.35 (s, 3H), 2.38 (m, 1H), 2.13 (m, 1H), 1.70 (d, J=2.6 Hz, 18H)

Step C. (1R,2S)-2-(3-[[5-chloro-6-(3-methoxyazetidin-1-yl)pyrimidin-4-yl]amino]-1H-indazol-6-yl)-5-methoxy-1H-spiro[cyclopropane-1,3-indol]-2-one

A mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[[5-chloro-6-(3-methoxyazetidin-1-yl) pyrimidin-4-yl]amino] indazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate (62.00 mg, 0.086 mmol, 1.00 equiv) and TFA (2.00 mL, 0.018 mmol, 0.20 equiv) in DCM (4.00 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 mm×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 48% B in 8 min, 254 nm; RT1: 7.28 min to afford Example 47 (25.0 mg, 55.91%) as a white solid. m/z (ESI, +ve ion)=518.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.68 (s, 1H), 10.42 (s, 1H), 8.93 (s, 1H), 7.83 (s, 1H), 7.53-7.22 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.58 (m, 1H), 5.71 (d, J=2.7 Hz, 1H), 4.44 (m, 2H), 4.25 (s, 1H), 4.05 (m, 2H), 3.17 (m, 7H), 2.32 (d, J=7.5 Hz, 1H), 1.98 (m, 1H).

Example 48. (1R,2S)-2-(3-{[2-chloro-1-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Example 49. (1R,2S)-2-(3-{[4-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 4-(2,6-dichloro-5-methoxypyrimidin-4-yl) morpholine

A mixture of 2,4,6-trichloro-5-methoxypyrimidine (200.00 mg, 0.937 mmol, 1.00 equiv) and morpholine (97.96 mg, 1.124 mmol, 1.2 equiv) in THF (5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of Water (10 mL) at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20-40 μm, 80 g; Mobile Phase A: Water (plus 5 mM NH 4 HCO 3 ); Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient: 40% B-60% B in 20 min; Detector: 254 nm. The fractions containing desired product were collected at 54% B and concentrated under reduced pressure to afford the title compound (130 mg, 52.53%) as an off-white solid. m/z (ESI +ve ion)=263.95 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 3.94-3.87 (m, 4H), 3.83-3.77 (m, 4H), 3.75 (s, 3H).

Step B. The mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[[2-chloro-5-methoxy-6-(morpholin-4-yl) pyrimidin-4-yl]amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (16b) and tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((4-chloro-5-methoxy-6-morpholinopyrimidin-2-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To a stirred mixture of 4-(2,6-dichloro-5-methoxypyrimidin-4-yl) morpholine (30.34 mg, 1.20 equiv) and tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl) indazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate (50.00 mg, 1.00 equiv) in toluene (1.25 mL) were added Pd 2 (dba) 3 (8.79 mg, 0.10 equiv) and XantPhos (5.56 mg, 0.10 equiv) and Cs 2 CO 3 (62.65 mg, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA 1/1) to afford a mixture of the title compounds (50 mg, 70%) as a yellow oil. m/z (ESI +ve ion)=748.35 [M+H] + .

Step C. (1R,2S)-2-(3-((2-chloro-5-methoxy-6-morpholinopyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one and (1R,2S)-2-(3-[[4-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-2-yl]amino]-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

The mixture of compounds from Step B (50.00 mg) in TFA (2.00 mL) and DCM (4.00 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min. Gradient: 20% B to 50% B in 8 min, 220 nm; RT1:7.30 min; RT2: 7.75 min) to afford Example 48 (8.1 mg) as an off-white solid. m/z (ESI +ve ion)=548.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.67 (s, 1H), 10.41 (s, 1H), 9.21 (s, 1H), 7.61-7.26 (m, 2H), 6.93 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.58 (m, 1H), 5.70 (d, J=1.6 Hz, 1H), 3.71 (t, J=4.5 Hz, 4H), 3.65 (s, 3H), 3.62 (t, J=4.6 Hz, 4H), 3.19 (t, J=8.5 Hz, 3H), 3.18 (m, 1H), 2.32 (m, 1H), 1.99 (m, 1H). Compound Example 49 (8.2 mg) was also obtained as an off-white solid from the collection of fractions from the HPLC. m/z (ESI +ve ion)=548.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.46 (s, 1H), 10.41 (s, 1H), 9.43 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.59 (m, 1H), 5.64 (d, J=2.0 Hz, 1H), 3.59 (s, 3H), 3.52 (m, 6H), 3.37 (s, 2H), 3.31 (m, 3H) 3.17 (t, J=7.2 Hz, 1H), 2.31 (m, 1H), 1.97 (m, 1H).

Example 50. (1R,2S)-2-(3-{[1-(2-hydroxyethyl)-3-methoxy-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 4-bromo-3-methoxy-1-[2-(oxan-2-yloxy)ethyl]pyrazole

To the mixture of 4-bromo-3-methoxy-1H-pyrazole (500.00 mg, 2.825 mmol, 1.00 equiv) in DMF (5.00 mL) was added Cs 2 CO 3 (1104.47 mg, 3.390 mmol, 1.2 equiv) at 25° C. After stirred for 30 min, 2-(2-bromoethoxy)oxane (708.75 mg, 3.390 mmol, 1.2 equiv) was added. The mixture was stirred for 3 h. The reaction was diluted with water (50 mL) and extracted with EA (20 mL×3). The combined organic layer was washed with brine (50 mL×2), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column eluted with 0-50% EA in PE to give the title compound (750 mg, 82.65%) as a colorless oil. m/z (ESI+ve ion)=305.00 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) δ 7.35 (s, 1H), 4.55 (t, J=3.3 Hz, 1H), 4.16-4.10 (m, 2H), 4.05-3.97 (m, 1H), 3.96 (s, 3H), 3.75-3.65 (m, 2H), 3.52-3.45 (m, 1H), 1.85-1.52 (m, 6H).

Step B. tert-butyl (1R,2S)-2-[1-tert-butoxycarbonyl)-3-([3-methoxy-1-[2-(oxan-2-yloxy)ethyl]pyrazol-4-yl]amino)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (110.00 mg, 0.211 mmol, 1.00 equiv) and 4-bromo-3-methoxy-1-[2-(oxan-2-yloxy)ethyl]pyrazole (77.38 mg, 0.253 mmol, 1.20 equiv) in a dry dioxane (2.00 mL) were added Cs 2 CO 3 (137.69 mg, 0.422 mmol, 2.00 equiv), EPhos (22.60 mg, 0.042 mmol, 0.20 equiv) and EPhos Pd G 4 (38.82 mg, 0.042 mmol, 0.20 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 12 h. The solvent was removed under reduced pressure. The residue was purified by Prep-TLC (rinsed with PE/EA=2/1) to give the title compound (15 mg, 9.05%) as yellow oil. m/z (ESI +ve ion)=745.55 [M+H] + .

Step C. (1R,2S)-2-(3-[[1-(2-hydroxyethyl)-3-methoxypyrazol-4-yl]amino]-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

To a mixture solution of TFA (0.40 mL), H 2 O (0.20 mL) and THF (0.40 mL) was added tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-([3-methoxy-1-[2-(oxan-2-yloxy)ethyl]pyrazol-4-yl]amino)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (14.00 mg, 0.019 mmol, 1.00 equiv). The mixture was stirred at 50° C. for 12 h. The solvent was removed under reduced pressure. The residue was purified with the following conditions: Column: XBridge Prep OBD C18 Column, 19×250 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 15% B to 35% B in 10 min; Detector: 254 & 220 nm; RT1: 8.62 min. The product-containing fractions was combined and concentrated to give Example 50 (2.7 mg) as a white solid. m/z (ESI +ve ion)=461.30 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.73 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 6.82 (t, J=8.4 Hz, 2H), 6.64-6.61 (m, 1H), 5.61 (d, J=2.4 Hz, 1H), 4.07-4.04 (m, 2H), 3.93 (s, 3H), 3.88-3.86 (m, 2H), 3.35 (s, 1H), 3.30 (s, 3H), 2.23-2.14 (m, 2H).

Example 51. (1R,2S)-2-(3-{[2-cyclopropyl-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 2-cyclopropyl-6-hydroxy-5-methoxy-3H-pyrimidin-4-one

Sodium 2-methylpropan-2-olate (1.48 g 15.419 mmol, 2.50 equiv) was added to MeOH (10.00 mL) in portions over 20 min at 0° C. To this solution were added 1,3-dimethyl 2-methoxypropanedioate (0.10 g, 0.617 mmol, 1.00 equiv) 1,3-dimethyl 2-methoxypropanedioate (1.00 g, 6.167 mmol, 1.00 equiv) and cyclopropanecarboximidamide (0.52 g, 6.167 mmol, 1.00 equiv). The mixture was heated to reflux for 12 h and then cooled to 0° C. The PH was adjusted to ˜4 with Conc. HCl and filtered. The solid was collected and lyophilized to give crude the title compound (500 mg, crude) as a white solid. m/z (ESI +ve ion)=183.10 [M+H] + .

›Step B. 4,6-dichloro-2-cyclopropyl-5-methoxypyrimidine

A mixture of crude 2-cyclopropyl-6-hydroxy-5-methoxy-3H-pyrimidin-4-one (500.00 mg) in POCl 3 (5.00 mL) was stirred for 3 h at 100° C. After cooled to room temperature, the mixture solution was added dropwise to cooled sat. aq. NaHCO 3 (150 mL). The mixture was extracted with EA (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column eluted with 0-20% EA in PE to give the title compound (370 mg) as a colorless oil. m/z (ESI +ve ion)=219.00 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 3.93 (s, 3H), 2.23-2.17 (m, 1H), 1.18-1.09 (m, 4H).

›Step C. 4-(6-chloro-2-cyclopropyl-5-methoxypyrimidin-4-yl)morpholine

To the mixture of 4,6-dichloro-2-cyclopropyl-5-methoxypyrimidine (370.00 mg, 1.689 mmol, 1.00 equiv) and TEA (205.09 mg, 2.027 mmol, 1.20 equiv) in EtOH (5.00 mL) was added morpholine (176.57 mg, 2.027 mmol, 1.20 equiv). The mixture was stirred at 25° C. for 12 h. The solvent was moved and the residue was purified by silica gel column, eluted with 0-50% EA in PE to give the title compound (280 mg, 58.39%) as colorless oil. m/z (ESI +ve ion)=270.15 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 3.82-3.73 (m, 8H), 3.72 (s, 3H), 2.08-2.01 (m, 1H), 1.04-0.94 (m, 4H).

Step D. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-cyclopropyl-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (80 mg, 0.154 mmol, 1.00 equiv) and 4-(6-chloro-2-cyclopropyl-5-methoxypyrimidin-4-yl)morpholine (49.74 mg, 0.185 mmol, 1.2 equiv) in a dry dioxane (2 mL) were added Cs 2 CO 3 (100.14 mg, 0.308 mmol, 2 equiv), CPhos (13.42 mg, 0.031 mmol, 0.2 equiv) and Pd 2 (dba) 3 ·CHCl 3 (31.81 mg, 0.031 mmol, 0.2 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h. The solvent was removed under reduced pressure. The residue was purified by silica gel column eluted with 0-100% of EA in PE to give crude the title compound (60 mg, 51.79%) as a white solid. m/z (ESI +ve ion)=754.55 [M+H] + .

Step E. (1R,2S)-2-(3-[[1-(2-hydroxyethyl)-3-methoxypyrazol-4-yl]amino]-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

The mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-cyclopropyl-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (60.00 mg, 0.060 mmol, 1.00 equiv) in DCM (3.00 mL) and TFA (0.30 mL) was stirred for 4 h. The solvent was removed under reduced pressure and the residue was purified with the following conditions: Column: XBridge Prep OBD C18 Column, 19×250 mm 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 35% B to 55% B in 10 min; Detector: 254&220 nm; RT1: 8.62 min. The product-containing fractions was combined and concentrated to give Example 51 (27.1 mg, 77.28%) as a white solid. m/z (ESI +ve ion)=554.40 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.59 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 6.92-6.89 (m, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.63-6.61 (m, 1H), 5.65 (d, J=2.8 Hz, 1H), 3.84-3.79 (m, 4H), 3.74 (s, 3H), 3.67-3.64 (m, 4H), 3.38-3.36 (m, 1H), 3.32 (s, 3H), 2.25-2.23 (m, 1H), 2.20-2.17 (m, 1H), 1.78-1.73 (m, 1H), 0.79-0.77 (m, 2H), 0.74-0.68 (m, 2H).

Example 52. (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxypyrimidin-4-yl}amino)-1H-indazol-6-yl]-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. (2S,6R)-4-(6-Chloro-5-methoxypyrimidin-4-yl)-2,6-dimethylmorpholine

To an oven-dried flask was added 4,6-dichloro-5-methoxypyrimidine (1.00 g, 5.59 mmol) followed by DMSO (19 mL), K 2 CO 3 (1.16 g, 8.34 mmol), and cis-2,6-dimethylmorpholine (0.64 mL, 5.9 mmol). The reaction mixture was stirred at room temperature for 1 h at which time it was quenched with sat. aqueous NH 4 Cl. The mixture was extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried with MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (5% to 30% EtOAc/hexanes, gradient elution) to afford the title compound (1.30 g, 90%) as a white solid. m/z (ESI, +ve ion)=258.2 [M+H] + .

Step B. Tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((6-((2S,6R)-2,6-dimethylmorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To an oven-dried flask was added (2S,6R)-4-(6-Chloro-5-methoxypyrimidin-4-yl)-2,6-dimethylmorpholine (36.4 mg, 0.141 mmol), tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (70.0 mg, 0.135 mmol), rac-binap Pd G4 (13.5 mg, 0.0134 mmol), BINAP (8.40 mg, 0.0134 mmol), Tripotassium phosphate (57.0 mg, 0.270 mmol) and 1,4-dioxane (3.4 mL). The mixture was degassed with bubbling argon for 10 min. At this time, the reaction mixture was heated to 70° C. for 2 h. The reaction mixture was cooled was cooled to room temperature and diluted with EtOAc and washed with sat. aqueous NaHCO 3 . The aqueous layer was extracted an additional three times with EtOAc. Combined organic layers were washed with brine, dried with MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (0% to 80% EtOAc/hexanes, a gradient elution) to provide the title compound (30 mg, 30%) as a white foam. m/z (ESI, +ve ion)=742.3 [M+H] + .

To an oven-dried flask was added tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((6-((2S,6R)-2,6-dimethylmorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (30 mg, 0.040 mmol) followed DCM (2.0 mL) and trifluoroacetic acid (0.15 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 2 h. At this time, the mixture was concentrated and purified by prep HPLC (20% to 40% ACN/H 2 O, 0.1% TFA modifier, gradient elution) to afford Example 52 (8.0 mg, 37%) as a white amorphous solid after lyophilization. m/z (ESI, +ve ion)=542.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ=12.99-12.60 (m, 1H), 10.45 (s, 1H), 9.81 (br s, 1H), 8.03 (s, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.44 (s, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.59 (dd, J=2.5, 8.6 Hz, 1H), 5.76-5.69 (m, 1H), 4.40 (br d, J=12.9 Hz, 2H), 3.69 (s, 3H), 3.68-3.59 (m, 2H), 3.34 (s, 3H), 3.19 (t, J=8.5 Hz, 1H), 2.72 (dd, J=10.9, 12.9 Hz, 2H), 2.34 (dd, J=4.7, 8.0 Hz, 1H), 1.99 (dd, J=4.7, 9.0 Hz, 1H), 1.14 (d, J=6.3 Hz, 6H).

Example 53. (1R,2S)-2-(3-((5-chloro-6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

›Step A. 4-(6-Amino-5-chloropyrimidin-4-yl)thiomorpholine 1,1-dioxide

To an oven-dried flask was added 5,6-dichloro-4-pyrimidinamine (1.00 g, 6.10 mmol) followed by toluene (9.0 mL) and thiomorpholine dioxide (0.850 mL, 6.31 mmol). The reaction mixture was heated to 80° C. for 16 hours and then cooled to room temperature. The reaction was then concentrated to a white solid to give the title compound (700 mg, 44%) as a white amorphous solid.

Step B. Tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((5-chloro-6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To an oven-dried flask was added tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (102 mg, 0.162 mmol), 4-(6-amino-5-chloropyrimidin-4-yl)thiomorpholine 1,1-dioxide (45 mg, 0.167 mmol), Xantphos Pd G4 (15.6 mg, 0.0162 mmol), and 1,4-dioxane (1.6 mL). The mixture was degassed with bubbling argon for 10 min. At this time, Cs 2 CO 3 (105 mg, 0.323 mmol) was added and the reaction mixture was heated to 100° C. for 1 h. The reaction mixture was cooled was cooled to room temperature and diluted with EtOAc and washed with sat. aqueous NaHCO 3 . The aqueous layer was extracted an additional three times with EtOAc. Combined organic layers were washed with brine, dried with MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (0% to 50% acetone/hexanes, a gradient elution) to provide the title compound (30 mg, 24%) as a white foam. m/z (ESI, +ve ion)=767.2 [M+H] + .

›Step C

To an oven-dried flask was added tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((5-chloro-6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (30 mg, 0.039 mmol) followed DCM (2.0 mL) and trifluoroacetic acid (0.15 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 2 h. At this time, the mixture was concentrated and purified by prep HPLC (20% to 40% ACN/H 2 O, 0.1% TFA modifier, gradient elution) to afford Example 53 (5.0 mg, 23%) as a white amorphous solid after lyophilization. m/z (ESI, +ve ion)=566.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ=12.75 (br s, 1H), 10.43 (s, 1H), 9.29 (s, 1H), 8.01 (s, 1H), 7.42 (s, 1H), 7.35 (d, J=8.3 Hz, 1H), 6.90 (dd, J=1.1, 8.5 Hz, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.60-6.55 (m, 1H), 5.71 (d, J=2.8 Hz, 1H), 3.94 (br s, 4H), 3.33 (s, 3H), 3.32-3.26 (m, 4H), 3.21-3.15 (m, 1H), 2.33 (dd, J=4.7, 8.0 Hz, 1H), 2.01-1.95 (m, 1H).

Example 54. (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

›Step A. 4-(6-Chloro-5-methoxypyrimidin-4-yl)thiomorpholine 1,1-dioxide

To an oven-dried flask was added 4,6-dichloro-5-methoxypyrimidine (1.00 g, 5.59 mmol) followed by DMSO (19 mL), K 2 CO 3 (1.16 g, 8.34 mmol), and thiomorpholine dioxide (0.75 mL, 5.6 mmol). The reaction mixture was stirred at room temperature for overnight at which time it was quenched with sat. aqueous NH 4 Cl. The mixture was extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried with MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (5% to 30% EtOAc/hexanes, gradient elution) to afford the title compound (973 mg, 63%) as a white solid. m/z (ESI, +ve ion)=278.0 [M+H] + .

Step B. Tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((6-(1,1-dioxidothiomorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-4-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To an oven-dried flask was added 4-(6-Chloro-5-methoxypyrimidin-4-yl)thiomorpholine 1,1-dioxide (74.7 mg, 0.2689 mmol), tert-butyl (1R,2S)-2-(3-amino-1-(tert-butoxycarbonyl)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1-carboxylate (70.0 mg, 0.135 mmol), Xantphos Pd G4 (13.0 mg, 0.134 mmol), and 1,4-dioxane (1.3 mL). The mixture was degassed with bubbling argon for 10 min. At this time. Cs 2 CO 3 (87.6 mg, 0.269 mmol) was added and the reaction mixture was heated to 100° C. for 2 h. The reaction mixture was cooled was cooled to room temperature and diluted with EtOAc and washed with sat. aqueous NaHCO 3 . The aqueous layer was extracted an additional three times with EtOAc. Combined organic layers were washed with brine, dried with MgSO 4 , filtered, and concentrated. The residue was purified by column chromatography (0% to 80% EtOAc/hexanes, a gradient elution) to provide the title compound (19 mg, 19%) as a white foam. m/z (ESI, +ve ion)=762.2 [M+H] + .

›Step C

To an oven-dried flask was added tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((6-(1,1-dioxidothiomorpholino)-5-methoxypyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (19 mg, 0.025 mmol) followed DCM (1.25 mL) and trifluoroacetic acid (0.10 mL, 1.3 mmol). The reaction mixture was stirred at room temperature for 3 h. At this time, the mixture was concentrated and purified by prep HPLC (20% to 40% ACN/H 2 O, 0.1% TFA modifier, gradient elution) to afford Example 54 (10 mg, 71%) as a white amorphous solid after lyophilization. m/z (ESI, +ve ion)=562.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ=12.78 (br s, 1H), 10.45 (s, 1H), 9.57 (br s, 1H), 7.99 (s, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.43 (s, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.75 (d, J=8.3 Hz, 1H), 6.59 (dd, J=2.7, 8.5 Hz, 1H), 5.73 (d, J=2.5 Hz, 1H), 4.15 (br s, 4H), 3.71 (s, 3H), 3.34 (s, 3H), 3.30-3.24 (m, 4H), 3.22-3.16 (m, 1H), 2.34 (dd, J=4.7, 8.0 Hz, 1H), 1.99 (dd, J=4.7, 9.0 Hz, 1H).

Example 55. (1R,2S)-2-(3-{[5-(2-hydroxyethyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. tert-butyl N-(5-bromo-3-methoxypyrazin-2-yl)-N-(tert-butoxycarbonyl)carbamate

To a stirred mixture of 5-bromo-3-methoxypyrazin-2-amine (2000.00 mg, 9.803 mmol, 1.00 equiv) and Boc 2 O (3209.09 mg, 14.705 mmol, 1.50 equiv) in THF (5.00 mL) were added DMAP (119.76 mg, 0.980 mmol, 0.10 equiv) and NaOH (784.15 mg, 19.606 mmol, 2.00 equiv). The resulting mixture was stirred for 2 hours at RT under N 2 atmosphere. The resulting mixture was extracted with EA (3×60 mL). The combined organic layers were washed with sat. brine (3×25 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (3:1) to afford the title compound (1.7 g, 42.5%) as white solid. m/z (ESI +ve ion-100)=403.85 [M+H−100] +

Step B. tert-butyl N-(tert-butoxycarbonyl)-N-{5-[(E)-2-ethoxyethenyl]-3-methoxypyrazin-2-yl}carbamate

To a stirred mixture of tert-butyl N-(5-bromo-3-methoxypyrazin-2-yl)-N-(tert-butoxycarbonyl)carbamate (990 mg, 2.449 mmol, 1.00 equiv) and tributyl[(E)-2-ethoxyethenyl]stannane (1768.85 mg, 4.898 mmol, 2 equiv) in DMF (15 mL, 193.826 mmol, 79.15 equiv) were added LiCl (363.37 mg, 8.572 mmol, 3.5 equiv) and Pd(PPh 3 ) 2 Cl 2 (171.89 mg, 0.245 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1.5 h at 80° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched by the addition of Water (15 mL) at room temperature. The resulting mixture was extracted with DCM (3×15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford the title compound (730 mg, 75.38%) as a white solid. m/z (ESI +ve ion)=396.10 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 6.53 (d, J=7.1 Hz, 1H), 5.40 (d, J=7.1 Hz, 1H), 4.11 (m, 2H), 3.97 (s, 3H), 1.42 (s, 21H).

›Step C. tert-butyl N-(tert-butoxycarbonyl)-N-[5-(2-hydroxyethyl)-3-methoxypyrazin-2-yl] carbamate

To a stirred mixture of tert-butyl N-(tert-butoxycarbonyl)-N-{5-[(E)-2-ethoxyethenyl]-3-methoxypyrazin-2-yl} carbamate (720.00 mg, 1.821 mmol, 1.00 equiv) in THF (5.50 mL) were added mercuric acetate (696.26 mg, 2.18 mmol, 1.20 equiv) in water (6.55 mL) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 15 min at 0° C. under nitrogen atmosphere. To the above mixture was added NaBH 4 (275.53 mg, 7.284 mmol, 4.00 equiv) in saturated K 2 CO 3 (aq.) (5.44 mL) dropwise at room temperature. The resulting mixture was stirred for additional 20 min at room temperature. The reaction was quenched by the addition of Water (10 mL). The resulting mixture was extracted with DCM (3×15 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1/1) to afford the title compound (600 mg, 89.21%) as a colorless solid. m/z (ESI +ve ion)=370.20 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ7.93 (s, 1H), 4.07-3.98 (m, 6H), 3.01 (t, J=5.8 Hz, 2H), 1.44 (s, 18H).

Step D. tert-butyl N-(tert-butoxycarbonyl)-N-(6-[2-[(tert-butyldimethylsilyl) oxy]ethyl]-3-methoxypyrazin-2-yl)carbamate

To a stirred mixture of tert-butyl N-(tert-butoxycarbonyl)-N-[5-(2-hydroxyethyl)-3-methoxypyrazin-2-yl] carbamate (166.00 mg, 0.449 mmol, 1.00 equiv) in DMF (4.00 mL) were added 1H-imidazole (73.42 mg, 0.000 mmol, 2.40 equiv) and TBDMS-Cl (81.27 mg, 0.539 mmol, 1.20 equiv) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (15 mL) at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (6/1) to afford the title compound (105 mg, 48.31%) as a yellow oil. m/z (ESI +ve ion)=484.30 [M+H] + .

›Step E. 6-[2-[(tert-butyl dimethylsilyl)oxy]ethyl]-3-methoxypyrazin-2-amine

Into a 50 mL round-bottom flask were added tert-butyl N-(tert-butoxycarbonyl)-N-(6-[2-[(tert-butyldimethylsilyl) oxy]ethyl]-3-methoxypyrazin-2-yl)carbamate (560.00 mg, 1 equiv) and 1,1,1,3,3,3-hexafluoropropan-2-ol (20.00 mL) at room temperature. The resulting mixture was stirred for 16 h at 60° C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (2/1) to afford the title compound (237 mg, 72.22%) as a white solid. m/z (ESI +ve ion)=284.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.33 (s, 1H), 5.98 (s, 2H), 3.85 (d, J=15.4 Hz, 5H), 2.63 (m, 2H), 0.81 (s, 9H), 0.06 (s, 6H).

Step F. tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methoxypyrazin-2-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To a stirred mixture of tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-iodo-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (100.00 mg, 0.158 mmol, 1.00 equiv) and 6-[2-[(tert-butyl dimethylsilyl)oxy]ethyl]-3-methoxypyrazin-2-amine (53.86 mg, 0.190 mmol, 1.20 equiv) in toluene (2.50 mL) were added Pd 2 (dba) 3 (14.50 mg, 0.016 mmol, 0.1 equiv) and XantPhos (9.16 mg, 0.016 mmol, 0.1 equiv) and Cs 2 CO 3 (103.19 mg, 0.317 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere and cooled down to room temperature. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3/1) to afford the title compound (84 mg, 67.40%) as a yellow solid. m/z (ESI +ve ion)=787.60 [M+H] + .

Step G: (1R,2S)-2-(3-((5-(2-hydroxyethyl)-3-methoxypyrazin-2-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

A mixture of tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((5-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methoxypyrazin-2-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (84.00 mg, 0.107 mmol, 1.00 equiv) and TFA (2.0) mL, 26.926 mmol, 252.27 equiv) in DCM (4.00 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with MeOH (5.00 mL). To the above mixture was added K 2 CO 3 (50.00 mg, 0.362 mmol, 3.39 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 h at room temperature then concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30 mm×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 45% B in 8 min, 254 nm; RT1: 6.58 min to afford Example 55 (21.5 mg, 42.63%) as a white solid. m/z (ESI +ve ion)=473.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.51 (s, 1H), 10.43 (s, 1H), 8.63 (s, 1H), 7.39 (m, 3H), 6.87 (d, J=9.2 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.59 (m, 1H), 5.72 (d, J=2.4 Hz, 1H), 4.60 (m, 1H), 3.97 (s, 3H), 3.68 (q, J=6.5 Hz, 2H), 3.33 (s, 3H), 3.35 (d, J=15.2 Hz, 2H), 2.51 (d, J=1.6 Hz, 2H), 1.98 (m, 1H).

Example 56. (1R,2S)-2-(3-{[6-(2-hydroxyethyl)-3-methoxypyrazin-2-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. tert-butyl N-(tert-butoxycarbonyl)-N-(6-chloro-3-methoxypyrazin-2-yl)carbamate

To a stirred mixture of 6-chloro-3-methoxypyrazin-2-amine (1500.00 mg, 9.400 mmol, 1.00 equiv) and Boc 2 O (3077.37 mg, 14.100 mmol, 1.5 equiv) in THE (10 mL) were added DMAP (114.84 mg, 0.940 mmol, 0.1 equiv) and Et 3 N (1902.43 mg, 18.801 mmol, 2 equiv). The resulting mixture was stirred for 2 hours at room temperature under N 2 atmosphere. The resulting mixture was extracted with EA (3×20 mL). The combined organic layers were washed with brine (3×15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (4:1) to afford the title compound (2.8 g, 82%) as a white solid. m/z (ESI, +ve ion)=204.1 [M+H−100−56] + .

Step B. tert-butyl N-(tert-butoxycarbonyl)-N-[6-[(E)-2-ethoxyethenyl]-3-methoxypyrazin-2-yl]carbamate

To a stirred mixture of tert-butyl N-(tert-butoxycarbonyl)-N-(6-chloro-3-methoxypyrazin-2-yl)carbamate (410.00 mg, 1.139 mmol, 1.00 equiv) and Pd(PPh 3 ) 2 Cl 2 (79.98 mg, 0.114 mmol, 0.10 equiv) in DMF (10.00 mL) were added tributyl[(E)-2-ethoxyethenyl]stannane (823.05 mg, 2.278 mmol, 2.00 equiv) and LiCl (169.08 mg, 3.987 mmol, 3.50 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1.5 h at 80° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched by the addition of water (15 mL) at room temperature. The resulting mixture was extracted with DCM (3×15 mL). The combined organic layers were washed with brine (2×25 mL). dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20-40 μm, 120 g; Mobile Phase A: Water (plus 5 mM NH 4 HCO 3 ); Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 50% B-60% B in 15 min: Detector: 254 nm. The fractions containing desired product were collected at 61% B and concentrated under reduced pressure to afford the title compound (400 mg, 88.77%) as a yellow oil. m/z=396.30 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.76 (s, 1H), 6.41 (d, J=7.0 Hz, 1H), 5.38 (d, J=7.0 Hz, 1H), 4.12-3.92 (m, 5H), 1.39 (d, J=3.2 Hz, 21H).

›Step C. tert-butyl N-(tert-butoxycarbonyl)-N-[6-(2-hydroxyethyl)-3-methoxypyrazin-2-yl] carbamate

To a stirred mixture of tert-butyl N-(tert-butoxycarbonyl)-N-[6-[(E)-2-ethoxyethenyl]-3-methoxypyrazin-2-yl] carbamate (333.00 mg, 0.842 mmol, 1.00 equiv) in THF (2.53 mg) was added mercuric acetate (322.02 mg, 1.010 mmol, 1.20 equiv) in water (3.03 mL) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 15 min at 0° C. under nitrogen atmosphere. To the above mixture was added NaBH 4 (127.43 mg, 3.368 mmol, 4.00 equiv) in saturated K 2 CO 3 , aq. (3.00 mL) dropwise at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20-40 μm, 80 g; Mobile Phase A: Water (plus 5 mM NH 4 HCO 3 ); Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 40% B-60% B in 20 min; Detector: 254 nm. The fractions containing desired product were collected at 55% B and concentrated under reduced pressure to afford the title compound (217 mg, 69.76%) as an off-white solid. m/z=370.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (s, 1H), 4.68 (t, J=5.2 Hz, 1H), 3.93 (s, 3H), 3.68 (m, 2H), 2.83 (t, J=6.7 Hz, 2H), 1.35 (s, 18H).

Step D. tert-butyl N-(tert-butoxycarbonyl)-N-(6-[2-[(tert-butyldimethylsilyl) oxy]ethyl]-3-methoxypyrazin-2-yl)carbamate

To a stirred mixture of tert-butyl N-(tert-butoxycarbonyl)-N-[6-[(E)-2-ethoxyethenyl]-3-methoxypyrazin-2-yl] carbamate (182.00 mg, 0.493 mmol, 1.00 equiv) in DMF (4.55 mL) was added 1H-imidazole (80.49 mg, 0.000 mmol, 2.40 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added TBS-Cl (89.11 mg, 0.592 mmol, 1.20 equiv) at 0° C. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (4:1) to afford the title compound (238 mg, 99.88%) as a dark yellow oil. m/z (ESI +ve ion)=484.25 [M+H] + .

›Step E. 6-[2-[(tert-butyldimethylsilyl) oxy]ethyl]-3-methoxypyrazin-2-amine

Into a 50 mL round-bottom flask were added tert-butyl N-(tert-butoxycarbonyl)-N-[6-[(E)-2-ethoxyethenyl]-3-methoxypyrazin-2-yl] carbamate (218.00 mg, 0.450 mmol) and 1,1,1,3,3,3-hexafluoropropan-2-ol (5.50 mL) at room temperature. The resulting mixture was stirred for 16 h at 60° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3/1) to afford the title compound (122 mg, 94%) as an off-white solid. m/z (ESI, +ve ion)=284.10 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 7.50-7.11 (m, 3H), 4.05-3.75 (m, 5H), 2.76 (t, J=6.6 Hz, 2H), 1.01-0.75 (m, 9H), 0.01 (d, J=0.7 Hz, 6H).

Step F. tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(6-[2-[(tert-butyldimethylsilyl) oxy]ethyl]-3-methoxypyrazin-2-yl)amino]indazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate

To a stirred mixture of 6-[2-[(tert-butyldimethylsilyl) oxy]ethyl]-3-methoxypyrazin-2-amine (53.80 mg, 1.20 equiv) and tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1 carboxylate (100.00 mg, 1.00 equiv) in toluene (2.5 mL) were added Pd 2 (dba) 3 (14.5 mg, 0.1 equiv) and XantPhos (9.15 mg, 0.1 equiv) and Cs 2 CO 3 (103.25 mg, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3/1) to afford the title compound (84.1 mg, 67.48%) as a dark yellow solid. m/z (ESI, +ve ion)=787.30 [M+H] + .

Step G. (1R,2S)-2-(3-[[6-(2-hydroxyethyl)-3-methoxypyrazin-2-yl]amino]-1H-indazol-6-yl)-5-methoxy-1H-spiro[cyclopropane-1,3-indol]-2-one

A mixture of tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(6-[2-[(tert-butyldimethylsilyl) oxy]ethyl]-3-methoxypyrazin-2-yl)amino]indazol-6-yl]-5-methoxy-2-oxospiro[cyclopropane-1,3-indole]-1-carboxylate (84.00 mg, 0.107 mmol, 1.00 equiv) and TFA (2.00 mL, 0.018 mmol, 0.16 equiv) in DCM (4.00 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. To the above mixture was added K 2 CO 3 (50.00 mg, 0.362 mmol, 3.39 equiv) in MeOH (5.00 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 mm×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 43% B in 8 min, 254 nm; RT1: 7.22 min to afford Example 56 (24.5 mg, 48.09%) as a white solid. m/z (ESI, +ve ion)=473.20 [M+H] + , 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.50 (s, 1H), 10.40 (s, 1H), 8.75 (s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.35 (d, J=6.0 Hz, 2H), 6.86 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.58 (m, 1H), 5.67 (d, J=2.0 Hz, 1H), 4.48 (m, 1H), 3.96 (s, 3H), 3.52 (d, J=6.2 Hz, 2H), 3.49 (m, 4H), 3.19 (m, 2H), 2.29 (m, 1H), 1.98 (m, 1H).

Example 57. 4-[5-methoxy-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-2-methylpyrimidin-4-yl]-1λ6-thiomorpholine-1,1-dione

›Step A. 4-(6-chloro-5-methoxy-2-methylpyrimidin-4-yl)-1lambda6-thiomor-pholine-1,1-dione

To a stirred solution of 4,6-dichloro-5-methoxy-2-methylpyrimidine (400.0 mg, 1.0 equiv) and 1lambda6-thiomorpholine-1,1-dione (308.0 mg, 1.1 equiv) in THF (12.0 mL) was added TEA (420.0 mg, 2.0 equiv) at room temperature. The resulting mixture was stirred for 20 h at 70° C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in PE to afford the title compound (400.0 mg, 65.7% yield) as a white solid. m/z (ESI, +ve ion)=292.00 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 4.35-4.33 (m, 4H), 3.78 (s, 3H), 3.15-3.12 (m, 4H), 2.53 (s, 3H).

Step B. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxy-2-methylpyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred solution of tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100.0 mg, 1.0 equiv) and 4-(6-chloro-5-methoxy-2-methylpyrimidin-4-yl)-1lambda6-thiomor-pholine-1,1-dione (72.9 mg, 1.3 equiv) in toluene (2.5 mL) were added Cs 2 CO 3 (125.1 mg, 2.0 equiv), XantPhos (19.9 mg, 0.2 equiv) and Pd 2 (dba) 3 (35.1 mg, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3×7 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% EtOAc in PE to afford the title compound (80.0 mg, 53.7%) as a yellow solid. m/z (ESI, +ve ion)=776.40 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.13 (s, 1H), 8.04 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 6.72-6.69 (m, 1H), 5.62 (d, J=0.0 Hz, 1H), 4.35-4.31 (m, 1H), 4.25 (s, 4H), 3.75 (s, 3H), 3.56-3.52 (m, 1H), 3.39 (s, 3H), 3.15 (s, 4H), 2.41-2.37 (m, 1H), 2.34 (s, 3H), 2.15-2.12 (m, 1H), 1.73-1.69 (m, 18H).

Step C. 4-[5-methoxy-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′H-spiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-2-methylpyrimidin-4-yl]-1lambda6-thiomorpholine-1,1-dione

To a stirred solution of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxy-2-methylpyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (80.0 mg) in DCM (4.0 mL) was added TFA (0.7 mL) dropwise at room temperature. The resulting mixture was stirred for 2 h at mom temperature. The resulting mixture was concentrated under vacuum. The crude product (50 mg) was purified by RP flash, eluted with ACN in water (5 mM NH 4 HCO 3 ), 10% to 50% gradient in 30 min to afford Example 39 (22.0 mg, 37.0%) as a white solid. m/z (ESI, +ve ion)=576.30 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.59 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.64-6.61 (m, 1H), 5.66 (d, J=4.0 Hz, 1H), 4.23 (s, 4H), 3.76 (s, 3H), 3.37 (d, J=8.0 Hz, 1H), 3.35-3.30 (m, 3H), 3.21-3.15 (m, 4H), 3.01 (s, 1H), 2.88 (s, 1H), 2.26-2.20 (m, 4H), 2.19-2.17 (m, 1H).

Example 58. 4-[5-chloro-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-2-methylpyrimidin-4-yl]-1λ6-thiomorpholine-1,1-dione

›Step A. 4-(6-amino-2-methylpyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione

The mixture of 6-chloro-2-methylpyrimidin-4-amine (1 g, 6.965 mmol, 1.00 equiv) and 1lambda6-thiomorpholine-1,1-dione (2.82 g, 20.895 mmol, 3 equiv) was stirred for 80° C. for 12 h. The reaction mixture was turned out to be white solid. The solid was triturated with EA (20 mL) for 2 h and filtered. The filter cake was collected and dried in vacuo to give the title compound (500 mg, 29.33%) as a white solid. m/z (ESI +ve ion)=243.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.74 (s, 2H), 5.70 (s, 1H), 4.00-3.98 (m, 4H), 3.16-3.13 (m, 4H), 2.27 (s, 3H).

›Step B. 4-(6-amino-5-chloro-2-methylpyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione

To a stirred mixture of 4-(6-amino-2-methylpyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione (500 mg, 2.064 mmol, 1.00 equiv) in THF (5 mL) was added NCS (220.44 mg, 1.651 mmol, 0.8 equiv) under nitrogen atmosphere. The mixture was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-100% of EA in PE to give the title compound (250 mg, 43.78%) as a colorless oil. m/z (ESI +ve ion)=277.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.89 (s, 2H), 3.85-3.83 (m, 4H), 3.24-3.21 (m, 4H), 2.25 (s, 3H).

Step C. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[5-chloro-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-2-methylpyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-[l-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100 mg, 0.158 mmol, 1.00 equiv) and 4-(6-amino-5-chloro-2-methylpyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione (52.59 mg, 0.190 mmol, 1.2 equiv) in toluene (2.5 mL) were added Cs 2 CO 3 (103.19 mg, 0.316 mmol, 2 equiv), XantPhos (18.33 mg, 0.032 mmol, 0.2 equiv) and Pd 2 (dba) 3 (29.00 mg, 0.032 mmol, 0.2 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h. The reaction mixture was filtered and washed with EA (5 mL×3). The filtrate was concentrated in vacuo and the residue was purified by silica gel column eluted with 0-50% EA in PE to give the title compound (90 mg, 72.83%) as a yellow solid. m/z (ESI +ve ion)=780.35 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ8.15 (s, 1H), 7.84-7.80 (m, 2H), 7.07-7.02 (m, 1H), 6.71-6.68 (m, 1H), 5.59 (d, J=2.8 Hz, 1H), 4.15-4.12 (m, 4H), 3.53 (t, J=8.4 Hz, 1H), 3.40 (s, 3H), 3.23 (s, 4H), 2.41-2.37 (m, 4H), 2.14-2.11 (m, 1H), 1.71 (d, J=5.2 Hz, 18H).

Step D. 4-[5-chloro-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′H-spiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-2-methylpyrimidin-4-yl]-1lambda6-thiomorpholine-1,1-dione

To the mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[5-chloro-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-2-methylpyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (80 mg, 0.103 mmol, 1.00 eq) in DCM (1 mL) was added TFA (0.1 mL). The mixture was stirred for 6 h. The solvent was removed under reduced pressure. The residue was purified by prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 42% B in 8 min: wavelength: 254 nm; RT1 (min): 7.5. The product-containing fractions were collected and concentrated in vacuo to give Example 58 (35 mg, 58.26%) as a white solid. m/z (ESI +ve ion)=580.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.68 (s, 1H), 10.42 (s, 1H), 9.16 (s, 1H), 7.40-7.37 (m, 2H), 6.91-6.88 (m, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.60-6.57 (m, 1H), 5.69 (d, J=2.4 Hz, 1H), 3.92 (s, 4H), 3.32 (s, 3H), 3.29-3.26 (m, 4H), 3.20 (t, J=8.4 Hz, 1H), 2.34-2.30 (m, 1H), 2.13 (s, 3H), 2.00-1.97 (m, 1H).

Example 59. (1R,2S)-2-(3-((2-cyclopropyl-6-(1,1-dioxidothiomorpholino)pyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

›Step A. 6-chloro-2-cyclopropylpyrimidin-4-amine

A mixture of 4,6-dichloro-2-cyclopropylpyrimidine (1.00 g, 5.290 mmol, 1.00 equiv) and NH 3 ·H 2 O (13.00 mL, 0.371 mmol, 0.07 equiv) in THF (6.50 mL) was stirred for 6 h at 70° C. under nitrogen atmosphere and then cooled down to room temperature. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford the title compound (860 mg, 95.85%) as an off-white solid. m/z=169.95 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 6.24 (s, 1H), 4.88 (s, 2H), 2.03 (m, 1H), 1.11 (m, 2H), 1.00 (m, 2H).

›Step B. 4-(6-amino-2-cyclopropylpyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione

Into a 25 mL round-bottom flask were added 6-chloro-2-cyclopropylpyrimidin-4-amine (725.00 mg, 4.275 mmol, 1.00 equiv) and thiomorpholine 1,1-dioxide (2890.00 mg, 21.385 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred for 16 h at 100° C. under nitrogen atmosphere and cooled down to room temperature. The resulting mixture was diluted with MeOH (5 mL). The residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20-40 um, 120 g; Mobile Phase A: Water (plus 5 mM NH 4 HCO); Mobile Phase B: ACN: Flow rate: 60 mL/min: Gradient: 20% B-40% B in 20 min; Detector: 254 nm. The fractions containing desired product were collected at 22% B and concentrated under reduced pressure to afford the title compound (1.07 g, 93.28%) as a white solid. m/z (ESI +ve ion)=269.05 [M+H] + . 1 H NMR (400 MHz, DMSO-dc) δ 6.17 (s, 2H), 5.56 (s, 1H), 3.93 (t, J=5.1 Hz, 4H), 3.07 (t, J=5.1 Hz, 4H), 1.77 (m, 1H), 0.92-0.74 (m, 4H).

Step C. tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-cyclopropyl-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)pyrimidin-4-yl]amino}indazol-6-yl]-5′-meth oxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100 mg, 0.158 mmol, 1.00 equiv) and 4-(6-amino-2-cyclopropylpyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione (50.99 mg, 0.190 mmol, 1.2 equiv) in toluene (2.5 mL) were added Pd 2 (dba) 3 (14.50 mg, 0.016 mmol, 0.1 equiv) and XantPhos (9.16 mg, 0.016 mmol, 0.1 equiv) and Cs 2 CO 3 (103.19 mg, 0.316 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (10 mL) at room temperature. The resulting mixture was extracted with DCM (3×8 mL). The combined organic layers were washed with brine (1×15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford the title compound (96 mg, 78.54%) as a yellow solid. m/z (ESI +ve ion)=772.50 [M+H] +

Step D. 4-[2-cyclopropyl-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′H-spiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyrimidin-4-yl]-1lambda6-thiomorpholine-1,1-dione

A mixture of tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-cyclopropyl-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)pyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (20.00 mg, 0.026 mmol, 1.00 equiv) and TFA (2.00 mL) in DCM (4.00 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 45% B in 8 min, 45% B: wavelength: 254 nm; RT1 (min): 6.88 to afford Example 59 (46.1 mg, 64.84%) as a white solid. m/z (ESI +ve ion)=572.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.36 (s, 1H), 10.42 (s, 1H), 9.74 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.08 (s, 1H), 6.92-6.85 (m, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.58 (m, 1H), 5.69 (d, J=2.8 Hz, 1H), 4.00 (d, J=6.5 Hz, 4H), 3.33 (s, 3H), 3.17 (m, 5H), 1.97 (m, 1H), 1.90 (m, 1H), 1.24 (s, 1H), 0.99-0.93 (m, 2H), 0.87 (m, 2H).

Example 60. (1R,2S)-2-(3-((6-(1,1-dioxidothiomorpholino)-2-methylpyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indolin]-2′-one

›Step A. 4-(6-amino-2-methylpyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione

The mixture of 6-chloro-2-methylpyrimidin-4-amine (1 g, 6.965 mmol, 1.00 equiv) and 1lambda6-thiomorpholine-1,1-dione (2.82 g, 20.895 mmol, 3 equiv) was stirred at 80° C. for 12 h. The reaction mixture was turned out to be white solid. The solid was triturated with EA (20 mL) for 2 h and filtered. The filter cake was collected and dried in vacuo to give title compound (500 mg, 29.33%) as a white solid. m/z (ESI +ve ion)=243.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.74 (s, 2H), 5.70 (s, 1H), 4.00-3.98 (m, 4H), 3.16-3.13 (m, 4H), 2.27 (s, 3H).

Step B. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-2-methylpyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred solution of 4-(6-amino-2-methylpyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione (49.9 mg, 1.3 equiv) and tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100.0 mg, 1.0 equiv) in toluene (2.5 mL) were added Cs 2 CO 3 (103.3 mg, 2.0 equiv) and XantPhos (16.5 mg, 0.2 equiv) and Pd 2 (dba) 3 (29.0 mg, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3×6 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% of EtOAc in PE to afford the title compound (100.0 mg, 84.7%) as a yellow solid. m/z (ESI, +ve ion)=746.40 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.82 (d, J=12.0 Hz, 1H), 7.75 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.71-6.68 (m, 1H), 5.57 (d, J=4.0 Hz, 1H), 4.35-4.31 (m, 4H), 4.17-4.12 (m, 1H), 3.55-3.50 (m, 1H), 3.42 (s, 3H), 3.17-3.11 (m, 4H), 2.49 (s, 3H), 2.40-2.37 (m, 1H), 2.14-2.11 (m, 1H), 1.70 (s, 18H).

Step C. 4-[6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′H-spiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-2-methylpyrimidin-4-yl]-1lambda6-thiomorpholine-1,1

To a stirred solution of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-2-methylpyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (90.0 mg) in DCM (4.0 mL) was added TFA (0.5 mL) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (50.0 mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ). Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 40% B in 8 min, 40% B; wavelength: 254 nm; RT1 (min): 6.6 to afford Example 60 (23.0 mg, 35.0% yield) as a white solid. m/z (ESI, +ve ion)=546.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.37 (s, 1H), 10.42 (s, 1H), 9.89 (s, 1H), 7.98 (d, J=4.0 Hz, 1H), 7.33 (s, 1H), 7.20 (s, 1H), 6.89 (d, J=4.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.60-6.57 (m, 1H), 5.69 (d, J=0.0 Hz, 1H), 4.04 (d, J=5.6 Hz, 4H), 3.17 (s, 5H), 2.50 (s, 3H), 2.33 (d, J=8.0 Hz, 4H), 1.99-1.95 (m, 1H).

Example 61. 5-methoxy-4-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-6-(morpholin-4-yl)pyrimidine-2-carbonitrile

›Step A. 6-hydroxy-5-methoxy-2-sulfanyl-3H-pyrimidin-4-one

To a stirred mixture of thiourea (3.00 g, 39.411 mmol, 1.00 equiv) and 1,3-dimethyl 2-methoxypropanedioate (6.39 g, 39.411 mmol, 1.00 equiv) in MeOH (80.00 mL) was added sodium 2-methylpropan-2-olate (7.58 g, 78.822 mmol, 2.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 7 h at 50° C. under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (2×40 mL). The aqueous layer was acidified to pH 1 with conc. HCl. The precipitated solids were collected by filtration and washed with water (2×10 mL) and dried to afford the title compound (4 g, 58.27%) as a yellow solid. m/z (ESI, +ve ion)=175.05 [M+H] + .

›Step B. 2-(ethylsulfanyl)-6-hydroxy-5-methoxy-3H-pyrimidin-4-one

To a stirred mixture of 6-hydroxy-5-methoxy-2-sulfanyl-3H-pyrimidin-4-one (4.00 g, 22.966 mmol, 1.00 equiv) and iodoethane (7.16 g, 0.000 mmol, 2.00 equiv) in water (120 mL) was added NaOH (1.84 g, 0.046 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with water (2×20 mL). The filtrate was acidified to pH 1 with HCl (aq.). The precipitated solids were collected by filtration and washed with water (2×30 mL) and dried to afford the title compound (2.27 g, 48.88%) as a yellow solid. m/z (ESI, +ve ion)=203.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.23 (s, 1H), 11.25 (s, 1H), 3.59 (d, J=6.0 Hz, 3H), 3.07 (q, J=7.3 Hz, 2H), 1.28 (t, J=7.3 Hz, 3H).

›Step C. 4,6-dichloro-2-(ethylsulfanyl)-5-methoxypyrimidine

A mixture of 2-(ethylsulfanyl)-6-hydroxy-5-methoxy-3H-pyrimidin-4-one (2.27 g, 11.225 mmol, 1.0) equiv) and PhNEt 2 (5.03 g, 0.034 mmol, 3.00 equiv) in POCl 3 (38.00 mL) was stirred for 3 h at 100° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched with sat. NaHCO 3 (aq. 30 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20-40 um, 120 g; Mobile Phase A: Water (plus 0.05% TFA); Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 60% B-70% B in 15 min; Detector: 254 nm. The fractions containing desired product were collected at 64% B and concentrated under reduced pressure to afford the title compound (2.5 g, 93.15%) as a dark green oil. m/z=238.95 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ3.87 (s, 3H), 3.13-3.09 (m, 2H), 1.71-1.46 (m, 3H).

›Step D. 4-[6-chloro-2-(ethylsulfanyl)-5-methoxypyrimidin-4-yl] morpholine

A mixture of 4,6-dichloro-2-(ethylsulfanyl)-5-methoxypyrimidine (400.00 mg, 1.673 mmol, 1.00 equiv) and morpholine (174.89 mg, 0.000 mmol, 1.20 equiv) in EtOH (10.00 mL) was stirred for 2 h at 85° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with DCM (3×15 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3/1) to afford the title compound (230 mg, 47.45%) as a white solid. m/z (ESI, +ve ion)=290.15 [M+H] + .

›Step E. 4-[6-chloro-2-(ethanesulfonyl)-5-methoxypyrimidin-4-yl] morpholine

A mixture of 4-[6-chloro-2-(ethylsulfanyl)-5-methoxypyrimidin-4-yl] morpholine (430.00 mg, 1.484 mmol, 1.00 equiv) and m-CPBA (896.24 mg, 5.194 mmol, 3.5 equiv) in DCM (10.75 mL) were stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was quenched with sat. Na 2 S 2 O 3 (aq., 15 mL) at room temperature. The resulting mixture was extracted with DCM (2×15 mL). The combined organic layers were washed with sat. NaHCO 3 (aq. 20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1) to afford the title compound (450 mg, 94.24%) as an off-white solid. m/z (ESI, +ve ion)=322.00 [M+H] + .

›Step F. 4-chloro-5-methoxy-6-(morpholin-4-yl) pyrimidine-2-carbonitrile

Into a 50 mL round-bottom flask were added 4-[6-chloro-2-(ethanesulfonyl)-5-methoxypyrimidin-4-yl] morpholine (465.00 mg, 1.445 mmol, 1.00 equiv) and DMSO (11.62 mL) at room temperature. To the above mixture was added NaCN (106.23 mg, 2.168 mmol, 1.5 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with Water (15 mL) at room temperature. The resulting mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (2/1) to afford the title compound (122 mg, 33.15%) as an off-white solid. m/z (ESI, +ve ion)=255.15 [M+H] + .

Step G. tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((2-cyano-5-methoxy-6-morpholinopyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate

To a stirred mixture of tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (70 mg, 0.134 mmol, 1.00 equiv) and 4-chloro-5-methoxy-6-(morpholin-4-yl) pyrimidine-2-carbonitrile (34.24 mg, 0.134 mmol, 1 equiv) in dioxane (2 mL) were added Methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2′,6′-bis(dimethylamino)-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium (II (15.35 mg, 0.013 mmol, 0.1 equiv) and 2′-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3′,6′-dimethoxy-N 2 ,N 2 ,N 6 ,N 6 -tetramethyl-[1.1′-biphenyl]-2,6-diamine (10.17 mg, 0.013 mmol, 0.1 equiv) and Cs 2 CO 3 (87.62 mg, 0.268 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched by the addition of Water (8 mL) at room temperature. The resulting mixture was extracted with DCM (3×5 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford the title compound (89 mg, 89.59%) as a brown yellow solid. m/z (ESI, +ve ion)=739.25 [M+H] + .

›Step H

A mixture of tert-butyl (1R,2S)-2-(1-(tert-butoxycarbonyl)-3-((2-cyano-5-methoxy-6-morpholinopyrimidin-4-yl)amino)-1H-indazol-6-yl)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-carboxylate (89 mg, 0.120 mmol, 1.00 equiv) and TFA (2 mL, 26.926 mmol, 223.52 equiv) in DCM (4 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 19×250 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: MeOH-HPLC; Flow rate: 25 mL/min; Gradient: 50% B to 60% B in 10 min, 60% B to 60% B in 15 min, 60% B; wavelength: 254 nm; RT1 (min): 9 to afford Example 61 (17.6 mg, 27.13%) as a pink solid. m/z (ESI, +ve ion)=539.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.72 (s, 1H), 10.42 (s, 1H), 9.40 (s, 1H), 7.47-7.39 (m, 2H), 6.96-6.91 (m, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.69-6.55 (m, 1H), 5.68 (d, J=2.4 Hz, 1H), 3.72 (d, J=7.2 Hz, 7H), 3.68-3.62 (m, 4H), 3.31 (s, 3H), 3.24-3.15 (m, 2H), 2.34-2.32 (m, 1H), 2.01-1.97 (m, 1H).

Example 62. 4-(1,1-dioxidothiomorpholino)-5-methoxy-6-((6-((1R,2S)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indolin]-2-yl)-1H-indazol-3-yl)amino)pyrimidine-2-carbonitrile

›Step A. 4-[6-chloro-2-(ethylsulfanyl)-5-methoxypyrimidin-4-yl]-1lambda6-thiomorpholine-1,1-dione

To a stirred mixture of 4,6-dichloro-2-(ethylsulfanyl)-5-methoxypyrimidine (800.00 mg, 3.346 mmol, 1.00 equiv) and 1lambda6-thiomorpholine-1,1-dione (452.28 mg, 3.346 mmol, 1.00 equiv) in dioxane (20.00 mL) were added TEA (1354.22 mg, 13.383 mmol, 4 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched by the addition of Water (20 mL) at room temperature. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1) to afford the title compound (443 mg, 39.19%) as a white solid. m/z (ESI, +ve ion)=338.15 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 4.36-4.29 (m, 4H), 3.76 (s, 3H), 3.17-3.12 (m, 4H), 3.08 (q, J=7.3 Hz, 2H), 1.40 (t, J=7.3 Hz, 3H).

›Step B. 4-[6-chloro-2-(ethanesulfonyl)-5-methoxypyrimidin-4-yl]-1lambda6-thiomorpholine-1,1-dione

A mixture of 4-[6-chloro-2-(ethylsulfanyl)-5-methoxypyrimidin-4-yl]-1lambda6-thiomorpholine-1,1-dione (417.00 mg, 1.234 mmol, 1.00 equiv) and m-CPBA (745.50 mg, 4.320 mmol, 3.50 equiv) in DCM (10.00 mL) was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was quenched with Na 2 S 2 O 3 (aq. 10 mL) at room temperature. The resulting mixture was extracted with DCM (2×15 mL). The combined organic layers were washed with NaHCO 3 (aq., 25 mL). dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3/1) to afford the title compound (400 mg, 87.62%) as an off-white solid. m/z (ESI, +ve ion)=370.00 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 4.27 (t, J=5.1 Hz, 4H), 3.81 (s, 3H), 3.56-3.48 (m, 2H), 3.34 (t, J=5.1 Hz, 4H), 1.29-1.25 (m, 3H).

›Step C. 4-chloro-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxypyrimidine-2-carbonitrile · 1 of 3

To a stirred mixture of 4-[6-chloro-2-(ethanesulfonyl)-5-methoxypyrimidin-4-yl]-1lambda6-thiomorpholine-1,1-dione (460 mg, 1.244 mmol, 1.00 equiv) and ACN (4.6 mL) in DMSO (11.5 mL) was added NaCN (91.43 mg, 1.866 mmol, 1.5 equiv) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0° C. under nitrogen atmosphere. The reaction was quenched by the addition of Water (10 mL) at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford the title compound (158 mg, 41.96%) as an off-white solid. m/z (ESI, +ve ion)=302.90 [M+H] + .

Step D. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-cyano-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxypyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred mixture of tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100 mg, 0.192 mmol, 1.00 equiv) and 4-chloro-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxypyrimidine-2-carbonitrile (69.78 mg, 0.230 mmol, 1.2 equiv) in dioxane (5.00 mL, 58.992 mmol, 307.25 equiv) were added CPhos (8.39 mg, 0.019 mmol, 0.1 equiv) and Pd 2 (dba) 3 ·CHCl 3 (19.88 mg, 0.019 mmol, 0.1 equiv) and Cs 2 CO 3 (125.17 mg, 0.384 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched by the addition of Water (10 mL) at room temperature. The residue was purified by reverse phase flash chromatography with the following conditions: Column: Spherical C18, 20-40 μm, 80 g; Mobile Phase A: Water (plus 5 mM NH 4 HCO 3 ); Mobile Phase B: ACN: Flow rate: 40 mL/min: Gradient: 60% B-80% B in 20 min; Detector: 254 nm. The fractions containing desired product were collected at 70% B and concentrated under reduced pressure to afford the title compound (54 mg, 35.73%) as an off-white solid. m/z (ESI, +ve ion)=787.25 [M+H] + .

Step E. 4-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxy-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′H-spiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl} amino) pyrimidine-2-carbonitrile

A mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-cyano-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxypyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (54 mg, 0.069 mmol, 1.00 equiv) and TFA (2 mL, 26.926 mmol, 392.35 equiv) in DCM (4 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 19×250 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: MeOH—HPLC: Flow rate: 25 mL/min: Gradient: 50% B to 60% B in 10 min, 60% B to 60% B in 15 min, 60% B; Wavelength: 254 nm; RT1 (min): 9 to afford Example 62 (10.7 mg, 26.31%) as a white solid. MS: m/z=587.25 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.59 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.62 (m, 1H), 5.58 (d, J=2.4 Hz, 1H), 4.26 (d, J=5.9 Hz, 4H), 3.83 (s, 3H), 3.42 (m, 1H), 3.37 (s, 3H), 3.24 (t, J=4.8 Hz, 4H), 2.25 (m, 1H), 2.19 (m, 1H).

Example 63. (1R,2S)-2-{3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(1,3-dimethylpyrazol-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100 mg, 0.158 mmol, 1.00 equiv) and 1,3-dimethylpyrazol-4-amine (21.12 mg, 0.190 mmol, 1.2 equiv) in toluene (2.5 mL) were added Cs 2 CO 3 (103.19 mg, 0.316 mmol, 2 equiv), XantPhos (18.33 mg, 0.032 mmol, 0.2 equiv) and Pd 2 (dba) 3 (29.00 mg, 0.032 mmol, 0.2 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h, then filtered and washed with EA (5 mL×3). The filtrate was concentrated in vacuo. The residue was purified by Prep-TLC (rinsed with EA/PE=1/1) to afford the title compound (60 mg, 58.55%) as a yellow solid. m/z (ESI +ve ion)=615.50 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.05 (s, 1H), 7.89 (s, 1H), 7.81 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.69 (d, J=9.2 Hz, 1H), 5.92 (s, 1H), 5.57 (d, J=1.6 Hz, 1H), 3.89 (s, 3H), 3.52-3.48 (m, 1H), 3.40 (d, J=1.2 Hz, 3H), 2.38-2.34 (m, 1H), 2.27 (s, 3H), 2.11-2.05 (m, 1H), 1.70 (s, 18H).

Step B. (1R,2S)-2-{3-[(1,3-dimethylpyrazol-4-yl)amino]-1H-indazol-6-yl}-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

The mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(1,3-dimethylpyrazol-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (55 mg, 0.089 mmol, 1.0) equiv) in TFA (0.5 mL) and DCM (5 mL) was stirred at 25° C. for 4 h. The solvent was removed under reduced pressure and the residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN: Flow rate: 60 mL/min: Gradient: 25% B to 35% B in 8 min; Wavelength: 254 nm: RT1 (min): 6.6. The product-containing fractions was collected and concentrated in vacuo to give Example 63 (8.8 mg, 22.54%) as an off-white solid. m/z (ESI +ve ion)=415.35 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.76 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.25 (s, 1H), 6.85-6.80 (m, 2H), 6.64-6.61 (m, 1H), 5.61 (d, J=2.4 Hz, 1H), 3.82 (s, 4H), 3.31 (s, 3H), 2.22 (s, 3H), 2.18-2.15 (m, 1H).

›Step C. 4-chloro-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxypyrimidine-2-carbonitrile · 2 of 3

Example 64. (1R,2S)-5′-methoxy-2-(3-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100 mg, 0.158 mmol, 1.00 equiv) and 1-methyl-3-(trifluoromethyl)pyrazol-4-amine (31.38 mg, 0.190 mmol, 1.2 equiv) in toluene (2.5 mL) were added Cs 2 CO 3 (103.19 mg, 0.316 mmol, 2 equiv), CPhos (13.83 mg, 0.032 mmol, 0.2 equiv) and Pd 2 (dba) 3 ·CHCl 3 (32.78 mg, 0.032 mmol, 0.2 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h. The reaction mixture was filtered and washed with EA (5 mL×3). The filtrate was concentrated in vacuo. The residue was purified by Prep-TLC (rinsed with EA/PE=1/2) to afford crude the title compound (23a) (80 mg, 75%) as a yellow solid. m/z (ESI +ve ion)=669.50 [M+H] + .

Step B. (1R,2S)-5′-methoxy-2-(3-{[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]amino}-1H-indazol-6-yl)-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

The mixture of crude tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (75 mg) in TFA (0.5 mL) and DCM (3 mL) was stirred for 4 h at 25° C. The solvent was removed under reduced pressure. The residue was purified by prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN: Flow rate: 60 mL/min: Gradient: 30% B to 50% B in 8 min, 50% B; wavelength: 254 nm; RT: 7 min. The product-containing fractions was concentrated in vacuo to give Example 64 (29.8 mg, 40.01% over two steps) as a white solid. m/z (ESI +ve ion)=469.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) S 11.81 (s, 1H), 10.40 (s, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.24 (s, 1H), 6.86-6.84 (m, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.60-6.57 (m, 1H), 5.70 (d, J=2.4 Hz, 1H), 3.91 (s, 3H), 3.33 (s, 3H), 3.17 (t, J=8.4 Hz, 1H), 2.31-2.27 (m, 1H), 2.00-1.98 (m, 1H). 1 H NMR (376 MHz, DMSO-d 6 ) δ −58.60 (s, 3F).

Example 65. (1R,2S)-5′-methoxy-2-{3-[(1-methyl-H-pyrazol-4-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(1-methylpyrazol-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100 mg, 0.158 mmol, 1.00 equiv) and 1-methylpyrazol-4-amine (18.46 mg, 0.190 mmol, 1.2 equiv) in toluene (2.5 mL) were added Cs 2 CO 3 (103.19 mg, 0.316 mmol, 2 equiv), CPhos (13.83 mg, 0.032 mmol, 0.2 equiv) and Pd 2 (dba) 3 ·CHCl 3 (32.78 mg, 0.032 mmol, 0.2 equiv) under argon atmosphere. After the mixture was stirred at 90° C. for 2 h, it was cooled down to room temperature, filtered and washed with EA (5 mL×3). The filtrate was concentrated in vacuo. The residue was purified by Prep-TLC (rinsed with EA/PE=1/2) to afford the title compound (30 mg, 31.54%) as a yellow solid. m/z (ESI +ve ion)=601.50 [M+H] + .

Step B. (1R,2S)-5′-methoxy-2-{3-[(1-methylpyrazol-4-yl)amino]-1H-indazol-6-yl}-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

The mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(1-methylpyrazol-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (30 mg, 0.050 mmol, 1.00 equiv) in TFA (0.2 mL) and DCM (2 mL) was stirred for 5 h. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 45% B in 8 min; Wavelength: 254 nm; RT1 (min): 6.5. The product-containing fractions were collected and concentrated in vacuo to give Example 65 (9.3 mg, 46.27%) as a white solid. m/z (ESI +ve ion)=401.30 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.87 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.52 (s, 1H), 7.26 (s, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.64-6.61 (m, 1H), 5.61 (d, J=2.4 Hz, 1H), 3.88 (s, 3H), 3.36-3.33 (s, 1H), 3.29 (s, 3H), 2.22-2.15 (m, 2H).

Example 66. 4-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-1-methyl-1H-pyrazole-3-carbonitrile

Step A. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(1-methylpyrazol-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100 mg, 0.158 mmol, 1.00 equiv) and 4-amino-1-methylpyrazole-3-carbonitrile (23.21 mg, 0.190 mmol, 1.2 equiv) in toluene (2.5 mL) were added Cs 2 CO 3 (103.19 mg, 0.316 mmol, 2 equiv), CPhos (13.83 mg, 0.032 mmol, 0.2 equiv) and Pd 2 (dba) 3 ·CHCl 3 (32.78 mg, 0.032 mmol, 0.2 equiv) under argon atmosphere. The mixture was stirred at 90° C. for 2 h and then cooled down to room temperature. The reaction mixture was filtered and washed with EA (5 mL×3). The filtrate was concentrated in vacuo. The residue was purified by Prep-TLC (rinsed with EA/PE=1/2) to afford crude title compound (25a) (28 mg, 22.61%) as a yellow solid. m/z (ESI +ve ion)=526.35 [M+H−100] + .

Step B. 4-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′H-spiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)-1-methylpyrazole-3-carbonitrile

The mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(1-methylpyrazol-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (26 mg, 0.033 mmol, 1.00 equiv) in TFA (0.5 mL) and DCM (2.5 mL) was stirred at 25° C. for 5 h. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN: Flow rate: 60 mL/min: Gradient: 18% B to 28% B in 8 min; wavelength: 254 nm; RT1 (min): 7. The product containing fractions were collected and concentrated in vacuo to give Example 66 (4.0 mg, 28.00%) as a yellow solid. m/z (ESI +ve ion)=426.35 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.36 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 6.85-6.79 (m, 2H), 6.62-6.60 (m, 1H), 5.76 (d, J=2.0 Hz, 1H), 4.37 (s, 3H), 3.40-3.38 (m, 1H), 3.25 (s, 3H), 2.31-2.28 (m, 1H), 2.22-2.18 (m, 1H).

›Step C. 4-chloro-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxypyrimidine-2-carbonitrile · 3 of 3

Example 67. (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxy-2-methylpyrimidin-4-yl}amino)-1H-indazol-6-yl]-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. (2R,6S)-4-(6-chloro-5-methoxy-2-methylpyrimidin-4-yl)-2,6-dimethylmorpholine

A mixture of 4,6-dichloro-5-methoxy-2-methylpyrimidine (300 mg, 1.554 mmol, 1.00 equiv) and (2R,6S)-2,6-dimethylmorpholine (179.00 mg, 1.554 mmol, 1 equiv) in THF (7.5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford the title compound (211 mg, 49.96%) as a colorless oil. m/z=272.00 [M+H] + .

Step B. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxy-2-methylpyrimidin-4-yl} amino)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred mixture of tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (80 mg, 0.154 mmol, 1.00 equiv) and (2R,6S)-4-(6-chloro-5-methoxy-2-methylpyrimidin-4-yl)-2,6-dimethylmorpholine (41.76 mg, 0.154 mmol, 1 equiv) in dioxane (4 mL, 47.216 mmol, 307.25 equiv) were added methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2′,6′-bis(dimethylamino)-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium (II) (17.54 mg, 0.015 mmol, 0.1 equiv) and 2′-(Bis(3,5-bis(trifluoromethyl)phenyl)phosphino)-3′,6′-dimethoxy-N 2 N 2 ,N 6 ,N 6 -tetramethyl-[1,1′-biphenyl]-2,6-diamine (11.63 mg, 0.015 mmol, 0.1 equiv) and Cs 2 CO 3 (100.14 mg, 0.308 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. T The reaction was quenched by the addition of Water (8 mL) at room temperature. The resulting mixture was extracted with DCM (3×8 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford the title compound (74.5 mg, 64.14%) as a yellow solid. m/z (ESI, +ve ion)=756.30 [M+H] + .

Step C. (1R,2S)-2-[3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxy-2-methylpyrimidin-4-yl}amino)-1H-indazol-6-yl]-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

A mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-({6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-methoxy-2-methylpyrimidin-4-yl} amino)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (74.5 mg, 0.099 mmol, 1.00 equiv) and TFA (2 mL, 26.926 mmol) in DCM (4 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 45% B in 8 min, 45% B; wavelength: 254 nm; RT1 (min): 7.2 to afford Example 67 (28.1 mg, 50.80%) as a white solid. m/z (ESI, +ve ion)=556.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.53 (s, 1H), 10.43 (s, 1H), 8.75 (s, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.37 (s, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.58 (m, 1H), 5.71 (d, J=2.4 Hz, 1H), 4.23 (d, J=12.8 Hz, 2H), 3.67 (t, J=8.6 Hz, 2H), 3.62 (s, 3H), 3.30 (s, 4H), 3.18-3.16 (m, 2H), 2.35-2.28 (m, 1H), 2.07 (s, 3H), 1.98 (m, 1H), 1.13 (d, J=6.4 Hz, 6H).

Example 68. (1R,2S)-2-(3-{[2-(2-hydroxyethyl)-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. methyl 2-(4-hydroxy-5-methoxy-6-oxo-1H-pyrimidin-2-yl)acetate

To a mixture of t-BuONa (12.01 g, 124.992 mmol, 2.5 equiv) in MeOH (100 mL) were added ethyl 2-carbamimidoylacetate hydrochloride (8.33 g, 49.997 mmol, 1.00 equiv) and 1,3-dimethyl 2-methoxypropanedioate (8.11 g, 49.997 mmol, 1 equiv). The mixture was stirred for 3 h at 70° C. The mixture was quenched with water (50 mL) and then MeOH was evacuated under reduced pressure and then extracted with CHCl 3 (3×30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and then concentrated under reduced pressure to afford the title compound (6 g, 56.03%) as a yellow oil. m/z (ESI, +ve ion)=215.05 [M+H] +

›Step B. methyl 2-(4,6-dichloro-5-methoxypyrimidin-2-yl)acetate

A mixture of methyl 2-(4-hydroxy-5-methoxy-6-oxo-1H-pyrimidin-2-yl)acetate (400.00 mg, 1 equiv) in POCl 3 (5.00 mL) was stirred for 3 h at 100° C. The mixture was concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluted with 20% EA in PE to afford the title compound (70 mg, 14.93%) as a yellow solid. m/z (ESI, +ve ion)=250.95 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.97 (s, 3H), 3.94 (s, 2H), 3.75 (s, 3H).

›Step C. methyl 2-[4-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-2-yl]acetate

To a mixture of methyl 2-(4,6-dichloro-5-methoxypyrimidin-2-yl)acetate (500 mg, 1.992 mmol, 1.00 equiv) and TEA (403.05 mg, 3.984 mmol, 2 equiv) in THF (10 mL, 123.430 mmol, 61.98 equiv) was added morpholine (190.86 mg, 2.191 mmol, 1.1 equiv) at 0° C. The resulting mixture was stirred for 16 h at room temperature. The reaction was concentrated under reduced pressure to afford the title compound (600 mg, 99.85%) as a yellow oil. m/z (ESI, +ve ion)=302.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.79-3.87 (m, 4H), 3.77 (d, J=4.4 Hz, 7H), 3.73 (d, J=2.1 Hz, 6H).

›Step D. 2-[4-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-2-yl]ethanol

To a mixture of methyl 2-[4-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-2-yl]acetate (1500 mg, 4.97 mmol, 1.00 equiv) in MeOH (50 mL) was added NaBH 4 (1128.5 mg, 29.82 mmol, 6 equiv) at 0° C. The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched with water (50 mL), extracted with EA (3×100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 and then concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluted with PE:EA=1:1 to afforded the title compound (800 mg, 58.790%) as a yellow oil. m/z (ESI, +ve ion)=274.15 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 4.01 (s, 2H), 3.80 (s, 8H), 3.74 (s, 3H), 2.96 (t, J=5.4 Hz, 2H).

›Step E. 4-(2-{2-[(tert-butyidimethylsilyl)oxy]ethyl}-6-chloro-5-methoxypyrimidin-4-yl)morpholine

To a mixture of 2-[4-chloro-5-methoxy-6-(morpholin-4-yl)pyrimidin-2-yl]ethanol (700 mg, 0.256 mmol, 1.00 equiv) and Imidazole (348.2 mg, 5.12 mmol, 2 equiv) in DMF (5 mL) was added TBSCl (578.2 mg, 3.84 mmol, 1.5 equiv). The resulting mixture was stirred for 16 h at room temperature. The mixture was concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluted with PE/EA 4/1 to afford the title compound (860 mg, 86.68%) as a colorless oil. m/z (ESI, +ve ion)=388.15 [M+H] + .

Step F. ter-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(2-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a mixture of 4-(2-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-6-chloro-5-methoxypyrimidin-4-yl)morpholine (58 mg, 0.149 mmol, 1.00 equiv), tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (77.82 mg, 0.149 mmol, 1 equiv) and Cs 2 CO 3 (97.42 mg, 0.298 mmol, 2 equiv) in dioxane (5 mL) were added CPhos (6.53 mg, 0.015 mmol, 0.1 equiv) and Pd 2 (dba) 3 ·CHCl 3 (15.47 mg, 0.015 mmol, 0.1 equiv) under N 2 atmosphere. The resulting mixture was stirred for 90° C. for 4 h. The mixture was concentrated under reduced pressure. The residue was purified with prep-TLC, eluted with PE/EA 1/1 to afford the title compound (20 mg, 15.34%) as a yellow oil. m/z (ESI, +ve ion)=872.40 [M+H] +

Step G. (1R,2S)-2-(3-{[2-(2-hydroxyethyl)-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

To a mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(2-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-5-methoxy-6-(morpholin-4-yl)pyrimidin-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1.3′-indole]-1′-carboxylate (100 mg, 0.115 mmol, 1.00 equiv) in DCM (2 mL) was added TFA (1 mL). The resulting mixture was stirred for 16 h at room temperature. The mixture was concentrated under reduced pressure. The residue was purified with prep-HPLC with following conditions: Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 40% B in 8 min, 40% B; wavelength: 254 nm to afford Example 68 (26 mg, 40.66%) as a white solid. m/z (ESI, +ve ion)=558.50 [M+H] + , 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.64 (d, J=8.4 Hz, 1H), 7.41 (d, J=1.2 Hz, 1H), 6.93 (dd, J=8.4, 1.4 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.63 (dd, J=8.5, 2.5 Hz, 1H), 5.65 (d, J=2.5 Hz, 1H), 3.75-3.85 (m, 9H), 3.73-3.71 (m, 4H), 3.38-3.37 (m, 1H), 3.30 (s, 3H), 2.71 (t, J=6.2 Hz, 2H), 2.24-2.18 (m, 2H).

Example 69. 4-[2-cyclopropyl-5-methoxy-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyrimidin-4-yl]-1λ6-thiomorpholine-1,1-dione

›Step A. 4-(6-chloro-2-cyclopropyl-5-methoxypyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione

To a stirred solution of 4,6-dichloro-2-cyclopropyl-5-methoxypyrimidine (400.0 mg, 1.0 equiv) and 1lambda6-thiomorpholine-1,1-dione (271.5 mg, 1.1 equiv) in THF (8.0 mL) was added TEA (369.5 mg, 2.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 70° C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-50% of EA in PE to the title compound (300.0 mg, 51.8% yield) as a white solid. m/z (ESI+ve ion)=318.05 [M+H] + .

Step B. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-cyclopropyl-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxypyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100 mg, 0.192 mmol, 1.00 equiv) and 4-(6-chloro-2-cyclopropyl-5-methoxypyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione (73.25 mg, 0.230 mmol, 1.2 equiv) in toluene (2.5 mL) were added Cs 2 CO 3 (125.17 mg, 0.384 mmol, 2 equiv), CPhos (16.77 mg, 0.038 mmol, 0.2 equiv) and Pd 2 (dba) 3 ·CHCl 3 (39.77 mg, 0.038 mmol, 0.2 equiv) under nitrogen atmosphere. The resulting mixture was stirred at 90° C. for 2 h. The mixture was filtered and washed with EA (5 mL×3). The filtrate was concentrated and the residue was purified by prep-TLC (rinsed with EA/PE=1/1) to give crude the title compound (50 mg, 25.97%) as a light yellow solid. m/z (ESI +ve ion)=802.65 [M+H] + .

Step C. 4-[2-cyclopropyl-5-methoxy-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′H-spiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyrimidin-4-yl]-1lambda6-thiomorpholine-1,1-dione

The mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[2-cyclopropyl-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)-5-methoxypyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (50 mg, 0.062 mmol, 1.00 equiv) in TFA (0.10 mL) and DCM (1.00 mL) was stirred at 25° C. for 12 h. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ). Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 8 min; wavelength: 254/220 nm; RT1 (min): 6. The product-containing fractions was collected and concentrated in vacuo to give Example 69 (36 mg, 95.48%) as a white solid. m/z (ESI +ve ion)=602.40 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.54 (s, 1H), 10.43 (s, 1H), 8.88 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.59-6.57 (m, 1H), 5.69 (d, J=2.4 Hz, 1H), 4.07-4.05 (m, 4H), 3.63 (s, 3H), 3.32 (s, 3H), 3.23-3.17 (m, 5H), 2.34-2.30 (m, 1H), 2.00-1.97 (m, 1H), 1.64-1.60 (m, 1H), 0.66-0.64 (m, 4H).

Example 70. 4-[5-chloro-2-cyclopropyl-6-({6-[(1R,2S)-5′-methoxy-2′-oxo-1′,2′-dihydrospiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl}amino)pyrimidin-4-yl]-1λ6-thiomorpholine-1,1-dione

›Step A. 4-(6-amino-5-chloro-2-cyclopropylpyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione

A mixture of 4-(6-amino-2-cyclopropylpyrimidin-4-yl)thiomorpholine 1,1-dioxide (400 mg, 1.491 mmol, 1.00 equiv) and NCS (238.86 mg, 1.789 mmol, 1.2 equiv) in THF (20 mL) was stirred for 5 h at 50° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford the title compound (420 mg, 93.06%) as an off-white solid. m/z (ESI, +ve ion)=302.90 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.81 (s, 2H), 3.87-3.80 (m, 4H), 3.24-3.17 (m, 4H), 1.82 (m, 1H), 0.87 (d, J=6.4 Hz, 4H).

Step B. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[5-chloro-2-cyclopropyl-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)pyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (80 mg, 0.127 mmol, 1.00 equiv) and 4-(6-amino-5-chloro-2-cyclopropylpyrimidin-4-yl)-1lambda6-thiomorpholine-1,1-dione (46.03 mg, 0.152 mmol, 1.2 equiv) in toluene (4 mL) were added Xantphos Pd G 4 (12.19 mg, 0.013 mmol, 0.1 equiv) and XantPhos (7.33 mg, 0.013 mmol, 0.1 equiv) and Cs 2 CO 3 (82.56 mg, 0.254 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 9 h at 90° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched by the addition of Water (10 mL) at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford the title compound (46b) (50 mg, 48.95%) as a brown yellow solid. m/z=806.35 [M+H] + .

Step C. 4-[5-chloro-2-cyclopropyl-6-({6-[(1R,2′)-5′-methoxy-2′-oxo-1′H-spiro[cyclopropane-1,3′-indol]-2-yl]-1H-indazol-3-yl} amino)pyrimidin-4-yl]-1lambda6-thiomorpholine-1,1-dione

A mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-{[5-chloro-2-cyclopropyl-6-(1,1-dioxo-1lambda6-thiomorpholin-4-yl)pyrimidin-4-yl]amino}indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (50 mg, 0.062 mmol, 1.00 equiv) and TFA (2 mL, 26.926 mmol, 434.23 equiv) in DCM (4 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 m mol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 40% B in 8 min, 40% B: wavelength: 254 nm; RT1 (min): 7.63 to afford Example 70 (16.1 mg, 42.24%) as a white solid. m/z (ESI, +ve ion)=606.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.67 (s, 1H), 10.42 (s, 1H), 9.13 (s, 1H), 7.40 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.58 (m, 1H), 5.68 (d, J=2.4 Hz, 1H), 3.91 (s, 4H), 3.27 (s, 4H), 3.20 (t, J=8.4 Hz, 1H), 2.50 (s, 3H), 2.35-2.28 (m, 1H), 1.99 (m, 1H), 1.63 (m, 1H), 0.66 (m, 4H).

Example 71. (1R,2S)-5′-methoxy-2-{3-[(3-methoxy-6-methylpyrazin-2-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 3-methoxy-6-methylpyrazin-2-amine

A solution of 6-chloro-3-methoxypyrazin-2-amine (200 mg, 1.253 mmol, 1.00 equiv) and Ni(dppp)Cl 2 (67.94 mg, 0.125 mmol, 0.1 equiv) in dioxane (3 mL) was stirred for 5 min at room temperature under nitrogen atmosphere. To the above mixture was added 1 M MeZnCl (5.01 mL, 5.012 mmol, 4 equiv) at room temperature. The resulting mixture was stirred for additional 3 min at room temperature. The resulting mixture was stirred for 4 h at 100° C. under nitrogen atmosphere then cooled down to room temperature. The reaction was quenched by the addition of Water (8 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×8 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH 20/1) to afford the title compound as a white solid. m/z (ESI +ve ion)=140.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.11-7.10 (m, 1H), 6.15 (s, 2H), 3.83 (s, 3H), 2.14 (d, J=0.84 Hz, 3H).

Step B. tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(3-methoxy-6-methylpyrazin-2-yl) amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred solution of 3-methoxy-6-methylpyrazin-2-amine (21.16 mg, 0.152 mmol, 1.2 equiv) and tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (80 mg, 0.127 mmol, 1.00 equiv) in toluene (1.5 mL) were added XantPhos (7.33 mg, 0.013 mmol, 0.1 equiv) and Pd 2 (dba) 3 (23.20 mg, 0.025 mmol, 0.2 equiv) and Cs 2 CO 3 (82.56 mg, 0.254 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere then quenched by the addition of Water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2/1) to afford the title compound (70 mg, 85.97%) as a yellow oil. m/z (ESI +ve ion)=643.50 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.66 (s, 1H), 7.46 (s, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.71-6.69 (m, 1H), 4.05 (s, 3H), 3.56-3.51 (m, 1H), 3.37 (s, 3H), 2.39-2.36 (m, 1H), 2.30 (s, 3H), 2.15-2.12 (m, 1H), 1.29 (s, 18H).

Step C. (1R,2S)-5′-methoxy-2-{3-[(3-methoxy-6-methylpyrazin-2-yl) amino]-1H-indazol-6-yl}-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

To a stirred mixture of tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(3-methoxy-6-methylpyrazin-2-yl) amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (65 mg, 0.101 mmol, 1.00 equiv) was added TFA (0 mL, 13.463 mmol, 133.12 equiv) and DCM (2 mL, 31.460 mmol, 311.07 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature under nitrogen atmosphere. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 50% B in 8 min, 50% B; wavelength: 254 nm; RT1 (min): 6.5 to afford Example 71 (13.5 mg, 30.17%) as a white solid. m/z (ESI +ve ion)=443.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.52 (s, 1H), 10.41 (s, 1H), 8.71 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 6.87 (d, J=9.2 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 6.59-6.57 (m, 1H), 5.71 (d, J=2.4 Hz, 1H), 3.94 (s, 3H), 3.32 (s, 3H), 3.21-3.16 (m, 1H), 2.34-2.28 (m, 1H), 2.07 (s, 3H), 2.00-1.97 (m, 1H).

Example 72. (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-5,6-dichloro-2-methylpyrimidine

To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)azetidine (200.0 mg, 1.0 equiv) and 4,5,6-trichloro-2-methylpyrimidine (210.7 mg, 1.0 equiv) in THF (5.0 mL) were added TEA (324.0 mg, 3.0 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with 0-50% EA in PE to afford the title compound (80.0 mg, 21.5%) as a white solid. m/z (ESI, +ve ion)=348.15 [M+H] + .

Step B. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(6-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-5-chloro-2-methylpyrimidin-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred solution of 4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-5,6-dichloro-2-methylpyrimidine (80.4 mg, 1.2 equiv) and tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (100.0 mg, 1.0 equiv) in toluene (2.5 mL) were added Cs 2 CO 3 (126.0 mg, 2.0 equiv) and XantPhos (40.0 mg, 0.2 equiv) and Pd 2 (dba) 3 (70.0 mg, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3×7 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 0-50% of EtOAc in PE to afford the title compound (100.0 mg, 62.5%) as a yellow solid. m/z (ESI, +ve ion)=832.40 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.70 (d, J=4.0 Hz, 1H), 6.68 (d, J=4.0 Hz, 1H), 5.59 (d, J=4.0 Hz, 1H), 4.71-4.68 (m, 1H), 4.61 (s, 2H), 4.20 (s, 2H), 3.55-3.50 (m, 1H), 3.38 (s, 3H), 2.39-2.36 (m, 1H), 2.31 (s, 3H), 2.14-2.11 (m, 1H), 1.70 (d, J=4.0 Hz, 18H), 0.93 (s, 9H), 0.11 (s, 6H).

Step D. (1R,2S)-2-(3-{[5-chloro-6-(3-hydroxyazetidin-1-yl)-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

To a stirred solution of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(6-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-5-chloro-2-methylpyrimidin-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (84.0 mg) in DCM (5.0 mL) was added TFA (1.5 mL) dropwise at room temperature. The resulting mixture was stirred for 28 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (50.0 mg) was purified by RP flash with the following conditions (column, silica gel; mobile phase. MeCN in water (5 mM NH 4 HCO 3 ), 100 to 50% gradient in 10 min; detector, UV 254 nm) to afford Example 72 (33.0 mg, 63.4%) as a white solid. m/z (ESI, +ve ion)=518.25 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.53 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.64-6.61 (m, 1H), 5.65 (d, J=4.0 Hz 1H), 4.61-4.57 (m, 3H), 4.14-4.11 (m, 2H), 3.38 (m, 1H), 3.34 (s, 3H), 2.27-2.17 (m, 5H).

Example 73. (1R,2S)-2-(3-{[6-(3-hydroxyazetidin-1-yl)-5-methoxy-2-methylpyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-6-chloro-5-methoxy-2-methylpyrimidine · 1 of 2

To a stirred mixture of 4,6-dichloro-5-methoxy-2-methylpyrimidine (300 mg, 1.554 mmol, 1.00 equiv) and 3-((tert-butyldimethylsilyl)oxy)azetidine (436.78 mg, 2.331 mmol, 1.5 equiv) in THF (7.5 mL) was added TEA (471.80 mg, 4.662 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 60° C. under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford the title compound (510 mg, 95.41%) as a white solid. m/z (ESI, +ve ion)=344.05 [M+H] + .

Step B. tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(6-{3-[(tert-butyldimethylsilyl) oxy] azetidin-1-yl}-5-methoxy-2-methylpyrimidin-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a stirred mixture of tert-butyl (1R,2S)-2-[3-amino-1-(tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (80 mg, 0.154 mmol, 1.00 equiv) and 4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-6-chloro-5-methoxy-2-methylpyrimidine (63.42 mg, 0.185 mmol, 1.2 equiv) in toluene (4 mL) were added CPhos (6.71 mg, 0.015 mmol, 0.1 equiv) and Pd 2 (dba) 3 ·CHCl 3 (15.91 mg, 0.015 mmol, 0.1 equiv) and Cs 2 CO 3 (100.14 mg, 0.308 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The reaction was quenched by the addition of Water (10 mL) at room temperature. The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford the title compound (85 mg, 59.45%) as a yellow solid. m/z (ESI, +ve ion)=828.70 [M+H] + .

Step C. (1R,2S)-2-(3-({[6-(3-hydroxyazetidin-1-yl)-5-methoxy-2-methylpyrimidin-4-yl] amino}-1H-indazol-6-yl)-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one

A mixture of tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(6-{3-[(tert-butyldimethylsilyl) oxy]azetidin-1-yl}-5-methoxy-2-methylpyrimidin-4-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (85 mg, 0.103 mmol, 1.00 equiv) and TFA (2 mL, 26.926 mmol, 262.31 equiv) in DCM (4 mL) was stirred for 16 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B in 8 min, 30% B; wavelength: 254 nm; RT1 (min): 7.8 to afford Example 73 (34.2 mg, 62.67%) as a white solid. m/z (ESI, +ve ion)=514.45 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.48 (s, 1H), 10.40 (s, 1H), 8.63 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 6.91-6.84 (m, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.58 (m, 1H), 5.71 (d, J=2.8 Hz, 1H), 5.60 (d, J=6.4 Hz, 1H), 4.53 (m, 1H), 4.31-4.23 (m, 2H), 4.09 (m, 1H), 3.82 (m, 2H), 3.58 (s, 3H), 3.18 (d, J=5.2 Hz, 3H), 2.31 (m, 1H), 2.04 (s, 3H), 1.98 (m, 1H).

Example 74. (1R,2S)-2-{3-[(1,3-dimethyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(2,5-dimethylpyrazol-3-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To a mixture of 2,5-dimethylpyrazol-3-amine (120 mg, 1.080 mmol, 1.00 equiv), tBuXPhos Pd G3 (171.53 mg, 0.216 mmol, 0.2 equiv), tert-butyl(1R,2S)-2-[1-(tert-butoxycarbonyl)-3-iodoindazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (68.18 mg, 0.1080 mmol, 1 equiv) and di-tert-butyl([2-[2,4,6-tris(propan-2-yl)phenyl]phenyl])phosphane (9.17 mg, 0.022 mmol, 0.2 equiv) in dioxane (6 mL) was added Cs2CO3 (703.54 mg, 2.160 mmol, 2 equiv). The resulting mixture was stirred for 1 h at 90° C. then concentrated under reduced pressure. The residue was purified with silica gel chromatography, eluted with 8% MeOH in DCM to afford the title compound (50 mg, 7.53%) as a yellow solid. m/z (ESI +ve ion)=615.40 [M+H]+

Step B. (1R,2S)-2-{3-[(2,5-dimethylpyrazol-3-yl)amino]-1H-indazol-6-yl}-5′-methoxy-1′H-spiro[cyclopropane-1,3′-indol]-2′-one; trifluoroacetic acid

To a mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(2,5-dimethylpyrazol-3-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (30 mg, 0.049 mmol, 1.00 equiv) in DCM (0.8 mL, 12.584 mmol, 257.85 equiv) was added TFA (0.2 mL, 2.693 mmol, 55.17 equiv). The resulting mixture was stirred for 2 h at room temperature and then concentrated under reduced pressure. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column, 19×250 mm, 5 μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 28% B to 33% B in 10 min, 33% B; wavelength: 254 nm; RT1 (min): 6 to afford Example 74 (9 mg, 34.89%) as an off-white solid. m/z (ESI, 4e ion)=415.05 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.68 (d, J=8.4 Hz, 1H), 7.40-7.39 (m, 1H), 6.93 (dd, J=8.5, 1.4 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.63 (dd, J=8.5, 2.5 Hz, 1H), 5.60 (d, J=2.5 Hz, 1H), 4.85 (s, 2H), 3.86 (s, 3H), 3.34-3.4 (m, 1H), 3.32 (s, 3H), 2.32 (s, 3H), 2.25-2.17 (m, 2H).

Example 75. (1R,2S)-5′-methoxy-2-{3-[(4-methoxy-1-methyl-1H-pyrazol-5-yl)amino]-1H-indazol-6-yl}spiro[cyclopropane-1,3′-indol]-2′(1′H)-one

Step A. tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(4-methoxy-2-methylpyrazol-3-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate

To the mixture of tert-butyl (1R,2S)-2-[3-amino-1-tert-butoxycarbonyl)indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1′-carboxylate (90 mg, 0.173 mmol, 1.00 equiv) and 5-iodo-4-methoxy-1-methylpyrazole (45.27 mg, 0.190 mmol, 1.1 equiv) in toluene (2.0 mL) were added Cs 2 CO 3 (112.66 mg, 0.346 mmol, 2 equiv) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline (29.08 mg, 0.035 mmol, 0.2 equiv) under nitrogen atmosphere. The mixture was stirred at 90° C. for 2 h. The mixture was filtered and washed with EA (3×5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (rinsed with EA) to give the title compound (30 mg, 24.76%) as a light yellow oil. m/z (ESI +ve ion)=631.60 [M+H] + .

›Step A. 4-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-6-chloro-5-methoxy-2-methylpyrimidine · 2 of 2

Step B. (1R,2S)-5′-methoxy-2-{3-[(4-methoxy-2-methylpyrazol-3-yl)amino]-1H-indazol-6-yl-}1′H-spiro[cyclopropane-1,3′-indol]-2′-one

The mixture of tert-butyl (1R,2S)-2-[1-(tert-butoxycarbonyl)-3-[(4-methoxy-2-methylpyrazol-3-yl)amino]indazol-6-yl]-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indole]-1-carboxylate (30 mg, 0.048 mmol, 1.00 equiv) in TFA (0.5 mL) and DCM (5 mL) was stirred at 25° C. for 8 h. The solvent was removed under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30×150 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH 4 HCO 3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min: Gradient: 20% B to 35% B in 8 min; wavelength: 254 nm; RT1 (min): 6.2. The product-containing fractions were concentrated in vacuo to give Example 75 (10.7 mg, 50.27%) as a white solid. m/z (ESI +ve ion)=431.15 [M+H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.35-7.28 (m, 3H), 6.85-6.79 (m, 2H), 6.64-6.62 (m, 1H), 5.59 (d, J=2.4 Hz, 1H), 3.71 (s, 3H), 3.67 (s, 3H), 3.31 (s, 4H), 2.12-2.14 (m, 2H).

Example 76. (1R,2S)-2-(3-{[5-chloro-2-cyclopropyl-6-(3-hydroxyazetidin-1-yl)pyrimidin-4-yl]amino}-1H-indazol-6-yl)-5′-methoxyspiro[cyclopropane-1,3′-indol]-2′(1′H)-one

›Step A. 6-{3-[(tert-butyidimethylsilyl)oxy]azetidin-1-yl}-2-cyclopropylpyrimidin-4-amine

Into a 25 mL round-bottom flask were added 6-chloro-2-cyclopropylpyrimidin-4-amine (400 mg, 2.358 mmol, 1.00 equiv) and 3-[(tert-butyldimethylsilyl)oxy]azetidine (883.71 mg, 4.716 mmol, 2 equiv) at room temperature. The resulting mixture was stirred for 16 h at 100° C. under nitrogen atmosphere. The mixture was cooled down to room temperature. The resulting mixture was diluted with DCM (3 mL). The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford the title compound (260 mg, 34.40%) as an off-white solid. m/z (ESI, +ve ion)=321.20 [M+H] + . 1 H NMR (400 MHz, Chloroform-d) δ 5.32 (s, 2H), 5.07 (s, 1H), 4.73 (m, 1H), 4.27-4.19 (m, 2H), 3.85 (m, 2H), 1.99 (m, 1H), 1.13 (p, J=4.0 Hz, 2H), 1.00 (m, 2H), 0.92 (s, 9H), 0.10 (s, 6H).

›Step B. 6-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-5-chloro-2-cyclopropylpyrimidin-4-amine

A mixture of 6-{3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl}-2-cyclopropylpyrimidin-4-amine (200 mg,

›Tables in the description — 2

TABLE 1B

Example No.	MS/ 1 H NMR
112	m/z (ESI + ve ion) = 465.20 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.58 (d,
	J = 8.4 Hz, 1H), 7.34 (s, 1H), 6.88-6.83 (m, 2H), 6.32 (d, J = 4.4 Hz, 1H), 6.19-6.05
	(m, 1H), 6.01 (s, 1H), 5.59 (s, 1H), 4.52-4.47 (m, 2H), 3.34-3.32 (m, 4H),
	2.25-2.16 (m, 5H). 19 F NMR (376 MHz, Methanol-d 4 ) δ −123.83.
113	m/z (ESI, +ve ion) = 528.30 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.85 (s,
	1H), 7.57 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 6.94-6.61 (m, 2H), 6.73-6.70 (m, 1H),
	5.71 (d, J = 2.4 Hz, 1H), 3.84-3.80 (m, 7H), 3.71-3.68 (m, 4H), 3.38-3.36 (m,
	4H), 3.34 (s, 3H), 2.29-2.25 (m, 1H), 2.22-2.19 (m, 1H).
115	m/z (ESI, +ve ion) = 455.20 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.36 (s,
	1H), 10.41 (s, 1H), 10.03 (s, 1H), 9.08 (s, 1H), 8.02-7.94 (m, 2H), 7.36 (s, 1H),
	6.91 (dd, J = 8.5, 1.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.59 (dd, J = 8.5, 2.6 Hz,
	1H), 5.71 (d, J = 2.6 Hz, 1H), 4.91-4.79 (m, 4H), 4.40-4.36 (m, 1H), 3.19 (t, J =
	8.4 Hz, 1H), 2.33 (dd, J = 8.0, 4.7 Hz, 1H), 1.99 (dd, J = 9.0, 4.7 Hz, 1H).
118	m/z (ESI + ve ion) = 489.15 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.38 (s,
	1H), 7.55-7.45 (m, 2H), 6.92 (dd, J = 8.5, 1.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H),
	6.65 (dd, J = 8.5, 2.5 Hz, 1H), 5.62 (d, J = 2.5 Hz, 1H), 4.81-4.69 (m, 4H), 4.20-
	4.16 (m, 1H), 3.38 (d, J = 8.4 Hz, 1H), 3.34-3.32 (m, 3H), 2.25 (dd, J = 7.9, 4.8 Hz,
	1H), 2.19 (dd, J = 9.1, 4.8 Hz, 1H)
120	m/z (ESI, +ve ion) = 504.15 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.94 (s,
	1H), 7.59 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 6.91-6.85 (m, 1H), 6.84 (d, J = 8.8 Hz,
	1H), 6.65-6.62 (m, 1H), 5.61 (d, J = 1.6 Hz, 1H), 4.46-4.41 (m, 1H), 3.97 (s, 2H),
	3.60 (s, 2H), 3.37 (d, J = 8.8 Hz, 1H), 3.33-3.16 (m, 3H), 2.27-2.24 (m, 1H), 2.19-
	2.17 (m, 1H)
123	m/z (ESI, +ve ion) = 461.15 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.89 (s,
	1H), 7.54 (d, J = 8.4 Hz, 1H), 7.18-7.15 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.65-
	6.63 (m, 1H), 5.56 (d, J = 2.4 Hz, 1H), 4.02 (s, 3H), 3.31 (s, 3H), 3.25 (t, J = 8.8 Hz,
	1H), 2.35 (s, 3H), 2.25-2.20 (m, 2H). 19 F NMR (376 MHz, Methanol-d 4 ) δ −136.60
	(s, 1F)
124	m/z (ESI, +ve ion) = 413.1 [M + H] + . 1H NMR (400 MHz, METHANOL-d4) δ ppm
	7.75 (s, 1 H) 7.46 (d, J = 8.10 Hz, 1 H) 7.31 (s, 1 H) 6.89-7.02 (m, 1H) 6.77-6.87
	(m, 2 H) 6.40-6.55 (m, 1 H) 5.92 (d, J = 7.60 Hz, 1 H) 3.90 (s, 3 H) 3.23-3.28 (m, 1
	H) 2.21 (s, 3H) 1.99-2.15 (m, 2 H)
126	m/z (ESI, +ve ion) = 427.1 [M + H] + . 1H NMR (400 MHz, MeOD) δ 7.85-7.68 (m,
	1H), 7.56-7.42 (m, 1H), 7.31 (d, J = 2.5 Hz, 1H), 6.87-6.67 (m, 3H), 5.78 (s, 1H),
	3.91 (s, 3H), 3.60-3.43 (m, 1H), 2.22 (s, 3H), 2.14-2.00 (m, 2H), 1.82 (s, 3H)
127	m/z (ESI, +ve ion) = 427.1 [M + H] + . 1H NMR (400 MHz, MeOD) δ 7.82-7.69 (m,
	1H), 7.49-7.41 (m, 1H), 7.33 (s, 1H), 6.97-6.87 (m, 2H), 6.84 (s, 1H), 6.77-6.69
	(m, 1H), 3.90 (s, 3H), 3.56-3.45 (m, 1H), 2.32-2.27 (m, 1H), 2.26 (s, 3H), 2.22
	(s, 3H), 2.15-2.06 (m, 1H)
129	m/z (ESI, +ve ion) = 431.2 [M + H] + . 1H NMR (400 MHz, MeOD) δ 7.74 (s, 1H),
	7.42 (d, J = 8.5 Hz, 1H), 7.26 (s, 1H), 7.04-6.94 (m, 1H), 6.80 (d, J = 8.5 Hz, 1H),
	6.70 (d, J = 7.4 Hz, 1H), 6.26 (t, J = 9.5 Hz, 1H), 3.89 (s, 3H), 3.18-3.08 (m, 1H),
	2.50-2.43 (m, 1H), 2.21 (s, 3H), 2.08-1.99 (m, 1H)
130	m/z (ESI, +ve ion) = 431.2 [M + H] + . 1H NMR (400 MHz, MeOD) δ 7.86 (s, 1H),
	7.58 (d, J = 8.7 Hz, 1H), 7.46 (s, 1H), 7.28-7.18 (m, 1H), 7.03 (d, J = 8.5 Hz, 1H),
	6.85-6.77 (m, 2H), 4.02 (s, 3H), 3.82-3.71 (m, 1H), 2.59-2.48 (m, 1H), 2.43-
	2.36 (m, 1H), 2.34 (s, 3H)
131	m/z (ESI, +ve ion) = 431.2 [M + H] + . 1H NMR (400 MHz, MeOD) δ 7.80-7.69 (m,
	1H), 7.51-7.43 (m, 1H), 7.34-7.29 (m, 1H), 6.84-6.76 (m, 1H), 6.64-6.56 (m,
	1H), 6.21 (t, J = 9.4 Hz, 1H), 5.93-5.80 (m, 1H), 3.90 (s, 3H), 3.60-3.44 (m, 1H),
	2.21 (s, 3H), 2.18-2.10 (m, 1H), 2.10-2.00 (m, 1H)
133	m/z (ESI, +ve ion) = 431.15 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.64 (s,
	1H), 10.63 (s, 1H), 8.98 (s, 1H), 7.92 (s, 1H), 7.49-7.39 (m, 2H), 6.93-6.79 (m,
	3H), 5.93-5.86 (m, 1H), 3.90 (s, 3H), 3.24 (t, J = 8.4 Hz, 1H), 2.56-2.38 (m, 1H),
	2.17 (s, 3H), 2.11-2.01 (m, 1H)
135	m/z (ESI, +ve ion) = 467.15 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.76 (s,
	1H), 10.65 (s, 1H), 9.60 (s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.46-7.39 (m, 2H), 7.16
	(s, 1H), 6.93-6.90 (m, 1H), 6.90-6.79 (m, 2H), 5.92-5.86 (m, 1H), 3.25 (t, J = 8.4
	Hz, 1H), 2.46-2.41 (m, 1H), 2.22 (s, 3H), 2.10-2.00 (m, 1H)
136	m/z (ESI, +ve ion) = 471.35 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 7.87 (s,
	1H), 7.63 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4
	Hz, 1H), 6.64-6.61 (m, 1H), 5.64 (s, 1H), 4.78-4.72 (m, 1H), 3.50-3.15 (m, 4H),
	2.31 (s, 3H), 2.27-2.17 (m, 2H), 1.46 (m, 6H).
137	m/z (ESI, +ve ion) = 481.0 [M + H] + . 1H NMR (400 MHz, DMSO) δ 12.74-12.58
	(m, 1H), 11.02 (d, J = 3.3 Hz, 1H), 9.01 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.51-
	7.32 (m, 3H), 7.02 (q, J = 3.1 Hz, 1H), 6.99-6.87 (m, 1H), 6.40 (s, 1H), 3.89 (d, J =
	3.0 Hz, 3H), 3.29 (s, 1H), 2.16 (d, J = 3.2 Hz, 3H), 2.10-2.04 (m, 2H)
138	m/z (ESI, +ve ion) = 497.2 [M + H] + . 1 H NMR (400 MHz, DMSO) δ 12.62 (s, 1H),
	10.82 (s, 1H), 9.01 (s, 1H), 7.91 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H),
	7.08-6.99 (m, 1H), 6.96-6.84 (m, 2H), 6.03 (s, 1H), 3.89 (s, 3H), 3.31-3.20 (m, 1H),
	2.16 (s, 3H), 2.11-2.01 (m, 2H)
139	m/z (ESI, +ve ion) = 497.2 [M + H] + . 1 H NMR (400 MHz, DMSO) δ 12.60 (s, 1H),
	10.55 (s, 1H), 8.97 (s, 1H), 7.91 (s, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.36 (s, 1H), 7.27
	(s, 1H), 7.23-7.11 (m, 1H), 6.92 (t, J = 8.3 Hz, 2H), 3.90 (s, 3H), 3.42 (s, 1H),
	2.36-2.26 (m, 2H), 2.19 (s, 3H)
140	m/z (ESI + ve ion) = 453.20 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.98 (s, 1H),
	7.92 (s, 1H), 7.41 (d, J = 7.6 Hz, 2H), 6.89 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.4 Hz,
	1H), 6.59-6.56 (m, 1H), 6.02 (s, 1H), 5.70 (d, J = 2.8 Hz, 1H), 3.33 (s, 3H), 3.21 (t,
	J = 8.4 Hz, 1H), 2.31 (dd, J = 4.8, 4.8 Hz, 1H), 2.172 (s, 3H), 1.991 (dd, J = 4.8, 4.4
	Hz, 1H), 1.85-1.81 (m, 1H), 0.96-0.91 (m, 2H), 0.67-0.63 (m, 2H)
141	m/z (ESI, +ve ion) = 521.20 [M + H] + . 1 H-NMR (400 MHz, Methanol-d 4 ) δ 8.23 (s,
	1H), 7.54 (d, J = 8.6 Hz, 1H), 7.46 (s, 1H), 7.17-6.80 (m, 3H), 6.66-6.63 (m, 1H),
	5.61 (d, J = 2.4 Hz, 1H), 4.48-4.47 (m, 4H), 4.22-4.18 (m, 1H), 3.33-3.32 (m,
	4H), 2.27-2.17 (m, 2H). 19 F NMR (376 MHz, Methanol-d 4 ) δ −83.99
142	m/z (ESI, +ve ion) = 449.15 [M + H]+. 1H-NMR (400 MHz, Methanol-d4) δ 7.89 (s,
	1H), 7.54 (d, J = 8.4 Hz, 1H), 7.17-7.13 (m, 1H), 6.93-6.90 (m, 1H), 6.85-6.80
	(m, 1H), 5.78-5.75 (m, 1H), 4.03 (s, 3H), 3.28 (t, J = 8.8 Hz, 1H), 2.35 (s, 3H),
	2.28-2.26 (m, 2H). 19F NMR (376 MHz, Methanol-d4) δ −123.62 (s, 1F), −136.88
	(s, 1F)
143	m/z (ESI, +ve ion) = 485.10 [M + H]+. 1H NMR (400 MHz, Methanol-d4) δ 8.15 (s,
	1H), 7.48 (d, J = 8.4 Hz, 1H), 7.20-7.14 (m, 1H), 6.97-6.79 (m, 3H), 5.75-5.73
	(m, 1H), 3.32-3.27 (m, 1H), 2.39 (s, 3H), 2.30-2.22 (m, 2H)
144	m/z (ESI, +ve ion) = 461.20 [M + H]+. 1H-NMR (400 MHz, Methanol-d4) δ 7.85 (s,
	1H), 7.64 (d, J = 6.0 Hz, 1H), 7.23 (d, J = 10.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H),
	6.65-6.62 (m, 1H), 5.59 (d, J = 2.4 Hz, 1H), 4.00 (s, 3H), 3.29 (s, 3H), 3.22-3.18
	(m, 1H), 2.29 (s, 3H), 2.23 (d, J = 8.4 Hz, 2H)
145	m/z (ESI, +ve ion) = 443.4 [M + H]+. 1 HNMR (500 MHz, DMSO) δ 12.52 (s, 1H),
	10.41 (s, 1H), 8.86 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.38 (s, 1H), 6.93
	(dd, J = 8.6, 1.1 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H),
	5.69 (d, J = 2.6 Hz, 1H), 4.09 (s, 3H), 3.31 (s, 3H), 3.18 (t, J = 8.4 Hz, 1H), 2.40 (s,
	3H), 2.33 (dd, J = 7.9, 4.8 Hz, 1H), 1.98 (dd, J = 9.0, 4.7 Hz, 1H).
146	m/z (ESI, +ve ion) = 483.20 [M + H]+. 1 H-NMR (400 MHz, DMSO-d6) δ 12.63 (s,
	1H), 10.40 (s, 1H), 8.82 (s, 1H), 7.92 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H),
	6.92 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.57-6.54 (m, 1H), 5.72 (d, J =
	2.4 Hz, 1H), 3.97 (d, J = 6.8 Hz, 2H), 3.32-3.31 (m, 3H), 3.22 (t, J = 8.8 Hz, 1H),
	2.32-2.30 (m, 1H), 2.19 (s, 3H), 2.01-1.97 (m, 1H), 1.31-1.29 (m, 1H), 0.60-
	0.57 (m, 2H), 0.38-0.37 (m, 2H)
147	m/z (ESI, +ve ion) = 493.20 [M + H]+. 1 H-NMR (400 MHz, Methanol-d4) δ 7.96 (s,
	1H), 7.59 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 6.94-6.92 (m, 1H), 6.84 (d, J = 7.6 Hz,
	1H), 6.64-6.61 (m, 1H), 6.33-6.31 (m, 1H), 5.62 (d, J = 2.4 Hz, 1H), 4.49-4.41
	(m, 2H), 3.38 (d, J = 8.4 Hz, 1H), 3.31 (s, 3H), 2.32 (s, 3H), 2.27-2.24 (m, 1H),
	2.20-2.19 (m, 1H)
148	m/z (ESI + ve ion) = 441.20 [M + H]+. 1 H NMR (400 MHz, Methanol-d4) δ
	7.61-7.57 (m, 2H), 7.35 (s, 1H), 6.90-6.83 (m, 3H), 6.67-6.61 (m, 2H), 5.62 (d,
	J = 2.4 Hz, 1H), 3.93 (s, 3H), 3.38-3.36 (m, 1H), 3.30 (s, 3H), 2.25-2.17 (m, 5H)
149	m/z (ESI, +ve ion) = 511.20 [M + H]+. 1 H-NMR (400 MHz, Methanol-d4) δ 8.02 (s,
	1H), 7.58 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 6.95-6.93 (d, J = 8 Hz, 1H), 6.85 (d, J =
	8.4 Hz, 1H), 6.64-6.62 (m, 1H), 5.63 (d, J = 2.4 Hz, 1H), 4.82-4.76 (m, 2H), 3.39-
	3.37 (m, 1H), 3.31 (s, 3H), 2.32 (s, 3H), 2.28-2.24 (m, 1H), 2.21-2.17 (m, 1H)
150	m/z (ESI, +ve ion) = 442.20 [M + H] + . 1 H-NMR (400 MHz, Methanol-d 4 ) δ 8.07 (d,
	J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 6.91-6.89 (m, 1H), 6.84 (d,
	J = 8.4 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.64-6.61 (m, 1H), 5.62 (d, J = 2.4 Hz,
	1H), 4.06 (s, 3H), 3.37 (d, J = 8.4 Hz, 1H), 3.30 (s, 3H), 2.39 (s, 3H), 2.25-2.22 (m,
	1H). 2.19-2.16 (m, 1H)
151	m/z (ESI, +ve ion) = 455.2 [M + H] + . 1 H NMR (400 MHz, DMSO) δ 12.42 (s, 1H),
	10.43 (s, 1H), 9.98 (s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 6.90
	(d, J = 8.5 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 5.69 (s, 1H),
	3.21-3.14 (m, 1H), 2.98-2.85 (m, 1H), 2.37-2.27 (m, 4H), 2.02-1.94 (m, 1H),
	1.22 (d, J = 6.6 Hz, 6H)
152	m/z (ESI, +ve ion) = 441.20 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.60 (s,
	1H), 10.41 (s, 1H), 8.93 (s, 1H), 8.03 (s, 1H), 7.39-7.35 (m, 2H), 6.89 (d, J = 8.0
	Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.59 (dd, J = 8.4, 2.4 Hz, 1H), 5.70 (d, J = 2.4 Hz,
	1H), 3.33 (s, 3H), 3.20 (t, J = 8.4 Hz, 1H), 2.68-2.59 (m, 2H), 2.33-2.31 (m, 1H),
	2.17 (s, 3H), 1.99 (dd, J = 9.6, 4.4 Hz, 1H), 1.20 (t, J = 7.2 Hz, 3H)
153	m/z (ESI, +ve ion) = 455.1 [M + H]+. 1 H NMR (500 MHz, DMSO) δ 12.52 (s, 1H),
	10.40 (s, 1H), 9.15 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 6.88 (d, J = 8.5
	Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H), 5.70 (d, J = 2.5 Hz,
	1H), 4.55 (t, J = 9.2 Hz, 2H), 3.31 (s, 3H), 3.22-3.10 (m, 3H), 2.31 (dd, J = 7.9, 4.7
	Hz, 1H), 2.22 (s, 3H), 1.97 (dd, J = 9.0, 4.7 Hz, 1H)
155	m/z (ESI, +ve ion) = 475.1 [M + H] + . 1 H NMR (400 MHz, DMSO) δ 12.70 (s, 1H),
	10.43 (s, 1H), 9.30 (s, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.48-7.34 (m, 2H), 6.90 (d,
	J = 8.4 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 5.69 (s, 1H), 3.89
	(s, 3H), 3.23-3.10 (m, 1H), 2.38-2.28 (m, 1H), 2.06 (s, 3H), 2.01-1.92 (m, 1H)
156	m/z (ESI, +ve ion) = 459.4 [M + H]+. 1 H NMR (500 MHz, DMSO) δ 12.67 (s, 1H),
	10.41 (s, 1H), 9.18 (s, 1H), 7.81 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 6.90
	(d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.6 Hz, 1H), 5.68 (d,
	J = 2.5 Hz, 1H), 3.89-3.82 (m, 3H), 3.52 (s, 3H), 3.32 (s, 3H), 3.20-3.15 (m, 1H),
	2.31 (dd, J = 7.9, 4.8 Hz, 1H), 1.97 (dd, J = 9.1, 4.6 Hz, 1H)
158	m/z (ESI, +ve ion) = 496.15 [M + H] + . 1 H-NMR (400 MHz, Methanol-d 4 ) δ 7.86 (s,
	1H), 7.58 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.36 (d, J = 1.6 Hz, 1H), 6.95 (d, J = 8.8
	Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.65-6.62 (m, 1H), 5.66 (d, J = 2.4 Hz, 1H), 4.05
	(s, 3H), 3.38-3.32 (m, 4H), 2.27-2.23 (m, 1H), 2.20-2.18 (m, 1H)
159	m/z (ESI, +ve ion) = 453.4 [M + H]+. 1 H NMR (500 MHz, MeOD) δ = 7.52 (d,
	J = 8.5, 1H), 7.43 (s, 1H), 6.92 (dd, J = 8.5, 1.0, 1H), 6.82 (d, J = 8.5, 1H), 6.61 (dd,
	J = 8.5, 2.6, 1H), 5.60 (d, J = 2.5, 1H), 3.37-3.33 (m, 1H), 3.30 (s, 3H), 2.88 (t, J = 7.8,
	2H), 2.70 (t, J = 7.4, 2H), 2.23 (dd, J = 7.9, 4.8, 1H), 2.17 (dd, J = 9.1, 4.8, 1H), 2.14-
	2.07 (m, 2H)
162	m/z (ESI, +ve ion) = 459.15 [M + H] + . 1 H NMR (400 MHz, Methanol-d 6 ) δ 8.34 (s,
	1H), 7.56 (d, J = 8.8 Hz, 1H), 7.47 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4
	Hz, 1H), 6.64-6.62 (m, 1H), 5.62 (d, J = 2.0 Hz, 1H), 3.80-3.60 (m, 1H), 3.31 (s,
	3H), 2.46 (s, 3H), 2.33 (s, 3H), 2.27-2.25 (m, 1H), 2.21-2.17 (m, 1H)
164	m/z (ESI, +ve ion) = 458.05 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.21 (s,
	1H), 10.42 (s, 1H), 8.15 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H),
	7.33 (s, 1H), 7.30 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 8.4 Hz,
	1H), 6.58 (dd, J = 10.8, 2.4 Hz, 1H), 5.70 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H), 3.76 (s,
	3H), 3.32 (s, 3H), 3.18 (t, J = 8.4 Hz, 1H), 2.34-2.31 (m, 1H), 2.00-1.96 (m, 1H)
165	m/z (ESI, +ve ion) = 473.3 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s,
	1H), 10.43 (s, 1H), 8.41 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H),
	7.45 (s, 1H), 7.03 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 8.4 Hz,
	1H), 6.58 (dd, J = 8.4, 2.6 Hz, 1H), 5.70 (d, J = 2.5 Hz, 1H), 3.32 (s, 3H), 3.20 (t, J =
	8.3 Hz, 1H), 2.37-2.31 (m, 1H), 1.98 (dd, J = 9.1, 4.7 Hz, 1H)
166	m/z (ESI, +ve ion) = 499.3 [M + H] + . 1 H NMR (400 MHz, DMSO) δ 12.30 (s, 1H),
	10.45 (s, 1H), 8.56-8.24 (m, 2H), 7.94 (s, 1H), 7.51-7.15 (m, 2H), 7.08-6.43
	(m, 3H), 5.71 (s, 1H), 4.01 (s, 3H), 3.21-3.11 (m, 4H), 2.99 (s, 3H), 2.51 (s, 3H),
	2.42-2.26 (m, 1H), 2.07-1.89 (m, 1H)
168	m/z (ESI, +ve ion) = 506.2 [M + H] + . 1 H NMR (400 MHz, DMSO) δ 12.47 (s, 1H),
	10.44 (s, 1H), 8.79 (s, 1H), 8.52-8.36 (m, 1H), 7.99-7.86 (m, 1H), 7.71-7.54
	(m, 1H), 7.38 (s, 1H), 7.01-6.87 (m, 1H), 6.82-6.68 (m, 1H), 6.68-6.50 (m, 1H),
	5.70 (s, 1H), 4.09 (s, 3H), 3.19 (s, 4H), 2.39-2.28 (m, 1H), 2.08-1.93 (m, 1H)
171	m/z (ESI, +ve ion) = 486.3 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.74 (s,
	1H), 10.42 (d, J = 8.5 Hz, 1H), 9.31 (s, 1H), 8.39 (s, 1H), 7.64 (d, J = 11.1 Hz, 1H),
	7.43 (d, J = 6.1 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd,
	J = 8.5, 2.5 Hz, 1H), 6.38 (t, J = 6.6 Hz, 1H), 5.72 (d, J = 2.5 Hz, 1H), 4.07 (s, 3H),
	3.31-3.26 (m, 3H), 3.19 (t, J = 8.4 Hz, 1H), 2.37-2.29 (m, 1H), 1.96 (dt, J = 30.4,
	15.2 Hz, 1H)
172	m/z (ESI, +ve ion) = 454.3 [M + H] + . 1 H NMR (500 MHz, DMSO) δ = 12.83 (s, 1H),
	10.42 (s, 1H), 9.77 (s, 1H), 8.17 (s, 1H), 7.44 (d, J = 8.7, 2H), 6.97-6.94 (m, 1H),
	6.74 (d, J = 8.4, 1H), 6.58 (dd, J = 8.4, 2.6, 1H), 5.68 (d, J = 2.5, 1H), 4.03 (s, 3H), 3.30
	(s, 3H), 3.20 (t, J = 8.5, 1H), 2.33 (dd, J = 7.9, 4.7, 1H), 1.99 (dd, J = 9.0, 4.7, 1H)
175	m/z (ESI, +ve ion) = 519.10 [M + H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 12.28 (s,
	1H), 10.40 (s, 1H), 8.66 (s, 1H), 8.14 (s, 1H), 7.88 (d, J = 8 Hz, 1H), 7.34 (t,
	J = 8 Hz, 2H), 7.21 (d, J = 8 Hz, 1H), 6.89 (d, J = 8 Hz, 1H), 6.75 (d, J = 8 Hz, 1H),
	6.59-6.57 (m, 1H), 5.70 (s, 1H), 4.01 (s, 3H), 3.32-3.28 (m, 3H), 3.18-3.12 (m, 3H),
	2.34-2.31 (m, 1H), 2.00-1.96 (m, 1H), 1.12-1.11 (d, J = 4 Hz, 3H)
176	m/z (ESI, +ve ion) = 498.10 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.10 (s,
	1H), 10.42 (s, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.86-7.83 (m, 2H), 7.33 (s, 1H), 7.02
	(d, J = 8.4 Hz, 1H), 6.88-6.86 (m, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.58-6.57 (m,
	1H), 5.70 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.44-3.31 (m, 3H), 3.20-3.16 (m, 1H),
	2.96 (s, 6H), 2.34-2.31 (m, 1H), 1.98-1.96 (m, 1H)
177	m/z (ESI + ve ion) = 484.10 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.14 (s,
	1H), 10.42 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 4.4 Hz, 1H), 7.81 (d, J =
	8.4 Hz, 1H), 7.74 (s, 1H), 7.33-7.29 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.88 (d, J =
	8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.58-6.57 (m, 1H), 5.71 (d, J = 2.4 Hz, 1H),
	3.94 (s, 3H), 3.33 (s, 3H), 3.20-3.16 (m, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.34-2.31
	(m, 1H), 2.00-1.96 (m, 1H)
178	m/z (ESI, +ve ion) = 533.30 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.43 (t,
	J = 1.9 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.41-7.34 (m, 2H), 7.20-7.17 (m, 1H),
	6.91 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.64-6.61 (m, 1H), 5.62 (d, J =
	2.5 Hz, 1H), 4.08 (d, J = 1.8 Hz, 3H), 3.39-3.37 (m, 1H), 3.32-3.29 (s, 4H), 2.26-
	2.22 (m, 1H), 2.20-2.17 (m, 1H), 1.26 (d, J = 6.8 Hz, 6H)
179	m/z (ESI, +ve ion) = 534.20 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.33 (d,
	J = 2.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.39 (s, 1H), 7.31-7.28 (m, 1H), 7.16 (d,
	J = 8.4 Hz, 1H), 6.91 (d, J = 9.2, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.64-6.61 (m, 1H),
	5.63 (d, J = 2.8 Hz, 1H), 4.07 (s, 3H), 3.33-3.30 (m, 4H), 2.66 (s, 6H), 2.25-2.18
	(m, 2H)
180	m/z (ESI, +ve ion) = 540.10 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.13 (s,
	1H), 10.42 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H),
	7.04 (d, J = 8.4 Hz, 1H), 6.90-6.87 (m, 2H), 6.75 (d, J = 8.4 Hz, 1H), 6.58-6.57
	(m, 1H), 5.70 (d, J = 2.8 Hz, 1H), 3.94 (s, 3H), 3.60-3.58 (m, 4 H), 3.52-3.49 (m,
	4H), 3.32 (s, 3H), 3.20-3.16 (m, 1H), 2.34-2.31 (m, 1H), 2.00-1.96 (m, 1H)
181	m/z (ESI, +ve ion) = 499.60 [M + H] + . 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.33 (d,
	J = 2.4 Hz, 1H), 7.73 (t, J = 5.2 Hz, 2H), 7.37 (s, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.84
	(d, J = 8.4 Hz, 1H), 6.64-6.61 (m, 1H), 5.62 (d, J = 2.4 Hz, 1H), 4.13 (s, 3H),
	3.38-3.36 (m, 1H), 3.29 (s, 3H), 3.10 (s, 6H), 2.25-2.17 (m, 2H)
182	m/z (ESI, +ve ion) = 456.10 [M + H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 12.52 (s,
	1H), 10.41 (s, 1H), 8.73 (s, 1H), 7.76 (s, 1H), 7.43-7.34 (m, 2H), 6.84 (d, J = 8.4
	Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.57-6.60 (m, 1H), 5.64 (d, J = 2.6 Hz, 1H), 3.33
	(s, 3H), 3.18 (t, J = 8.4 Hz, 1H), 2.70 (s, 6H), 2.28-2.31 (m, 1H), 2.06 (s, 3H),
	1.96-1.99 (m, 1H)
184	m/z (ESI, +ve ion) = 547.1 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.39 (s, 1H),
	10.44 (s, 1H), 8.58 (s, 1H), 8.46-8.35 (m, 1H), 7.97-7.87 (m, 1H), 7.73-7.64
	(m, 1H), 7.36 (s, 1H), 6.97-6.87 (m, 1H), 6.79-6.71 (m, 1H), 6.64-6.53 (m, 1H),
	5.70 (s, 1H), 5.16 (t, J = 12.8 Hz, 2H), 4.46 (t, J = 12.7 Hz, 2H), 4.05 (s, 3H), 3.32
	(s, 3H), 3.23-3.11 (m, 1H), 2.40-2.27 (m, 1H), 2.04-1.92 (m, 1H)
186	m/z (ESI, +ve ion) = 493.05 [M + H] + . 1 H NMR (400 MHz, Methanol-d 6 ) δ 7.82 (s,
	1H), 7.28 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.76-6.60 (m, 2H), 5.76 (d, J = 2.4 Hz,
	1H), 3.98 (s, 3H), 3.40 (s, 3H), 3.35-3.34 (m, 1H), 2.27-2.24 (m, 1H), 2.17-2.10
	(m, 1H), 1.93 (s, 3H)
187	m/z (ESI, +ve ion) = 443.05 [M + H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 12.68 (s,
	1H), 10.42 (s, 1H), 9.07 (s, 1H), 7.92 (s, 1H), 7.39 (d, J = 7.7 Hz, 2H), 6.89 (d, J =
	8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.57-6.60 (m, 1H), 5.67 (d, J = 2.5 Hz, 1H),
	3.48 (s, 3H), 3.33 (s, 3H), 3.19 (t, J = 8.4 Hz, 1H), 2.30-2.33 (m, 1H), 2.14 (s, 3H),
	1.97-2.00 (m, 1H)
188	m/z (ESI, +ve ion) = 553.25 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.34 (s,
	1H), 10.43 (s, 1H), 8.47 (s, 1H), 8.39 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H),
	7.60 (d, J = 8.2 Hz, 1H), 7.36 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 8.4 Hz,
	1H), 6.60-6.57 (m, 1H), 5.70 (d, J = 2.0 Hz, 1H), 4.92 (s, 2H), 4.75-4.71 (m, 4H),
	4.20 (s, 2H), 4.08 (s, 3H), 3.30 (s, 3H), 3.19 (t, J = 8.4 Hz, 1H), 2.35-2.32 (m, 1H),
	2.00-1.97 (m, 1H
190	m/z (ESI, +ve ion) = 562.05 [M + H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 12.62 (s,
	1H), 10.42 (s, 1H), 9.11 (s, 1H), 7.79 (s, 1H), 7.47-7.44 (m, 2H), 6.76 (t, J = 16 Hz,
	2H), 6.59-6.57 (m, 1H), 5.62 (d, J = 4 Hz, 1H), 3.82 (s, 3H), 3, 75-3.72 (s, 2H),
	3.69-3.64 (m, 2H), 3.34 (s, 3H), 3.20 (t, J = 16 Hz, 1H), 2.93-2.89 (m, 2H), 2.51-
	2.50 (m, 2H), 2.36-2.32 (m, 1H), 2.00-1.98 (m, 1H)
191	m/z (ESI, +ve ion) = 485.10 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.32 (s,
	1H), 10.43 (s, 1H), 8.46-8.40 (m, 2H), 8.30 (d, J = 4.8 Hz, 1H), 7.93 (d, J = 8.4 Hz,
	1H), 7.61 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4
	Hz, 1H), 6.59-6.57 (m, 1H), 5.70 (d, J = 2.0 Hz, 1H), 4.12 (s, 3H), 3.33 (s, 3H),
	3.20-3.14 (m, 1H), 2.83 (d, J = 4.4 Hz, 3H), 2.35-2.32 (m, 1H), 2.00-1.97 (m,
	1H)
192	m/z (ESI, +ve ion) = 526.15 [M + H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 12.55 (s,
	1H), 10.40 (s, 1H), 8.87 (s, 1H), 7.73 (s, 1H), 7.54 (d, J = 8 Hz, 1H), 7.39 (s, 1H),
	6.84 (d, J = 12 Hz, 1H), 6.76 (d, J = 8 Hz, 1H), 6.63-6.60 (m, 1H), 5.66 (s, 1H),
	4.60-4.53 (m, 4H), 3.81-3.74 (m, 6H), 3.31 (s, 4H), 3.22-3.18 (t, J = 16 Hz, 1H),
	2.33-2.30 (m, 1H), 2.01-1.98 (m, 1H)
196	m/z (ESI, +ve ion) = 506.05 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.60 (s,
	1H), 10.41 (s, 1H), 8.98 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.42-7.32 (m, 3H), 6.81
	(dd, J = 8.2, 1.3 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.60 (dd, J = 8.4, 2.6 Hz, 1H),
	5.65 (d, J = 2.5 Hz, 1H), 3.98 (s, 3H), 3.33 (s, 3H), 3.18 (t, J = 8.5 Hz, 1H), 2.74 (s,
	3H), 2.34-2.28 (m, 1H), 1.99-1.96 (m, 1H)
197	m/z (ESI, +ve ion) = 499.20 [M + H] + . 1 H-NMR. (400 MHz, Methanol-d 4 ) δ 7.71 (d,
	J = 1.2 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.30 (d, J = 1.6 Hz, 1H), 6.93
	(d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.64-6.61 (m, 1H), 5.67 (d, J = 2.4
	Hz, 1H), 4.03 (s, 3H), 3.37-3.33 (m, 1H), 3.32 (s, 3H), 3.12 (s, 6H), 2.24-2.17 (m,
	2H)
198	m/z (ESI, +ve ion) = 499.10 [M + H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 12.43 (s,
	1H), 10.42 (s, 1H), 8.56 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H),
	7.39 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.57-6.60 (m, 1H),
	5.70 (d, J = 2.5 Hz, 1H), 4.03 (s, 3H), 3.31 (s, 3H), 3.19 (t, J = 8.4 Hz, 1H), 2.97 (d,
	J = 5.4 Hz, 6H), 2.32-2.35 (m, 1H), 1.97-2.00 (m, 1H)
199	m/z (ESI, +ve ion) = 540.15 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.19 (s,
	1H), 10.43 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H),
	7.34 (s, 1H), 7.04 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.76 (d,
	J = 8.0 Hz, 1H), 6.60-6.57 (m, 1H), 5.70 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H), 3.61 (s,
	4H), 3.54 (s, 4H), 3.30 (s, 3H), 3.20-3.16 (m, 1H), 2.34-2.31 (m, 1H), 2.00-1.97
	(m, 1H)
200	m/z (ESI, +ve ion) = 499.20 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.61 (s,
	1H), 10.42 (s, 1H), 9.09 (s, 1H), 7.99 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H),
	6.88 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.68 (s,
	1H), 3.92 (s, 3H), 3.83-3.79 (m, 1H), 3.63-3.57 (m, 3H), 3.34-3.24 (m, 3H),
	3.22-3.17 (m, 2H), 2.33-2.30 (m, 1H), 2.09-1.92 (m, 3H)
201	m/z (ESI, +ve ion) = 499.20 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.61 (s,
	1H), 10.42 (s, 1H), 9.10 (s, 1H), 7.99 (s, 1H), 7.42-7.38 (m, 2H), 6.86 (d, J = 8.4
	Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.60-6.57 (m, 1H), 5.67 (d, J = 2.4 Hz, 1H), 3.92
	(s, 3H), 3.87-3.83 (m, 1H), 3.65-3.61 (m, 1H), 3.53-3.49 (m, 2H), 3.34-3.24
	(m, 3H), 3.22-3.17 (m, 2H), 2.33-2.30 (m, 1H), 2.05-1.92 (m, 2H), 1.90-1.87
	(m, 1H)
202	m/z (ESI, +ve ion) = 520.15 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.47 (s,
	1H), 10.42 (s, 1H), 8.60 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H),
	7.59 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), 6.98-6.91 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H),
	6.59 (dd, J = 8.4, 2.6 Hz, 1H), 5.69 (d, J = 2.6 Hz, 1H), 4.58-4.52 (m, 2H), 3.32 (s,
	3H), 3.22-3.20 (m, 1H), 3.18 (s, 3H), 2.35-2.32 (m, 1H), 2.01-1.98 (m, 1H), 1.47
	(t, J = 7.0 Hz, 3H)
205	m/z (ESI, +ve ion) = 504.15 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.32 (s,
	1H), 10.41 (s, 1H), 8.40-8.37 (m, 2H), 7.92 (d, J = 8.8 Hz, 1H), 7.49-7.46 (m,
	1H), 7.36 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.60-6.58 (m,
	1H), 5.71 (d, J = 2.0 Hz, 1H), 4.04 (s, 3H), 3.32 (s, 3H), 3.19 (t, J = 8.4 Hz, 1H),
	2.35-2.31 (m, 1H), 2.01-1.97 (m, 1H), 1.63 (d, J = 13.2 Hz, 6H)
206	m/z (ESI, +ve ion) = 516.20 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.26 (s,
	1H), 10.41 (s, 1H), 8.20 (s, 1H), 8.01 (d, J = 12.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H),
	7.35 (s, 1H), 6.91 (t, J = 6 Hz, 2H), 6.75 (d, J = 8.4 Hz, 1H), 6.60-6.57 (m, 1H),
	5.70 (d, J = 2.0 Hz, 1H), 4.03 (s, 3H), 3.35 (s, 3H), 3.19-3.12 (m, 1H), 3.14 (s, 3H),
	2.92 (s, 3H), 2.34-2.31 (m, 1H), 2.08-1.98 (m, 1H)
207	m/z (ESI, +ve ion) = 558.25 [M + H] + . 1 H-NMR (400 MHz, Methanol-d 4 ) δ 7.77 (d,
	J = 12.0 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 6.96-6.92 (m, 2H), 6.84 (d,
	J = 8.8 Hz, 1H), 6.64-6.61 (m, 1H), 5.61 (d, J = 2.8 Hz, 1H), 3.99 (s, 3H),
	3.77-3.68 (m, 6H), 3.48 (s, 2H), 3.38-3.32 (m, 1H), 3.30 (s, 3H), 2.26-2.23 (m, 2H)
209	m/z (ESI, +ve ion) = 520.1 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.42 (s, 1H),
	10.38 (s, 1H), 8.74 (s, 1H), 8.46-8.27 (m, 1H), 7.95-7.79 (m, 1H), 7.63-7.50
	(m, 1H), 7.32 (s, 1H), 6.94-6.82 (m, 1H), 6.74-6.64 (m, 1H), 6.58-6.47 (m, 1H),
	5.76-5.57 (m, 2H), 4.00 (s, 3H), 3.26 (s, 3H), 3.18-3.04 (m, 2H), 2.35-2.23 (m,
	1H), 1.99-1.88 (m, 1H), 1.16-0.99 (m, 3H)
210	m/z (ESI, +ve ion) = 534.4 [M + H]+. 1 HNMR (400 MHz, DMSO-d6) δ 12.33 (s,
	1H), 10.43 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.34 (d, J =
	17.1 Hz, 2H), 7.18 (q, J = 5.0 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 8.4 Hz,
	1H), 6.58 (dd, J = 8.5, 2.5 Hz, 1H), 5.69 (d, J = 2.5 Hz, 1H), 3.92 (s, 3H), 3.31 (s,
	3H), 3.18 (t, J = 8.4 Hz, 1H), 2.43 (s, 3H), 2.39 (d, J = 5.0 Hz, 3H), 2.33 (dd, J = 7.9,
	4.7 Hz, 1H), 1.98 (dd, J = 9.0, 4.6 Hz, 1H)
211	m/z (ESI, +ve ion) = 485.4 [M + H]+. 1 H NMR: (400 MHz, DMSO-d6) δ 12.67 (s,
	1H), 10.43 (s, 1H), 9.33 (s, 1H), 7.41 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 9.1 Hz, 1H),
	6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.5 Hz, 1H), 5.71 (d, J = 2.5 Hz, 1H),
	4.74 (dd, J = 6.4, 2.5 Hz, 1H), 4.26 (dd, J = 15.7, 2.8 Hz, 1H), 3.97 (d, J = 15.7 Hz,
	1H), 3.32 (s, 3H), 3.24-3.10 (m, 1H), 2.33 (dd, J = 7.8, 4.6 Hz, 1H), 2.23 (s, 3H),
	1.98 (dd, J = 9.1, 4.7 Hz, 1H), 1.47 (d, J = 6.5 Hz, 3H)
213	m/z (ESI, +ve ion) = 482.2 [M + H] + . 1 H NMR (500 MHz, DMSO) δ = 12.87 (s, 1H),
	10.43 (s, 1H), 10.18 (s, 1H), 7.47-7.43 (m, 2H), 6.88 (dd, J = 8.5, 0.9, 1H), 6.75 (d,
	J = 8.4, 1H), 6.58 (dd, J = 8.5, 2.6, 1H), 5.60 (d, J = 2.6, 1H), 3.31 (s, 3H), 3.19 (t,
	J = 8.4, 1H), 2.94-2.67 (m, 10H), 2.30 (dd, J = 7.9, 4.7, 1H), 2.13-2.04 (m, 2H),
	1.98 (dd, J = 9.0, 4.7, 1H)
214	m/z (ESI, +ve ion) = 513.15 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.29 (s,
	1H), 10.41 (s, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.15 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H),
	7.36 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.4 Hz,
	1H), 6.59 (dd, J = 8.4, 2.6 Hz, 1H), 5.69 (d, J = 2.6 Hz, 1H), 4.49-4.44 (m, 2H),
	3.32 (s, 3H), 3.19 (t, J = 8.4 Hz, 1H), 3.15 (s, 3H), 2.99 (s, 3H), 2.32-2.30 (m, 1H),
	2.00-1.97 (m, 1H). 1.44 (t, J = 7.0 Hz, 3H)
215	m/z (ESI, +ve ion) = 511.25 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.05 (s,
	1H), 10.42 (s, 1H), 8.43 (d, J = 8.8 Hz, 1H), 7.94-7.90 (m, 2H), 7.78 (d, J = 8.4 Hz,
	1H), 7.30 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 7.6
	Hz, 1H), 5.71 (s, 1H), 4.05-3.99 (m, 5H), 3.33 (s, 3H), 3.20-3.16 (m, 1H), 2.56-
	2.51 (m, 2H), 2.33 (d, J = 4.8 Hz, 1H), 2.07-2.03 (m, 2H), 2.00-1.98 (m, 1H)
216	m/z (ESI + ve ion) = 576.20 [M + H] + . 1 H-NMR (400 MHz, Methanol-d 4 ) δ 8.15 (s,
	1H), 7.64 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.29-7.26 (m, 1H), 7.17 (d, J = 8.4 Hz,
	1H), 6.90 (d, J = 8, 4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.64-6.62 (m, 1H), 5.64 (d,
	J = 2.4 Hz, 1H), 4.08 (s, 3H), 3.65-3.61 (m, 4H), 3.37 (d, J = 8.4 Hz, 1H), 3.31 (s,
	3H), 3.01-2.88 (m, 4H), 2.27-2.24 (m, 1H), 2.20-2.17 (m, 1H)
217	m/z (ESI, +ve ion) = 479.1 [M + H]+. 1 H NMR (400 MHz, DMSO) δ: 12.64 (s, 1H),
	10.44 (s, 1H), 9.08 (s, 1H), 8.55 (s, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.49-7.55 (m,
	2H), 7.41 (s, 1H), 7.35 (br. s., 1H), 6.89 (d, J = 7.1 Hz, 1H), 6.75 (d, J = 8.8 Hz,
	1H), 6.60 (d, J = 8.5 Hz, 1H), 5.75 (s, 1H), 4.07 (s, 3H), 3.36 (s, 3H), 3.21 (t,
	J = 9.7 Hz, 1H), 2.33 (s, 1H), 1.99 (s, 1H)
218	m/z (ESI, +ve ion) = 515.2 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.26 (s, 1H),
	10.37 (s, 1H), 8.44-8.25 (m, 2H), 7.94-7.77 (m, 1H), 7.41-7.19 (m, 2H), 6.97-
	6.79 (m, 1H), 6.78-6.62 (m, 1H), 6.62-6.45 (m, 1H), 5.64 (s, 1H), 3.97 (s, 3H),
	3.72 (s, 3H), 3.15-3.06 (m, 1H), 2.34-2.20 (m, 1H), 2.02-1.83 (m, 1H)
219	m/z (ESI, +ve ion) = 528.2 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.27 (s, 1H),
	10.37 (s, 1H), 9.60-9.49 (m, 1H), 8.48-8.28 (m, 2H), 7.94-7.80 (m, 1H), 7.59-
	7.46 (m, 1H), 7.36-7.23 (m, 1H), 6.93-6.79 (m, 1H), 6.76-6.63 (m, 1H), 6.58-
	6.45 (m, 1H), 5.63 (s, 1H), 4.80 (s, 1H), 4.05 (s, 3H), 3.15-3.07 (m, 1H), 3.07-
	2.99 (m, 1H), 2.33-2.20 (m, 1H), 1.97-1.86 (m, 1H), 0.96 (s, 6H)
220	m/z (ESI, +ve ion) = 511.4 [M + H]+. NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H),
	10.43 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.79
	(d, J = 2.2 Hz, 1H), 7.32 (s, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H),
	6.58 (dd, J = 8.4, 2.4 Hz, 1H), 5.70 (d, J = 2.2 Hz, 1H), 3.98 (s, 3H), 3.79 (t,
	J = 7.0 Hz, 2H), 3.31 (s, 3H), 3.17 (t, J = 8.4 Hz, 1H), 2.46 (t, J = 8.0 Hz, 2H), 2.33
	(dd, J = 7.7, 4.7 Hz, 1H), 2.12-2.03 (m, 2H), 1.97 (dd, J = 8.9, 4.7 Hz, 1H)
221	m/z (ESI, +ve ion) = 534.4 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.33 (s,
	1H), 10.43 (s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.34 (d, J =
	17.1 Hz, 2H), 7.18 (q, J = 5.0 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 8.4 Hz,
	1H), 6.58 (dd, J = 8.5, 2.5 Hz, 1H), 5.69 (d, J = 2.5 Hz, 1H), 3.92 (s, 3H), 3.31 (s,
	3H), 3.18 (t, J = 8.4 Hz, 1H), 2.43 (s, 3H), 2.39 (d, J = 5.0 Hz, 3H), 2.33 (dd, J = 7.9,
	4.7 Hz, 1H), 1.98 (dd, J = 9.0, 4.6 Hz, 1H)
222	m/z (ESI + ve ion) = 535.15 [M + H]+. 1 H-NMR (400 MHz, DMSO-d6) δ 12.43 (s,
	1H), 10.42 (s, 1H), 8.69 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H),
	7.50 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz,
	1H), 6.60-6.58 (m, 1H), 5.71 (d, J = 2.4 Hz, 1H), 4.06 (s, 3H), 3.32 (s, 3H), 3.21-
	3.17 (m, 1H), 2.81 (s, 6H), 2.35-2.32 (m, 1H), 2.01-1.96 (m, 1H).
223	m/z (ESI, +ve ion) = 549.10 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.45 (s,
	1H), 10.42 (s, 1H), 8.53 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H),
	7.47 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), 6.97-6.90 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H),
	6.59 (dd, J = 8.4, 2.6 Hz, 1H), 5.69 (d, J = 2.6 Hz, 1H), 4.51 (q, J = 7.0 Hz, 2H),
	3.32 (s, 3H), 3.20 (t, J = 8.5 Hz, 1H), 2.81 (s, 6H), 2.34-2.32 (m, 1H), 2.00-1.98
	(m, 1H), 1.46 (t, J = 7.0 Hz, 3H)
224	m/z (ESI, +ve ion) = 549.10 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s,
	1H), 10.42 (s, 1H), 8.53 (s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H),
	7.47 (d, J = 8.1 Hz, 1H), 7.39 (s, 1H), 6.97-6.90 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H),
	6.59 (dd, J = 8.4, 2.6 Hz, 1H), 5.69 (d, J = 2.6 Hz, 1H), 4.51 (q, J = 7.0 Hz, 2H),
	3.32 (s, 3H), 3.20 (t, J = 8.5 Hz, 1H), 2.81 (s, 6H), 2.34-2.32 (m, 1H), 2.00-1.98
	(m, 1H), 1.46 (t, J = 7.0 Hz, 3H
225	m/z (ESI, +ve ion) = 504.20 [M + H]+. 1 H NMR (400 MHz, Chloroform-d) δ
	7.93-7.90 (m, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 12 Hz, 2H), 6.93 (d, J = 8 Hz,
	1H), 6.84 (d, J = 4.4 Hz, 1H), 6.64-6.61 (m, 1H), 5.66 (d, J = 2.4 Hz, 1H), 4.06 (s,
	3H), 3.42 (s, 1H), 3.36 (d, J = 8.8 3H), 2.26-2.20 (m, 1H), 2.19-2.16 (m, 1H), 1.81
	(s, 3H), 1.79 (s, 3H).
226	m/z (ESI, +ve ion) = 486.4 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.17 (s, 1H),
	10.41 (s, 1H), 8.53 (d, J = 2.1 Hz, 1H), 7.92-7.84 (m, 2H), 7.68 (d, J = 2.2 Hz,
	1H), 7.31 (s, 1H), 6.89-6.84 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.4,
	2.5 Hz, 1H), 5.70 (d, J = 2.5 Hz, 1H), 4.96 (s, 1H), 3.96 (s, 3H), 3.17 (t, J = 8.4 Hz,
	1H), 2.37-2.27 (m, 1H), 2.01-1.92 (m, 1H), 1.43 (s, 6H). 3 protons are under
	water peak at 3.30 ppm
227	m/z (ESI, +ve ion) = 520.25 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s,
	1H), 10.41 (s, 1H), 8.64 (s, 1H), 8.27 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H),
	6.93 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.60-6.58 (m, 1H), 5.71 (d, J =
	2.4 Hz, 1H), 4.04 (s, 3H), 3.33 (s, 3H), 3.31 (s, 3H), 3.19 (t, J = 8.4 Hz, 1H), 2.51 (s,
	3H), 2.34-2.33 (m, 1H), 2.00-1.97 (m, 1H).
229	m/z (ESI, +ve ion) = 505.10 [M + H]+. 1 H-NMR (400 MHz, Methanol-d4) δ 8.02 (d,
	J = 2.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.84
	(d, J = 8.4 Hz, 1H), 6.64-6.61 (m, 1H), 5.62 (d, J = 2.4 Hz, 1H), 4.16 (s, 3H), 3.38
	(d, J = 8.4 Hz, 1H), 3.31 (s, 3H), 2.26-2.17 (m, 2H), 1.82 (s, 3H), 1.78 (s, 3H).
230	m/z (ESI, +ve ion) = 525.25 [M + H]+. 1 H-NMR (400 MHz, Methanol-d4) δ 8.24 (d,
	J = 8.4 Hz, 1H), 7.73-7.67 (m, 2H), 7.40 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.84 (d,
	J = 8.4 Hz, 1H), 6.64-6.61 (m, 1H), 5.62 (d, J = 2.4 Hz, 1H), 4.20 (s, 3H), 3.38 (d,
	J = 8.4 Hz, 2H), 3.33-3.31 (s, 4H), 2.26-2.05 (m, 2H), 1.19-1.12 (m, 1H), 0.58-
	0.54 (m, 2H), 0.36-0.32 (m, 2H)
231	m/z (ESI + ve ion) = 513.25 [M + H]+. 1H-NMR (400 MHz, Methanol-d4) δ 8.23 (d,
	J = 8.4 Hz, 1H), 7.73-7.66 (m, 2H), 7.40 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.84 (d,
	J = 8.4 Hz, 1H), 6.64-6.61 (m, 1H), 5.62 (d, J = 2.4 Hz, 1H), 4.18 (s, 4H), 3.38 (d,
	J = 8.4 Hz, 1H), 3.30 (s, 3H), 2.26-2.17 (m, 2H), 1.31 (d, J = 6.4 Hz, 6H)
232	m/z (ESI + ve ion) = 567.25 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.31 (s,
	1H), 10.41 (s, 1H), 8.48-8.32 (m, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.2 Hz,
	1H), 7.36 (s, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.59 (dd, J =
	8.4, 2.6 Hz, 1H), 5.71 (d, J = 2.6 Hz, 1H), 5.13 (s, 1H), 4.59 (d, J = 6.6 Hz, 1H),
	4.00 (s, 3H), 3.82 (s, 1H), 3.67 (d, J = 11.8 Hz, 3H), 3.32 (s, 3H), 3.21-3.17 (m,
	1H). 2.33 (m, 1H), 2.04-1.75 (m, 5H)
233	m/z (ESI, +ve ion) = 459.4 [M + H]+. NMR (400 MHz,) δ 12.45 (s, 1H), 10.42 (s,
	1H), 8.41 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 6.87 (d, J = 8.5 Hz, 1H),
	6.74 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 8.5, 2.4 Hz, 1H), 6.29 (s, 1H), 5.67 (d,
	J = 2.4 Hz, 1H), 3.88 (s, 3H), 3.31 (s, 3H), 3.27 (s, 3H), 3.18 (t, J = 8.4 Hz, 1H),
	2.30 (dd, J = 7.8. 4.8 Hz, 1H), 1.97 (dd, J = 9.0, 4.6 Hz, 1H)
235	m/z (ESI, +ve ion) = 541.3 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.58 (s, 1H),
	10.44 (s, 1H), 8.75 (s, 1H), 7.83 (s, 1H), 7.47-7.37 (m, 2H), 7.34 (s, 1H), 6.87 (d,
	J = 8.4 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 5.75 (s, 1H),
	4.59-4.37 (m, 1H), 4.31-4.08 (m, 5H), 3.93 (s, 3H), 3.88-3.74 (m, 2H), 3.26-3.11
	(m, 5H), 2.40-2.28 (m, 1H), 2.04-1.94 (m, 1H)
236	m/z (ESI, +ve ion) = 500.2 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.71 (s, 1H),
	10.47 (s, 1H), 9.31 (s, 1H), 7.78 (s, 1H), 7.54-7.34 (m, 2H), 6.90 (d, J = 8.5 Hz,
	1H), 6.77 (d, J = 8.5 Hz, 1H), 6.65-6.55 (m, 1H), 5.72 (s, 1H), 4.01 (s, 3H), 3.33
	(s, 3H), 3.25-3.10 (m, 4H), 2.98 (s, 3H), 2.38-2.29 (m, 1H), 2.05-1.96 (m, 1H)
237	m/z (ESI, +ve ion) = 514.3 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.69 (s, 1H),
	10.43 (s, 1H), 9.21 (s, 1H), 7.77 (s, 1H), 7.48-7.37 (m, 2H), 6.89 (d, J = 8.5 Hz,
	1H), 6.74 (d, J = 8.8 Hz, 1H), 6.67-6.52 (m, 1H), 5.71 (s, 1H), 4.52-4.38 (m, 2H),
	3.23-3.06 (m, 4H), 2.97 (s, 3H), 2.33 (s, 1H), 1.76 (s, 1H), 1.43 (s, 3H)
238	m/z (ESI, +ve ion) = 513.25 [M + H]+. 1 H NMR (400 MHz, Methanol-d4) δ 8.08 (s,
	1H), 7.70 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 6.94-6.91 (m, 1H), 6.84 (d, J = 8.4 Hz,
	1H), 6.64-6.61 (m, 1H), 5.62 (d, J = 2.4 Hz, 1H), 4.06 (s, 3H), 3.38-3.36 (m, 1H),
	3.30 (s, 3H), 3.14 (s, 3H), 2.97 (s, 3H), 2.26-2.18 (m, 5H)
239	m/z (ESI, +ve ion) = 490.20 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.32 (s,
	1H), 10.42 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.43 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H),
	7.42 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 6.93-6.91 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H),
	6.60-6.57 (m, 1H), 5.71 (d, J = 2.4 Hz, 1H), 4.05 (s, 3H), 3.32 (s, 3H), 3.21-3.17
	(m, 1H), 2.78 (s, 3H), 2.34-2.37 (m, 1H), 2.00-1.97 (m, 1H)
240	m/z (ESI, +ve ion) = 490.20 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.32 (s,
	1H), 10.42 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.43 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H),
	7.42 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 8.4 Hz,
	1H), 6.60-6.57 (m, 1H), 5.71 (d, J = 2.4 Hz, 1H), 4.05 (s, 3H), 3.33 (s, 3H),
	3.21-3.17 (m, 1H), 2.78 (s, 3H), 2.35-2.32 (m, 1H), 2.08-1.97 (m, 1H)
241	m/z (ESI, +ve ion) = 506.15 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s,
	1H), 10.42 (s, 1H), 9.28 (s, 1H), 8.54 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H),
	7.37 (s, 1H), 6.95-6.92 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.60-6.58 (m, 1H), 5.71
	(d, J = 2.4 Hz, 1H), 4.09 (s, 3H), 3.33 (s, 3H), 3.32-3.21 (s, 4H), 2.35-2.32 (m,
	1H), 2.01-1.98 (m, 1H).
242	m/z (ESI, +ve ion) = 507.20 [M + H] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 12.80 (s,
	1H), 10.42 (s, 1H), 9.76 (s, 1H), 8.03 (s, 1H), 7.44-7.41 (m, 2H), 6.92-6.90 (m,
	1H), 6.75 (d, J = 8.4 Hz, 1H), 6.60-6.57 (m, 1H), 5.71 (d, J = 2.4 Hz, 1H), 4.09 (s,
	3H). 3.33 (s, 3H), 3.21-3.15 (m, 4H), 2.35-2.31 (m, 1H), 2.00-1.97 (m, 1H)
243	m/z (ESI, +ve ion) = 551.20 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.27 (s,
	1H), 10.42 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H),
	7.35 (s, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz,
	1H), 6.60-6.57 (m, 1H), 5.71 (d, J = 2.4 Hz, 1H), 3.98 (s, 3H), 3.32-3.21 (m, 3H),
	3.19 (t, J = 8.0 Hz, 1H), 2.87 (s, 2H), 2.34-2.31 (m, 1H), 2.05-1.97 (m, 1H), 0.69
	(s, 4H), 0.59 (s, 4H).
244	m/z (ESI, +ve ion) = 535.15 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s,
	1H), 10.42 (s, 1H), 8.60-8.57 (m, 1H), 8.52 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.93
	(d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H),
	6.75 (d, J = 8.4 Hz, 1H), 6.60-6.52 (m, 1H), 6.29-6.01 (m, 1H), 5.71 (d, J = 2.8
	Hz, 1H), 4.14 (s, 3H), 3.78-3.66 (m, 2H), 3.30 (s, 3H), 3.21-3.17 (m, 1H), 2.34-
	2.31 (m, 1H), 2.00-1.97 (m, 1H)
245	m/z (ESI, +ve ion) = 567.30 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s,
	1H), 10.41 (s, 1H), 8.40 (d, J = δ 0 Hz, 1H), 8.24 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H),
	7.34 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.92-6.90 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H),
	6.60-6.57 (m, 1H), 5.71 (d, J = 2.4 Hz, 1H), 4.53 (s, 2H), 4.01 (s, 3H), 3.32 (d, J =
	5.6 Hz, 3H), 3.20 (t, J = 8.4 Hz, 1H), 2.34-2.31 (m, 1H), 2.01-1.97 (m, 1H), 1.86
	(d, J = 12 Hz, 1H), 1.61 (d, J = 5.2 Hz, 4H), 1.49 (d, J = 2.8 Hz, 1H), 1.29 (d, J = 6.8
	Hz, 6H)
246	m/z (ESI, +ve ion) = 567.20 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.29 (s,
	1H), 10.42 (s, 1H), 8.41-8.37 (m, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.30
	(d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.59 (d, J =
	2.4 Hz, 1H), 5.71 (d, J = 2.6 Hz, 1H), 4.39-4.36 (m, 1H), 4.28-4.26 (m, 1H),
	4.13-4.09 (m, 1H), 4.01 (s, 4H), 3.32-3.29 (m, 5H), 3.19 (t, J = 8.4 Hz, 1H), 3.00-2.98
	(m, 1H). 2.34-2.31(m, 1H), 2.00-1.93 (m, 1H), 1.83-1.80 (m, 3H).
247	m/z (ESI, +ve ion) = 510.10 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (s,
	1H), 10.42 (s, 1H), 9.55 (s, 1H), 8.29 (d, J = 2.1 Hz, 1H), 8.19 (d, J = 2.2 Hz, 1H),
	7.45 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 8.4 Hz,
	1H), 6.60 (dd, J = 8.4, 2.6 Hz, 1H), 5.71 (d, J = 2.6 Hz, 1H), 3.34 (s, 3H), 3.25 (s,
	3H), 3.20 (t, J = 8.4 Hz, 1H), 2.34-2.32 (m, 1H), 2.08-1.94 (m, 1H)
249	m/z (ESI, +ve ion) = 504.15 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.29 (s,
	1H), 10.42 (s, 1H), 9.32 (s, 1H), 8.23 (s, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.51 (d, J =
	5.9 Hz, 1H), 7.34 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.59
	(dd, J = 8.5, 2.6 Hz, 1H), 5.71 (d, J = 2.6 Hz, 1H), 4.04 (s, 3H), 3.33 (s, 3H), 3.19 (t,
	J = 8.5 Hz, 1H), 2.35-2.32 (m, 1H), 2.01-1.97 (m, 1H), 1.63 (d, J = 13.5 Hz, 6H)
250	m/z (ESI, +ve ion) = 549.20 [M + H]+. 1 H NMR (400 MHz, Methanol-d4) δ 8.25 (d,
	J = 8.1 Hz, 1H), 7.73-7.70 (m, 2H), 7.40 (s, 1H), 6.95-6.93 (m, 1H), 6.84 (d, J =
	8.4 Hz, 1H), 6.64-6.61 (m, 1H), 5.62 (d, J = 2.4 Hz, 1H), 4.78-4.76 (m, 1H),
	4.73-4.69 (m, 1H), 4.66-4.63 (m, 1H), 4.60-4.52 (m, 2H), 4.18 (s, 3H), 3.39-3.34
	(m, 1H), 3.31 (s, 3H), 2.27-2.23 (m, 1H), 2.21-2.17 (m, 1H)
251	m/z (ESI, +ve ion) = 503.20 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.56 (s,
	1H), 10.43 (s, 1H), 8.47 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H),
	7.56 (d, J = 8.4 Hz, 1H), 7.41 (s, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.4 Hz,
	1H), 6.61-6.53 (m, 1H), 5.71 (d, J = 2.4 Hz, 1H), 3.35 (s, 3H), 3.22-3.18 (m, 1H),
	3.07 (s, 3H), 2.99 (s, 3H), 2.35-2.32 (m, 1H), 2.08-1.91 (m, 1H)
252	m/z (ESI, +ve ion) = 486.20 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.33 (s,
	1H), 10.41 (s, 1H), 8.17 (s, 1H), 8.05 (s, 1H), 7.77-7.75 (m, 2H), 7.38 (s, 1H),
	6.93-6.91 (m, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.61-6.58 (m, 1H). 5.71 (d, J = 2.4 Hz,
	1H), 3.34 (s, 3H), 3.25 (t, J = 8.4 Hz, 1H), 2.57 (s, 3H), 2.34-2.31 (m, 1H),
	2.00-1.98 (m, 1H)
253	m/z (ESI, +ve ion) = 499.25 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s,
	1H), 10.42 (s, 1H), 9.18 (s, 1H), 8.14 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H),
	7.26 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.62-6.55 (m, 1H),
	5.71 (d, J = 2.4 Hz, 1H), 4.00 (s, 3H), 3.33 (s, 3H), 3.19 (t, J = 8.4 Hz, 1H), 3.07 (s,
	3H), 3.00 (s, 3H), 2.37-2.29 (m, 1H), 2.03-1.95 (m, 1H)
254	m/z (ESI + ve ion) = 533.20 [M + H]+. 1 H-NMR (400 MHz, DMSO-d6) δ 12.57 (s,
	1H), 10.41 (s, 1H), 8.93 (s, 1H), 7.52 (s, 1H), 7.38 (d, J = 6.6 Hz, 2H), 6.87 (d, J =
	8.5 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.62-6.55 (m, 1H), 5.71 (d, J = 2.4 Hz, 1H),
	4.42 (t, J = 8.7 Hz, 4H), 4.06 (s, 3H), 3.88-3.79 (m, 1H), 3.33 (s, 3H), 3.18 (t, J =
	8.5 Hz, 1H), 2.33-2.30 (m, 1H), 2.00-1.97 (m, 1H)
255	m/z (ESI, +ve ion) = 577.15 [M + H]+. 1 H-NMR (400 MHz, Methanol-d4) δ 7.96 (d,
	J = 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.35 (d, J = 1.6 Hz, 1H), 6.96
	(d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.64-6.62 (m, 1H), 5.65 (d,
	J = 2.4 Hz, 1H), 4.07 (s, 3H), 3.75-3.73 (m, 4H), 3.37 (d, J = 8.4 Hz, 1H), 3.32
	(s, 3H), 3.04-3.01 (m, 4H), 2.27-2.25 (m, 1H). 2.19-2.14 (m, 1H)
256	m/z (ESI, +ve ion) = 603.20 [M + H]+. 1 H-NMR (400 MHz, Methanol-d4) δ 7.94 (d,
	J = 1.9 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.33 (d, J = 2.0 Hz, 1H), 6.95
	(d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.65-6.62 (m, 1H), 5.65 (d,
	J = 2.8 Hz, 1H), 4.39 (s, 2H), 4.07 (s, 3H), 3.51-3.50 (m, 3H), 3.38 (d,
	J = 11.2 Hz, 3H), 2.67 (d, J = 10.8 Hz, 2H), 2.27-2.24 (m, 1H), 2.21-2.17 (m, 1H),
	2.00-1.93 (m, 4H)
257	m/z (ESI, +ve ion) = 532.60 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s,
	1H), 10.43 (s, 1H), 8.42-8.40 (m, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.49-7.47 (m,
	1H), 7.36 (s, 1H), 6.93-6.91 (m, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.60-6.58 (m, 1H),
	5.71 (d, J = 2.4 Hz, 1H), 4.02 (s, 3H), 3.32 (d, J = 2.0 Hz, 3H), 3.19 (t, J = 8.4 Hz,
	1H), 2.35-2.32 (m, 1H), 2.01-1.87 (m, 5H), 1.03-0.95 (m, 6H)
259	m/z (ESI, +ve ion) = 576.15 [M + H]+. 1 H-NMR (400 MHz, Methanol-d4) δ 8.02 (d,
	J = 1.9 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 2.0 Hz, 2H), 6.95 (d,
	J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.65-6.62 (m, 1H), 5.65 (d, J = 2.4 Hz, 1H),
	4.08 (s, 3H), 4.04-4.02 (m, 2H), 3.46-3.42 (m, 4H), 3.40-3.37 (m, 3H), 2.27-2.24
	(m, 1H), 2.20-2.17 (m, 1H), 1.91-1.81 (m, 2H), 1.80-1.70 (m, 2H)
260	m/z (ESI, +ve ion) = 453.2 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.52 (s, 1H),
	10.44 (s, 1H), 8.89 (s, 1H), 8.41-8.29 (m, 1H), 7.96-7.88 (m, 1H), 7.63-7.54
	(m, 1H), 7.38 (s, 1H), 6.95-6.91 (m, 1H), 6.80-6.70 (m, 1H), 6.58 (s, 1H), 5.69
	(s, 1H), 4.04 (s, 3H), 3.32 (s, 3H), 3.21-3.15 (m, 1H), 2.33 (s, 1H), 2.00 (s, 1H)
261	[0059] m/z (ESI, +ve ion) = 531.20 [M + H]+. 1 H NMR (400 MHz, Methanol-d4)
	δ 8.17-8.13 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.37 (s, 1H), 7.29-7.25 (m, 1H),
	7.16-7.13 (m, 1H), 6.89-6.82 (m, 2H), 6.63-6.60 (m, 1H), 5.62 (d, J = 2.4 Hz,
	1H), 4.03 (s, 3H), 3.37-3.29 (m, 4H), 2.24-2.19 (m, 1H), 2.18-2.15 (m, 1H),
	2.00-1.88 (m, 4H), 1.12-1.01 (m, 6H)
262	m/z (ESI, +ve ion) = 520.25 [M + H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.43 (s,
	1H), 10.41 (s, 1H), 9.29 (s, 1H), 8.55 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H),
	7.37 (s, 1H), 6.93 (dd, J = 8.4, 1.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.59 (dd, J =
	8.5, 2.6 Hz, 1H), 5.71 (d, J = 2.6 Hz, 1H), 4.09 (s, 3H), 3.37-3.34 (m, 2H), 3.33 (s,
	3H), 3.19 (t, J = 8.5 Hz, 1H), 2.34 (dd, J = 7.9, 4.7 Hz, 1H), 1.99 (dd, J = 9.0,
	4.7 Hz, 1H), 1.14 (t, J = 7.4 Hz, 3H)
263	m/z (ESI, +ve ion) = 511.3 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.57 (s, 1H),
	10.43 (s, 1H), 8.72 (s, 1H), 7.88-7.76 (m, 1H), 7.44-7.37 (m, 2H), 7.37-7.28
	(m, 1H), 6.96-6.82 (m, 1H), 6.81-6.70 (m, 1H), 6.66-6.53 (m, 1H), 5.75 (s, 1H),
	4.43-4.27 (m, 2H), 4.10-3.96 (m, 2H), 3.92 (s, 3H), 3.22-3.10 (m, 1H), 2.39-
	2.30 (m, 1H), 2.30-2.17 (m, 2H), 2.05-1.91 (m, 1H)
264	m/z (ESI, +ve ion) = 541.3 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.54 (s, 1H),
	10.43 (s, 1H), 8.61 (s, 1H), 7.61 (s, 1H), 7.46-7.40 (m, 1H), 7.39 (s, 1H), 7.21 (s,
	1H), 6.96-6.79 (m, 1H), 6.81-6.69 (m, 1H), 6.68-6.52 (m, 1H), 5.74 (s, 1H),
	3.91 (s, 3H), 3.65-3.56 (m, 4H), 3.56-3.49 (m, 4H), 3.22-3.13 (m, 1H), 2.39-
	2.28 (m, 1H), 2.03-1.93 (m, 1H)
265	m/z (ESI, +ve ion) = 496.25 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s,
	1H), 10.42 (s, 1H), 8.26 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H),
	7.19 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.60-6.58 (m, 1H),
	5.71 (d, J = 2.4 Hz, 1H), 4.34 (s, 2H), 3.98 (s, 3H), 3.35 (s, 3H), 3.19-3.14 (m, 1H),
	3.04 (s, 3H), 2.34-2.31 (m, 1H), 2.01-1.97 (m, 1H)
266	m/z (ESI, +ve ion) = 496.20 [M + H]+. 1 H-NMR (400 MHz, DMSO-d6) δ 12.27 (s,
	1H), 10.41 (s, 1H), 8.16 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H),
	7.36 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.91-6.89 (m, 1H), 6.76 (d, J = 8.4 Hz, 1H),
	6.60-6.57 (m, 1H), 5.70 (d, J = 2.8 Hz, 1H), 4.64 (s, 2H), 3.99 (s, 3H), 3.33 (s, 3H),
	3.19 (t, J = 8.0 Hz, 1H), 3.06 (s, 3H), 2.34-2.30 (m, 1H), 2.00-1.97 (m, 1H)
267	m/z (ESI, +ve ion) = 563.25 [M + H]+. 1 H NMR (400 MHz, Methanol-d4) δ 8.08 (s,
	1H), 7.59 (d, J = 8.4 Hz, 1H), 7.47-7.44 (m, 2H), 6.97 (d, J = 8.4 Hz, 1H), 6.85 (d,
	J = 8.4 Hz, 1H), 6.64-6.62 (m, 1H), 5.65 (d, J = 2.4 Hz, 1H), 4.01 (s, 3H),
	3.94-3.88 (m, 2H), 3.69-3.66 (m, 2H), 3.38-3.33 (m, 4H), 2.27-2.14 (m, 4H)
268	m/z (ESI, +ve ion) = 547.25 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s,
	1H), 10.41 (s, 1H), 9.16 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.33
	(d, J = 1.6 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.61-6.58
	(m, 1H), 5.74 (d, J = 2.8 Hz, 1H), 4.01 (s, 3H), 3.70-3.67 (m, 4H), 3.34-3.285 (m,
	3H), 3.21-3.19 (m, 1H), 2.35-2.33 (m, 1H), 2.04-1.99 (m, 3H)
269	m/z (ESI, +ve ion) = 577.25 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.64 (s,
	1H), 10.41 (s, 1H), 9.07 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.40-7.36 (m, 3H), 6.90
	(d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.59 (dd, J = 8.5, 2.6 Hz, 1H), 5.72 (d,
	J = 2.5 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.12 (d, J = 6.0 Hz, 2H), 3.97 (s, 3H), 3.34
	(s, 3H), 3.19 (t, J = 8.4 Hz, 1H), 2.34-2.31 (m, 1H), 2.00-1.97 (m, 1H), 1.46 (s,
	3H)
270	m/z (ESI, +ve ion) = 591.30 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s,
	1H), 10.42 (s, 1H), 9.15 (s, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 2H),
	7.33 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.59 (dd,
	J = 8.4, 2.6 Hz, 1H), 5.74 (d, J = 2.6 Hz, 1H), 4.77 (d, J = 6.0 Hz, 2H), 4.13 (d, J =
	6.0 Hz, 2H), 3.82 (s, 3H), 3.35 (s, 3H), 3.19 (t, J = 8.5 Hz, 1H), 2.50 (s, 3H),
	2.34-2.32 (m, 1H), 2.00-1.97 (m, 1H), 1.56 (s, 3H)
271	m/z (ESI, +ve ion) = 472.3 [M + H]+. 1 H NMR (400 MHz, DMSO) δ 12.19 (s, 1H),
	10.43 (s, 1H), 8.44 (s, 1H), 7.97 (s, 1H), 7.94-7.86 (m, 1H), 7.55 (s, 1H), 7.33 (s,
	1H), 6.94-6.83 (m, 1H), 6.79-6.71 (m, 1H), 6.64-6.52 (m, 1H), 5.70 (s, 1H),
	5.12 (s, 1H), 4.76-4.59 (m, 1H), 3.97 (s, 3H), 3.34-3.27 (m, 6H), 3.23-3.11 (m,
	1H), 2.38-2.29 (m, 1H), 2.02-1.92 (m, 1H)
273	m/z (ESI, +ve ion) = 604.25 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.69 (s,
	1H), 10.42 (s, 1H), 9.06 (s, 1H), 7.83 (s, 1H), 7.42 (d, J = 4.8 Hz, 2H), 7.23 (s, 1H),
	6.90 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.63-6.56 (m, 1H), 5.74 (d, J =
	1.6 Hz, 1H), 4.29-4.19 (m, 2H), 3.34 (s, 3H), 3.19 (t, J = 8.4 Hz, 1H), 2.95-2.92
	(m, 4H), 2.50 (s, 1H), 2.38-2.31 (s, 4H), 2.17 (s, 3H), 2.03-1.95 (m, 1H), 1.44 (t,
	J = 6.8 Hz, 3H)
275	m/z (ESI, +ve ion) = 535.15 [M + H]+. 1 H-NMR (400 MHz, Methanol-d4) δ 8.01 (d,
	J = 2.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.43-7.41 (m, 2H), 6.96-6.94 (m, 1H),
	6.84 (d, J = 8.4 Hz, 1H), 6.64-6.61 (m, 1H), 5.66 (d, J = 2.8 Hz, 1H), 4.32-4.27
	(m, 2H), 3.39-3.36 (m, 1H), 3.32 (s, 3H), 2.56 (s, 3H), 2.26-2.23 (m, 1H), 2.20-
	2.17 (m, 1H), 1.56 (t, J = 6.8 Hz, 3H)
277	m/z (ESI, +ve ion) = 473.25 [M + H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s,
	1H), 10.41 (s, 1H), 8.33 (s, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.36 (s, 1H), 6.88 (d, J =
	8.4 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.59-6.57 (m, 1H), 6.25 (s, 1H), 5.68 (d, J =
	2.4 Hz, 1H), 4.14 (d, J = 7.2 Hz, 2H), 3.33 (s, 3H), 3.27 (s, 3H), 3.20-3.19 (m,
	1H), 2.32-2.29 (m, 1H), 2.00-1.96 (m, 1H), 1.39 (t, J = 6.8 Hz, 3H)

TABLE 2

	PLK4 IC 50	CTG IC 50	[Aurora A IC 50 (nM)]/	[Aurora B IC 50 (nM)]/
Ex. No.	(nM)	(nM)	[PLK4 IC 50 (nM)]	[PLK4 IC 50 (nM)]
1	3.495
2	29.34		318.03	15.6544
3	9.948
4	3.955		465.4867	11.45133
5	2.178
6	18.18
7	4.559		693.5732	47.26914
8	492.3		17.60918	32.98802
9	0.6944	99.73	4791.187	240.6394
10	1.587	438.1	954.6314	103.0876
11	4.876	2952.3	3277.276	77.87121
12	4.959	2025.5
13	2.99		667.5585	10.30435
14	36.03		74.16042	3.866223
15	45.66
16	2.181		605.6855	11.76066
17	4.304		1145.911	34.89777
18	22.9
19	24.81
20	2.254	262.7	4489.796	306.8323
21	41.73
22	39.8
23	5.048	45.9	215.5309	170.7409
24	2.255
25	34.18		249.6489	28.10123
26	3.853
27	2.083
28	0.375
29	5.967
30	31.24		36.20359	6.18758
31	3.02		207.053	22.16887
32	3.938		911.8842	17.5546
33	5.911		355.9465	8.474031
34	3.215		893.3126	19.95956
35	7.525		67.29568	2.162126
36	6.173		218.2083	5.700632
37	12.46		1799.358	49.51043
38	14.09		43.69056	2.760823
39	26.43		30.38214	1.018161
40	15.21		67.06114	2.783037
41	2.711	844.1	2257.47	471.4128
42	36.24		1053.808	42.30132
43	14.49		1347.136	21.90476
44	20.66		1269.119	45.11133
45	15.49		137.8309	4.60297
46	2.521	1428.99	2542.642	135.8985
47	1.302	610.5	1879.416	104.3011
18	3.277	741.5	1948.123	292.3406
49	19.1		253.4031	53.19372
50	61.69		361.809	27.4923
51	1.232	143.3	3031.656	1241.883
52	7.011	2260	2009.699	55.0706
53	1.251		4028.777	251.7986
54	33.24	10000	1504.212	117.2684
55	1.247		3251.804	17.89896
56	3.837	2683	1047.694	423.7686
57	5.08	3959.798	3527.559	831.2992
58	2.316	157.4	1393.782	140.6736
59	8.442		108.4696	39.23241
60	7.355		69.69409	7.854521
61	9.745	2385	588.8148	955.0539
62	16.91	10000	540.9225	946.7771
63	72.22		56.84021	16.68513
64	86.96		210.2116	98.83855
65	44.19		82.48473	5.356415
66	2340		21.36752	7.606838
67	1.342	4394.315	4976.155	499.9255
68	7.38	2476	4761.518	1347.967
69	2.981	686.1	1785.978	480.7112
70	1.101	80.33505	1376.93	512.7157
71	3.062	988.6843	420.9667	38.66754
72	0.997	42.71	2006.018	405.2156
73	7.045	10000	3290.277	346.7708
74	3.312		293.0556	37.13768
75	157.2		173.4097	23.27608
76	0.434	93.46214	3304.147	535.4839
77	1.757	725.1	6738.759	1577.689
78	0.35	61.37396	5660	1778.857
79	91.86		210.5378	6.98563
80	2.365	293.5	346.5116	54.12262
81	3.633	965	1478.393	220.4239
82	6.207		187.8524	38.55325
83	2.238	277.2	908.4004	333.3333
84	1.278	394.8	39123.63	3151.017
85	1.91	107.2	5554.974	3067.539
86	21.2	459.3	1414.623	669.3396
87	1.58	235.2	973.4177	133.9241
88	2.672	1813.308	1997.754	44.7979
89	2.317	10000	1736.729	314.3289
90	17.81		1505.334	44.32903
91	4.019	3202.9	436.427	79.87061
92	8.838		132.8355	76.36343
93	24.34		1733.361	1055.053
94	5.612	4602	533.856	41.732
95	1.306	319	2386.677	54.26493
96	11.35	56.55534	511.3656	351.8943
97	1.139	221.649	309.2186	520.2809
98	7.554	65.76947	787.0003	305.5335
99	5.802	565.24	155.05	129.9724
100	1.734	566.93	382.0069	230.4498
101	11.33	2288.9	1271.845	1002.648
102	6.162		114.7355	74.69977
103	2.796		416.6667	977.1102
107	5.704	729.7	1455.295	174.4215
108	4.366	1091	3889.143	230.6459
109	6.759	1871	50000	11070
110	3.908		679.6315	232.1904
111	1.535		234.7231	144.4951
112	23.7		197.5105	121.8987
113	10.65	2517	1888.2629	231.7370
114	2.091	10000	590.1482	811.5734
115	8.039	3462	132.6035	186.3415
116	2.89	133.5	788.5813	483.7370
117	2.321	108.7	1388.1947	906.5058
118	7.321	2359	457.0413	902.3357
119	1.588	2664	870.2770	973.5516
120	3.815	10000	444.0366	684.6657
121	1.794	5324	875.6967	230.8807
122	73.1		11.1709	11.86593
123	4.798	2110	667.5698	84.09754
124	13.57		38.03242	35.89535
125	0.8331	159.6	1323.9707	495.7388
126	9.014	459.3	66.2192	92.0568
127	2196		22.76867	22.7686
128	2.887	1492	2750.2597	1337.0280
129	34.52		18.1054	17.1349
130	603.1		58.4811	60.1890
131	53.78		105.7084	40.8516
132	2.149	618	5290.8329	249.5114
133	8.322	192.8	43.3910	45.1453
134	1.79	782.4	8849.1620	969.2737
135	70.77		28.3312	62.6112
136	19.43		2573.3401	979.4132
137	97.2		62	72
138	27.33		70	36
139	3175		7.4	9.6
140	16.56	7758	814	537
141	13.13		327.4181	891.0891
142	21.48		13.818	26.308
143	84.74		14.621	40.607
144	1.413	750.1	852.7955	61.4367
145	5.819	2915	1001.5467	280.8043
146	1.491	655.1	3512.4078	745.8082
147	4.223	1303	2292.2093	483.0689
148	6.87	3569	397.3799	338.8646
149	3.153	844.2	3193.7837	879.4799
150	8.128	3156	720.7185	366.7569
151	9.743		61.2440	96.3153
152	7.156		502.7949	107.8116
153	1.906	875.6	1254.4596	123.6097
154	0.976	260.1	1373.9754	655.2254
155	1.035	192.2	305.4106	68.0773
156		493.8
157	1.947	287.9	510.6317	303.9548
158	8.591		704.9238	51.7286
159	1.962	1298	309.7350	58.0530
160	1.932	310.2	545.5487	149.5859
161	2.21	351.7	291.4932	258.4163
162	8.394		648.6776	105.2895
163	1.524	226.3	2164.0420	389.4357
164	6.277	1637	397.0049	161.2235
165	4.682	1063	111.2559	76.9329
166	0.802	80.6	1151.3716	68.4539
167	1.18	212.3	295.5932	916.9492
168	1.966	1620	946.5921	265.0051
169	0.995	188.5	666.9347	431.4573
170	1.358	325.7	694.1090	587.9234
171	5.871	1517	1176.6309	259.2403
172	4.09	1263	324.94	202.96
173	2.666	331.7	301.0878	314.9287
174	1.921	392.3	365.8511	353.7741
175	3.569	2209	14009.5265	8627.0664
176	2.843	1552	1725.2902	1300.3869
177	4.255	3675	11750.8813	11750.8813
178	3.294	630.8	15179.1135	15179.1135
179	3.811	948	13119.9160	5384.4135
180	2.854	740.8	5455.5011	1996.8465
181	7.576		2415.5227	3693.2418
182	4.454		53.6821	198.8774
183	1.245	125	534.2169	322.5703
184	6.998	882	7144.8985	7144.8985
185	1.956	134	3240.7975	180.1636
186	1.779	537	641.9337	232.5464
187	6.116	563	109.5814	112.2793
188	6.27	760	7974.4817	191.7065
189	1.045	112	383.7321	514.5455
190	2.661	5115	129.5378	279.1432
191	2.266	494	2416.5931	84.9956
192	1.639	1180	2835.2654	678.4625
193	1.134	390	1463.8448	138.8889
194	0.965	126	805.6995	103.7306
195	1.56	160	3459.6154	740.3846
196	3.318	1673	732.3689	100.8137
197	1.076	1082	1243.4944	73.8197
198	8.692	10000	5752.4160	5752.4160
199	0.716	108	439.9441	57.7095
200	3.256		906.0197	523.3415
201	1.706	455	485.6389	229.0739
202	2.68	422	1031.3433	321.4179
203	1.042	324	2922.2649	333.7812
204	0.81	122	342.9630	222.8395
205	1.642	3445	737.5152	235.7491
206	0.806		618.8586	80.2233
207	0.952		497.3739	111.6597
208	0.8967	402	7904	2471
209	1.537	605.8	273.2595	254.6519
210	1.348	65.47	462.3887	316.5430
211	8.658		531.9935	218.4107
212	1.585	161	353.1230	280
213	2.131	189.7	92.2102	225.3871
214	1.011	32.23	953.01681	59.0999
215	2.098	191.6	986.6539	53.57483
216	2.688	766.4	7712.05357	18601.19048
217	1.189	450.2	416.7367	170.9840
218	0.955	73.81	806.5968	70.8586
219	2.504	510.1	763.5782	64.2571
220	6.013		1042.4081	498.7527
221	2.802	848.9	511.06352	1463.5974
222	1.359	456	446.1368	546.4311
223	2.304	163.1	1004.7743	445.3125
224	4.016	2023	12450.1992	12450.1992
225	6.118		1884.6028	381.4972
226	4.747	2146	2759.6376	474.6155
227	2.209	532.3	917.1570	478.9497
228	1.347	180.4	813.6599	340.4602
229	7.847		1669.4278	130.8780
230	2.434	394.6	12432.2103	213.4346
231	1.56	397.3	4955.7692	316.7307
232	1.033	141	651.7909	105.5179
233	3.572	4799	332.3068	107.2788
234	2.294	276.3	608.9799	831.7349
235	2.169		2053.4808	260.3503
236	2.262		949.6021	114.8983
237	2.943		3385.3211	369.01121
238	1.361	133.4	536.07641	582.2189
239	1.69	948.6	1429.5857	466.8047
240	2.179	421.9	735.1996	102.4323
241	2.493	1105	2066.9875	253.4697
242	6.519	5509	307.7159	129.0381
243	1.149	187.9	479.1122	164.5778
244	2.91	545.3	1578.3505	312.26804
245	0.738	131	1730.3523	319.6476
246	0.843	68.38	426.8090	176.8683
247	3.734	1013	1434.9223	423.6743
248	1.239	119.6	683.4543	206.5375
249	6.563		2585.7077	451.7751
250	6.188		819.6509	110.6011
251	1.332	287	1734.2342	268.6936
252	9.282		518.4227	365.8694
253	5.982		709.6288	88.7161
254	5.19	2164	297.6878	96.18497
255	1.164	380.3	840.1202	566.4948
256	0.6498	309.7	1143.4287	1152.50846
257	3.91	1592	1259.8465	324.5524
258	1.413	167.6	1100.4954	464.7558
259	0.9708	899.9	1294.8084	835.2904
260	9.327		1330.5457	294.8429
261	7.91		5824.2730	2807.8381
262	1.389	507.4	3488.1209	526.70986
263	0.65	599.4	1133.6923	181.6923
264	0.785	859.9	307.8980	66.6751
265	1.981	1067	686.01716	725.3912
266	2.344	791.6	723.9761	154.9914
267	1.569	325.1	789.0376	406.8833
268	0.874	123.5	1159.03890	769.9084
269	0.89	1346	191.7977	138.7640
270	0.564	268.9	473.58156	1790.7801
271	6.042		825.7199	492.8831
272	0.833	77.83	3273.7094	448.8595
273	1.453	1703	3483.1383	2831.3833
274	0.763	72.26	2560.9436	961.3368
275	0.59		2162.7118	230
276	2.614	4085	377.9648	2173.2976
277	2.198		1120.5641	1049.1355
278	0.804		1269.9004	423.6318
279	1.336		37425.1497	2792.6646
280	1.932		727.2256	309.1097
CFI-	0.4962	9.082	86.3160	12.0435
400495

description truncated at 500,000 characters

Stored text is truncated at the source; the tail of the description is not held.

Claims as granted

22 claims

Classifications

18 codes

IPC · International Patent Classification

Section A — Human necessities

A61K31/675
A61K31/553
A61K31/5377
A61K31/513
A61K31/497
A61K31/4439
A61K31/416

Section C — Chemistry; metallurgy

C07F9/6558
C07D498/08
C07D498/04
C07D491/107
C07D491/048
C07D413/14
C07D405/14
C07D403/12
C07D403/04
C07D401/14
C07D403/14

Claim changes

Soon

Coming soonHow the claims changed between publication and grant

See which claims were amended, added or cancelled during examination, with every added and removed word marked.

AmendedAddedCancelledUnchanged

The published claims of this application are not paired with the granted ones in what we hold.

File wrapper

⤢ drag to zoom

USPTOApplicanthover for detail · click to open

Pendency

1.8 y

648 days filing → grant

Office actions

non-final + final

Responses

no RCE

Examiner

Kahsay Habte

art unit 1624 · TC 1600

Law firm

Law firm · Log in to unlock

Citations: 54 back · 0 forward

See the full prosecution history — every USPTO and applicant action on this file, in order.

Documents

Log in to open the documents of this file: the application as filed, every office action and response, the notice of allowance.

Chain of title

⤢ drag to zoom

Titlehover for detail · click to open

See the full assignment history — every owner this patent has passed through, with recordation dates and reel/frame numbers.