TW202508575A - Compounds, compositions, and methods - Google Patents

Abstract

The present disclosure relates generally to small molecule modulators of Mucolipin-1 (TRPML1), and their use as therapeutic agents.

Description

Compounds, compositions and methods

The present disclosure generally relates to small molecule modulators of transmucolipin-1 (TRPML1) and their use as therapeutic agents.

Transient receptor potential mucolipin 1, also known as mucolipin-1 (TRPML1 or ML-1), is a member of the transient receptor potential (TRP) ion channel superfamily. Electrophysiological experiments on isolated lysosomes have shown that TRPML1 is a non-selective cation channel localized in late endosomes and lysosomes (LEL) (Dong X. et al., Nature 2008 , 455, 7215 , 992). Wild-type human TRPML1 has six transmembrane domains in each monomer unit, which are assembled together to form a tetramer containing an ion pore in the middle of the complex. TRPML1 is permeable to a variety of monovalent and divalent cations, including Na ⁺ , K ⁺ , Ca2 ⁺ , Fe2 ⁺ , and Zn2 ⁺ . The release of ^Ca2+ from the LEL to the cytosol via TRPML1 is associated with a variety of physiological processes, including activation of transcription factor EB (TFEB), lysosomal transport, exocytosis, phagosome formation, autophagy, and lysosomal biogenesis (Venkatachalam, K. et al., "TRPML1-Dependent Process as Therapeutic Targets." TRP Channels as Therapeutic Targets , Arpad Szallasi, ed., Academic Press, 2015 , pp. 469-482). TRPML1 conductance to other ions such as Fe ²⁺ and Zn ²⁺ plays an important role in the regulation of trace metals in lysosomal depots (Du et al., Cell Reports 2021 , 37 , 109848). Loss of function (LoF) in TRPML1 leads to accumulation of Fe ²⁺ and Zn ²⁺ in lysosomes and impaired signaling.

The TRPML1 protein is encoded by the MCOLN-1 gene (Di Paola, S. et al., Cell Calcium 2018 , 69 , 112). LoF mutations in MCOLN-1 can cause the somatic cryptic lysosomal storage disease (LSD) type IV mucolipidosis (MLIV). The two main mutations that cause MLIV are in the third intron, causing splice variants that delete exons 4 to 5 and a deletion of approximately 6 kb spanning exons 6 to 7. These two mutations are present in approximately 95% of patients diagnosed with MLIV, causing severe developmental defects, including cognitive impairment, motor disability, and retinal degeneration. Patients with these mutations typically do not survive puberty. The underlying cause of these devastating symptoms is associated with LoF TRPML1-dependent lysosomal accumulation and dysfunction leading to neuroinflammation and neurodegeneration.

Endogenous lipids have been found to regulate the activity of TRPML1. Phosphatidylinositol-3,5-bisphosphate (PI(3,5)P ₂ ) is an endogenous lipid enriched in the LEL that stimulates TRPML1 activity (Dong X. et al., Nature Communications 2010 , 1, 38 ). Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P ₂ ) is mainly found in the plasma membrane and inhibits TRPML1 activity on the plasma membrane during its transport to the LEL. TRPML1 is enhanced by H ⁺ concentration, with the optimal pH being consistent with the pH of mature lysosomes (pH approximately 4.5) (Dong et al., 2008).

Mutations in the enzyme complex that mediates PI(3,5) _P2 metabolism cause neurodegenerative diseases. PIKfyve kinase is required for PI(3,5) _P2 synthesis, and abrogation of its activity causes defects in LEL transport and TRPML1 activity (Zolov et al., PNAS 2012 , 109, 43 , 17472). The LoF mutation in Figure 4 (phosphoinositide phosphatase) is associated with Charcot-Marie-Tooth Disease (CMT4J). The FIG4 gene has been implicated as a genetic factor in 1-2% of patients with amyotrophic lateral sclerosis (ALS) (Chow et al., American Journal of Human Genetics 2009 , 84 , 85). The LoF in Figure 4 results in reduced PI(3,5) _P2 levels and impaired TRPML1 function. Variants of VAC14, a scaffold protein in the PI(3,5) _P2 metabolic complex, are also associated with Parkinson's disease (PD) and pediatric schizophrenia. Dysfunction in TRPML1 is proposed as a potential mechanism for these PI(3,5) _P2- deficient mutations. Preclinical studies have demonstrated that TRPML1 activation can be beneficial in these disease models, indicating the therapeutic potential of TRPML1 agonism in CMT, ALS, PD and other neurodegenerative diseases (Dong X. et al., Nature 2008 , 455, 7215 , 992).

TRPML1 has been associated with LSD. Niemann-Pick (NP) disease is hereditary and is primarily caused by the accumulation of lipids, including sphingomyelin and cholesterol, which leads to severe neurological symptoms. Sphingomyelin accumulation in lysosomes inhibits TRPML1 activity. Activation of TRPML1 in NP disease cell models reduces lipid accumulation, thereby restoring lysosomal trafficking of TRPML1 (Shen et al., Nature Communications 2012 , 3 , 731). Increasing TPRML-1 activity through overexpression of TFEB increases lysosomal exocytosis and rescues the pathogenesis of mucopolysaccharidoses in cell culture and in vivo disease models. Many LSDs are described by lysosomal dysfunctions, including trafficking, maturation, exocytosis, lipid and biomolecule accumulation, and Ca2 ⁺ homeostasis. TRPML1 plays a major role in these processes and is therefore an attractive target for the treatment of LSDs (Di Paola et al., 2018).

Lysosomal function in neurons is associated with neurodegenerative diseases (Cesan et al., Experimental Cell Research 2012 , 318, 11 , 1245; Ghavami et al., Progress in Neurobiology 2014 , 112, 24). Specifically, TRPML1 activity is associated with hallmarks of Alzheimer's Disease (AD). Patients infected with human immunodeficiency virus (HIV) may experience premature cognitive decline associated with the accumulation of Aβ and sphingomyelin in cellular compartments. The agonistic effect of TRPML1 in the HIV-pg120-induced sphingomyelin and Aβ accumulation model using primary neurons demonstrated the clearance of these biomolecules (Bae et al., Journal of Neuroscience 2014 , 34, 34 , 11485). Furthermore, TFEB activation, a downstream effect of TRPML1 activation, reduces Tau pathology in preclinical models (Polito et al., EMBO Molecular Medicine 2014 , 6, 9 , 1142). These studies suggest the therapeutic potential of TRPML1 in AD.

Duchenne muscular dystrophy (DMD) is caused by mutations in the protein dystrophin, which weakens the plasma membrane of muscle cells. Patients with DMD experience severe muscle damage during contraction (Yu et al., Science Advances 2020 , 6 , eaaz2736). TRPML1 activation rescues these phenotypes in a mouse model of DMD, suggesting a broad therapeutic approach to treat this heterologous disease.

Targeting TRPML1 with small molecule modulators has been shown to rescue hallmark phenotypes of neurodegenerative diseases, LSDs, prion and prion-like diseases, and muscular dystrophy-related diseases in cell-based and animal disease models. TRPML1 malfunction is intricately involved in many important cellular processes and may be a therapeutic target for a variety of human diseases. Several tool molecules exist that modulate TRPML1, but are unsuitable as human drugs due to their reduced potency, physicochemical properties, and in vivo pharmacokinetic properties. Many of the diseases associated with TRPML1 activity described above do not have effective curative treatments. Therefore, there is a great need for the development of clinically relevant small molecule modulators of TRPML1.

Therefore, there is a need to develop TRPML1 modulators to rescue impaired lysosomal function and cellular autophagy, especially in neurodegenerative diseases.

Provided herein are compounds or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof that are useful for treating and/or preventing diseases mediated at least in part by TRPML1.

In certain embodiments, compounds that activate TRPML1 are provided.

In another embodiment, a pharmaceutical composition is provided, comprising a compound as described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof and a pharmaceutically acceptable carrier.

In another embodiment, a method for treating a disease or condition mediated at least in part by TRPML1 is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

The present disclosure also provides compositions (including pharmaceutical compositions) comprising the compounds or their pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers or prodrugs, kits, methods of using (or administering) and preparing the compounds or their pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers or prodrugs and intermediates thereof.

The disclosure further provides compounds or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers or prodrugs thereof, or combinations thereof, for use in methods of treating a disease, disorder or condition mediated at least in part by TRPML1.

Additionally, the present disclosure provides the use of a compound or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug, or a combination thereof, for the manufacture of a medicament for treating a disease, disorder, or condition mediated at least in part by TRPML1.

The description herein describes exemplary embodiments of the present invention. However, it should be recognized that such description is not intended to be a limitation of the scope of the present disclosure, but is provided as a description of exemplary embodiments.

Cross-references to related applications

This application claims the benefit of U.S. Provisional Application No. 63/515,017, filed on July 21, 2023, pursuant to 35 USC §119(e), the entire text of which is incorporated by reference. 1. Definitions

A dash ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O) _NH2 is attached through the carbon atom. Dashes at the beginning or end of a chemical group are for convenience; a chemical group may be drawn with or without one or more dashes without losing its ordinary meaning. Wavy or dotted lines drawn along a straight line in a structure indicate a designated point of attachment of a group. The order in which chemical groups are written or named does not indicate or imply any directionality or stereochemistry unless required chemically or structurally.

The prefix " _Cuv " indicates that the following group has u to v carbon atoms. For example, " _C1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

Reference herein to "about" a value or parameter includes (and describes) embodiments of that value or parameter itself. In certain embodiments, the term "about" includes an indicated amount ± 10%. In other embodiments, the term "about" includes an indicated amount ± 5%. In certain other embodiments, the term "about" includes an indicated amount ± 1%. The term "about X" also includes an explanation of "X". Unless the context clearly dictates otherwise, the singular forms "one/one" and "the" also include plural indicators. Thus, for example, reference to a "compound" includes a plurality of such compounds, and reference to an "assay" includes reference to one or more assays known to those skilled in the art and their equivalents.

"Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., _C1-20 alkyl), 1 to 12 carbon atoms (i.e., _C1-12 alkyl), 1 to 8 carbon atoms (i.e., _C1-8 alkyl), 1 to 6 carbon atoms (i.e., _C1-6 alkyl), or 1 to 4 carbon atoms (i.e., _C1-4 alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, dibutyl, isobutyl, tertiary butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons are encompassed; thus, for _example , "butyl" includes n-butyl (i.e., -( _CH2 ) _3CH3 ), dibutyl (i.e., -CH( _CH3 ) _CH2CH3 ) _, isobutyl (i.e., _-CH2CH ( _CH3 ) ₂ ) _, and tertiary butyl (i.e., -C( _CH3 ) ₃ ); and "propyl" includes n-propyl (i.e., -( _CH2 ) _2CH3 ) and isopropyl (i.e., -CH( _CH3 ) ₂ ).

Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, divalent heteroaryl groups, etc. may also be referred to as "alkylene" or "alkylenyl" groups (e.g., methylene, ethyl, and propyl), "arylene" or "arylenyl" groups (e.g., propyl or naphthyl (for arylene) or quinolyl (for heteroarylene)), respectively. In addition, unless otherwise expressly indicated, where a combination of groups is referred to herein as a moiety (e.g., cycloalkylalkyl, arylalkyl, heterocycloalkylalkyl, heteroarylalkyl), the group is defined by its components and the last-mentioned group contains the atoms that connect the moiety to the rest of the molecule.

"Alkenyl" refers to an alkyl group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., _C2-20 alkenyl), 2 to 12 carbon atoms (i.e., _C2-12 alkenyl), 2 to 8 carbon atoms (i.e., _C2-8 alkenyl), 2 to 6 carbon atoms (i.e., _C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., _C2-4 alkenyl). Examples of alkenyl include, for example, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

"Alkynyl" refers to an alkyl group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., _C2-20 alkynyl), 2 to 12 carbon atoms (i.e., _C2-12 alkynyl), 2 to 8 carbon atoms (i.e., _C2-8 alkynyl), 2 to 6 carbon atoms (i.e., _C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., _C2-4 alkynyl). The term "alkynyl" also includes those groups having one double bond and one double bond.

"Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, di-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

"Aminyl" refers to the radical ^-NRyRz , wherein ^{Ry and Rz are} independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

"Carbamimidoyl" refers to -C( ^NRy )( ^NRz2 ), wherein ^Ry and ^Rz are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted _as defined herein.

"Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings including fused systems (e.g., bicyclic or tricyclic). As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., _C6-20 aryl), 6 to 12 carbon ring atoms (i.e., _C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., _C6-10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is a heteroaryl group, regardless of the point of attachment. If one or more aryl groups are fused to a heterocyclic group, the resulting ring system is a heterocyclic group, regardless of the point of attachment. If one or more aryl groups are fused to a cycloalkyl group, the resulting ring system is a cycloalkyl group, regardless of the point of attachment.

"Arylalkyl" or "aralkyl" refers to the radical "aryl-alkyl-".

"Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings including fused, bridged and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl (i.e., cyclic groups having at least one double bond) and carbocyclic fused ring systems having at least one ^sp3 carbon atom (i.e., at least one non-aromatic ring). As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., _C3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., _C3-12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., _C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., _C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., _C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., _C3-6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, independent of attachment to the rest of the molecule. Furthermore, when two substitution sites are present on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecyl.

"Cycloalkylalkyl" refers to the radical "cycloalkyl-alkyl-".

"Halo" refers to an atom occupying Group VIIA of the periodic table, such as fluorine, chlorine, bromine or iodine.

"Haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a suffix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may be (but need not be) the same halogen. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

"Haloalkoxy" refers to an alkoxy group as defined above in which one or more (eg 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

"Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any attached hydrogen atoms), except any terminal carbon atom, are each independently replaced with the same or different heteroatom radicals, provided that the point of attachment to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, 1, 2, or 3 carbon atoms may be independently replaced with the same or different heteroatom radicals. Heteroatom groups include, but are not limited to, -NR ^y -, -O-, -S-, -S(O)-, -S(O) ₂ -, and the like, wherein R ^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of heteroalkyl groups include ethers (e.g. _{, -CH2OCH3} , -CH( _CH3 ) _OCH3 , _-CH2CH2OCH3 , _{-CH2CH2OCH2CH2OCH3} , etc.) _{, thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3 , -CH2CH2SCH2CH2SCH3 , etc. ) , sulfides (} e.g., _-CH2S ( _{O ) 2CH3} , _{-CH ( CH3 ) S (} O _{) 2CH3} , _-CH2CH2S ( _O ) _2CH3 , _-CH2CH2S (O _{) 2CH2CH2OCH3 , etc.} ), _and amines ⁽ e.g. _{, -CH2NRyCH3 , -CH} ( _{CH3 )} ^NRyCH3 , _{-CH2CH2NRyCH3} , ^{-CH2CH2NRyCH2CH2NRyCH3 ,} etc., wherein ^Ry is hydrogen, alkyl, _alkenyl , _alkynyl , cycloalkyl, _heterocyclo , aryl, _heteroalkyl ^or _heteroaryl ; each of _which may be optionally substituted as defined herein). As used herein, heteroalkyl includes 2 to 10 _carbon atoms, 2 to 8 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

"Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more heteroaryl atoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., _C1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., _C3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., _C3-8 heteroaryl), and 1 to 5 heteroaryl atoms, 1 to 4 heteroaryl atoms, 1 to 3 heteroaryl atoms, 1 to 2 heteroaryl atoms, or 1 heteroaryl atom, wherein the heteroaryl atoms are independently selected from nitrogen, oxygen, and sulfur. In certain instances, heteroaryl includes a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each of which independently has 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indole, oxazolyl, indolyl, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxoionyl pyridinyl, 1-oxoionyl pyrimidinyl, 1-oxoionyl pyrazinyl, 1-oxoionyl pyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinindyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl may be attached via any one of the rings of the fused system. Any aromatic ring containing at least one heteroatom with single or multiple fused rings is considered a heteroaryl, regardless of attachment to the rest of the molecule (i.e., attachment via any of the fused rings). Heteroaryl does not encompass or overlap aryl as defined above.

"Heteroarylalkyl" refers to the radical "heteroaryl-alkyl-".

"Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. The term "heterocyclic group" includes heterocycloalkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups and spiro heterocyclic groups. The heterocyclic group may be a single ring or multiple rings, wherein the multiple rings may be fused, bridged or spiro-connected, and may contain one or more (e.g., 1 to 3) pendoxy groups (=O) (e.g., -C(O), -S(O)-, -S(O) _2- , etc.) or N-oxide ( ^-O- ) moieties. Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered a heterocyclic radical, regardless of attachment to the rest of the molecule. For example, fused ring systems such as 6,7-dihydro- 5H -cyclopenta[b]pyridinyl, decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8-tetrahydroquinazolinyl are heterocyclic radicals, regardless of attachment (i.e., attachment may be through a carbon atom or a heteroatom). Furthermore, the term heterocyclo is intended to encompass any non-aromatic ring containing at least one heteroatom which may be fused to a cycloalkyl, aryl or heteroaryl ring independently of attachment to the rest of the molecule. As used herein, a heterocyclic group has 2 to 20 ring carbon atoms (i.e., _C2-20 heterocyclic group), 2 to 12 ring carbon atoms (i.e., C2-12 _heterocyclic group), 2 to 10 ring carbon atoms (i.e., _C2-10 heterocyclic group), 2 to 8 ring carbon atoms (i.e., _C2-8 heterocyclic group), 3 to 12 ring carbon atoms (i.e., _C3-12 heterocyclic group), 3 to 8 ring carbon atoms (i.e., _C3-8 heterocyclic group), or 3 to 6 ring carbon atoms (i.e., C having 1 to ₅ ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatoms, wherein the ring heteroatoms are independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclic groups include, for example, azacyclobutanyl, azathiophene, benzodioxacyclopentenyl, benzo[b][1,4]dioxacyclopentyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxacyclohexenyl, benzopyranonyl, benzofuranonyl, dioxacyclopentanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, ... The term "heterocyclic group" includes 1-oxo-1,1-di ... Examples of spiroheterocyclic rings include, for example, bicyclic and tricyclic ring systems such as oxaheterobicyclo[2.2.2]octanyl, 2-oxahetero-7-azaspiro[3.5]nonanyl, 2-oxahetero-6-azaspiro[3.4]octanyl, and 6-oxahetero-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, wherein the heterocyclic group may be attached via any ring of the fused system.

"Heterocycloalkyl" refers to the radical "heterocyclo-alkyl-".

"Oxime" refers to the group ^-CRy (=NOH), wherein ^Ry is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

The term "optionally present" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. In addition, the term "optionally substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

As used herein, the term "substituted" refers to any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclo, heteroaryl and/or heteroalkyl) wherein at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond with a non-hydrogen atom, such as, but not limited to, halogen, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, halogenalkyl, halogenalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, pendoxy, thioketone, N-oxide, azido, oxime, thiocyanate, amidino, guanidino, cycloalkylalkyl, arylalkyl, heterocyclicalkyl, heteroarylalkyl, -NR ^g R ^h , -NR ^g C(O)R ^h , -NR ^g C(O)NR ^g R ^h , -NR ^g C(O)OR ^h , -NR ^g S(O) _1-2 R ^h , -C(O)R ^g , -C(O)OR ^g , -OC(O)OR ^g , -OC(O)R ^g , -C(O)NR ^g R ^h , -C(NR ^g )R ^h , -OC(O)NR ^g R ^h , -C(O)NR ^g C(O)R ^h or -N(C(O)R ^g )C(O)R ^h , -SR ^g , -S(O)R ^g , -S(O) ₂ R ^g , -OS(O) _1-2 R ^g , -S(O) _1-2 OR ^g , -NR ^g S(O) _1-2 NR ^g R ^h , =NSO ₂ R ^g , =NNR ^g R ^h , -NR ^g NR ^g R ^h , =NOR ^g , -S(O) _1-2 NR ^g R ^h , -NR ^g S(O) _1-2 R ^h , -CH ₂ S(O) _1-2 R ^g , -CH ₂ S(O) _1-2 NR ^g R ^h , -SF ₅ , -SCF ₃ or -Si(R ^y ) ₃ wherein each alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, halogenalkyl, halogenalkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, cycloalkylalkyl, arylalkyl, heterocyclicalkyl and heteroarylalkyl is independently substituted with one to three pendoxy groups, halogen groups, cyano groups, hydroxyl groups, alkoxy groups or alkyl groups, and the alkyl group is substituted with pendoxy groups, halogen groups, cyano groups, hydroxyl groups or alkoxy groups; each R ^y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl or heteroaryl; and each R ^g and R ^{Rg and Rh} are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, sulfanyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, halogenalkyl, heterocyclic, heterocyclicalkyl, heteroaryl or heteroarylalkyl; or ^Rg and ^Rh on the same atom or any two ^Rg and ^Rh on different atoms together with the atoms to which they are attached form a heterocyclic group which is optionally substituted with a pendoxy group, a halogen group, a cyano group, a hydroxyl group, an alkoxy group or an alkyl group, and the alkyl group is optionally substituted with a pendoxy group, a halogen group, a cyano group, a hydroxyl group or an alkoxy group.

Polymers or similar indefinite structures obtained by defining substituents with unlimited additional substituents (e.g., substituted aryl with substituted alkyl, which is itself substituted by substituted aryl, which is further substituted by substituted heteroalkyl, etc.) are not intended to be included herein. Unless otherwise noted, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, consecutive substitution of a substituted aryl with two other substituted aryl groups is limited to aryl substituted with ((substituted aryl) substituted aryl). Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. The term "substituted" when used to modify a chemical group may describe other chemical groups as defined herein.

In certain embodiments, as used herein, the phrase "one or more" refers to one to five. In certain embodiments, as used herein, the phrase "one or more" refers to one to three.

Any compound or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compound. Such forms of the compound may also be referred to as "isotopically enriched analogs." Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced with atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I, respectively. Various isotope-labeled compounds of the present disclosure, for example, those compounds into which radioactive isotopes (such as ³ H and ¹⁴ C) are incorporated. Such isotope-labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays) or radiotherapy of patients.

The term "isotopically enriched analogs" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogens are replaced with deuterium, such as hydrogens on carbon atoms. Such compounds exhibit increased resistance to metabolism and, therefore, can be used to extend the half-life of any compound when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens are replaced with deuterium.

Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as extended in vivo half-life, reduced dosage requirements and/or improved therapeutic index. ¹⁸ F, ³ H or ¹¹ C labeled compounds may be used in PET or SPECT or other imaging studies. Isotope-labeled compounds of the present disclosure and their prodrugs may generally be prepared by implementing the procedures disclosed in the schemes or in the examples and preparations described below, by substituting readily available isotope-labeled reagents for non-isotope-labeled reagents. It is to be understood that deuterium in this context is considered a substituent in the compounds described herein.

The concentration of such heavier isotopes, specifically deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," that position should be understood to be hydrogen with its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

In many cases, the compounds of the present disclosure are capable of forming acid salts and/or base salts by virtue of the presence of amine groups and/or carboxyl groups or groups similar thereto.

Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, mixtures of stereoisomers, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human medical use.

The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if the compound described herein is obtained in the form of an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to the customary procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines such as alkylamines (i.e., _NH2 (alkyl)), dialkylamines (i.e., HN(alkyl) ₂ ), trialkylamines (i.e., N(alkyl) ₃ ), substituted alkylamines (i.e., _NH2 (substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl) ₂ ), tri(substituted alkyl)amines (i.e., N(substituted alkyl) ₃ ), alkenylamines (i.e., _NH2 (alkenyl)), dialkenylamines (i.e., HN(alkenyl) ₂ ), trialkenylamines (i.e., N(alkenyl) ₃ ), substituted alkenylamines (i.e., _NH2 (substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl) ₂ ), tri(substituted alkenyl)amine (i.e., N(substituted alkenyl) ₃ ), mono-, di- or tri-cycloalkylamine (i.e., NH ₂ (cycloalkyl), HN(cycloalkyl) ₂ , N(cycloalkyl) ₃ ), mono-, di- or tri-arylamine (i.e., NH ₂ (aryl), HN(aryl) ₂ , N(aryl) ₃ ), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, it is generally understood by those skilled in the art that a compound includes both amide and imidic acid tautomers. Thus, an amide-containing compound is understood to include its imidic acid tautomers. Likewise, an imidic acid-containing compound is understood to include its amide tautomers.

The compounds of the present disclosure or their pharmaceutically acceptable salts include asymmetric centers and may therefore give rise to mirror image isomers, non-mirror image isomers and other stereoisomeric forms which may be defined by absolute stereochemistry as ( R )- or ( S )-, or for amino acids as (D)- or (L)-. The present disclosure is intended to include all such possible isomers as well as racemic and optically pure forms thereof. Optically active (+) and (-), ( R )- and ( S )-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and/or fractional crystallization. Conventional techniques for the preparation/isolation of individual mirror image isomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

"Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but with different three-dimensional structures (non-interchangeable). The present disclosure encompasses various stereoisomers or mixtures thereof, and includes "mirror isomers", which refers to two stereoisomers in which the molecule is a non-superimposable mirror image of each other.

"Non-mirror isomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

The relative centers of compounds as drawn herein are indicated graphically using a "fat key" style (bold or parallel lines), and absolute stereochemistry is depicted using a wedge key (bold or parallel lines).

"Prodrug" means any compound that releases an active parent drug according to the structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein in such a way that the modifications are cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in the compounds described herein in such a way that the modifications are cleaved in conventional manipulations or in vivo to the parent compound. Prodrugs include compounds described herein wherein a hydroxyl, amino, carboxyl or hydroxyl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl, amino or hydroxyl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives) of hydroxyl functional groups in the compounds described herein, amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), and the like. The preparation, selection, and use of prodrugs are discussed in the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Volume 14 of the ACS Symposium Series; "Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated by reference in its entirety. 2. Compounds

Provided herein are compounds that are TRPML1 activators. In certain embodiments, compounds of Formula I are provided: I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L, X ¹ and t are independently as defined herein.

In certain embodiments, compounds of Formula I are provided: I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer or a mixture of stereoisomers, wherein: X ¹ is N or CR ⁷ ; L is a bond, C _1-2 alkylene, C ₂ alkenylene, C ₂ alkynylene, -CH ₂ -C(O)NR ¹¹ -*, -C(O)-, -S(O)-, -S(O) ₂ -, -C(O)O-*, -C(O)NR ¹¹ -*, -S(O)NR ¹¹ -* or -S(O) ₂ NR ¹¹ -*; wherein the * bond is connected to R ⁴ ; R ¹ is a halogen, a cyano, a nitro, -CD ₃ , a C _1-6 alkyl, a C _2-6 alkenyl, a C _2-6 alkynyl, a C _3-10 Cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹¹ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O)N(R ¹¹ ) ₂ , -NR ¹¹ C(O)R ¹¹ , -NR ¹¹ S(O)R ¹¹ , -NR ¹¹ S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O) ₂ N(R ¹¹ ) ₂ , -NR ¹¹ C(O)N(R ¹¹ ) ₂ , -NR ¹¹ S(O)N(R ¹¹ ) ₂ , -NR ¹¹ S(O) ₂ N(R ¹¹ ) ₂ , -OC(O)N(R ¹¹ ) ₂ or -NR ¹¹ C(O)OR ¹¹ ; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl group is independently substituted with one to five Z ^1a as appropriate; R ² is a halogen group, -CD ₃ , a C _1-6 alkyl, a C _2-6 alkenyl, a C _2-6 alkynyl, a C _3-10 cycloalkyl, a heterocyclic group, an aryl or a heteroaryl group; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C 3-10 The C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted by one to five Z ^1a as appropriate; or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-10 cycloalkyl or heterocyclic group; wherein the C _3-10 cycloalkyl or the heterocyclic group is independently substituted by one to five Z ^1a as appropriate; R ³ is: or ; R ⁴ is C _1-6 alkyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted by one to five Z ^1a as appropriate; each R ⁵ is independently halogen, cyano, C _1-6 alkyl, C _{1-6 halogenalkyl, C 2-6} alkenyl or C _2-6 alkynyl; or two R ⁵ together form a C 3-6 cycloalkyl or a _4-6 membered heterocyclic group; wherein the C _3-6 cycloalkyl or the 4-6 membered heterocyclic group is independently substituted by one to five Z ^1a as appropriate; or two R ⁵ together with the carbon atoms to which they are attached form a C _3-6 cycloalkyl or a 4-6 membered heterocyclic group; wherein the C _3-10 cycloalkyl or heterocyclic group is independently substituted by one to five Z ^1a as appropriate; or R ¹ and R ⁵ together with the carbon atom to which they are attached form a C _3-10 cycloalkyl or heterocyclic group; wherein the C _3-10 cycloalkyl or heterocyclic group is independently substituted by one to five Z ^1a as appropriate; or R ⁴ and R ⁵ together with the _atom to which they are attached form a heterocyclic group or heteroaryl; wherein the heterocyclic group or heteroaryl is independently substituted by one to five Z ^1a as appropriate; R ⁶ and R ⁷ are each independently hydrogen, hydroxyl, halogen, cyano, C _1-6 alkyl, C R ^a and R ^b are each independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, ^- (CH ₂ ⁾ _{0-2 -C 3-7} cycloalkyl and _3-7 membered heterocyclic group; each R ⁸ is independently -C(O)N(R ¹¹ ) ₂ , C _1-6 alkyl or C _1-6 haloalkyl; _wherein the C _1-6 alkyl or _the C _1-6 haloalkyl is independently substituted with cyano, -N(R ¹³ ) ₂ , halo, hydroxyl or C _1-6 alkoxy; or two R ⁸ and the carbon atom to which they are connected may form a side group, a condensed or spiro group. wherein the C _3-7 cycloalkyl or the 4-7 membered heterocyclic group is independently substituted by a halogen group, a hydroxyl group, _a C 1-6 alkyl group, a C _1-6 halogen group, a C _1-6 alkoxy group or a C _1-6 halogen alkoxy group; R ⁹ is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _3-10 cycloalkyl group or a -OC _3-10 cycloalkyl group; wherein the C _1-6 alkyl group, the C _1-6 alkoxy group, the C _3-10 cycloalkyl group or the -OC _3-10 cycloalkyl group is independently substituted by one to five Z ^1a ; each R ¹¹ is independently hydrogen, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C 1-6 alkoxy group or a -OC _3-10 cycloalkyl group; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; t is 0, 1 or 2; m is ₁ or 2; n is 1, 2 or ₃ ; m1 is 0, 1 or 2; n1 is 0, 1, 2 or 3; m2 is 0, 1 or 2; n2 is 0, 1, 2 or 3; wherein m + n is 2, 3 or 4; m1 + n1 is 0, 1, 2, 3 or 4; m2 + n2 is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R 13 , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N( ^{R 13} ) ₂ , -S(O) ₂ N(R ¹³ ) _{2 wherein} ^each C 1-6 alkyl, ^{C 2-6} alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted _{with one} to five Z 1b as ^appropriate ; each R ¹³ is independently hydrogen, C ^1-6 alkyl, C ^{2-6 alkenyl, C 2-6} _{alkynyl ,} C ^3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl group; wherein each C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C 1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group; wherein each C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to _five Z 1b as appropriate; The group consisting of: -C _2-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C ^3-10 cycloalkyl, -C 1-6 halogen, -C 3-10 cycloalkyl, -C _1-6 aryl, -C _2-6 alkylene group, -C ^2-6 alkynyl, -C _1-6 halogen _, -C _3-10 cycloalkyl, -C _1-6 aryl, -C _1-6 alkylene group, -C _{2-6 alkynyl} , ^{-C 2-6} _halogen , -C ^{3-10 cycloalkyl} , ^{-C 1-6} _{aryl ,} -C ^1-6 alkylene group ^... -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _{1-6 alkyl)-, -N(C 2-6} alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C _3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C 1-6 haloalkyl, C _3-10 cycloalkyl, _{heterocycloalkyl} , _aryl and _heteroaryl and is independently substituted with ^one to five independently selected substituents selected from halogen, cyano, -OH, _-SH , -NH _{2 , -NO} ² , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclo, aryl and heteroaryl.

In certain embodiments, compounds of Formula I' are provided: I' or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X ¹ and t are independently as defined herein.

In certain embodiments, compounds of Formula I' are provided: I' or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein: X ¹ is N or CR ⁷ ; R ¹ is halogen, cyano, nitro, _{C 1-6} alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R 11 , -C(O)OR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O)N(R ¹¹ ) ² , ^{-NR 11} _C (O)R ¹¹ , -NR ¹¹ S(O)R ^wherein _the C 1-6 alkyl, ^the C 2-6 alkenyl ^, the _C ^2-6 _{alkynyl ,} the C ^{3-10 cycloalkyl} , the heterocyclic group, ^{the aryl} group or the ^heteroaryl group is independently substituted _{with one to five Z} 1a ^; R ² is halogen, C _2-6 ^alkynyl , _{C 3-10} ^cycloalkyl _, the _heterocyclic group, the aryl group or the ^{heteroaryl group ;} wherein the C _1-6 alkyl, the C _2-6 alkenyl, _the C _2-6 alkynyl, the C _3-10 cycloalkyl, the _heterocyclic group, the aryl, or the heteroaryl is independently substituted with one to _five Z ^1a as appropriate; or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-10 cycloalkyl or heterocyclic group; wherein the C _{3-10 cycloalkyl} or the heterocyclic group is independently substituted with one to five Z ^1a as appropriate; R ³ is: or ; R ⁴ is C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted by one to five Z ^1a as appropriate; each R ⁵ is independently halogen, cyano, C _1-6 alkyl, C _1-6 halogenalkyl, C _2-6 alkenyl or C _2-6 alkynyl; or two R ⁵ together form a C _3-6 cycloalkyl or a 4-6 membered heterocyclic group; wherein the C 3-6 cycloalkyl or the 4-6 membered heterocyclic group is independently substituted by one to five Z ^1a as appropriate; or two R ⁵ together with the carbon atoms to which they are attached form a C _3-6 cycloalkyl or a 4-6 membered heterocyclic group; wherein the C _3-10 cycloalkyl or heterocyclic group is independently substituted by one to five Z ^1a as appropriate; or R ¹ and R ⁵ together with the carbon atom to which they are attached form a C _3-10 cycloalkyl or heterocyclic group; wherein the C _3-10 cycloalkyl or heterocyclic group is independently substituted by one to five Z ^1a as appropriate; or R ⁴ and R ⁵ together with the _atom to which they are attached form a heterocyclic group or heteroaryl; wherein the heterocyclic group or heteroaryl is independently substituted by one to five Z ^1a as appropriate; R ⁶ and R ⁷ are each independently hydrogen, hydroxyl, halogen, cyano, C _1-6 alkyl, C R ^a and R ^b are each independently hydrogen, C _{1-6 alkyl, C 1-6 haloalkyl} , -(CH ₂ ) _0-2 -C _3-7 cycloalkyl and ^3-7 membered heterocyclic group; each R ⁸ is independently C _{1-6 alkyl} or C _1-6 haloalkyl; wherein the C _1-6 alkyl or _the C _1-6 haloalkyl is independently substituted by a halogen group, a hydroxyl group or _{a C 1-6 alkoxy} group as appropriate; or two ^{R 8 and} the carbon atom to which they are attached may together form a pendoxy group, _or a fused or spiro C _3-7 cycloalkyl, or a fused or spiro 4-7 membered heterocyclic group; wherein the C wherein the _{C 3-7} cycloalkyl or the 4-7 membered heterocyclic group is independently substituted by a halogen group, a hydroxyl group, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group or a C _1-6 haloalkoxy group; R ⁹ is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _3-7 cycloalkyl group or a -OC _3-7 cycloalkyl group; wherein the C _1-6 alkyl group, the C _1-6 alkoxy group, the C _3-7 cycloalkyl group or the -OC _3-7 cycloalkyl group is independently substituted by one to five Z ^1a ; each R ¹¹ is independently hydrogen, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; wherein each C wherein m + n is ₂ , ₃ or 4; m1 + n1 is 0, _{1, 2} , 3 or 4; m2 + n2 is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; each Z ^1a is independently halogen, cyano, -NO 2 , C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclo, aryl or heteroaryl, optionally substituted by one to five Z 1a; t is 0, 1 or 2; m is 1 or 2; n is 1, 2 or 3; m1 is 0, 1 or 2; n1 is 0, 1, 2 or 3; m2 is 0, 1 or 2; n2 is 0, 1, 2 or 3; wherein m + n is 2, 3 or 4; m1 + n1 is 0, 1, 2, 3 or 4; m2 + n2 is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 Cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one _{to five} Z 1b as appropriate; The _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as the case may be; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) _2- , -N(C1-6 alkyl)-, -N( _C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N( _C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N( _C3-10 cycloalkyl)-, -N(heterocyclo)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N( _C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from the group consisting of _five halogen groups, cyano, ^-OH , -SH, -NH 2 , -NO 2 , -SF ⁵ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _{3-10 cycloalkyl} , _{heterocycloalkyl , aryl} and heteroaryl. The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl groups, C _1-6 alkoxy groups, C _1-6 halogenalkoxy groups, -S(O) ₂ C _1-6 alkyl groups or heteroaryl groups.

In certain embodiments, R ¹ is C _1-6 alkyl.

In certain embodiments, R ¹ is methyl.

In certain embodiments, R ² is -CD ₃ or C _1-6 alkyl.

In certain embodiments, ^R2 is methyl.

In certain embodiments, R ¹ is C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or the heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogenalkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; and R ² is C _1-6 alkyl.

In certain embodiments, R ¹ is C _1-6 alkyl and R ² is C _1-6 alkyl.

In certain embodiments, R ¹ and R ² are methyl.

In certain embodiments, R ¹ and R ² together with the carbon atoms to which they are attached form a C _3-10 cycloalkyl or heterocyclic group; wherein the C _3-10 cycloalkyl or the heterocyclic group is independently substituted with one to five Z ^1a as the case may be.

In certain embodiments, R ¹ and R ² together with the carbon atoms to which they are attached form a C _3-6 cycloalkyl or a 4-6 membered heterocyclic group; wherein the C _3-6 cycloalkyl or the 4-6 membered heterocyclic group is independently substituted with one to five Z ^1a as the case may be.

In certain embodiments, R ¹ and R ² together with the carbon atom to which they are attached form a C _3-10 cycloalkyl group optionally substituted with one to five Z ^1a .

In certain embodiments, R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group optionally substituted with one to five Z ^1a .

In certain embodiments, ^R1 and ^R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl group which is optionally substituted with one or two hydroxyl groups, halogen groups, cyano groups, _C1-6 alkyl groups, _C1-6 halogen groups, _{C1-6 alkoxy} groups or heteroaryl groups.

In certain embodiments, R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group which is optionally substituted with a hydroxyl group.

In certain embodiments, R ¹ and R ² together with the carbon atom to which they are attached form a heterocyclic group which is optionally substituted with one to five Z ^1a .

In certain embodiments, R ¹ and R ² together with the carbon atom to which they are attached form a 4-6 membered heterocyclic group which is optionally substituted with one to five Z ^1a .

In certain embodiments, R ¹ and R ² together with the carbon atoms to which they are attached form a heterocyclic group.

In certain embodiments, ^R1 and ^R2 together with the carbon atoms to which they are attached form a 4-6 membered heterocyclic group.

In certain embodiments, R ¹ and R ² together with the carbon atom to which they are attached form a C _3-4 cycloalkyl group which is optionally substituted with a hydroxyl group.

In certain embodiments, R ¹ and R ² together with the carbon atom to which they are attached form an unsubstituted C _3-5 cycloalkyl.

In certain embodiments, ^R3 is .

In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, n is 2. In some embodiments, n is 3.

In some embodiments, m + n is 3. In some embodiments, m + n is 2. In some embodiments, m and n are both 1.

In certain embodiments, ^R3 is .

In some embodiments, m1 is 0. In some embodiments, m1 is 1. In some embodiments, m1 is 2. In some embodiments, m1 is 1 or 2. In some embodiments, m1 is 0 or 1.

In some embodiments, n1 is 0. In some embodiments, n1 is 1. In some embodiments, n1 is 2. In some embodiments, n1 is 3. In some embodiments, n1 is 1, 2, or 3. In some embodiments, n1 is 1 or 2. In some embodiments, n1 is 0 or 1.

In some embodiments, m2 is 0. In some embodiments, m2 is 1. In some embodiments, m2 is 2. In some embodiments, m2 is 1 or 2. In some embodiments, m2 is 0 or 1.

In some embodiments, n2 is 0. In some embodiments, n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments, n2 is 1, 2, or 3. In some embodiments, n2 is 1 or 2. In some embodiments, n2 is 0 or 1.

In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 1 or 2. In some embodiments, p is 0, 1 or 2. In some embodiments, p is 0, 1, 2 or 3. In some embodiments, p is 1, 2 or 3.

In certain embodiments, each R ⁸ is independently -C(O)N(R ¹¹ ) ₂ , C _1-6 alkyl or C _1-6 halogenalkyl; wherein the C _1-6 alkyl is independently substituted by cyano, -N(R ¹³ ) ₂ , halogen, hydroxy or C _1-6 alkoxy as appropriate; or two R ⁸ together with the carbon atom to which they are attached may form a pendoxy group or a bridged 4-7 membered heterocyclic group.

In certain embodiments, each R ⁸ is independently C _1-6 alkyl.

In certain embodiments, or two R ⁸ together with the carbon atom to which they are attached form a bridged 4-7 member heterocyclic group. In the case where two R ⁸ together form a fused C _3-7 cycloalkyl or a fused 4-7 member heterocyclic group, it should be understood that when two R ⁸ form a bridged ring, the bridge portion comprises at least one (e.g., 1-3) atom (e.g., a carbon atom, such as -(CH ₂ ) _1-3 ). In addition, in the case where two R ⁸ together form a fused C _3-7 cycloalkyl or a fused 4-7 member heterocyclic group, it should be understood that the two R ⁸ forming the fused ring are connected to adjacent atoms on the R ³ portion.

In certain embodiments, p is 1 or 2; and each R ⁸ is methyl.

In certain embodiments, R ⁹ is C _1-6 alkyl, C _1-6 alkoxy or C _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy or the C _3-10 cycloalkyl is independently optionally substituted with one to five halogen groups, cyano groups, hydroxyl groups, -S(O) ₂ C _1-6 alkyl, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C(O)NHC _1-6 alkyl ₂ , -C(O)N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenalkyl, C _1-6 halogenalkoxy, C wherein the _heterocyclic group is optionally further substituted by a halogen group or a C _1-6 alkoxy group.

In certain embodiments, R ⁹ is C _1-6 alkyl, C _1-6 alkoxy or C _3-7 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy or the C _3-7 cycloalkyl is independently substituted with one to five halogen groups, C _1-6 alkyl, C _{1-6 alkoxy, C 1-6 halogenalkyl} or C _3-7 cycloalkyl, as the case may be.

In certain embodiments, R ⁹ is C _1-6 alkyl, optionally substituted with one to five halogen groups, C _1-6 alkyl groups, C 1-6 alkoxy groups, C _1-6 halogen groups or C _3-7 cycloalkyl groups. In certain embodiments, R ⁹ is C _1-6 alkyl _groups .

In certain embodiments, R ⁹ is C _1-6 alkoxy optionally substituted by one to five halogen groups, C _1-6 alkyl groups, C 1-6 alkoxy groups, C _1-6 halogen alkyl groups or C _3-7 cycloalkyl groups. In certain embodiments, R ⁹ is C _1-6 alkoxy optionally _substituted by one to five halogen groups.

In certain embodiments, R ⁹ is C _3-8 cycloalkyl optionally substituted with one to five halogen groups, C _1-6 alkyl groups or C _1-6 haloalkyl groups. In certain embodiments, R ⁹ is _C 3-7 cycloalkyl optionally substituted with one to five halogen groups, C _1-6 alkyl groups or C _1-6 haloalkyl groups.

In certain embodiments, R ⁹ is: , , , , , , , , , , , , , , , or .

In certain embodiments, the moiety -C(O)-R ⁹ is: , , , , , , , , , , , , , , , or .

In some embodiments, ^X1 is N.

In certain embodiments, X ¹ is CR ⁷ .

In certain embodiments, R ⁶ is hydrogen.

In certain embodiments, R ⁷ is hydrogen.

In certain embodiments, X ¹ is N; and R ⁶ is hydrogen.

In certain embodiments, L is a bond, C _1-2 alkylene, -CH ₂ -C(O)NR ¹¹ -*, -C(O)-, -S(O) ₂ -, -C(O)O-*, or -C(O)NR ¹¹ -*; wherein the * bond is connected to R ⁴ .

In some embodiments, L is a bond.

In certain embodiments, L is C _1-2 alkylene.

In certain embodiments, L is -CH ₂ -C(O)NR ¹¹ -*; wherein the * bond is connected to R ⁴ .

In certain embodiments, wherein L is -C(O)-.

In certain embodiments, wherein L is -S(O) ₂ -.

In certain embodiments, L is -C(O)O-*; wherein the * bond is connected to R ⁴ .

In certain embodiments, L is -C(O)NR ¹¹ -*; wherein the * bond is connected to R ⁴ .

In certain embodiments, R ⁴ is C _1-6 alkyl optionally substituted with one to five Z ^1a . In certain embodiments, R ⁴ is C _1-3 alkyl optionally substituted with one to five Z ^1a .

In certain embodiments, L is C _1-2 alkylene, -CH ₂ -C(O)NR ¹¹ -*, -C(O)-, -S(O) ₂ -, -C(O)O-*, or -C(O)NR ¹¹ -*; wherein the * bond is connected to R ⁴ ; and R ⁴ is C _1-6 alkyl optionally substituted with one to five Z ^1a . In certain embodiments, R ⁴ is C _1-3 alkyl optionally substituted with one to five Z ^1a .

In certain embodiments, R ⁴ is C _3-10 cycloalkyl optionally substituted with one to five Z ^1a . In certain embodiments, R ⁴ is C _3-6 cycloalkyl optionally substituted with one to five Z ^1a .

In certain embodiments, L is a bond or -C(O)-; and ^R4 is a _C3-10 cycloalkyl group optionally substituted with one to five ^{Z1a groups} . In certain embodiments, ^R4 is a _C3-6 cycloalkyl group optionally substituted with one to five Z1a ^groups .

In certain embodiments, R ⁴ is aryl optionally substituted with one to five Z ^1a . In certain embodiments, R ⁴ is phenyl optionally substituted with one to five Z ^1a .

In certain embodiments, L is a bond; and R ⁴ is aryl optionally substituted with one to five Z ^1a . In certain embodiments, L is a bond; and R ⁴ is phenyl optionally substituted with one to five Z ^1a .

In certain embodiments, R ⁴ is heteroaryl optionally substituted with one to five Z ^1a .

In certain embodiments, L is a bond; and R ⁴ is heteroaryl optionally substituted with one to five Z ^1a .

In certain embodiments, R ⁴ is 6-membered heteroaryl optionally substituted with one to five Z ^1a .

In certain embodiments, R ⁴ is a 6-membered heteroaryl group which is optionally substituted with cyano.

In certain embodiments, R ⁴ is pyridinyl optionally substituted with cyano.

In certain embodiments, R ⁴ is pyridinyl substituted with cyano.

In certain embodiments, R ⁴ is 4-cyanopyridin-2-yl.

In certain embodiments, ^R4 is 4-cyanopyridin-2-yl, 4-cyano-5-fluoro-pyridin-2-yl, 2-cyanopyridin-4-yl, 6-cyanopyrimidin-4-yl, 6-cyanopyridazin-4-yl, 4-cyanopyrimidin-2-yl, 5-cyanopyridazin-3-yl, [1,2,4]triazolo[4,3-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-c]pyrimidin-7-yl, imidazo[1,2-c]pyrimidin-7-yl, imidazo[1,2-a]pyrazin-6-yl, 5-aminopyridin-6-yl, 5-aminopyridin-7 ...6-yl, 5-aminopyridin-7-yl, 5-aminopyridin-7-yl, 5-aminopyridin-7-yl, 5-aminopyridin-7-yl, 5-amino oxazine-2-yl, 5-cyano-1-methyl-1H-pyrazol-3-yl, 3-cyano-5-fluorophenyl, 3,5-dicyanophenyl, 1-methyl-2-oxo-4-pyridyl, 6-aminopyrimidin-4-yl, 4-cyano-6-(hydroxymethyl)-2-pyridyl, 6-cyano-2-(trifluoromethyl)pyrimidin-4-yl, 7-(3-cyano-5-methylsulfonylphenyl), 5-cyano-2-methoxypyridin-3-yl, 5-cyano-2-oxo-1H-pyridin-3-yl, 7 -(6-cyano-2-methoxypyrimidin-4-yl), 6-chloro-4-cyanopyridin-2-yl, 7-(3-cyano-5-methylsulfanylphenyl), 5-cyano-1-methyl-2-oxo-3-pyridinyl, 2-cyano-5-fluoro-4-pyridinyl, 6-cyano-2-oxo-1,2-dihydropyrimidin-4-yl, 6-cyano-3-methyl-2-oxo-1,2-dihydropyrimidin-4-yl, 1-acetylpyrrolidin-3-yl, 7-(3-cyanocyclopentyl), 1H -pyrazolo[4,3-c]pyridin-6-yl, 3-cyanocyclobutyl, 2-chloro-6-cyanopyrimidin-4-yl, 3-cyanocyclohexyl, 3-cyano-3-methylcyclobutyl, 3-ethoxycarbonylcyclobutyl, 2-cyano-5-fluoropyridin-4-yl, cyclobutyl, 3-hydroxycyclobutyl, 3-(hydroxymethyl)-3-methyl-cyclobutyl, 2-chloro-5-fluoropyridin-4-yl, 6-chloropyridin-4-yl, 2-cyano-5-fluoropyridin-4-yl or 6-cyano-3-methylpyridin-4-yl.

In certain embodiments, L is a bond; and ^R4 is 4-cyanopyridin-2-yl, 4-cyano-5-fluoro-pyridin-2-yl, 2-cyanopyridin-4-yl, 6-cyanopyrimidin-4-yl, 6-cyanopyrimidin-4-yl, 4-cyanopyrimidin-2-yl, 5-cyanopyrimidin-3-yl, [1,2,4]triazolo[4,3-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-c]pyrimidin-7-yl, imidazo[1,2-c]pyrimidin-7-yl, imidazo[1,2-a]pyrazin-6-yl, 5-aminopyridin-6-yl, 5-aminopyridin-7 ...6-yl, 5-aminopyridin-7-yl, 5-aminopyridin-7- oxazine-2-yl, 5-cyano-1-methyl-1H-pyrazol-3-yl, 3-cyano-5-fluorophenyl, 3,5-dicyanophenyl, 1-methyl-2-oxo-4-pyridyl, 6-aminopyrimidin-4-yl, 4-cyano-6-(hydroxymethyl)-2-pyridyl, 6-cyano-2-(trifluoromethyl)pyrimidin-4-yl, 7-(3-cyano-5-methylsulfonylphenyl), 5-cyano-2-methoxypyridin-3-yl, 5-cyano-2-oxo-1H-pyridin-3-yl, 7 -(6-cyano-2-methoxypyrimidin-4-yl), 6-chloro-4-cyanopyridin-2-yl, 7-(3-cyano-5-methylsulfanylphenyl), 5-cyano-1-methyl-2-oxo-3-pyridinyl, 2-cyano-5-fluoro-4-pyridinyl, 6-cyano-2-oxo-1,2-dihydropyrimidin-4-yl, 6-cyano-3-methyl-2-oxo-1,2-dihydropyrimidin-4-yl, 1-acetylpyrrolidin-3-yl, 7-(3-cyanocyclopentyl), 1H -pyrazolo[4,3-c]pyridin-6-yl, 3-cyanocyclobutyl, 2-chloro-6-cyanopyrimidin-4-yl, 3-cyanocyclohexyl, 3-cyano-3-methylcyclobutyl, 3-ethoxycarbonylcyclobutyl, 2-cyano-5-fluoropyridin-4-yl, cyclobutyl, 3-hydroxycyclobutyl, 3-(hydroxymethyl)-3-methyl-cyclobutyl, 2-chloro-5-fluoropyridin-4-yl, 6-chloropyridin-4-yl, 2-cyano-5-fluoropyridin-4-yl or 6-cyano-3-methylpyridin-4-yl.

In certain embodiments, R is ^methyl , ethyl, cyclobutyl, 2-cyanocyclopropan-1-yl, 3-cyanocyclobutan-1-yl, 1-methylcyclobutan-1-yl, 3-cyanopropanoyl, cyclopropylmethyl, 3-fluorocyclobutan-1-yl, 2,2-difluorocyclobutan-1-yl, 2,2-difluorocyclopropan-1-yl, 1-fluorocyclobutan-1-yl, 1-(cyanomethyl)cyclopropan-1-yl, 1-methyl- 1H -pyrazol-4-yl, 2-cyano-1-methylcyclopropan-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-cyanocyclobutan-1-yl, 2-cyano-2-methylcyclopropan-1-yl, 1-methyl- 1H -pyrazol-5-yl, ... -pyrazol-1-ylmethyl, 2-(1-methyl- 1H -pyrazol-4-yl)ethyl, pyrrolidin-1-ylmethyl, pyrrolidin-2-yl or pyrrolidin-3-yl.

In certain embodiments, L is C _1-2 alkylene, -CH ₂ -C(O)NR ¹¹ -*, -C(O)-, -S(O) ₂ -, -C(O)O-*, or -C(O)NR ¹¹ -*; wherein the * bond is connected to R ⁴ . ^R4 is methyl, ethyl, cyclobutyl, 2-cyanocyclopropan-1-yl, 3-cyanocyclobutan-1-yl, 1-methylcyclobutan-1-yl, 3-cyanopropanoyl, cyclopropylmethyl, 3-fluorocyclobutan-1-yl, 2,2-difluorocyclobutan-1-yl, 2,2-difluorocyclopropan-1-yl, 1-fluorocyclobutan-1-yl, 1-(cyanomethyl)cyclopropan-1-yl, 1-methyl- 1H -pyrazol-4-yl, 2-cyano-1-methylcyclopropan-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1-cyanocyclobutan-1-yl, 2-cyano-2-methylcyclopropan-1-yl, 1-methyl- 1H -pyrazol-5-yl, 1H -pyrazol-1-ylmethyl, 2-(1-methyl- 1H -pyrazol-4-yl)ethyl, pyrrolidin-1-ylmethyl, pyrrolidin-2-yl or pyrrolidin-3-yl.

In some embodiments, t is 0.

In certain embodiments, compounds of Formula IA are provided: IA or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein each R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , L, m, n and p are independently as defined herein.

In certain embodiments, compounds of Formula IA' are provided: IA' or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, mixture of stereoisomers thereof, wherein each R ¹ , R ² , R ⁴ , R ⁸ , R ⁹ , m, n and p are independently as defined herein.

In certain embodiments, compounds of Formula IA' are provided: IA' or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein: R ¹ is halogen, cyano, nitro, _{C 1-6} alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R 11 , -C(O)OR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O)N(R ¹¹ ) ² , -NR ¹¹ C(O)R ₁₁ , ^{-NR 11 S} (O)R ¹¹ , -NR ^{11 wherein} _the C ^1-6 alkyl, the C 2-6 alkenyl, the C ^2-6 _alkynyl , the C ^{3-10 cycloalkyl} , the heterocyclic group, ^the _aryl or the ^{heteroaryl group} _{is independently} substituted _{with one} to five Z ^1a ; R ₂ is a halogen group, ^a C _1-6 alkyl group, ^a C ^2-6 alkenyl group, a C _{2-6 alkynyl} group, ^a C _{3-10 cycloalkyl} group, a _heterocyclic group, a aryl group or a _heteroaryl ^{group ;} wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _{2-6 alkynyl, the C 3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted by one to five Z 1a as appropriate; or R 1 and R 2 together with the carbon atom to which they are attached form a C 3-10 cycloalkyl or heterocyclic group; wherein the C 3-10 cycloalkyl or} ^{the heterocyclic} _{group is} independently substituted by one to five Z 1a as appropriate; R ⁴ is a C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C _1-6 alkyl, the C 2-6 alkenyl, the C 2-6 alkynyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted by one to ^five Z ^1a as appropriate; The _3-10 membered cycloalkyl, the heterocyclic group, the aryl group or the heteroaryl group is independently substituted by one to five Z ^1a ; each R ⁸ is independently C _1-6 alkyl or C _1-6 halogenalkyl; wherein the C _1-6 alkyl or the C _1-6 halogenalkyl is independently substituted by a halogen group, a hydroxyl group or a C _1-6 alkoxy group; or two R ⁸ and the carbon atom to which they are connected may form a side group, or a fused or spiro C _3-7 cycloalkyl, or a fused or spiro 4-7 membered heterocyclic group; wherein the C _3-7 cycloalkyl or the 4-7 membered heterocyclic group is independently substituted by a halogen group, a hydroxyl group, a C _1-6 alkyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy group or a C R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl or -OC _3-7 cycloalkyl _; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-7 cycloalkyl or the -OC _3-7 cycloalkyl is independently substituted with one to five Z ^1a as appropriate; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; m is 1 or 2; n is 1, 2 or 3; wherein m + n is 2, 3 or 4; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R 13 ) 2 ^wherein _each C ^1-6 _alkyl , C _2-6 alkenyl ^{, C 2-6 alkynyl} _, C ^{3-10 cycloalkyl} , heterocyclic ^group , ^aryl or heteroaryl group is independently _substituted with _{one to five Z} ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl _, C _2-6 alkenyl, _C ^2-6 alkynyl, C ^3-10 cycloalkyl, _heterocyclic group, ^aryl or _heteroaryl ^group wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloyl, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocycloyl, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L 1 -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ^{1 -C} _2-6 wherein each L ¹ is independently -O-, -NH-, -S-, -S ^(O) -, -S ⁽ O) ² -, -N ⁽ C 1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 haloalkyl)-, _-N (C _3-10 cycloalkyl)-, -N(heterocyclo)-, -N(aryl)-, -N(heteroaryl)-, -C(O) _{-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl} )-, -C(O)N(C _2-6 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10 cycloalkyl)-, -N(heterocyclo)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C in the embodiment of the present invention, Z 1b and L 1 are each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 ^alkynyl _, C _{1-6 haloalkyl , C 3-10} cyclo ^... The _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are further independently optionally substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, _-NH2 , _-NO2 , _-SF5 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups.

In certain embodiments, compounds of Formula IB are provided: IB or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each of R ¹ , R ² , R ⁴ and R ⁹ is independently as defined herein.

In certain embodiments of Formula IB, R ¹ is halogen, cyano, nitro, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ^{11 , -SR 11 , -C(O)R 11} , -C(O)OR 11 , -S(O)R 11 , -S(O) 2 R ¹¹ , -C(O)N(R 11 ) ² , -NR 11 C(O)R ¹¹ , -NR ^{11 S} (O)R ¹¹ , -NR 11 S(O) ₂ R 11 , -S ⁽ O)N(R ¹¹ ) ₂ , -S(O)N(R ^{11 ) 2} , -NR ¹¹ C(O)R ¹¹ , -NR ^{11 S(O)R 11 , -NR 11} S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O)N(R ₁₁ ) 2 ^wherein _the C _{1-6 alkyl} , the C 2-6 alkenyl, ^the C 2-6 ^alkynyl , the C ^{3-10 cycloalkyl} , the heterocyclic _group , ^the _aryl or the ^heteroaryl group is independently _substituted with one to ^five Z 1a as appropriate; R ² is halogen, -CD _{3 ,} C ^1-6 alkyl, C _{2-6 alkenyl} , C _2-6 alkynyl, C _3-10 cycloalkyl, ^the heterocyclic group, the _{aryl or} the ^heteroaryl group; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocycloyl, the aryl or the heteroaryl is independently substituted by one to five Z ^1a as appropriate; or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-10 cycloalkyl or heterocycloyl; wherein the C _3-10 cycloalkyl or the heterocycloyl is independently substituted by one to five Z 1a as appropriate; R ⁴ is a C 1-6 alkyl, a C _3-10 cycloalkyl, a heterocycloyl, an aryl or a heteroaryl; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C 3-10 cycloalkyl, the heterocycloyl, the aryl or the heteroaryl is independently substituted by one to five Z ^1a as appropriate; wherein the _{C 3-10} cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 _3-10 cycloalkyl, heterocyclic group, aryl group or heteroaryl group is independently substituted by one to five Z ^1a groups as appropriate; each Z ^{1a group} is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ^{13 wherein} _each C ^1-6 alkyl, C 2-6 alkenyl _, C 2-6 _alkynyl , C 3-10 ^{cycloalkyl , heterocycloalkyl, aryl or heteroaryl is independently substituted with one to five Z 1b; each R 13 is independently} _{hydrogen , C 1-6} ^alkyl _, ^{C 2-6 alkenyl} _, ^C _{3-10 cycloalkyl ,} ^{heterocycloalkyl} _, ^{aryl or} _{heteroaryl ;} wherein each C _1-6 alkyl _, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloyl, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, _{heterocycloyl} , aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _2-6 -C _1-6 haloalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C _{2-6 alkynyl)-, -N(C 1-6 haloalkyl )} -, -N(C _3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C in the embodiment of the present invention, Z 1b and L 1 are each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 ^alkynyl _, C _{1-6 haloalkyl , C 3-10} cyclo ^... The _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are further independently optionally substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, _-NH2 , _-NO2 , _-SF5 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups.

In certain embodiments of Formula IB, R ¹ is halogen, cyano, nitro, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ^{11 , -SR 11 , -C(O)R 11} , -C(O)OR 11 , -S(O)R 11 , -S(O) 2 R ¹¹ , -C(O)N(R 11 ) ² , -NR 11 C(O)R ¹¹ , -NR ^{11 S} (O)R ¹¹ , -NR 11 S(O) ₂ R 11 , -S ⁽ O)N(R ¹¹ ) ₂ , -S(O)N(R ^{11 ) 2} , -NR ¹¹ C(O)R ¹¹ , -NR ^{11 S(O)R 11 , -NR 11} S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O)N(R ₁₁ ) 2 ^wherein _the C _{1-6 alkyl} , the C 2-6 alkenyl, ^the C 2-6 ^alkynyl , the C ^{3-10 cycloalkyl} , the heterocyclic _group , ^the _aryl or the ^heteroaryl group is independently _substituted with one to ^five Z 1a as appropriate; R ² is halogen, -CD _{3 ,} C ^1-6 alkyl, C _{2-6 alkenyl} , C _2-6 alkynyl, C _3-10 cycloalkyl, ^the heterocyclic group, the _{aryl or} the ^heteroaryl group; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocycloalkyl, the aryl or the heteroaryl is independently substituted with one to five Z ^1a as appropriate; R ⁴ is a C _1-6 alkyl, a C _3-10 cycloalkyl, a heterocycloalkyl, an aryl or a heteroaryl; wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocycloalkyl, the aryl or the heteroaryl is independently substituted with one to five Z ^1a as appropriate; R ⁹ is a C _1-6 alkyl, _{a C 1-6 alkoxy} , a C _3-10 cycloalkyl or -OC wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _{3-10 cycloalkyl} is independently substituted with one to five Z ^1a as appropriate; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6} alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R 13 , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ ^{R 13 ,} -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 The _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as the case may be; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) _2- , -N(C1-6 alkyl)-, -N( _C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N( _C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N( _C3-10 cycloalkyl)-, -N(heterocyclo)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N( _C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ² , -SF ⁵ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _{3-10 cycloalkyl} , _{heterocycloalkyl} , _aryl and heteroaryl _. The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments of Formula IB, R ¹ and R ² together with the carbon atoms to which they are attached form a C _3-10 cycloalkyl or heterocyclic group; wherein the C _3-10 cycloalkyl or the heterocyclic group is independently substituted with one to five Z ^1a ; R ⁴ is a C _1-6 alkyl, a C _3-10 cycloalkyl, a heterocyclic group, an aryl or a heteroaryl; wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is a C _1-6 alkyl, a C _1-6 alkoxy, a C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C 3-10 wherein the -OC _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a ; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 Cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one _{to five} Z 1b as appropriate; The _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as the case may be; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) _2- , -N(C1-6 alkyl)-, -N( _C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N( _C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N( _C3-10 cycloalkyl)-, -N(heterocyclo)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N( _C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ² , -SF ⁵ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _{3-10 cycloalkyl} , _{heterocycloalkyl} , _aryl and heteroaryl _. The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments of Formula IB, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogen alkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; R ² is -CD ₃ or C _1-6 alkyl; or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group optionally substituted with one to five Z ^1a ; R ⁴ is a C _3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; wherein the C wherein the _{C 3-10} cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 _3-10 cycloalkyl, heterocyclic group, aryl group or heteroaryl group is independently substituted by one to five Z ^1a groups as appropriate; each Z ^{1a group} is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ^{13 wherein} _each C ^1-6 alkyl, C 2-6 alkenyl _, C 2-6 _alkynyl , C 3-10 ^{cycloalkyl , heterocycloalkyl, aryl or heteroaryl is independently substituted with one to five Z 1b; each R 13 is independently} _{hydrogen , C 1-6} ^alkyl _, ^{C 2-6 alkenyl} _, ^C _{3-10 cycloalkyl ,} ^{heterocycloalkyl} _, ^{aryl or} _{heteroaryl ;} wherein each C _1-6 alkyl _, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloyl, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, _{heterocycloyl} , aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _2-6 -C _1-6 haloalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C _{2-6 alkynyl)-, -N(C 1-6 haloalkyl )} -, -N(C _3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C in the embodiment of the present invention, Z 1b and L 1 are each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 ^alkynyl _, C _{1-6 haloalkyl , C 3-10} cyclo ^... The _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are further independently optionally substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, _-NH2 , _-NO2 , _-SF5 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups.

In certain embodiments of Formula IB, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or the heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogen alkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; R ² is -CD ₃ or C _1-6 alkyl; R ⁴ is C _3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the C _3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are independently optionally substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a as appropriate; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl} , heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R 13 , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N( ^{R 13} ) ₂ , -S(O) ₂ N(R ¹³ ) _{2 wherein} ^each C 1-6 alkyl, ^{C 2-6} alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted _{with one} to five Z 1b as ^appropriate ; each R ¹³ is independently hydrogen, C ^1-6 alkyl, C ^{2-6 alkenyl, C 2-6} _{alkynyl ,} C ^3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl group; wherein each C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C 1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group; wherein each C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to _five Z 1b as appropriate; The group consisting of: -C _2-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C ^3-10 cycloalkyl, -C 1-6 halogen, -C 3-10 cycloalkyl, -C _1-6 aryl, -C _2-6 alkylene group, -C ^2-6 alkynyl, -C _1-6 halogen _, -C _3-10 cycloalkyl, -C _1-6 aryl, -C _1-6 alkylene group, -C _{2-6 alkynyl} , ^{-C 2-6} _halogen , -C ^{3-10 cycloalkyl} , ^{-C 1-6} _{aryl ,} -C ^1-6 alkylene group ^... -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _{1-6 alkyl)-, -N(C 2-6} alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C _3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C 1-6 haloalkyl, C _3-10 cycloalkyl, _{heterocycloalkyl} , _aryl and _heteroaryl and is independently substituted with ^one to five independently selected substituents selected from halogen, cyano, -OH, _-SH , -NH _{2 , -NO} ² , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclo, aryl and heteroaryl.

In certain embodiments of Formula IB, R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group which is optionally substituted with one to five Z ^1a ; R ⁴ is a C _3-10 cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group; wherein the C _3-10 cycloalkyl group, the heterocycloalkyl group, the aryl group or the heteroaryl group is independently substituted with one to five Z ^1a ; R ⁹ is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _3-10 cycloalkyl group or a -OC _3-10 cycloalkyl group; wherein the C _1-6 alkyl group, the C _1-6 alkoxy group, the C _3-10 cycloalkyl group or the -OC _3-10 cycloalkyl group is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; where each C _1-6 alkyl, C wherein each C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as the case may be; each R ¹³ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, _heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as the case may be; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _{1-6 alkyl, C 2-6} alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl in the present invention, the present invention is a C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 haloalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl group; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C 2-6 alkynyl)-, -C(O)N(C 1-6 haloalkyl)-, -C(O)N(C _3-10 cycloalkyl)-, -N(heterocycloalkyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C 2-6 alkynyl)-, -C(O)N(C _1-6 haloalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH 2 , -NO 2 , -SF 5 , C 1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to ^five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ² , -NO ₂ , -SF 5 , C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1-6 halogenalkyl, C 3-10} cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , -SF ₅ , C _1-6 alkyl, C The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments, compounds of formula IC are provided: IC or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each of R ¹ , R ⁴ and R ⁹ is independently as defined herein.

In certain embodiments of Formula IC, R ¹ is halogen, cyano, nitro, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ¹¹ , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O) 2 R ¹¹ , -C(O)N(R 11 ) ² , -NR 11 C(O)R ¹¹ , -NR ^{11 S} (O)R ¹¹ , -NR 11 S(O) ₂ R 11 , -S ⁽ O)N(R ¹¹ ) ₂ , -S(O)N(R ^{11 ) 2} , -NR ¹¹ C(O)R ¹¹ , -NR ^{11 S(O)R 11 , -NR 11} S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O)N(R ₁₁ ) 2 ^wherein _the C ^1-6 alkyl _group , the C 2-6 alkenyl group, the C ^2-6 alkynyl group, the C ^{3-10 cycloalkyl} group, the heterocyclic group, the aryl group or the ^heteroaryl group is independently substituted with _one to _five Z 1a; R ⁴ is C ^1-6 alkyl _group , C ^3-10 cycloalkyl group, heterocyclic _{group, aryl group} or ^heteroaryl group; wherein the C _1-6 alkyl group, the C _{2-6 alkenyl group, the C 2-6} alkynyl group, the C 3-10 cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is independently substituted with one to five Z ^1a ; R ⁴ is C _1-6 alkyl group, C _3-10 cycloalkyl ^group , heterocyclic group, aryl group or heteroaryl group; wherein the C _1-6 alkyl group, the C _2-6 alkenyl group, the C 2-6 alkynyl group, the C _3-10 cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is independently substituted with one to five Z 1a; wherein the _{C 3-10} cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 _3-10 cycloalkyl, heterocyclic group, aryl group or heteroaryl group is independently substituted by one to five Z ^1a groups as appropriate; each Z ^{1a group} is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ _{wherein each} C ^1-6 alkyl, C 2-6 alkenyl, C 2-6 _alkynyl , C ^{3-10 cycloalkyl} , heterocycloalkyl _{, aryl or heteroaryl is independently substituted with one to five} ^Z _{1b ; each} ^{R 13 is} independently hydrogen, ^C _1-6 alkyl, C ^2-6 alkenyl, _C ^{2-6 alkynyl} , _{C 3-10 cycloalkyl , heterocycloalkyl} , _aryl ^{or heteroaryl ;} wherein each C _1-6 alkyl _, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloyl, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, _{heterocycloyl} , aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _2-6 -C _1-6 haloalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C _{2-6 alkynyl)-, -N(C 1-6 haloalkyl )} -, -N(C _3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C in the embodiment of the present invention, Z 1b and L 1 are each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 ^alkynyl _, C _{1-6 haloalkyl , C 3-10} cyclo ^... The _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are further independently optionally substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, _-NH2 , _-NO2 , _-SF5 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups.

In certain embodiments of Formula IC, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogen alkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; R ⁴ is C _1-6 alkyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocycloalkyl, the aryl or the heteroaryl is independently optionally substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a as appropriate; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl} , heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R 13 , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N( ^{R 13} ) ₂ , -S(O) ₂ N(R ¹³ ) _{2 wherein} ^each C 1-6 alkyl, ^{C 2-6} alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted _{with one} to five Z 1b as ^appropriate ; each R ¹³ is independently hydrogen, C ^1-6 alkyl, C ^{2-6 alkenyl, C 2-6} _{alkynyl ,} C ^3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl group; wherein each C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C 1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group; wherein each C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to _five Z 1b as appropriate; The group consisting of: -C _2-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C ^3-10 cycloalkyl, -C 1-6 halogen, -C 3-10 cycloalkyl, -C _1-6 aryl, -C _2-6 alkylene group, -C ^2-6 alkynyl, -C _1-6 halogen _, -C _3-10 cycloalkyl, -C _1-6 aryl, -C _1-6 alkylene group, -C _{2-6 alkynyl} , ^{-C 2-6} _halogen , -C ^{3-10 cycloalkyl} , ^{-C 1-6} _{aryl ,} -C ^1-6 alkylene group ^... -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _{1-6 alkyl)-, -N(C 2-6} alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C _3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C 1-6 haloalkyl, C _3-10 cycloalkyl, _{heterocycloalkyl} , _aryl and _heteroaryl and is independently substituted with ^one to five independently selected substituents selected from halogen, cyano, -OH, _-SH , -NH _{2 , -NO} ² , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclo, aryl and heteroaryl.

In certain embodiments of Formula IC, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or the heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogen alkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; R ⁴ is C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl groups; wherein the C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl groups are independently substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C 1-6 halogen alkoxy groups, -S(O) 2 C 1-6 alkyl or heteroaryl groups. wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a as the case may be; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _{1-6 alkyl} , _{C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl , heterocyclic group} , aryl or heteroaryl is independently substituted with one to five Z ^1a as the case may be; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R 13 , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N( ^{R 13} ) ₂ , -S(O) ₂ N(R ¹³ ) _{2 wherein} ^each C 1-6 alkyl, ^{C 2-6} alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted _{with one} to five Z 1b as ^appropriate ; each R ¹³ is independently hydrogen, C ^1-6 alkyl, C ^{2-6 alkenyl, C 2-6} _{alkynyl ,} C ^3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl group; wherein each C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C 1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group; wherein each C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to _five Z 1b as appropriate; The group consisting of: -C _2-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C ^3-10 cycloalkyl, -C 1-6 halogen, -C 3-10 cycloalkyl, -C _1-6 aryl, -C _2-6 alkylene group, -C ^2-6 alkynyl, -C _1-6 halogen _, -C _3-10 cycloalkyl, -C _1-6 aryl, -C _1-6 alkylene group, -C _{2-6 alkynyl} , ^{-C 2-6} _halogen , -C ^{3-10 cycloalkyl} , ^{-C 1-6} _{aryl ,} -C ^1-6 alkylene group ^... -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _{1-6 alkyl)-, -N(C 2-6} alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C _3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C 1-6 haloalkyl, C _3-10 cycloalkyl, _{heterocycloalkyl} , _aryl and _heteroaryl and is independently substituted with ^one to five independently selected substituents selected from halogen, cyano, -OH, _-SH , -NH _{2 , -NO} ² , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclo, aryl and heteroaryl.

In certain embodiments, compounds of formula ID are provided: ID or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each of R ⁴ , R ⁹ and Z ^1a is independently as defined herein.

In certain embodiments of Formula ID, R ⁴ is C _1-6 alkyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C 2-6 alkenyl, C _2-6 cycloalkyl ... wherein _{each C 1-6 alkyl} , C _2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , _{C 1-6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, _heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ^{13 , -C(O)R 13} , -C(O)OR ¹³ , -S(O) ^{R 13 ,} -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein each R ¹³ is independently hydrogen, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z 1b; each Z 1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO 2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C ^1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with _one to five Z ^1b ; in the embodiment of the present invention, the present invention is _{-L 1 -C 1-6} halogenalkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl ^{, -L 1 -C 1-6 halogenalkyl, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -aryl} _or ^-L ₁ ^{-heteroaryl ;} _and ^each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C 1-6 -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C _1-6 haloalkyl)-, -C(O)N(C _3-10 cycloalkyl)-, -C(O)N( _{heterocycloyl} )-, -C(O)N( _aryl )-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O) ₂ NH-; wherein each of Z ^1b and L ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl _.

In certain embodiments of Formula ID, R ⁴ is C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 alkyl, the C _1-6 alkoxy, the C 3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z 1a; each R 11 is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C 2-6 alkynyl, C 1-6 alkyl, C ^2-6 alkynyl, C _1-6 alkyl, C 2-6 alkynyl, C 1-6 alkyl, C _2-6 alkynyl, C 1-6 alkyl, C _1-6 alkoxy, C 3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C 1-6 alkyl, the C _{1-6 alkoxy, the C 3-10 cycloalkyl or -OC 3-10} cycloalkyl is independently substituted with one to five Z ^1a ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted by one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , _{C 1-6} alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, _heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR 13 , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ _{, -S(O) 2} ^{R 13} , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein each R ¹³ is independently hydrogen, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z 1b; each Z 1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO 2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C ^1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with _one to five Z ^1b ; in the embodiment of the present invention, the present invention is _{-L 1 -C 1-6} halogenalkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl ^{, -L 1 -C 1-6 halogenalkyl, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -aryl} _or ^-L ₁ ^{-heteroaryl ;} _and ^each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C 1-6 -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C _1-6 haloalkyl)-, -C(O)N(C _3-10 cycloalkyl)-, -C(O)N( _{heterocycloyl} )-, -C(O)N( _aryl )-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O) ₂ NH-; wherein each of Z ^1b and L ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl _.

In certain embodiments, compounds of formula IE are provided: IE or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each of R ¹ , R ² , R ⁴ and R ⁹ is independently as defined herein.

In certain embodiments of Formula IE, R ¹ is halogen, cyano, nitro, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ¹¹ , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O) 2 R ¹¹ , -C(O)N(R 11 ) ² , -NR 11 C(O)R ¹¹ , -NR ^{11 S} (O)R ¹¹ , -NR 11 S(O) ₂ R 11 , -S ⁽ O)N(R ¹¹ ) ₂ , -S(O)N(R ^{11 ) 2} , -NR ¹¹ C(O)R ¹¹ , -NR ^{11 S(O)R 11 , -NR 11} S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O)N(R ₁₁ ) 2 ^wherein _the C _{1-6 alkyl} , the C 2-6 alkenyl, ^the C 2-6 ^alkynyl , the C ^{3-10 cycloalkyl} , the heterocyclic _group , ^the _aryl or the ^heteroaryl group is independently substituted with one to ^five Z 1a as appropriate; R ² is halogen, -CD _{3 ,} C ^1-6 alkyl, _{C 2-6 alkenyl} , C _2-6 alkynyl, C _3-10 cycloalkyl, ^the heterocyclic group, the _{aryl or} the ^heteroaryl group; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocycloyl, the aryl or the heteroaryl is independently substituted by one to five Z ^1a as appropriate; or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-10 cycloalkyl or heterocycloyl; wherein the C _3-10 cycloalkyl or the heterocycloyl is independently substituted by one to five Z 1a as appropriate; R ⁴ is a C 1-6 alkyl, a C _3-10 cycloalkyl, a heterocycloyl, an aryl or a heteroaryl; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C 3-10 cycloalkyl, the heterocycloyl, the aryl or the heteroaryl is independently substituted by one to five Z ^1a as appropriate; wherein the _{C 3-10} cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 _3-10 cycloalkyl, heterocyclic group, aryl group or heteroaryl group is independently substituted by one to five Z ^1a groups as appropriate; each Z ^{1a group} is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ^{13 wherein} _each C ^1-6 alkyl, C 2-6 alkenyl _, C 2-6 _alkynyl , C 3-10 ^{cycloalkyl , heterocycloalkyl, aryl or heteroaryl is independently substituted with one to five Z 1b; each R 13 is independently} _{hydrogen , C 1-6} ^alkyl _, ^{C 2-6 alkenyl} _, ^C _{3-10 cycloalkyl ,} ^{heterocycloalkyl} _, ^{aryl or} _{heteroaryl ;} wherein each C _1-6 alkyl _, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloyl, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, _{heterocycloyl} , aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _2-6 -C _1-6 haloalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C _{2-6 alkynyl)-, -N(C 1-6 haloalkyl )} -, -N(C _3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C in the embodiment of the present invention, Z 1b and L 1 are each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 ^alkynyl _, C _{1-6 haloalkyl , C 3-10} cyclo ^... The _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are further independently optionally substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, _-NH2 , _-NO2 , _-SF5 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups.

In certain embodiments of Formula IE, R ¹ is halogen, cyano, nitro, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ^{11 , -SR 11 , -C(O)R 11} , -C(O)OR 11 , -S(O)R 11 , -S(O) 2 R ¹¹ , -C(O)N(R 11 ) ² , -NR 11 C(O)R ¹¹ , -NR ^{11 S} (O)R ¹¹ , -NR 11 S(O) ₂ R 11 , -S ⁽ O)N(R ¹¹ ) ₂ , -S(O)N(R ^{11 ) 2} , -NR ¹¹ C(O)R ¹¹ , -NR ^{11 S(O)R 11 , -NR 11} S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O)N(R ₁₁ ) 2 ^wherein _the C _{1-6 alkyl} , the C 2-6 alkenyl, ^the C 2-6 ^alkynyl , the C ^{3-10 cycloalkyl} , the heterocyclic _group , ^the _aryl or the ^heteroaryl group is independently _substituted with one to ^five Z 1a as appropriate; R ² is halogen, -CD _{3 ,} C ^1-6 alkyl, C _{2-6 alkenyl} , C _2-6 alkynyl, C _3-10 cycloalkyl, ^the heterocyclic group, the _{aryl or} the ^heteroaryl group; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocycloalkyl, the aryl or the heteroaryl is independently substituted with one to five Z ^1a as appropriate; R ⁴ is a C _1-6 alkyl, a C _3-10 cycloalkyl, a heterocycloalkyl, an aryl or a heteroaryl; wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocycloalkyl, the aryl or the heteroaryl is independently substituted with one to five Z ^1a as appropriate; R ⁹ is a C _1-6 alkyl, _{a C 1-6 alkoxy} , a C _3-10 cycloalkyl or -OC wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _{3-10 cycloalkyl} is independently substituted with one to five Z ^1a as appropriate; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6} alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R 13 , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ ^{R 13 ,} -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 The _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as the case may be; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) _2- , -N(C1-6 alkyl)-, -N( _C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N( _C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N( _C3-10 cycloalkyl)-, -N(heterocyclo)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N( _C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ² , -SF ⁵ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _{3-10 cycloalkyl} , _{heterocycloalkyl} , _aryl and heteroaryl _. The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments of Formula IE, R ¹ and R ² together with the carbon atoms to which they are attached form a C _3-10 cycloalkyl or heterocyclic group; wherein the C _3-10 cycloalkyl or the heterocyclic group is independently substituted with one to five Z ^1a ; R ⁴ is a C _1-6 alkyl, a C _3-10 cycloalkyl, a heterocyclic group, an aryl or a heteroaryl; wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is a C _1-6 alkyl, a C _1-6 alkoxy, a C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C 3-10 wherein the -OC _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a ; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 Cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one _{to five} Z 1b as appropriate; The _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as the case may be; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) _2- , -N(C1-6 alkyl)-, -N( _C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N( _C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N( _C3-10 cycloalkyl)-, -N(heterocyclo)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N( _C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ² , -SF ⁵ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _{3-10 cycloalkyl} , _{heterocycloalkyl} , _aryl and heteroaryl _. The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments of Formula IE, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C 1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogen alkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; R ² is -CD ₃ or C _1-6 alkyl; or R ¹ and R ² together with the carbon atoms to which they are attached form a C _3-6 cycloalkyl group optionally substituted with one to five Z ^1a ; R ⁴ is C _1-6 alkyl, C 1-6 alkoxy groups, C 1-6 halogen alkoxy groups, -S(O) 2 C _1-6 alkyl or heteroaryl groups. wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a as the case may be; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to _five Z ^1a as the case may be; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted by one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , _{C 1-6} alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, _heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR 13 , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ _{, -S(O) 2} ^{R 13} , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein each R ¹³ is independently hydrogen, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z 1b; each Z 1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO 2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C ^1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with _one to five Z ^1b ; in the embodiment of the present invention, the present invention is _{-L 1 -C 1-6} halogenalkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl ^{, -L 1 -C 1-6 halogenalkyl, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -aryl} _or ^-L ₁ ^{-heteroaryl ;} _and ^each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C 1-6 -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C _1-6 haloalkyl)-, -C(O)N(C _3-10 cycloalkyl)-, -C(O)N( _{heterocycloyl} )-, -C(O)N( _aryl )-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O) ₂ NH-; wherein each of Z ^1b and L ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl _.

In certain embodiments of Formula IE, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or the heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogen alkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; R ² is -CD ₃ or C _1-6 alkyl; R ⁴ is C _1-6 alkyl, C _3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the C _1-6 alkyl, the C 3-10 cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are wherein the _{C 3-10} cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 _3-10 cycloalkyl, heterocyclic group, aryl group or heteroaryl group is independently substituted by one to five Z ^1a groups as appropriate; each Z ^{1a group} is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ^{13 wherein} _each C ^1-6 alkyl, C 2-6 alkenyl _, C 2-6 _alkynyl , C 3-10 ^{cycloalkyl , heterocycloalkyl, aryl or heteroaryl is independently substituted with one to five Z 1b; each R 13 is independently} _{hydrogen , C 1-6} ^alkyl _, ^{C 2-6 alkenyl} _, ^C _{3-10 cycloalkyl ,} ^{heterocycloalkyl} _, ^{aryl or} _{heteroaryl ;} wherein each C _1-6 alkyl _, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloyl, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, _{heterocycloyl} , aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _2-6 -C _1-6 haloalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C _{2-6 alkynyl)-, -N(C 1-6 haloalkyl )} -, -N(C _3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C in the embodiment of the present invention, Z 1b and L 1 are each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 ^alkynyl _, C _{1-6 haloalkyl , C 3-10} cyclo ^... The _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are further independently optionally substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, _-NH2 , _-NO2 , _-SF5 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups.

In certain embodiments of Formula IE, R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group which is optionally substituted with one to five Z ^1a ; R ⁴ is a C _1-6 alkyl group, a C _3-10 cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; wherein the C _1-6 alkyl group, the C _3-10 cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is independently optionally substituted with one to five Z ^1a ; R ⁹ is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _3-10 cycloalkyl group or a -OC _3-10 cycloalkyl group; wherein the C _1-6 alkyl group, the C _1-6 alkoxy group, the C _3-10 cycloalkyl group or the -OC wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1a ; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b are independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _-C (O)-, -C(O)O-, -C(O _{)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl )} -, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C 1-6 halogenalkyl)-, -C(O)N(C 3-10 cycloalkyl)-, -N(heterocycloyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C _1-6 halogenalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ² , -SF ⁵ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _{3-10 cycloalkyl} , _{heterocycloalkyl} , _aryl and heteroaryl _. The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments, compounds of Formula IF are provided: IF or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each of R ¹ , R ⁴ and R ⁹ is independently as defined herein.

In certain embodiments of Formula IF, R ¹ is halogen, cyano, nitro, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ¹¹ , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O) 2 R ¹¹ , -C(O)N(R 11 ) ² , -NR 11 C(O)R ¹¹ , -NR ^{11 S} (O)R ¹¹ , -NR 11 S(O) ₂ R 11 , -S ⁽ O)N(R ¹¹ ) ₂ , -S(O)N(R ^{11 ) 2} , -NR ¹¹ C(O)R ¹¹ , -NR ^{11 S(O)R 11 , -NR 11} S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O)N(R ₁₁ ) 2 ^wherein _the C ^1-6 alkyl _group , the C 2-6 alkenyl group, the C ^2-6 alkynyl group, the C ^{3-10 cycloalkyl} group, the heterocyclic group, the aryl group or the ^heteroaryl group is independently substituted with _one to _five Z 1a; R ⁴ is C ^1-6 alkyl _group , C ^3-10 cycloalkyl group, heterocyclic _{group, aryl group} or ^heteroaryl group; wherein the C _1-6 alkyl group, the C _{2-6 alkenyl group, the C 2-6} alkynyl group, the C 3-10 cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is independently substituted with one to five Z ^1a ; R ⁴ is C _1-6 alkyl group, C _3-10 cycloalkyl ^group , heterocyclic group, aryl group or heteroaryl group; wherein the C _1-6 alkyl group, the C _2-6 alkenyl group, the C 2-6 alkynyl group, the C _3-10 cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is independently substituted with one to five Z 1a; wherein the _{C 3-10} cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 _3-10 cycloalkyl, heterocyclic group, aryl group or heteroaryl group is independently substituted by one to five Z ^1a groups as appropriate; each Z ^{1a group} is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ^{13 wherein} _each C ^1-6 alkyl, C 2-6 alkenyl _, C 2-6 _alkynyl , C 3-10 ^{cycloalkyl , heterocycloalkyl, aryl or heteroaryl is independently substituted with one to five Z 1b; each R 13 is independently} _{hydrogen , C 1-6} ^alkyl _, ^{C 2-6 alkenyl} _, ^C _{3-10 cycloalkyl ,} ^{heterocycloalkyl} _, ^{aryl or} _{heteroaryl ;} wherein each C _1-6 alkyl _, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloyl, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, _{heterocycloyl} , aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _2-6 -C _1-6 haloalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C _{2-6 alkynyl)-, -N(C 1-6 haloalkyl )} -, -N(C _3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C in the embodiment of the present invention, Z 1b and L 1 are each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 ^alkynyl _, C _{1-6 haloalkyl , C 3-10} cyclo ^... The _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are further independently optionally substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, _-NH2 , _-NO2 , _-SF5 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups.

In certain embodiments of Formula IF, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogen alkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; R ⁴ is C _1-6 alkyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently optionally substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a as appropriate; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl} , heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R 13 , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N( ^{R 13} ) ₂ , -S(O) ₂ N(R ¹³ ) _{2 wherein} ^each C 1-6 alkyl, ^{C 2-6} alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted _{with one} to five Z 1b as ^appropriate ; each R ¹³ is independently hydrogen, C ^1-6 alkyl, C ^{2-6 alkenyl, C 2-6} _{alkynyl ,} C ^3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl group; wherein each C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C 1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group; wherein each C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to _five Z 1b as appropriate; The group consisting of: -C _2-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C ^3-10 cycloalkyl, -C 1-6 halogen, -C 3-10 cycloalkyl, -C _1-6 aryl, -C _2-6 alkylene group, -C ^2-6 alkynyl, -C _1-6 halogen _, -C _3-10 cycloalkyl, -C _1-6 aryl, -C _1-6 alkylene group, -C _{2-6 alkynyl} , ^{-C 2-6} _halogen , -C ^{3-10 cycloalkyl} , ^{-C 1-6} _{aryl ,} -C ^1-6 alkylene group ^... -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _{1-6 alkyl)-, -N(C 2-6} alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C _3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C 1-6 haloalkyl, C _3-10 cycloalkyl, _{heterocycloalkyl} , _aryl and _heteroaryl and is independently substituted with ^one to five independently selected substituents selected from halogen, cyano, -OH, _-SH , -NH _{2 , -NO} ² , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclo, aryl and heteroaryl.

In certain embodiments, compounds of formula IG are provided: IG or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each of R ⁴ , R ⁹ and Z ^1a is independently as defined herein.

In certain embodiments of Formula IG, R ⁴ is C _1-6 alkyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C 2-6 alkenyl, C _2-6 cycloalkyl ... wherein _{each C 1-6 alkyl} , C _2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , _{C 1-6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, _heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR 13 , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O) ^{R 13 ,} -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein each R ¹³ is independently hydrogen, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z 1b; each Z 1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO 2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C ^1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with _one to five Z ^1b ; in the embodiment of the present invention, the present invention is _{-L 1 -C 1-6} halogenalkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl ^{, -L 1 -C 1-6 halogenalkyl, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -aryl} _or ^-L ₁ ^{-heteroaryl ;} _and ^each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C 1-6 -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C _1-6 haloalkyl)-, -C(O)N(C _3-10 cycloalkyl)-, -C(O)N( _{heterocycloyl} )-, -C(O)N( _aryl )-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O) ₂ NH-; wherein each of Z ^1b and L ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl _.

In certain embodiments of Formula IG, R ⁴ is C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a ; R ⁹ is C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl or -OC 3-10 cycloalkyl; wherein the C 1-6 alkyl, the C 1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z 1a; each R 11 is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _{2-6 alkynyl, C 1-6} alkyl, C _2-6 alkynyl, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkyl, C _2-6 alkynyl, C _{1-6 alkyl, C 2-6} alkynyl, C ^1-6 alkyl, C _2-6 alkynyl, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkyl, C _2-6 alkynyl, C 1-6 alkyl, C _1-6 alkoxy, C 3-10 cycloalkyl or -OC ^3-10 cycloalkyl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted by one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , _{C 1-6} alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, _heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR 13 , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ _{, -S(O) 2} ^{R 13} , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein each R ¹³ is independently hydrogen, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z 1b; each Z 1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO 2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C ^1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with _one to five Z ^1b ; in the embodiment of the present invention, the present invention is _{-L 1 -C 1-6} halogenalkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl ^{, -L 1 -C 1-6 halogenalkyl, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -aryl} _or ^-L ₁ ^{-heteroaryl ;} _and ^each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C 1-6 -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C _1-6 haloalkyl)-, -C(O)N(C _3-10 cycloalkyl)-, -C(O)N( _{heterocycloyl} )-, -C(O)N( _aryl )-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O) ₂ NH-; wherein each of Z ^1b and L ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl _.

In certain embodiments of Formula IG, R ⁴ is C _1-6 alkyl which is optionally substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C 1-6 alkoxy, the C 3-10 cycloalkyl or the -OC 3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl group or heteroaryl group is independently substituted by one to five Z ^1a groups as appropriate; each Z ^{1a group} is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ^{13 wherein} _each C ^1-6 alkyl, C 2-6 alkenyl _, C 2-6 _alkynyl , C 3-10 ^{cycloalkyl , heterocycloalkyl, aryl or heteroaryl is independently substituted with one to five Z 1b; each R 13 is independently} _{hydrogen , C 1-6} ^alkyl _, ^{C 2-6 alkenyl} _, ^C _{3-10 cycloalkyl ,} ^{heterocycloalkyl} _, ^{aryl or} _{heteroaryl ;} wherein each C _1-6 alkyl _, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocycloyl, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, _{heterocycloyl} , aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _2-6 -C _1-6 haloalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -N(C 1-6 alkyl)-, -N(C 2-6 alkenyl)-, -N(C _{2-6 alkynyl)-, -N(C 1-6 haloalkyl )} -, -N(C _3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkynyl)-, -N(C 1-6 haloalkyl)-, -N(C 3-10 cycloalkyl)-, -N(heterocyclic)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C in the embodiment of the present invention, Z 1b and L 1 are each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 ^alkynyl _, C _{1-6 haloalkyl , C 3-10} cyclo ^... The _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are further independently optionally substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, _-NH2 , _-NO2 , _-SF5 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups.

In certain embodiments, compounds of formula IH are provided: IH or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each of R ¹ , R ² and R ⁹ is independently as defined herein.

In certain embodiments of Formula IH, R ¹ is halogen, cyano, nitro, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O)N(R ¹¹ ) ₂ , -NR ¹¹ C(O)R ¹¹ , -NR ¹¹ S(O)R ¹¹ , -NR ¹¹ S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O ₎ N(R ¹¹ ) ₂ , -NR ¹¹ C(O)N(R ¹¹ ) ₂ , -NR ¹¹ S(O)N(R ¹¹ ) ₂ , -NR ¹¹ S(O) ₂ N(R ¹¹ ) ₂ , -OC(O)N(R ¹¹ ) ₂ or -NR ¹¹ C(O)OR ¹¹ ; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a as appropriate; R ² is halogen, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocycloalkyl, the aryl or the heteroaryl is independently substituted by one to five Z ^1a as appropriate; or R ¹ and R ² together with the carbon atom to which they are attached form _a C _3-10 cycloalkyl or heterocycloalkyl; wherein the C _3-10 cycloalkyl or the heterocycloalkyl is independently substituted by one to five Z ^1a as appropriate; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C wherein the -OC _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a ; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 Cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one _{to five} Z 1b as appropriate; The _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as the case may be; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) _2- , -N(C1-6 alkyl)-, -N( _C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N( _C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N( _C3-10 cycloalkyl)-, -N(heterocyclo)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N( _C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ² , -SF ⁵ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _{3-10 cycloalkyl} , _{heterocycloalkyl} , _aryl and heteroaryl _. The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments of Formula IH, R ¹ is halogen, cyano, nitro, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O)N(R ¹¹ ) ₂ , -NR ¹¹ C(O)R ¹¹ , -NR ¹¹ S(O)R ¹¹ , -NR ¹¹ S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O ₎ N(R ¹¹ ) ₂ , -NR ¹¹ C(O)N(R ¹¹ ) ₂ , -NR ¹¹ S(O)N(R ¹¹ ) ₂ , -NR ¹¹ S(O) ₂ N(R ¹¹ ) ₂ , -OC(O)N(R ¹¹ ) ₂ or -NR ¹¹ C(O)OR ¹¹ ; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted with one to five Z ^1a as appropriate; R ² is halogen, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocycloalkyl, the aryl or the heteroaryl is independently substituted with one to five Z ^1a as the case may be; R ⁹ is C _1-6 alkyl, C 1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein _{the C 1-6 alkyl} , the C _1-6 alkoxy, the C _3-10 cycloalkyl or -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a as the case may be; each R ¹¹ _is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted by one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , _{C 1-6} alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, _heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR 13 , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ _{, -S(O) 2} ^{R 13} , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein each R ¹³ is independently hydrogen, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z 1b; each Z 1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO 2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C ^1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with _one to five Z ^1b ; in the embodiment of the present invention, the present invention is _{-L 1 -C 1-6} halogenalkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl ^{, -L 1 -C 1-6 halogenalkyl, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -aryl} _or ^-L ₁ ^{-heteroaryl ;} _and ^each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C 1-6 -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C _1-6 haloalkyl)-, -C(O)N(C _3-10 cycloalkyl)-, -C(O)N( _{heterocycloyl} )-, -C(O)N( _aryl )-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O) ₂ NH-; wherein each of Z ^1b and L ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl _.

In certain embodiments of Formula IH, R ¹ and R ² together with the carbon atoms to which they are attached form a C _3-10 cycloalkyl or heterocyclic group; wherein the C _3-10 cycloalkyl or the heterocyclic group is independently substituted with one to five Z ^1a as appropriate; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a as appropriate; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 alkyl ... wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted by one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , _{C 1-6} alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, _heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR 13 , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ _{, -S(O) 2} ^{R 13} , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein each R ¹³ is independently hydrogen, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z 1b; each Z 1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO 2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C ^1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with _one to five Z ^1b ; in the embodiment of the present invention, the present invention is _{-L 1 -C 1-6} halogenalkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl ^{, -L 1 -C 1-6 halogenalkyl, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -aryl} _or ^-L ₁ ^{-heteroaryl ;} _and ^each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C 1-6 -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C _1-6 haloalkyl)-, -C(O)N(C _3-10 cycloalkyl)-, -C(O)N( _{heterocycloyl} )-, -C(O)N( _aryl )-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O) ₂ NH-; wherein each of Z ^1b and L ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl _.

In certain embodiments of Formula IH, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogen alkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; R ² is -CD ₃ or C _1-6 alkyl; or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group optionally substituted with one to five Z ^1a ; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _{3-10 cycloalkyl} is independently substituted with one to five Z ^1a as appropriate; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6} alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R 13 , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ ^{R 13 ,} -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 3-10 The _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as the case may be; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) _2- , -N(C1-6 alkyl)-, -N( _C2-6 alkenyl)-, -N(C2-6 alkynyl)-, -N( _C1-6 haloalkyl)-, -N(C3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N(C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N( _C3-10 cycloalkyl)-, -N(heterocyclo)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N( _C1-6 alkyl)-, -C(O)N( _C2-6 alkenyl)-, -C(O)N( _C2-6 alkynyl)-, -C(O)N(C1-6 haloalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ² , -SF ⁵ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _{3-10 cycloalkyl} , _{heterocycloalkyl} , _aryl and heteroaryl _. The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments of Formula IH, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or the heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogen alkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; R ² is -CD ₃ or C _1-6 alkyl; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy groups, C _3-10 cycloalkyl groups or -OC _3-10 cycloalkyl groups; wherein the C _1-6 alkyl, the C _1-6 alkoxy groups, the C _3-10 cycloalkyl groups or the -OC wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1a ; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b are independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C _1-6 alkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _-C (O)-, -C(O)O-, -C(O _{)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl )} -, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C 1-6 halogenalkyl)-, -C(O)N(C 3-10 cycloalkyl)-, -N(heterocycloyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C _1-6 halogenalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ² , -SF ⁵ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _{3-10 cycloalkyl} , _{heterocycloalkyl} , _aryl and heteroaryl _. The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments of Formula IH, R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group which is optionally substituted with one to five Z ^1a ; R ⁹ is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _3-10 cycloalkyl group or a -OC _3-10 cycloalkyl group; wherein the C _1-6 alkyl group, the C _1-6 alkoxy group, the C _3-10 cycloalkyl group or the -OC _3-10 cycloalkyl group is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-10 cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; wherein each C _1-6 alkyl group, a C 2-6 alkenyl group, a C _3-10 cycloalkyl group _{C 2-6} alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as the case may be; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ _{wherein each} C 1-6 alkyl ^{, C} 2-6 _alkenyl , C ^2-6 alkynyl ^{, C 3-10} cycloalkyl, heterocycloalkyl _, aryl or ^{heteroaryl is} independently substituted _{with one} to _five Z ^1b ; _each R ¹³ _is independently hydrogen, C _1-6 alkyl, C ^2-6 _alkenyl , _C ^{2-6 alkynyl ,} _C ^3-10 cycloalkyl, heterocycloalkyl, aryl _or ^heteroaryl _. wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L _{1 -C 1-6} alkyl _, -L ¹ -C ^2-6 alkenyl, -L ¹ -C _2-6 alkynyl, wherein the L ¹ is -O-, -NH-, -S-, -S ^{( O) -} , -S ^{(O) 2} _- , -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C ^2-6 alkynyl)-, -N(C _1-6 haloalkyl)-, -N(C _{3-10 cycloalkyl )} -, -N( _heterocyclo )-, -N( _aryl )-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C in which each of Z 1b and L 1 is C _1-6 alkyl, C _2-6 ^alkenyl , C _2-6 alkynyl _, C _{1-6 haloalkyl , C 3-10 cyclo} ^... The _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are further independently optionally substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, _-NH2 , _-NO2 , _-SF5 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups.

In certain embodiments, compounds of Formula II are provided: II or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein R ¹ and R ⁹ are independently as defined herein.

In certain embodiments of Formula II, R ¹ is halogen, cyano, nitro, -CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclo, aryl, heteroaryl, -N(R ¹¹ ) ₂ , -OR ¹¹ , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -S(O)R 11 , -S(O) 2 R ¹¹ , -C(O)N(R 11 ) ² , -NR 11 C(O)R ¹¹ , -NR ^{11 S} (O)R ¹¹ , -NR 11 S(O) ₂ R 11 , -S ⁽ O)N(R ¹¹ ) ₂ , -S(O)N(R ^{11 ) 2} , -NR ¹¹ C(O)R ¹¹ , -NR ^{11 S(O)R 11 , -NR 11} S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O)N(R ₁₁ ) 2 ^wherein _the C _{1-6 alkyl} , the C 2-6 alkenyl, ^the C 2-6 ^alkynyl , the C ^{3-10 cycloalkyl} , the heterocyclic _group , ^the _aryl or the ^heteroaryl group is independently substituted with one to ^five Z 1a as appropriate; R ² is halogen, -CD _{3 ,} C ^1-6 alkyl, _{C 2-6 alkenyl} , C _2-6 alkynyl, C _3-10 cycloalkyl, ^the heterocyclic group, the _{aryl or} the ^heteroaryl group; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocycloalkyl, the aryl or the heteroaryl is independently substituted with one to five Z ^1a as the case may be; R ⁹ is C _1-6 alkyl, C 1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein _{the C 1-6 alkyl} , the C _1-6 alkoxy, the C _3-10 cycloalkyl or -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a as the case may be; each R ¹¹ _is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted by one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , _{C 1-6} alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, _heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR 13 , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ _{, -S(O) 2} ^{R 13} , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein each R ¹³ is independently hydrogen, C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl ; wherein each C 1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z 1b; each Z 1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO 2 , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C ^1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with _one to five Z ^1b ; in the embodiment of the present invention, the present invention is _{-L 1 -C 1-6} halogenalkyl, -L ¹ -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl ^{, -L 1 -C 1-6 halogenalkyl, -L 1 -C 3-10 cycloalkyl, -L 1 -heterocyclic group, -L 1 -aryl} _or ^-L ₁ ^{-heteroaryl ;} _and ^each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C 1-6 -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C _1-6 haloalkyl)-, -C(O)N(C _3-10 cycloalkyl)-, -C(O)N( _{heterocycloyl} )-, -C(O)N( _aryl )-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O) ₂ NH-; wherein each of Z ^1b and L ¹ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C 1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclic group, aryl and heteroaryl _.

In certain embodiments of Formula II, R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl, C _1-6 alkoxy groups, C _1-6 halogen alkoxy groups, -S(O) ₂ C _1-6 alkyl or heteroaryl groups; R ⁹ is C _1-6 alkyl, C _1-6 alkoxy groups, C _3-10 cycloalkyl groups or -OC _3-10 cycloalkyl groups; wherein the C _1-6 alkyl, the C _1-6 alkoxy groups, the C _3-10 cycloalkyl groups or the -OC _3-10 cycloalkyl groups are independently optionally substituted with one to five Z ^each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O) ₂ N(R ¹³ ) ₂ , -NR ¹³ C(O)N(R ¹³ ) ₂ , -NR ¹³ S(O)N(R ¹³ ) ₂ , -NR ¹³ S(O) ₂ N(R ¹³ ) ₂ , -OC(O)N(R ¹³ ) ₂ or -NR ¹³ C(O)OR ¹³ wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C in the embodiment of the present invention, the present invention is _{-L 1} -C _1-6 alkyl, -L 1 _{-C 2-6} alkenyl, -L ¹ -C _2-6 alkynyl, -L ¹ -C _1-6 haloalkyl, -L ¹ -C _3-10 cycloalkyl, ^{-L 1} _{-heterocyclic} group, -L ¹ _-aryl or -L ¹ _-heteroaryl ; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ² _- , -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C _2-6 alkynyl)-, -N(C 2-6 -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C 2-6 alkynyl)-, -C(O)N(C 1-6 haloalkyl)-, -C(O)N(C _3-10 cycloalkyl)-, -N(heterocycloalkyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C 2-6 alkynyl)-, -C(O)N(C _1-6 haloalkyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenalkyl, C 3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally further independently substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, -NH ₂ , -NO ² , -SF ⁵ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _{3-10 cycloalkyl} , _{heterocycloalkyl} , _aryl and heteroaryl _. The invention also includes a C _2-6 alkenyl, a C _2-6 alkynyl, a C _1-6 halogenalkyl, a C _1-6 alkoxy, a C _1-6 halogenalkoxy, a C _3-10 cycloalkyl, a heterocyclo, an aryl and a heteroaryl.

In certain embodiments, compounds of formula IJ are provided: IJ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein each R ⁹ and Z ^1a are independently as defined herein.

In certain embodiments of Formula IJ, R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl or -OC _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, the C _3-10 cycloalkyl or the -OC _3-10 cycloalkyl is independently substituted with one to five Z ^1a ; each R ¹¹ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a is substituted; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR 13 , -SR ¹³ , -C(O)R ¹³ , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ ^{R 13 ,} -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N(R ¹³ ) ₂ , -S(O)N(R ₁₃ ) 2 ^wherein each C ^1-6 _alkyl , C 2-6 ^alkenyl , C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, ^aryl or ^heteroaryl is independently substituted _{with one} to five _Z 1b as appropriate ^; each R ¹³ is independently hydrogen, C _1-6 alkyl, C ^2-6 alkenyl, C _2-6 alkynyl, C ^3-10 _cycloalkyl , heterocyclic group, aryl or ^heteroaryl ; wherein each C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein each C The _{C 1-6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as the case may be; each Z ^1b is independently halogen, cyano, -OH, -SH, -NH ₂ , -NO ₂ , C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C 3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L 1 -C _1-6 alkyl, -L 1 _{-C 2-6} alkenyl, -L 1 -C 2-6 alkynyl, -L ¹ -C _1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, heterocyclic group, aryl, heteroaryl, -L ¹ -C 1-6 alkyl, -L 1 -C _2-6 alkenyl, -L ¹ -C _2-6 alkynyl, -L 1 -C 1-6 halogenalkyl, -L ¹ -C _3-10 cycloalkyl, -L ¹ -heterocyclic group, -L ¹ -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _1-6 alkyl)-, -N(C _2-6 alkenyl)-, -N(C 2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C _3-10 cycloalkyl)-, -N( _heterocyclic group)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C in the embodiment of the present invention, Z 1b and L 1 are each C _1-6 alkyl, C _2-6 alkenyl, C ^2-6 alkynyl, C _{1-6 haloalkyl} , C _3-10 cycloalkyl, C ^2-6 alkynyl, C _{1-6 haloalkyl} , C _2-6 alkynyl ... The _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are further independently optionally substituted with one to five independently selected substituents selected from halogen, cyano, -OH, -SH, _-NH2 , _-NO2 , _-SF5 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C3-10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups.

In certain embodiments of any of Formulas IB-IF, R ⁹ is C _1-6 alkyl, C _1-6 alkoxy, or C _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy, or the C _3-10 cycloalkyl is independently optionally substituted with one to five halogen groups, cyano groups, hydroxyl groups, -S(O) ₂ C _1-6 alkyl, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C(O)NHC _1-6 alkyl ₂ , -C(O)N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenalkyl, C _1-6 halogenalkoxy, C 1-6 wherein the _heterocyclic group is optionally further substituted by a halogen group or a C _1-6 alkoxy group.

In certain embodiments, a compound selected from Table 1 or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer or mixture of stereoisomers thereof is provided: Table 1

In certain embodiments, a compound selected from Table 2 or a pharmaceutically acceptable salt thereof is provided. Table 2 3. Methods

"Treatment" or "treating" is an approach used to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting a disease or disorder (e.g., reducing one or more symptoms produced by the disease or disorder, and/or reducing the extent of the disease or disorder); b) slowing or preventing the development of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder, and/or preventing or delaying the spread of the disease or disorder (e.g., metastasis)); and/or c) alleviating the disease, that is, causing clinical symptoms to regress (e.g., improving the disease state, causing partial or complete regression of the disease or disorder, enhancing the effect of another agent, delaying disease progression, improving quality of life and/or prolonging survival).

"Prevention" or "preventing" refers to any treatment of a disease or disorder that causes clinical symptoms of the disease or disorder not to develop. In certain embodiments, the compounds may be administered to individuals (including humans) who are at risk for the disease or disorder or have a family history of the disease or disorder.

"Subject" refers to an animal that has been or will be the subject of treatment, observation, or experimentation, such as a mammal (including a human). The methods described herein can be used in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof, means an amount sufficient to effect treatment to provide a therapeutic benefit, such as improvement in symptoms or reduction in disease progression, when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to reduce symptoms of a disease or disorder as described herein. The therapeutically effective amount may vary depending on the subject and the disease or disorder being treated, the weight and age of the subject, the severity of the disease or disorder, and the mode of administration, all of which factors can be readily determined by one skilled in the art.

The methods described herein can be applied to cell populations in vivo or in vitro. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of isolated cell populations include ex vivo cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used in vitro to determine the optimal schedule and/or dosage for administering the compounds of the disclosure for a given indication, cell type, subject, and other parameters. Information gathered from such use can be used for experimental purposes or in a clinic to set up an in vivo treatment regimen. Other in vitro uses for which the compounds and compositions described herein may be applicable are described below or will become apparent to those skilled in the art. The compounds can be further characterized to examine safety or tolerable dosage in human or non-human subjects. Such properties can be examined using methods generally known to those skilled in the art.

In some embodiments, modulation of TRPML1 comprises activation of TRPML1.

In certain embodiments, provided herein is a method of treating a disease or condition that can be treated by activating TRPML1, the method comprising administering to a subject in need thereof a compound described herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically labeled derivative, or composition described herein.

In certain embodiments, compounds that activate TRPML1 are provided, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof. In certain embodiments, compounds provided herein (e.g., compounds of Formula I or subformulae thereof) or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof activate TRPML1.

In certain embodiments, a method of activating TRPML1 activity is provided, comprising contacting a cell with an effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Activation can be performed in vitro or in vivo.

In certain embodiments, provided are compounds disclosed herein (e.g., compounds of Formula I or subformulae thereof) or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof for use in activating TRPML1 activity (e.g., in vitro or in vivo).

In certain embodiments, the disclosure provides the use of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for the manufacture of a medicament for activating TRPML1 activity (e.g., in vitro or in vivo).

In certain embodiments, the disclosure provides the use of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof), or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for the manufacture of a medicament for treating a disease or condition mediated at least in part by TRPML1.

In certain embodiments, a method for treating a disease or condition mediated at least in part by TRPML1 is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

In certain embodiments, a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof is provided for use in treating a disease or disorder mediated at least in part by TRPML1 in a subject in need thereof.

In certain embodiments, a method of treating a disease or condition treatable by modulating lysosomes is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

In certain embodiments, a method of treating a disease or disorder selected from the group consisting of: fibrosis, neurodegenerative or neurological diseases or disorders, lysosomal storage diseases or disorders, lysosomal transport diseases or disorders, glycogen storage diseases or disorders, cholesterol ester storage diseases or disorders, muscle diseases (e.g., muscular dystrophy), diseases associated with aging (e.g., photoaging of the skin), macular degeneration (e.g., Stargardt's The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

In certain embodiments, the disorder or disease is aging, bone disease, cardiovascular disease, congenital developmental disorder, eye disease, blood and solid malignancies, infectious disease, inflammatory disease, liver disease, metabolic disease, neurodegenerative or neurological disease or disorder, pancreatitis, kidney disease, skeletal muscle disorder, obesity, lysosomal storage disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, inclusion body myositis, Paget's disease, or lung disease. Neurodegenerative or neurological disease or disorder

In certain embodiments, treatment comprises reducing one or more symptoms or features of neurodegeneration.

In certain embodiments, a method for treating a neurodegenerative or neurological disease or disorder is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

Transient receptor potential channel mucolipin 1 (TRPML1) is a cation channel that transports Ca2 ⁺ , Fe2 ⁺ , and Zn2 ⁺ . The main function of TRPML1 is to induce the release of Ca2 ⁺ from the endolysosomal compartment, which is an important process for endolysosomal function. Dysfunction of TRPML1-related endolysosomal pathways has been widely observed in preclinical and clinical samples of late-onset neurodegenerative diseases. Functions regulated by TRPML1 include TFEB family-dependent lysosomal biogenesis, maturation of late endosomes to lysosomes; endolysosomal trafficking; nutrient sensing and adaptation; lysosomal localization, exocytosis, fission, clearance, and reformation; autophagy, phagocytosis, and clearance of aggregated proteins and pathogens. Loss-of-function mutations in the human TRPML1 gene MCOLN1 cause mucolipidosis type IV (MLIV), a rare latent lysosomal storage disease (LSD). MLIV is characterized by neurodegeneration, psychomotor impairment, ophthalmic and intestinal defects. Cells from MLIV patients display multiple endolysosomal abnormalities, including defective endolysosomal trafficking, vacuolization, altered localization of endolysosomal compartments, impaired lysosomal maturation, pH dysregulation, and defective autophagy.

TRP channels are involved in perturbations of Ca2 ⁺ homeostasis in intracellular calcium stores in neurons and non-neuronal cells, and their dysfunction leads to several neuronal disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). TRPs are involved in neurite outgrowth, receptor signaling, and excitotoxic cell death in the central nervous system.

In some embodiments, the neurodegenerative or neurological disease or disorder is selected from the group consisting of Parkinson's disease, GBA-Parkinson's disease, LRRK2 Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, FTDP-17, corticobasal degeneration, Lewy body dementia, Pick's disease, and multiple system atrophy. Alzheimer's disease

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by severe memory loss and behavioral changes. The underlying pathology involves the accumulation of extracellular amyloid aggregates and intracellular neurofibrillary tangles called senile plaques, leading to selective loss of synapses and neurons in the hippocampus and cerebral cortical regions. Although the amyloid and tau hypotheses are the traditional theories to explain AD, calcium homeostasis has recently received attention as a key factor in the pathogenesis of AD.

Calcium is an essential intracellular messenger that binds to a variety of proteins, receptors, and ion channels to regulate a variety of physiological functions. During neurodegeneration, neurons become ineffective in regulating calcium levels. Enhanced pathological changes induce neurotoxicity and interleukins, leading to dysregulation of calcium homeostasis and predisposing neurons to excitotoxicity and apoptosis.

In certain embodiments, a method for treating Alzheimer's disease is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Parkinson's disease

Parkinson's disease (PD) is the second major neurodegenerative disorder associated with aging after AD. Parkinson's disease is a movement disorder characterized by the breakdown of dopaminergic neurons (DN) in the substantia nigra (SN), which worsens over time. Lewy bodies are cytoplasmic inclusions formed by α-synaptophysin and are considered the main pathological hallmark of PD. Several factors in PD can lead to DN loss in the SN, such as oxidative stress, mitochondrial dysfunction, protein aggregation, and altered calcium homeostasis. Studies have reported that TRP channels can promote some of the mechanisms that drive disease progression.

In certain embodiments, a method for treating Parkinson's disease is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Huntington's disease

Huntington's disease (HD) is a somatic neurodegenerative disorder triggered by polyglutamine expansion in the huntingtin protein and manifested by cognitive impairment, loss of medium spiny neurons (MSNs) in the striatum, and convulsive movements. It has been reported that various channels alter K ⁺ homeostasis, such as striatal astrocytes expressing Kir4.1 channels in mutant HTT protein, disrupt extracellular K ⁺ homeostasis, thus causing overexcitation in neurons, i.e., HD motor symptoms in striatal neurons. However, normal Kir4.1 channels are ubiquitous astrocytic K ⁺ channels that play an important role in balancing the resting membrane potential of cells in the brain and buffering K ⁺ ions. In addition, HD mHTT protein has been shown to modify high voltage stimulated Ca2 ⁺ channels. In addition to dysfunction in Ca2 ⁺ channels, other ion channels have also shown reduced expression in several HD mouse models. Therefore, modifications in these ion channels disrupt ion homeostasis in cortical pyramidal neurons, thereby affecting synaptic integration, neurotransmitter release and genetic expression, which plays a central role in the cortical dysfunction in HD.

In certain embodiments, a method for treating Huntington's disease is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurological disorder characterized by progressive loss of motor neurons in the brainstem, motor cortex, and spinal cord, resulting in muscle weakness, atrophy, and contraction. The disease is associated with axonal hyperexcitability due to a continuous conduction of sodium ions (Na ⁺ ) and a subsequent decrease in the conduction of potassium ions (K ⁺ ). The tongue muscles, which are stimulated by motor neurons, are also susceptible to ALS degeneration, which is associated with differential expression of voltage-gated calcium channels (VGCCs).

In certain embodiments, a method for treating amyotrophic lateral sclerosis is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. Lysosomal storage disease

In certain embodiments, a method for treating a lysosomal storage disease or disorder is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

In some embodiments, the lysosomal storage disease or disorder is selected from the group consisting of Niemann-Pick disease, Gaucher's disease, neuropathic Gaucher's disease, neuroleptic lipofuscinosis, sphingolipidosis, Farber disease, Krabbe disease, galactosialidase, gangliosidosis, Gaucher's disease, lysosomal acid lipase deficiency, sulfatides, mucopolysaccharidoses, mucolipidoses, lipidoses, and oligosaccharidoses. In some embodiments, the lysosomal storage disease is selected from the group consisting of sphingolipidoses, Farber disease, Krabbe disease, galactosialidase, Fabry disease, Schindler disease, beta-galactosidase disorders, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activator deficiency, Sandhoff disease, Tay-Sachs disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie syndrome, syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, I cell disease, pseudo-Hurler polydystrophy, phosphotransferase deficiency, mucolipin 1 deficiency, Santavuori-Haltia disease, Jansky-Bielchowsky disease, Batten-Spielmeyer-Vogt disease, Kufs disease disease), Finnish variant neurocephaloid lipofuscinosis, late infantile variant neurocephaloid lipofuscinosis, neurocephaloid lipofuscinosis type 7, northern epileptic neurocephaloid lipofuscinosis, Turkish late infantile neurocephaloid lipofuscinosis, German/Serbian late infantile neurocephaloid lipofuscinosis, congenital histoplasmosis D deficiency, Wolman disease, alpha-mannosidosis, beta-mannosidosis, asparaginyl glucosaminuria, and fucosidosis. In some embodiments, the lysosomal storage disease is selected from the group consisting of Niemann-Pick disease, Gaucher's disease, neuropathic Gaucher's disease, and neurofibromatous lipofuscinosis.

In certain embodiments, a method for treating a lysosomal transport disease or disorder is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. In some embodiments, the lysosomal transport disease or disorder is selected from the group consisting of cystinosis, pycnodystrophy, Salla disease, sialic acid storage disease, and infantile free sialic acid storage disease.

In certain embodiments, a method for treating a glycogen storage disease or disorder is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein (e.g., a compound of Formula I or a subformula thereof) or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. In some embodiments, the glycogen storage disease or disorder is selected from the group consisting of Pompe disease and Danon disease .

In certain embodiments, a method for treating fibroids is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound capable of modulating TRPML, or a therapeutically effective amount of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable formulation.

In some embodiments, the fibroid disease is selected from the group consisting of polycystic kidney disease, pancreatic cysts in polycystic kidney disease, Bardet-Biedl syndrome, nephrotic syndrome, Joubert syndrome, Meckel-Gruber syndrome, oral-facial-digital syndrome, Senior Loken syndrome, Birt-Hogg-Dube syndrome, Leber's congenital amaurosis, Alstrom syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, syndrome, Sensenbrenner syndrome, and primary ciliary dyskinesia. In some embodiments, the ciliary disease is autosomal dominant polycystic nephropathy, autosomal recessive polycystic nephropathy, or pancreatic cysts associated with autosomal dominant polycystic nephropathy. In some embodiments, the ciliary disease is polycystic nephropathy. In some embodiments, the ciliary disease is autosomal dominant polycystic nephropathy.

Other embodiments include the use of the compounds disclosed herein in therapy. Combination therapy

In some embodiments of the methods and uses described herein, the methods or uses further comprise the use of one or more additional therapeutic agents.

In some embodiments, the additional therapeutic agent is selected from the group consisting of: mTOR inhibitors, V2 receptor antagonists, tyrosine kinase inhibitors, somatostatin analogs, glucosamine synthase inhibitors, microRNA-17 inhibitors, siRNA against p53, KEAP1-Nrf2 activators, xanthine oxidase inhibitors, PPARγ agonists, metformin, and β-hydroxybutyrate.

In some embodiments, the additional therapeutic agent is selected from the group consisting of tolvaptan, lixivaptan, mozavaptan, satavaptan, sirolimus, tacrolimus, everolimus, bosutinib, tesavatinib, imatinib, gefitinib, erlotinib, dasatinib, octreotide, pasireotide, venglustat, eliglustat, miglustat, microRNA-17 inhibitors, bardoxolone methyl, methyl), allopurinol, oxypurinol, pioglitazone, rosiglitazone, lobeglitazone, metformin, and beta-hydroxybutyrate.

In some embodiments, the additional therapeutic agent is selected from the group consisting of: immunomodulators, calcineurin phosphatase inhibitors, renin-angiotensin-aldosterone system inhibitors, antiproliferative agents, alkylating agents, corticosteroids, angiotensin converting enzyme inhibitors, adrenocortical hormone stimulators, angiotensin receptor blockers, sodium-glucose transporter 2 inhibitors, dual sodium-glucose transporter 1/2 inhibitors, nuclear factor-1 (Erythroid-derived 2)-like 2 agonists, interleukin receptor 2 inhibitors, interleukin receptor 5 inhibitors, endothelin 1 receptor antagonists, beta blockers, corticosteroid receptor antagonists, cyclo or thiazide diuretics, calcium channel blockers, statins, short-, intermediate-, or long-acting insulins, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, sulfonylureas, apoptosis signaling regulating kinase-1, chymosin inhibitors, selective glycine cation inhibitors, renin inhibitors, interleukin-33 inhibitors, farnesoid X receptor agonists, soluble Sex guanylate cyclase stimulators, thromboxane receptor antagonists, xanthine oxidase inhibitors, erythropoietin receptor agonists, cannabinoid receptor type 1 inverse agonists, NADPH oxidase inhibitors, anti-vascular endothelial growth factor B, anti-fibrotic agents, enkephalinase inhibitors, dual CD80/CD86 inhibitors, CD40 antagonists, cellular cholesterol and lipid blockers, PDGFR antagonists, Slit-directed ligand 2, APOL1 inhibitors, Nrl2 activators/NF-kB inhibitors, somatostatin receptor agonists, PPAR gamma agonists, AMP-activated protein kinase stimulators, tyrosine kinase inhibitors, glucocereamine synthase inhibitors, arginine vasopressin receptor 2 antagonists, xanthine oxidase inhibitors, vasopressin receptor 2 antagonists, anti-amyloid beta antibodies, anti-Tau antibodies, anti-synaptophysin antibodies, dopamine prodrivers (e.g., L-DOPA), dopamine agonists (e.g., bromocriptine, cabergoline, pergolide, pramipexole, and apomorphine), MAO-B inhibitors (e.g., rasagiline and selegili ne), anticholesterol agents (e.g., orphenadrine, procyclidine, and trihexyphenidyl), β-glucocerebrosidase activity enhancers (e.g., ambroxol and afegostat), amantadine, and agents capable of treating Alzheimer's disease (e.g., acetylcholinesterase inhibitors such as tacrine, rivastigmine, galantamine, donepezil, and NMDA receptor antagonists such as memantine).

In some embodiments, the additional therapeutic agent is selected from the group consisting of COX inhibitors including aryl carboxylic acids (e.g., salicylic acid, acetylsalicylic acid, diflunisal, magnesium choline trisalicylate, salicylates, benoylates, flufenamic acid, mefenamic acid, meclofenamic acid, or triflumic acid). acid), arylalkanoic acids (e.g., diclofenac, fenclofenac, alclofenac, fentiazac, ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen, suprofen, indoprofen, tiaprofenic acid, acid, benoxaprofen, pirprofen, tolmetin, zomepirac, clopinac, indomethacin, or sulindac), enolic acids (e.g., phenylbutazone, oxyphenbutazone, azapropazone, feprazone, piroxicam, or isoxicam); treatments for pulmonary hypertension, including prostanoids (e.g., epoprostenol, illoprost, or treprostinil); endothelin receptor antagonists (e.g., bosentan, ambrisentan, or macitinib); macitentan); phosphodiesterase-5 inhibitors (e.g., sildenafil or tadalafil); sGC stimulators (e.g., riociguat); rho-kinase inhibitors (e.g., Y-27632, fasudil, or H-1152P); epoprostenol derivatives (e.g., prostacyclin, treprostinil, beraprost); ost or iloprost); serotonin blockers (such as sarpogrelate); endothelin receptor antagonists (besentan, sitaxsentan, ambrisentan, or TBC3711); PDE inhibitors (such as sildenafil, tadalafil, udenafil, or vardenafil); fil); soluble guanylate cyclase inhibitors (such as riociguat or vericiguat); calcium channel blockers (such as amlodipine, bepridil, cletiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, aranidipine, bamidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine) , isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, or perhexiline); tyrosine kinase inhibitors (e.g., imatinib); inhaled nitric oxide and nitric oxide donors (e.g., inhaled nitrites); IκB inhibitors (e.g., IMD 1041); prostacyclin receptor agonists (e.g., selexipag); hematopoietic stimulants (e.g., TXA 127 (angiotensin (1-7)), darbepoetin alfa, erythropoietin, or epoetin alfa); anticoagulants and platelet inhibitors, diuretics, dietary and nutritional supplements (e.g., acetyl-L-carnitine, octacosanol, evening primrose oil, vitamin B6, tyrosine, phenylalanine, or vitamin C, L-dopa); immunosuppressants (for transplantation and autoimmune-related RKD); antihypertensives (for hypertension-related RKD, such as angiotensin converting enzyme inhibitors and vasopressin receptor blockers); insulin (for diabetic RKD); lipid/cholesterol lowering agents (e.g. HMG-CoA reductase inhibitors, such as atorvastatin or simvastatin); and treatments for hyperphosphatemia or hyperparathyroidism associated with CKD (e.g. sevelamer acetate, cinacalcet). 4. Kit

Also provided herein are kits comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof, and suitable packaging. In certain embodiments, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof, and labels and/or instructions for using the compounds to treat indications, including the diseases or disorders described herein.

Also provided herein are articles of manufacture comprising a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof in a suitable container. The container may be a vial, can, ampoule, pre-filled syringe, or intravenous bag. 5. Pharmaceutical Compositions and Modes of Administration

The compounds provided herein are generally administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions are also provided herein, containing one or more compounds described herein or their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers or prodrugs and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd edition (G.S. Banker and C.T. Rhodes, eds.).

The pharmaceutical composition can be administered in a single dose or in multiple doses. The pharmaceutical composition can be administered by various methods including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition can be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation.

One mode of administration is parenteral, for example by injection. Forms that can be incorporated into the pharmaceutical compositions described herein for administration by injection include aqueous or oily suspensions or emulsions containing, for example, sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

Oral administration can be another route of administration of the compounds described herein. Administration can be performed, for example, via capsules or enteric coated tablets. In preparing pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the active ingredient is typically diluted with an excipient and/or encapsulated in a carrier such that it may be in the form of a capsule, sachet, paper, or other container. When an excipient is used as a diluent, the excipient may be in the form of a solid, semisolid, or liquid material that serves as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may additionally include lubricants such as talc, magnesium stearate, and mineral oils; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoate; sweeteners; and flavor correctors.

Compositions comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug may be formulated by employing procedures known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation used in the methods disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusions of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches may be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

For the preparation of solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. When such preformulation compositions are referred to as homogeneous, the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form that provides an advantage of prolonged action, or protection from the acidic conditions of the stomach. For example, a tablet or pill may include an inner dose component and an outer dose component, the latter being in the form of a coating on the former. The two components may be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to delay release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as wormwood, cetyl alcohol, and cellulose acetate.

Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the composition is administered by the oral or nasal respiratory route to obtain local or systemic effect. In other embodiments, the composition in a pharmaceutically acceptable solvent may be aerosolized by the use of an inert gas. The aerosolized solution may be inhaled directly from the aerosolizing device, or the aerosolizing device may be attached to a mask curtain or intermittent positive pressure ventilator. Solution, suspension or powder compositions may be administered from a device that delivers the formulation in an appropriate manner, in one embodiment, orally or nasally.

The amount of the compound in the pharmaceutical composition or formulation can vary within a range used by those skilled in the art. Typically, the formulation will contain about 0.01-99.99 wt % of the compound of the present disclosure, based on the total formulation, in terms of weight percent (wt %), with the remainder being one or more suitable pharmaceutical formulations. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below. Formulation Example 1 - Tablet Formulation

Mix the following ingredients thoroughly and compress into single scored tablets. Element Amount per tablet, mg Compounds of the Disclosure 400 Corn starch 50 Cross-linked sodium carboxymethyl cellulose 25 lactose 120 Magnesium stearate 5 Formulation Example 2 - Capsule Formulation

Mix the following ingredients thoroughly and load into hard shell gelatin capsules Element Amount per capsule, mg Compounds of the Disclosure 200 Lactose, spray dry 148 Magnesium stearate 2 Formulation Example 3 - Suspended Formulation

The following ingredients are mixed to form a suspension for oral administration. Element quantity Compounds of the Disclosure 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl 4-hydroxybenzoate 0.15 g Propyl 4-hydroxybenzoate 0.05 g granulated sugar 25.0 g Sorbitol (70% solution) 13.00 g Veegum K (Vanderbilt Co.) 1.0 g Taste enhancers 0.035 mL Coloring agent 0.5 mg Distilled water Sufficient volume up to 100 mL Formulation Example 4 - Injectable Formulation

The following ingredients are mixed to form an injectable formulation. Element quantity Compounds of the Disclosure 0.2 mg-20 mg Sodium acetate buffer solution, 0.4 M 2.0 mL HCl (1N) or NaOH (1N) Sufficient amount to the appropriate pH Water (distilled, sterile) Sufficient volume up to 20 mL Formulation Example 5 - Suppository Formulation

Suppositories with a total weight of 2.5 g were prepared by mixing the compounds of the present disclosure with Witepsol® H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) and had the following composition: Element quantity Compounds of the Disclosure 500 mg Witepsol® H-15 Remaining amount 6. Give medicine

The specific dosage level of the compounds of the present application for any particular individual will depend on a variety of factors, including the activity of the specific compound employed, the age, weight, general health, sex, diet, administration time, administration route and excretion rate, drug combination, and severity of the particular disease of the individual undergoing treatment. For example, the dosage can be expressed as milligrams of the compound described herein per kilogram of individual body weight (mg/kg). Doses between about 0.1 mg/kg and 150 mg/kg may be appropriate. In certain embodiments, about 0.1 mg/kg and 100 mg/kg may be appropriate. In other embodiments, doses between 0.5 mg/kg and 60 mg/kg may be appropriate. In certain embodiments, dosages of about 0.0001 to about 100 mg/kg body weight/day, about 0.001 to about 50 mg/kg body weight, or about 0.01 to about 10 mg/kg body weight may be appropriate. Normalization to the weight of the subject is particularly useful when adjusting dosages between subjects of widely different sizes, such as occurs when using a drug in children and adults or when converting an effective dose in a non-human subject (such as a dog) to a dose suitable for a human subject. 7. Synthesis of Compounds

Compounds can be prepared using the methods disclosed herein and conventional modifications thereof, which will be apparent in light of the disclosure herein and methods well known in the art. In addition to the teachings herein, customary and well known synthetic methods may also be used. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially from, for example, Sigma Aldrich or other chemical suppliers.

It should be understood that where typical process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by one skilled in the art through routine optimization procedures.

In addition, the use of protecting groups ("PG") may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, PGM, Greene, TW and Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and references cited therein. For example, protecting groups for alcohols such as hydroxyl groups include silyl ethers (including trimethylsilyl (TMS), tributyldimethylsilyl (TBDMS), triisopropylsiloxymethyl (TOM), and triisopropylsilyl (TIPS) ether), which can be removed by acid or fluoride ions, such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt _3. Other protecting groups for alcohols include acetyl, which is removed by acid or base; benzyl, which is removed by acid or base; benzyl, which is removed by hydrogenation; methoxyethoxymethyl ether, which is removed by acid; dimethoxytrityl, which is removed by acid; methoxymethyl ether, which is removed by acid; tetrahydropyranyl or tetrahydrofuranyl, which is removed by acid; and trityl, which is removed by acid. Examples of protecting groups for amines include benzyloxycarbonyl, removed by hydrogenolysis; p-methoxybenzylcarbonyl, removed by hydrogenolysis; tert-butyloxycarbonyl, removed by strong concentrated acid (such as HCl or _CF3COOH ) or by heating to above about 80°C; 9-fluorenylmethoxycarbonyl, removed by base (such as piperidine); acetyl, removed by treatment with base; benzoyl, removed by treatment with base; benzyl, removed by hydrogenolysis; carbamate, removed by acid and mild heating; p-methoxybenzyl, removed by hydrogenolysis; 3,4-dimethoxybenzyl, removed by hydrogenolysis; p-methoxyphenyl, removed by ammonium( _IV )nitrate; tosyl, removed by concentrated acid (such as HBr or _H2SO4 ) and strong reducing agents (liquid ammonia containing sodium or sodium naphthide); troc (trichloroethyl chloroformate), removed by inserting Zn in the presence of acetic acid; and sulfonamides (Nosyl and Nps), removed by sadium iodide or tributyltin hydroxide.

In addition, the compounds of the present disclosure may contain one or more chiral centers. Thus, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual mirror image isomers or non-mirror image isomers or as stereoisomer-enriched mixtures. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.

The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials can be obtained from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Other starting materials may be prepared by procedures described in standard reference texts such as Fieser and Fieser, Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), or obvious modifications thereof: Rodd, Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March, Advanced Organic Chemistry, (John Wiley, and Sons, 5th edition, 2001), and Larock, Comprehensive Organic Transformations (VCH Publishers Inc., 1989). General Synthesis

Scheme I illustrates a general method that can be used to synthesize compounds described herein (e.g., Formula I and Formula I'), wherein ^X1 , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , R8, ^R9 , L, t, ^p , m, n, ml, m2, n1, and n2 are each independently as defined herein, and LG is a leaving group (e.g., a halogen group, etc.). Scheme I

In Scheme I, compounds of Formula I or Formula I' can be prepared by contacting compound I-1 or I'-1 with amine I-2 under suitable coupling reaction conditions, followed by functionalization or deprotection as appropriate. After the reaction is complete, the compound of Formula I or Formula I' can be recovered and purified by known techniques such as neutralization, extraction, precipitation, chromatography, filtration, and the like. In addition, further derivatization of the product formed by the process outlined in Scheme I can provide additional compounds of Formula I or Formula I'.

It should be understood that the starting compounds shown in Scheme I can be prepared using conventional methods or purchased from commercial sources. For example, the compounds of Formula I-1 and Formula I'-1 used in Scheme I to provide compounds of Formula I or Formula I' wherein t is 0 (i.e., Formula I-8 or Formula II-8 below) can be provided in Scheme II. In Scheme II, L, X ¹ , R ¹ , R ² , R ³ , R ⁴ and R ⁶ are each independently as defined herein, and each LG is independently a leaving group (e.g., a halogen group, etc.). Scheme II

In Scheme II, compound II-4 is prepared by deprotonating compound II-1 using a strong base (e.g., NaH) and adding compound II-2 and compound II-3 (wherein R ² and R ³ are the same), or adding compound II-2 followed by compound II-3 (wherein R ² and R ³ are different). For compounds in which R ¹ and R ² form a ring together, only a single reagent is added, which is difunctionalized to include two leaving groups so that the two leaving groups allow the formation of a spirocycle. Reduction of compound II-4 provides compound II-5. Compound II-5 is reacted with compound I-6 or II-6 under suitable coupling conditions (e.g., nucleophilic aromatic substitution reaction conditions) to provide compound I-7 or II-7. As shown in Scheme I, compound I-7 or II-7 is contacted with compound I-2 to provide a compound of formula I-8 or formula II-8. After the reaction is completed, the compound of formula I-8 or formula II-8 can be recovered and purified by known techniques such as neutralization, extraction, precipitation, chromatography, filtration and similar techniques. In addition, further derivatization of the product formed by the process outlined in Scheme II can provide additional compounds of formula I.

Further derivatization of the compounds or any intermediates provided by the steps outlined in Scheme I or Scheme II provides additional compounds of Formula I, Formula I-8 or Formula II-8. It should be understood that any compound or intermediate shown in Scheme I or Scheme II can be prepared using conventional methods or purchased from commercial sources. In addition, any intermediate or any product obtained by the process outlined in Scheme I or Scheme II can be derivatized in any step to provide various compounds of Formula I, Formula I-8 or Formula II-8. In certain embodiments, various substituents of the compounds or intermediates used in Scheme I or Scheme II are as defined herein (e.g., for Formula I).

Scheme III shows an exemplary method for further derivatization of, for example, R ^3. In Scheme III, each of R ⁸ , R ⁹ , p, m, n, ml, m2, nl and n2 is independently as defined herein, and LG is a leaving group (eg, halogen, alkoxy, etc.).

In Scheme III, the BOC protected R ³ moiety is deprotected to liberate the free amine, which can then be functionalized with compound III-1 to provide the desired product.

In certain embodiments, a process for providing a compound of formula I is provided, the process comprising: 1) making a compound of formula I-1: I-1 and I-2 compounds: I-2

contacting under conditions sufficient to provide a compound of Formula I, wherein L, ^X1 , ^R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 and t are each independently as defined herein. In certain embodiments, the conditions include a base, such as an organic base, such as DIEA.

In certain embodiments, a process for providing a compound of formula I' is provided, the process comprising: 1) making a compound of formula I'-1: I'-1 and I-2 compounds: I-2

contacting under conditions sufficient to provide a compound of Formula I, wherein X ¹ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and t are each independently as defined herein. In certain embodiments, the conditions include a base, such as an organic base, such as DIEA .

The following examples are included to demonstrate specific embodiments of the present disclosure. Those skilled in the art will appreciate that the techniques disclosed in the following examples represent techniques that have worked well in the practice of the present disclosure and, as such, may be considered to constitute specific modes of practice of the present disclosure. However, those skilled in the art will appreciate in light of the present disclosure that many changes may be made to the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure. General Experimental Methods

Unless otherwise noted, reagents and solvents were obtained from commercial suppliers and used without purification or drying. ^1H NMR was recorded using a Bruker NMR tuned to 400 MHz with TMS used as internal standard. LC-MS analysis was performed on a Waters UPLC with a SQD-2 mass detector (single quadrupole). HPLC analysis was performed on a WATERS Acquity UPLC H CLASS or Acquity Arc system (with PDA and ELSD detectors). p-HPLC purification was performed using the following columns: Waters Xbridge Prep OBD 150 × 40 mm × 10 µm, Waters Xbridge BEH 100 × 30 mm × 10 µm, or Phenomenex Luna C18 100 × 40 mm × 3 µm.

General Method 1 : To a solution of AlCl ₃ in THF was added LiAlH ₄ (2.5 M in THF). The mixture was stirred at 20 °C for 10 min, then cooled to -40 °C. The substrate dissolved in THF was added to the reaction and stirred at -40 °C under N ₂ atmosphere for 2 h. The mixture was quenched by Na ₂ SO ₄ .10H ₂ O, filtered, and washed with THF. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography as specified.

General Method 2: To a solution of the amine in DMSO are added _K2CO3 and 2 _- fluoropyridine-4-carbonitrile. The mixture is stirred at 80 °C for 16 h. The mixture is poured into water and extracted with EtOAc (3x). The combined organic phases are washed with brine, dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. The residue is triturated with MTBE and filtered to give the desired product.

General Method 3: A mixture of aryl chloride starting material, starting amine and base in NMP was degassed and purged with _N2 three times. The mixture was stirred at 140 °C under _N2 atmosphere for 16 h (or until the reaction was complete). The reaction was cooled to room temperature and then poured into _H2O , followed by extraction with EtOAc (3x). The combined organic phases were washed with brine, dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. The crude mixture was purified as specified.

General Method 4: The Boc protected starting material was dissolved in HCl/EtOAc (4N) and stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to give the desired compound and used in the next step without additional purification.

General Method 5: The starting material amine was dissolved in an aprotic solvent followed by the addition of the base. The reaction was cooled to 0 °C under _N2 and the acid chloride or chloroformate was added dropwise. The mixture was stirred at 20 ° _C for 2 h. The reaction mixture was poured into _H2O and extracted with DCM (3x). The combined organic layers were washed with brine, dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The reaction crude was purified as specified.

General Method 6: The amine-containing solvent is added to a solution of the acid starting material, coupling reagent and base. The mixture is stirred at 20-60 °C for 1-12 h. The mixture is poured into _H2O and extracted with EtOAc (3x). The combined organic phases are washed with brine, dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. The crude material is purified as indicated. Example 1 ( 2R , 5S )-4-[7-(4- cyano-2-pyridinyl)spiro[ 6H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclopropane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester

4'- Chlorospiro [ cyclopropane -1,5' -pyrrolo [2,3-d] pyrimidin ]-6'( 7'H ) -one : To a mixture of NaH (3.54 g, 88.46 mmol, 60% purity) in DMF (100 mL) at 0 °C under _N2 was added 4-chloro-5,7-dihydro- 6H -pyrrolo[2,3-d]pyrimidin-6-one (3.0 g, 17.7 mmol). The mixture was stirred at 20 °C for 2 h and then cooled to 0 °C. 1,2-Dibromoethane (10.0 g, 53.1 mmol) was added. The reaction mixture was stirred at 20 °C for 12 h. The mixture was poured into aqueous _NH4Cl solution (300 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) to give 4'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7' H )-one (1.8 g, 52% yield).

4'- Chloro -6',7'- dihydrospiro [ cyclopropane -1,5'- pyrrolo [2,3-d] pyrimidine ] : General method 1- AlCl ₃ (1.84 g, 13.8 mmol), THF (20 mL), LiAlH ₄ (2.5 M in THF, 5.5 mL), 4'-chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7' H )-one (900 mg, 4.6 mmol) in THF (20 mL). The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give 4'-chloro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine] (200 mg, 24% yield).

2-(4'- Chlorospiro [ cyclopropane -1,5' -pyrrolo [2,3-d] pyrimidine ]-7'( 6'H ) -yl ) isonicotinecarbonitrile : General Method 2- 4'-Chloro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine] (400 mg, 2.20 mmol), DMSO (2 mL), _K2CO3 (913 mg _, 6.61 mmol) and 2-fluoropyridine-4-carbonitrile (403 mg, 3.30 mmol). Product: 2-(4'-Chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (200 mg, 32% yield).

( 2R , 5S )-tert-butyl 4-[7-(4- cyano -2 -pyridinyl ) spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclopropane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylate (1) : General method 3- 2-(4'-Chlorospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (200 mg, 0.70 mmol), ( 2R , 5S )-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (453 mg, 2.11 mmol), DIEA (456 mg, 3.52 mmol) and NMP (4 mL). The crude reaction material was purified by p-HPLC under the following conditions: mobile phase: [ _H2O (10 mM _{NH4HCO3 )} -ACN]; gradient: 65%-95% B over 8.0 min to give ( 2R , 5S )-4-[7-(4-cyano-2-pyridinyl)spiro[ 6H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclopropane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (117 mg, 36% yield). Example 2 2-[4-[(2 S ,5 R )-4-(2,2 -dimethylpropanoyl )-2,5 -dimethylpiperazin - 1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclopropane ]-7- yl ] pyridine -4- carbonitrile

2-(4'-(( 2S , 5R )-2,5 -dimethylpiperazin- 1- yl ) spiro [ cyclopropane -1,5' -pyrrolo [2,3-d] pyrimidin ]-7'( 6'H ) -yl ) isonicotinecarbonitrile hydrochloride: General Method Tributyl 4- ( 2R , 5S )-4-(7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (30 mg, 0.07 mmol) and HCl/EtOAc (4N, 2 mL). Product: 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (23 mg, 89% yield).

2-[4-[( 2S , 5R )-4-(2,2 -dimethylpropanoyl )-2,5 -dimethylpiperazin- 1 -yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1' -cyclopropane ]-7- yl ] pyridine -4- carbonitrile (2) : General Method 3- 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (22 mg, 0.06 mmol), DCM (1 mL), TEA (17 mg, 0.17 mmol) and 2,2-dimethylpropanoyl chloride (8.00 mg, 0.07 mmol). The residue was purified by p-HPLC under the following conditions: mobile phase: [ _H2O (10 mM _NH4HCO3 ) _-ACN ]; gradient: 45%-75% B over 8.0 min to give 2-[4-[( 2S , 5R )-4-(2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclopropane]-7-yl]pyridine-4-carbonitrile (3.46 mg, 14% yield). Example 3 (2 R , 5 S )-4-[7-(4- cyano -2 -pyridinyl ) spiro [6 H -pyrrolo [2,3-d] pyrimidine - 5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

4'- Chlorospiro [ cyclobutane -1,5' -pyrrolo [2,3-d] pyrimidin ]-6'( 7'H ) -one: To a mixture of 4-chloro-5,7-dihydro- 6H -pyrrolo[2,3-d]pyrimidin-6-one (2 g, 11.8 mmol) in THF (30 mL) at -78 °C under _N2 was added LiHMDS (1 M in n-hexane, 27.1 mL). The mixture was stirred at -78 °C for 0.5 h, followed by the addition of 1,3-diiodopropane (4.54 g, 15.3 mmol). The mixture was stirred at 20 °C for 16 h. The mixture was poured into _NH4Cl (60 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give 4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7' H )-one (0.9 g, 36%).

4'- Chloro -6',7'- dihydrospiro [ cyclopropane -1,5'- pyrrolo [2,3-d] pyrimidine ] : General method 1- AlCl ₃ (1.53 g, 11.5 mmol), THF (20 mL), LiAlH ₄ (2.5 M in THF, 4.6 mL), 4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'(7' H )-one (800 mg, 3.8 mmol). The residue was purified by silica gel column chromatography (SiO ₂ , PE:EtOAc = 1:1 to 0:1) to give 4'-chloro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine] (200 mg, 27% yield).

2-(4'- Chlorospiro [ cyclobutane -1,5' -pyrrolo [2,3-d] pyrimidine ]-7'( 6'H ) -yl ) isonicotinecarbonitrile : General method 2-4' -Chloro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine] (170 mg, 0.87 mmol), DMSO (2 mL), _K2CO3 (360 mg, _2.6 mmol) and 2-fluoropyridine-4-carbonitrile (159 mg, 1.3 mmol). Product: 2-(4'-Chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (140 mg, 54%).

( 2R , 5S )-tert-butyl 4-[7-(4- cyano -2 -pyridinyl ) spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylate (3) : General method 3- 2-(4'-Chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (70 mg, 0.26 mmol), ( 2R , 5S )-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (151 mg, 0.71 mmol), DIEA (152 mg, 1.18 mmol) and NMP (4 mL). The crude product was purified by preparative HPLC under the following conditions: mobile phase: [H ₂ O (10 mM FA)-ACN]; gradient: 60%-90% B over 8.0 min to give (2 R ,5 S )-4-[7-(4-cyano-2-pyridinyl)spiro[6 H -pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (22.1 mg, 20% yield). Example 4 (2 R ,5 S )-4-[7-(4- cyano -2 -pyridinyl )-5,5- dimethyl -6 H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

4- Chloro -5,5 -dimethyl -6,7- dihydro - 5H - pyrrolo [2,3-d] pyrimidine: General method 1- AlCl ₃ (2.02 g, 15.2 mmol), THF (10 mL), LiAlH ₄ (2.5 M in THF, 6.07 mL), 4-chloro-5,5-dimethyl-5,7-dihydro- 6H -pyrrolo[2,3-d]pyrimidin-6-one (1 g, 5.1 mmol) in THF (10 mL). The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give 4-chloro-5,5-dimethyl-6,7-dihydro- 5H -pyrrolo[2,3-d]pyrimidine (100 mg, 11%).

2-(4- Chloro -5,5 -dimethyl -5H -pyrrolo [2,3-d] pyrimidin -7( 6H ) -yl ) isonicotinecarbonitrile : General method 2- 4-Chloro-5,5-dimethyl-6,7-dihydro- 5H -pyrrolo[2,3-d]pyrimidine (100 mg, 0.54 mmol), DMSO (2 mL), _K2CO3 (226 mg, 1.63 mmol) and 2-fluoropyridine _- 4-carbonitrile (100 mg, 0.82 mmol). Product: 2-(4-Chloro-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-7( 6H )-yl)isonicotinecarbonitrile (100 mg, 64%).

( 2R , 5S )-4-[7-(4- cyano -2 -pyridinyl )-5,5 -dimethyl - 6H - pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester (4) : General method 3-2- (4-Chloro-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-7( 6H )-yl)isocyanate (100 mg, 0.35 mmol), ( 2R , 5S )-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (113 mg, 0.53 mmol), DIEA (226 mg, 1.75 mmol) and NMP (2 mL). The crude mixture was purified by preparative HPLC (neutral) under the following conditions: mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 55%-85% B over 8.0 min to give (2 R ,5 S )-4-[7-(4-cyano-2-pyridinyl)-5,5-dimethyl-6 H -pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (117 mg, 36%). Example 5 (2 R ,5 S )-4-[7-(4- cyano -2 -pyridinyl ) spiro [6 H -pyrrolo [2,3-d] pyrimidin -5,1'- cyclopentane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

4'- Chlorospiro [ cyclopentane -1,5' -pyrrolo [2,3-d] pyrimidin ]-6'( 7'H ) -one: To a solution of 4-chloro-5,7-dihydro- 6H -pyrrolo[2,3-d]pyrimidin-6-one (2.0 g, 11.8 mmol) in THF (30 mL) was added LiHMDS (1 M in hexanes, 29.5 mL) at _-78 °C under N2. The mixture was stirred at -78 °C for 0.5 h, followed by the addition of 1,4-diiodobutane (4.4 g, 14.2 mmol). The mixture was stirred at 20 °C for 16 h. The mixture was poured into _NH4Cl (60 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give 4'-chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7' H )-one (1.1 g, 42% yield).

4'- Chloro -6',7'- dihydrospiro [ cyclopentane -1,5'- pyrrolo [2,3-d] pyrimidine ] : General Procedure 1 - _AlCl3 (1.97 g, 14.8 mmol) in THF (20 mL), _LiAlH4 (2.5 M in THF, 5.9 mL), 4'-chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine]-6'( 7'H )-one (1.1 g, 4.9 mmol) in THF (20 mL). The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 1:2) to give 4'-chloro-6',7'-dihydrospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine] (180 mg, 17% yield).

2-(4'- Chlorospiro [ cyclopentane -1,5' -pyrrolo [2,3-d] pyrimidine ]-7'( 6'H ) -yl ) isonicotinecarbonitrile : General method 2-4' -Chloro-6',7'-dihydrospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine] (176 mg, 0.84 mmol), DMSO (2 mL), _K2CO3 (348 mg, 2.52 _mmol ) and 2-fluoropyridine-4-carbonitrile (154 mg, 1.26 mmol). Product: 2-(4'-Chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (100 mg, 38%).

( 2R , 5S )-tert-butyl 4-[7-(4- cyano -2 -pyridinyl ) spiro [ 6H - pyrrolo [2,3-d] pyrimidin -5,1'- cyclopentane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylate (5) : General method tert-butyl 3- ( 2R , 5S )-2,5-dimethylpiperazine-1-carboxylate (206 mg, 0.96 mmol), 2-(4'-chlorospiro[cyclopentane-1,5'-pyrrolo[2,3-d]pyrimidin]-7'( 6'H )-yl)isonicotinecarbonitrile (100 mg, 0.33 mmol), DIEA (207 mg, 1.60 mmol) and NMP (4 mL). The crude mixture was concentrated under reduced pressure and purified by preparative HPLC (neutral) under the following conditions: mobile phase: _{[ H2O} (10 mM _NH4HCO3 )-ACN]; gradient: 45%-75% B over 8.0 min to give ( 2R , 5S )-4-[7-(4-cyano-2-pyridinyl)spiro[ 6H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclopentane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (17.26 mg, 11%). Example 6 ( 2R )-4-[7-(4- cyano -2 -pyridinyl ) spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2- methylpiperazine -1- carboxylic acid tributyl ester

( 2R )-tert-butyl 4-[7-(4- cyano -2 -pyridinyl ) spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2- methylpiperazine -1- carboxylate (6) : General method 3- 2-(4'-Chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (130 mg, 0.44 mmol), ( 2R )-tert-butyl 2-methylpiperazine-1-carboxylate (262 mg, 1.31 mmol), NMP (1 mL) and DIEA (282 mg, 2.18 mmol). The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give ( 2R )-4-[7-(4-cyano-2-pyridinyl)spiro[ 6H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tert-butyl ester (90 mg, 45%). Example 7 ( 3S )-4-[7-(4- cyano -2 -pyridinyl ) spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-3- methylpiperazine -1- carboxylic acid tert-butyl ester

( 3S )-4-[7-(4- cyano -2 -pyridinyl ) spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-3- methylpiperazine -1- carboxylic acid tributyl ester (7) : General method 3-2- (4'-Chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (200 mg, 0.67 mmol), ( S )-3-methylpiperazine-1-carboxylic acid tributyl ester (404 mg, 2.02 mmol), NMP (3 mL) and DIEA (434 mg, 3.36 mmol). The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give the product (270 mg, 50% purity). The product was further purified by preparative HPLC under the following conditions: mobile phase: [A: water containing 10 mM FA, B: CH ₃ CN; % B in A: 50%-80%], 8 minutes to give pure (3 S )-4-[7-(4-cyano-2-pyridinyl)spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-3-methylpiperazine-1-carboxylic acid tributyl ester (11.9 mg, 38%). Example 8 2-[4-[( 2S )-4-(2,2 -dimethylpropanoyl )-2- methylpiperazin- 1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

( S )-2-(4'-(2- methylpiperazin- 1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-7'( 6'H ) -yl ) isonicotinatecarbonitrile hydrochloride : General Method 4 - ( S )-4-(7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-3-methylpiperazine-1-carboxylic acid tributyl ester (150 mg, 0.32 mmol) in EtOAc (1 mL) and HCl/EtOAc (4 mL). Product: ( S )-2-(4'-(2- methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (140 mg).

( S )-2-(4'-(2- methyl -4- t-pentanoylpiperazin- 1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-7'( 6'H ) -yl ) isonicotinecarbonitrile (8) : General Method 5- ( S )-2-(4'-(2-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (90 mg, 0.25 mmol) in DCM (1 mL), TEA (76 mg, 0.75 mmol) and t-pentanoyl chloride (120 mg, 0.10 mmol). The crude residue was purified by preparative HPLC under the following conditions: mobile phase: [A: water containing 10 mM FA, B: CH ₃ CN; % of B in A: 35%-75%], 8 min to give ( S )-2-(4'-(2-methyl-4-t-pentanoylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile (16.7 mg, 15%). Example 9 2-[4-[(2 S ,5 R )-4-(2,2 -dimethylpropanoyl )-2,5 -dimethylpiperazin - 1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-(4'-(( 2S , 5R )-2,5 -dimethylpiperazin- 1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-7'( 6'H ) -yl ) isonicotinecarbonitrile hydrochloride: General Method Tributyl 4- ( 2R , 5S )-4-(7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (310 mg, 0.65 mmol), HCl/EtOAc (4N, 5 mL). Product: 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (240 mg, 89%).

2-[4-[( 2S , 5R )-4-(2,2 -dimethylpropanoyl )-2,5 -dimethylpiperazin- 1 -yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile (9) : General Method 5-2- (4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (30 mg, 0.07 mmol) in DCM (1 mL), TEA (22 mg, 0.22 mmol) and 2,2-dimethylpropanoyl chloride (11 mg, 0.09 mmol). The crude material was purified by p-HPLC under the following conditions: mobile phase: _{[ H2O} (10 mM _NH4HCO3 )-ACN]; gradient: 60%-95% B over 8.0 min to give 2-[4-[( 2S , 5R )-4-(2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[ 6H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (14 mg, 43%). Example 10 2-[4-[(3 R )-4-(2,2 -dimethylpropanoyl )-3- methylpiperazin- 1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

( R )-2-(4'-(3- methylpiperazin- 1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-7'( 6'H ) -yl ) isonicotinatecarbonitrile hydrochloride: General Method 4- ( R )-4-(7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2-methylpiperazine-1-carboxylic acid tributyl ester (70 mg, 0.15 mmol) in EtOAc (1 mL), HCl/EtOAc (4N, 5 mL). Product: (R )-2-(4'-(3-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (70 mg, >99%).

2-[4-[( 3R )-4-(2,2 -dimethylpropanoyl )-3- methylpiperazin- 1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile (10) : General Method 5- ( R )-2-(4'-(3-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isocyanate carbonitrile hydrochloride (35 mg, 0.09 mmol) in DCM (1 mL), TEA (27 mg, 0.26 mmol) and trivaleryl chloride (21 mg, 0.18 mmol). The resulting residue was purified by preparative HPLC under the following conditions: mobile phase: [A: water containing 10 mM NH ₄ HCO ₃ , B: CH ₃ CN; % of B in A: 47%-75%], 8 min to give 2-[4-[(3 R )-4-(2,2-dimethylpropanoyl)-3-methylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (11 mg, 28%). Example 11 (2 R , 5 S )-4-[7-(4- cyano -2 -pyridinyl ) spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid 2,2,2- trifluoroethyl ester

( 2R , 5S )-2,2,2- trifluoroethyl 4-[7-(4- cyano -2 -pyridinyl ) spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine - 1-carboxylate ( 11 ) : General Method 5- ( R )-2-(4'-(3-methylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (35 mg, 0.09 mmol) in DCM (1 mL), TEA (27 mg, 0.26 mmol) and 2,2,2-trifluoroethyl chloroformate (29 mg, 0.18 mmol). The resulting residue was purified by preparative HPLC under the following conditions: mobile phase: [A: water containing 10 mM FA, B: CH ₃ CN; % of B in A: 40%-80%] for 8 min to give (2 R ,5 S )-4-[7-(4-cyano-2-pyridinyl)spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid 2,2,2-trifluoroethyl ester (6.5 mg, 15%). Example 12 2-[4-[(2 S ,5 R )-4-( bicyclo [2.1.1] hexane -1- carbonyl )-2,5 -dimethylpiperazin -1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-( Bicyclo [2.1.1] hexane -1- carbonyl )-2,5 -dimethylpiperazin- 1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7- yl ] pyridine -4- carbonitrile (12) : General Method 6- [2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (30 mg, 0.07 mmol) in DMF (1 mL), bicyclo[2.1.1]hexane-1-carboxylic acid (14 mg, 0.11 mmol), HATU (33 mg, 0.09 mmol) and DIEA (28 mg, 0.22 mmol). The resulting mixture was purified by preparative HPLC under the following conditions: mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 60%-90% B over 8.0 min to give 2-[4-[(2 S ,5 R )-4-(bicyclo[2.1.1]hexane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1′-cyclobutane]-7-yl]pyridine-4-carbonitrile (10.5 mg, 30%). Example 13 2-[4-[(2 S ,5 R )-4-(3- methoxy -2,2 -dimethylpropanoyl )-2,5 -dimethylpiperazin -1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-(3- methoxy -2,2 -dimethylpropanoyl )-2,5 -dimethylpiperazin-1 - yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile (13) : General method 6- [3-methoxy-2,2-dimethylpropanoic acid (48 mg, 0.36 mmol) in DMF (1 mL), HATU (111 mg, 0.29 mmol), DIEA (94 mg, 0.73 mmol) and 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6'H ) -4-carbonitrile were added. )-yl)isonicotinate carbonitrile hydrochloride (100 mg, 0.24 mmol). The resulting residue was purified by preparative HPLC under the following conditions: mobile phase: [H ₂ O (0.2% FA)-ACN]; gradient: 40%-75% B over 8.0 min to give 2-[4-[(2 S ,5 R )-4-(3-methoxy-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1′-cyclobutane]-7-yl]pyridine-4-carbonitrile (18 mg, 14%). Example 14 2-[4-[(2 S , 5 R )-4-(2- methoxy -2- methylpropanoyl )-2,5 -dimethylpiperazin -1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-(2- methoxy -2 -methylpropanoyl )-2,5 -dimethylpiperazin -1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7- yl ] pyridine -4- carbonitrile (14) : General Method 6- [2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isocyanate carbonitrile hydrochloride (100 mg, 0.27 mmol) in DMF (1 mL), 2-methoxy-2-methyl-propionic acid (47 mg, 0.40 mmol), HATU (121 mg, 0.32 mmol) and DIEA (103 mg, 0.80 mmol). The resulting mixture was purified by preparative HPLC under the following conditions: mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 55%-85% B over 8.0 min to give 2-[4-[(2 S ,5 R )-4-(2-methoxy-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1′-cyclobutane]-7-yl]pyridine-4-carbonitrile (18 mg, 14%). Example 15 2-[4-[(2 S ,5 R )-4-( cyclobutanecarbonyl )-2,5 -dimethylpiperazin- 1 -yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-( cyclobutanecarbonyl )-2,5 -dimethylpiperazin- 1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile (15) : General Procedure 5-2- (4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isobutanecarbonitrile hydrochloride (0.1 g, 0.24 mmol), TEA (74 mg, 0.73 mmol) in DCM (1 mL), cyclobutanecarbonyl chloride (34 mg, 0.29 mmol). The resulting residue was purified by preparative HPLC (FA conditions) under the following conditions: mobile phase: [ _H2O (0.2% FA)-ACN]; gradient: 30%-70% B over 8.0 min to give 2-[4-[( 2S , 5R )-4-(cyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[ 6H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (15 mg, 13%). Example 16 2-[4-[(2 S ,5 R )-2,5 -dimethyl -4-(1- methylcyclobutanecarbonyl ) piperazin -1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-2,5 -dimethyl -4-(1- methylcyclobutanecarbonyl ) piperazin- 1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile (16) : General method 6-1 -Methylcyclobutanecarboxylic acid (33 mg, 0.29 mmol), PYAOP (151 mg, 0.29 mmol) and THF (2 mL) containing DIEA (156 mg, 1.21 mmol), 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6'H )- )-yl)isonicotinatecarbonitrile hydrochloride (0.1 g, 0.24 mmol). The mixture was stirred at 50 °C under _N2 for 12 h. The resulting residue was purified by preparative HPLC (FA) under the following conditions: mobile phase: [ _H2O (0.2% FA)-ACN]; gradient: 40%-80% B over 8.0 min to give 2-[4-[( 2S , 5R )-2,5-dimethyl-4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]spiro[ 6H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (20.2 mg, 18%). Example 17 2-[4-[(2 S ,5 R )-4-(3,3 -difluoro - 2,2-dimethylpropanoyl )-2,5 -dimethylpiperazin -1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine - 5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-(3,3 -difluoro - 2,2-dimethylpropanoyl )-2,5 -dimethylpiperazin- 1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile (17) : General method 6-3,3 -difluoro-2,2-dimethylpropanoic acid (50 mg, 0.36 mmol) in DMF (1 mL), HATU (111 mg, 0.29 mmol), DIEA (94 mg, 0.73 mmol) and 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6'H ) -4-carbonitrile were added. )-yl)isonicotinate carbonitrile hydrochloride (100 mg, 0.24 mmol). The resulting residue was purified by preparative HPLC under the following conditions: mobile phase: A: H ₂ O containing 10 mM NH ₄ HCO ₃ , B: ACN; % of B in A: 35%-70%; 8.0 minutes to give 2-[4-[(2 S ,5 R )-4-(3,3-difluoro-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (14.7 mg, 12%). Example 18 2-[4-[(2 S ,5 R )-4-(3- fluoro -2,2 -dimethylpropanoyl )-2,5 -dimethylpiperazin -1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-(3- Fluoro -2,2 -dimethylpropanoyl )-2,5 -dimethylpiperazin - 1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile (18) : General procedure A mixture of 3 -fluoro-2,2-dimethylpropanoic acid (13 mg, 0.11 mmol) in DMF (0.5 mL), HATU (33 mg, 0.09 mmol), DIEA (28 mg, 0.22 mmol) and 2-(4'-((2S,5R)-2,5-dimethylpiperazin-1-yl) spiro [cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'(6'H)-1-yl)-4-(3-Fluoro-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1- yl )spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-1-yl)-3-(3-fluoro-2,2-dimethylpropanoic acid (13 mg, 0.11 mmol) in DMF (0.5 mL) was stirred for 2 h. )-yl)isonicotinate carbonitrile hydrochloride (30 mg, 0.07 mmol). The resulting residue was purified by preparative HPLC under the following conditions: mobile phase: A: H ₂ O containing 10 mM NH ₄ HCO ₃ , B: ACN; % of B in A: 40%-70%; 8.0 minutes to give 2-[4-[(2 S ,5 R )-4-(3-fluoro-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (12.4 mg, 36%). Example 19 2-[4-[(2 S ,5 R )-4-(2 -cyclopropyl -2- methylpropionyl )-2,5 -dimethylpiperazin- 1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-(2 -cyclopropyl -2- methylpropanoyl )-2,5 -dimethylpiperazin -1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile (19) : General method 6-2 -Cyclopropyl-2-methyl-propionic acid (14 mg, 0.109 mmol), HATU (33 mg, 0.087 mmol), DIEA (28 mg, 0.218 mmol) in DMF (2 mL), 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6'H )- )-yl)isonicotinate carbonitrile hydrochloride (0.03 g, 0.073 mmol). The resulting residue was purified by preparative HPLC under the following conditions: mobile phase: A: [H ₂ O (0.2% FA)-ACN], B: MeCN; B% in A: 25%-65%, 8 minutes to give 2-[4-[(2 S ,5 R )-4-(2-cyclopropyl-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (8.4 mg, 24%). Example 20 2-[4-[(2 S ,5 R )-4-( bicyclo [ 1.1.1] pentane -1- carbonyl )-2,5 -dimethylpiperazin -1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-( Bicyclo [1.1.1] pentane -1- carbonyl )-2,5 -dimethylpiperazin -1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile (20) : General procedure 6- Bicyclo[1.1.1]pentane-1-carboxylic acid (41 mg, 0.364 mmol), HATU (110 mg, 0.291 mmol), DIEA (94 mg, 0.728 mmol) in DMF (2 mL) and 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6'H )- )-yl)isonicotinate carbonitrile hydrochloride (0.1 g, 0.243 mmol). The resulting residue was purified by preparative HPLC under the following conditions: mobile phase: A: [H ₂ O (0.2% FA)-ACN], B: MeCN; B% in A: 25%-65%, 8 minutes to give 2-[4-[(2 S ,5 R )-4-(bicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (17.1 mg, 15%). Example 21 2-[4-[(2 S ,5 R )-2,5 -dimethyl -4-[1-( trifluoromethyl ) cyclobutanecarbonyl ] piperazin -1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-2,5 -dimethyl -4-[1-( trifluoromethyl ) cyclobutanecarbonyl ] piperazin -1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine - 5,1'- cyclobutane ]-7 -yl ] pyridine -4- carbonitrile (21) : General Method 6-2- (4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isocyanate carbonitrile hydrochloride (100 mg, 0.24 mmol), 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (61 mg, 0.36 mmol) in DMF (2 mL), DIEA (157 mg, 1.21 mmol) and HATU (111 mg, 0.29 mmol). The mixture was heated to 50 °C for 16 h. The resulting residue was purified by preparative HPLC under the following conditions: mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 56%-88% B over 8.0 min to give 2-[4-[(2 S ,5 R )-2,5-dimethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (1.83 mg, 1.2%). Example 22 2-[4-[(2 S ,5 R )-4-(2,2 -difluoro -1- methylcyclopropanecarbonyl )-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-(2,2 -difluoro -1- methylcyclopropanecarbonyl )-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7- yl ] pyridine -4- carbonitrile (22) : General Method 2,2- difluoro-1-methyl-cyclopropanecarboxylic acid (24 mg, 0.18 mmol) in DMF (1 mL), HATU (55 mg, 0.15 mmol), DIEA (47 mg, 0.36 mmol) and 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6'H ) -4-carbonitrile were added. )-yl)isonicotinate carbonitrile hydrochloride (50 mg, 0.12 mmol). The mixture was purified by preparative HPLC under the following conditions: mobile phase: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; B% in A: 60%-90%, 8.0 minutes to give 2-[4-[(2 S ,5 R )-4-(2,2-difluoro-1-methylcyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (19.9 mg, 33%). Example 23 2-[4-[(2 S ,5 R )-4-(3,3 -difluoro - 2,2-dimethylbutyryl )-2,5 - dimethylpiperazin -1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-(3,3 -difluoro -2,2- dimethylbutyric acid )-2,5 -dimethylpiperazin-1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile (23) : General method A mixture of 3,3-difluoro-2,2-dimethyl-butyric acid (55 mg, 0.36 mmol) in DMF (1 mL), 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6'H ) -yl)isonicotine carbonitrile hydrochloride (100 mg, 0.24 mmol), HATU (110 mg, 0.29 mmol) and DIEA (94 mg, 0.73 mmol). The resulting mixture was purified by preparative HPLC under the following conditions: mobile phase: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; B% in A: 50%-90%, 8.0 minutes to give 2-[4-[(2 S ,5 R )-4-(3,3-difluoro-2,2-dimethylbutyryl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (3.13 mg, 3%). Example 24 2-[4-[(2 S ,5 R )-4-(4,4 -difluoro - 2,2-dimethylbutyryl )-2,5 -dimethylpiperazin -1- yl ] spiro [6 H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2-[4-[( 2S , 5R )-4-(4,4 -difluoro - 2,2-dimethylbutyryl )-2,5 -dimethylpiperazin-1- yl ] spiro [ 6H - pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7- yl ] pyridine -4- carbonitrile (24) : General Method 6- [2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (50 mg, 0.12 mmol) in DMF (1 mL), 4,4-difluoro-2,2-dimethyl-butyric acid (27 mg, 0.18 mmol), HATU (55 The resulting mixture was purified by preparative HPLC under the following conditions: mobile phase A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % B in A: 60%-90%, 8.0 min to give 2-[4-[(2 S ,5 R )-4-(4,4-difluoro-2,2-dimethylbutyryl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1′-cyclobutane]-7-yl]pyridine-4-carbonitrile (6.52 mg, 11%). Example 25 (2 R , 5 S )-4-[7-(4- cyano -2 -pyridinyl )-3'- hydroxyspiro [6 H -pyrrolo [2,3-d] pyrimidine - 5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

Tributyl ((1,3- dibromopropan- 2- yl ) oxy ) dimethylsilane : To a solution of 1,3-dibromopropan-2-ol (6.5 g, 29.8 mmol) in DCM (70 mL) at 0 °C were added imidazole (2.23 g, 32.8 mmol), DMAP (364 mg, 3.0 mmol) and TBSCl (4.95 g, 32.8 mmol). The mixture was stirred at 20 °C for 12 h. The mixture was quenched with _H2O (30 mL) and extracted with DCM (3 x 40 mL). The combined organic layers were washed with brine (20 mL), dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE:EtOAc = 100:1 to 5:1) to give tert-butyl((1,3-dibromoprop-2-yl)oxy)dimethylsilane (6.2 g, 63%).

3-(( Tributyldimethylsilyl ) oxy )-4'- chlorospiro [ cyclobutane -1,5' -pyrrolo [2,3 -d ] pyrimidin ]-6'( 7'H ) -one : To a mixture of 4-chloro-5,7-dihydro- 6H -pyrrolo[2,3 -d ]pyrimidin-6-one (2 g, 11.8 mmol) in DMSO (60 mL) at 20 °C under _N2 was added NaH (1.09 g, 27.1 mmol, 60% dispersion in mineral oil). The mixture was stirred at 20 °C for 0.5 h, followed by the addition of tributyl((1,3-dibromoprop-2-yl)oxy)dimethylsilane (4.70 g, 14.2 mmol). The mixture was stirred at 20 °C for 16 h. The mixture was quenched with saturated aqueous NH ₄ Cl solution (100 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (80 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 4:1) to give 3-((tributyldimethylsilyl)oxy)-4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-6'(7' H )-one (1.9 g, 47%).

3-(( Tributyldimethylsilyl ) oxy )-4'- chloro -6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ] : General Procedure 1 - THF (42.5 mL) containing AlCl ₃ (2.00 g, 15.0 mmol), LiAlH ₄ (2.5 M in THF, 6.00 mL) and 3-((tributyldimethylsilyl)oxy)-4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-6'(7' H )-one (1.7 g, 5.0 mmol). The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give 3-((tributyldimethylsilyl)oxy)-4'-chloro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine] (500 mg, 31%).

2-(4'- Chloro -3- hydroxyspiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-7'(6' H ) -yl ) isonicotinecarbonitrile: General method 2- (2-Fluoroisonicotinecarbonitrile (281 mg, 2.30 mmol), 3-((tributyldimethylsilyl)oxy)-4'-chloro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine] (500 mg, 1.53 mmol), DMSO (10 mL), K ₂ CO ₃ (636 mg, 4.60 mmol). The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (110 mg, 23%).

(2R , 5S ) -4-[7-(4- cyano -2 -pyridinyl )-3'- hydroxyspiro [6H - pyrrolo [ 2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester (25) : General method 3-2- (4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (50 mg, 0.16 mmol), ( 2R , 5S )-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (102 mg, 0.48 mmol), NMP (1 mL), DIEA (103 mg, 0.80 mmol). The resulting residue was purified by preparative HPLC using the following conditions: mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % of B in A: 38%-67%, 8 min to give (2 R ,5 S )-4-[7-(4-cyano-2-pyridinyl)-3'-hydroxyspiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (2.29 mg, 3%). Example 38 (2R)-4-[7-(4- cyano -2 -pyridinyl )-3'- fluorospiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2- methylpiperazine -1- carboxylic acid tributyl ester

2-(4'- Chloro -3- fluorospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-7'(6' H ) -yl ) isonicotinecarbonitrile : To a solution of 2-(4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile (80 mg, 0.25 mmol) in DCM (1 mL) was added DAST (123 mg, 0.76 mmol) at 0° C. The mixture was stirred at 20° C. for 2 h. The mixture was quenched with H ₂ O (2 mL) and extracted with DCM (3×2 mL). The combined organic layers were washed with brine (2 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4'-chloro-3-fluorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile (35 mg, 43%).

(2R)-4-[7-(4-Cyano-2-pyridinyl)-3'-fluorospiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tributyl ester: General method 3- 2-(4'-Chloro-3-fluorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (15 mg, 0.05 mmol), ( R )-2-methylpiperazine-1-carboxylic acid tributyl ester (19 mg, 0.1 mmol), DIEA (6 mg, 0.05 mmol) in NMP (0.3 mL) at 80 °C for 16 h. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 80 × 40 mm × 3 μm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % of B in A: 40%-70%, 8 min) to give (2R)-4-[7-(4-cyano-2-pyridinyl)-3'-fluorospiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tributyl ester (4 mg, 16%). Example 55 (2R,5S)-4-[7-(4- cyano -2 -pyridinyl )-1',1' -difluorospiro [6H -pyrrolo [2,3-d] pyrimidine -5,3'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

2-(4'- Chloro -3 -hydroxyspiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-7'(6' H ) -yl ) isonicotinecarbonitrile: To a solution of 2-(4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile (180 mg, 0.57 mmol) in DCM (3 mL) was added Dess-Martin Periodinane (1.22 g, 2.87 mmol). The mixture was stirred at 40 °C for 5 h. The mixture was poured into aqueous NaHCO ₃ solution (10 mL) and extracted with DCM (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give 2-(4'-chloro-3-oxospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'(6' H )-yl)isonicotinecarbonitrile (110 mg, 62%).

2-(4'- Chloro -3,3 -difluorospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-7'(6' H ) -yl ) isonicotinecarbonitrile : To a solution of 2-(4'-chloro-3-oxospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile (110 mg, 0.35 mmol) in DCE (2 mL) was added EtOH (33 mg, 0.71 mmol) and DAST (1.14 g, 7.06 mmol) at 0 °C. The mixture was stirred at 50 °C for 4 h. The mixture was poured into aqueous NaHCO ₃ solution (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4'-chloro-3,3-difluorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'(6' H )-yl)isonicotinecarbonitrile (100 mg, 85%).

(2R,5S)-4-[7-(4-cyano-2-pyridinyl)-1',1'-difluorospiro[6H-pyrrolo[2,3-d]pyrimidine-5,3'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester: General method Tributyl 3-( 2R , 5S )-2,5-dimethylpiperazine-1-carboxylate (51 mg, 0.24 mmol), DIEA (46 mg, 0.36 mmol), 2-(4'-chloro-3,3-difluorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (40 mg, 0.12 mmol) in NMP (1 mL). The mixture was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 µm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: CH ₃ CN; % of B in A: 55% - 90%, 8 min) to give (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-1',1'-difluorospiro[6H-pyrrolo[2,3-d]pyrimidine-5,3'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (7 mg, 11%). Example 56 (2R,5S)-4-((1r,3S)-7'-(4- cyanopyridin- 2- yl )-3- hydroxy -3- methyl -6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3-d] pyrimidine ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

2-(4'- Chloro -3- hydroxy -3- methylspiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-7'( 6'H ) -yl ) isonicotinecarbonitrile: To _a solution of 2-(4'-chloro-3-oxospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'( 6'H )-yl)isonicotinecarbonitrile (50 mg, 0.16 mmol) in THF (1 mL) was added _CH3MgBr (3 M in THF, 0.24 mmol, 0.08 mL) at 0 °C under N2. The mixture was stirred at 20 °C for 2 h. The mixture was poured into aqueous _NH4Cl solution (3 mL) and extracted with EtOAc (3 x 1 mL). The combined organic phases were washed with brine (1 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:EtOAc = 1:1) to give 2-(4'-chloro-3-hydroxy-3-methylspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'(6' H )-yl)isonicotinecarbonitrile (29 mg, 55%).

(2 R , 5 S )-4-((1 r , 3 S )-7'-(4-cyanopyridin-2-yl)-3-hydroxy-3-methyl-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester: General method 3-(2 R , 5 S )-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (28 mg, 0.13 mmol), DIEA (34 mg, 0.27 mmol), 2-(4'-chloro-3-hydroxy-3-methylspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'(6' H )-yl)isonicotinecarbonitrile (29 mg, 0.88 mmol) in NMP (0.2 mL) at 140 °C for 12 h. The mixture was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 µm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: CH ₃ CN; % of B in A: 35%-90%, 8 min) to give (2 R ,5 S )-4-((1 r ,3 S )-7'-(4-cyanopyridin-2-yl)-3-hydroxy-3-methyl-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (8 mg, 19%). Example 62 (2R,5S)-4-[7-(6- cyanopyridazin- 4- yl ) spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

5- Chloropyridazine -3- carbonitrile: To a solution of 3,5-dichloropyridazine (200 mg, 1.34 mmol) in DMF (2 mL) at 25 °C under _N2 , DPPF (74 mg, 0.13 mmol), Pd2(dba) ₃ ( ₆₁ mg, 0.07 mmol), Zn(CN) ₂ (158 mg, 1.34 mmol) were added. The mixture was stirred at 90 °C for 5 h. The reaction mixture was diluted with _H2O (10 mL) at 0 °C. The aqueous phase was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO ₂ , PE:EtOAc = 3:1) to give 5-chloropyridazine-3-carbonitrile (80 mg, 42%).

5-(4'- Chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)pyridazine-3-carbonitrile: General Method 2-( 4'-Chloro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine] (80 mg, 0.41 mmol), 5-chloropyridazine-3-carbonitrile (74 mg, 0.53 mmol), K ₂ CO ₃ (170 mg, 1.23 mmol) in DMSO (2 mL). The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 0:1) to give 5-(4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)pyridazine-3-carbonitrile (50 mg, 49%).

(2R,5S)-4-[7-(6-cyanopyridazin-4-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester: General method 3- 5-(4'-Chlorospiro[cyclobutane-1,5'-pyrrolo[2,3 -d ]pyrimidine]-7'( 6'H )-yl)pyridazine-3-carbonitrile (50 mg, 0.17 mmol), DIEA (108 mg, 0.84 mmol), 2,5-dimethylpiperazine-1-carboxylate (72 mg, 0.33 mmol) in NMP (1 mL). The residue was purified by preparative HPLC (Phenomenex Gemini-NX C18 100 × 30 mm × 10 mm × 10 μm; mobile phase; mobile phase: [A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % of B in A: 50%-80%] 8.0 min) to give (2R,5S)-4-[7-(6-cyanopyridazin-4-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (35 mg, 28%). Examples 68A and 68B (2R,5S)-4-[(5R)-7-(4- cyano -2 -pyridinyl )-5-( methoxymethyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine- 1- carboxylic acid tributyl ester and (2R,5S)-4-[(5S)-7-(4- cyano -2 -pyridinyl )-5-( methoxymethyl )-5- methyl -6H- pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

4- Chloro -7-(2,4 -dimethoxybenzyl )-5-( methoxymethyl )-5- methyl -6,7- dihydro - 5H - pyrrolo [2,3- d ] pyrimidine : To a solution of (4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidin-5-yl)methanol (200 mg, 0.57 mmol) in DMF (2 mL) was added NaH (34 mg, 0.86 mmol, 60% dispersion in mineral oil) at 0°C. The mixture was stirred at 0°C for 0.5 h, and MeI (162 mg, 1.14 mmol) was added at 0°C. The mixture was stirred at 0°C for 1.5 h. The mixture was quenched by _H2O (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (10 mL) and dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 4-chloro-7-(2,4-dimethoxybenzyl)-5-(methoxymethyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine (130 mg, 62%).

4- Chloro-5-(methoxymethyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidine : A mixture of 4-chloro-7-(2,4-dimethoxybenzyl)-5-(methoxymethyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine (130 mg, 0.36 mmol) in TFA (2 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 70 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO ₂ , PE:EtOAc = 1:1) to give 4-chloro-5-(methoxymethyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine (75 mg, 98%).

2-(4- Chloro-5-(methoxymethyl)-5-methyl- 5H -pyrrolo[2,3 -d ]pyrimidin-7( 6H )-yl)isonicotinecarbonitrile: General Method 3- 2-Fluoropyridine-4-carbonitrile (45 mg, 0.36 mmol), 4-chloro-5-(methoxymethyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ] _pyrimidine (65 mg, 0.30 mmol), _K2CO3 (126 mg, 0.91 mmol) in DMF (1 _mL ) at 80 °C for 16 h. The combined organic layers were washed with brine (6 mL) and dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4-chloro-5-(methoxymethyl)-5-methyl- 5H -pyrrolo[2,3- d ]pyrimidin-7( 6H )-yl)isonicotinecarbonitrile (75 mg, 78%).

(2R,5S)-4-[(5R)-7-(4- cyano -2 -pyridinyl )-5-( methoxymethyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester and (2R,5S)-4-[(5S)-7-(4- cyano -2 -pyridinyl )-5-( methoxymethyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester : General method 3-( 2R , 5S )-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (76 mg, 0.36 mmol), 2-(4-chloro-5-(methoxymethyl)-5-methyl- 5H -pyrrolo[2,3- d ]pyrimidin-7( 6H )-yl)isonicotinecarbonitrile (75 mg, 0.24 mmol), DIEA (153 mg, 1.19 mmol) in NMP (1 mL) at 140 °C for 16 h. The residue was purified by preparative HPLC (column: 2-Phenomenex Gemini C18 75 × 40 mm × 3 μm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % of B in A: 50%-80%, 8 min) to obtain (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-5-(methoxymethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (5 mg, 4%, peak 1 (68A); 6 mg, 5%, peak 2 (68B)) as two separate non-mirror image isomers. Examples 74 and 75 (2R,5S)-4-((1s,3R)-7'-(4- cyanopyridin -2- yl )-3- fluoro -6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3-d] pyrimidin ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester and (2R,5S)-4-((1r,3S)-7'-(4- cyanopyridin- 2- yl )-3- fluoro -6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3-d] pyrimidin ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

2-((1 s ,3 s )-4'- chloro -3- fluorospiro [ cyclobutane -1,5'- pyrrolo [2,3- d ] pyrimidine ]-7'(6' H ) -yl ) isonicotinoid carbonitrile and 2-((1 r ,3 r )-4'- chloro -3- fluorospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-7'(6' H ) -yl ) isonicotinoid carbonitrile : To a solution of 2-(4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinoid carbonitrile (200 mg, 0.64 mmol) in DCM (2 mL) at 0 °C was added DAST (308 mg, 1.91 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into _H2O (4 mL) and extracted with DCM (3 x 2 mL). The combined organic phases were washed with brine (3 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , PE:EtOAc = 4:1 to 3:1) to give 2-((1 s ,3 s )-4'-chloro-3-fluorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile (30 mg, 15%) and 2-((1 r ,3 r )-4'-chloro-3-fluorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile (30 mg, 15%).

( 2R , 5S )-tert-butyl 4-(( 1r ,3S)-7'-(4 - cyanopyridin- 2 - yl )-3 -fluoro -6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4' - yl )-2,5 -dimethylpiperazine -1- carboxylate : General method tert-butyl 3-( 2R , 5S )-2,5-dimethylpiperazine-1-carboxylate (41 mg, 0.19 mmol), NMP (1 mL), DIEA (37 mg, 0.29 mmol) in NMP (1 mL) at 80 °C for 16 hours. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 3 μm; mobile phase: [A: water containing 0.2% FA, B: CH ₃ CN; % of B in A: 55%-85%], 8 min) to give (2 R ,5 S )-4-((1 s ,3 R )-7'-(4-cyanopyridin-2-yl)-3-fluoro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (3 mg, 7%, peak 1 (74)) and (2 R ,5 S )-4-((1 r ,3 S )-tributyl 7'-(4-cyanopyridin-2-yl)-3-fluoro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (13 mg, 28%, peak 2 (75)). Examples 77A and 77B (5S)-7-(4- cyano -2 -pyridinyl )-4-[(2S,5R)-2,5 -dimethyl -4-[(2- methylpropan -2- yl ) oxycarbonyl ] piperazin- 1- yl ]-5- methyl -6H -pyrrolo [2,3-d] pyrimidine -5- carboxylic acid ethyl ester and (5R)-7-(4- cyano -2 -pyridinyl )-4-[(2S,5R)-2,5 -dimethyl -4-[(2- methylpropan -2- yl ) oxycarbonyl ] piperazin- 1- yl ]-5- methyl -6H -pyrrolo [2,3-d] pyrimidine -5- carboxylic acid ethyl ester

Ethyl 4- chloro -5- methyl -6,7- dihydropyrrolo [2,3-d] pyrimidine -5 -carboxylate: A mixture of ethyl 4-chloro-7-[(2,4-dimethoxyphenyl)methyl]-5-methyl-6H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (518 mg, 1.32 mmol) in TFA (5 mL) was stirred at ₇₀ °C under N2 for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( PE:EA = 5:1 to 4:1) to give ethyl 4-chloro-5-methyl-6,7-dihydropyrrolo[2,3-d]pyrimidine-5-carboxylate (300 mg, 93%).

4- Chloro -7-(4- cyanopyridin- 2- yl )-5- methyl -6,7 - dihydro -5H- pyrrolo [2,3- d ] pyrimidine -5- carboxylic acid ethyl ester: General method 3- 4-Chloro-5-methyl-6,7-dihydro-5H-pyrrolo[2,3- d ]pyrimidine-5-carboxylate (106 mg, 0.439 mmol), ₂ -fluoroisonicotinecarbonitrile (0.161 mg, 1.32 mmol), _K2CO3 (0.182 g, 1.32 mmol) in DMSO (1 mL) at 80 °C under _N2 for 16 h. The combined organic layers were washed with brine (3 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO ₂ , PE:EA = 3:1 ) to give ethyl 4-chloro-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine-5-carboxylate (80 mg, 52%).

(5S)-7-(4-cyano-2-pyridinyl)-4-[(2S,5R)-2,5-dimethyl-4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]-5-methyl-6H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester and (5R)-7-(4-cyano-2-pyridinyl)-4-[(2S,5R)-2,5-dimethyl-4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]-5-methyl-6H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester: General Method 3- 4-Chloro-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine-5-carboxylate (80 mg, 0.233 mmol), tributyl ( 2R , 5S )-2,5-dimethylpiperazine-1-carboxylate (10 mg, 0.465 mmol), DIEA (0.150 g, 1.16 mmol) in NMP (1 mL). The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 3 μm; mobile phase: A: water containing 0.2% FA, B: MeCN; % B in A: 55%-90%, 8 min) to give ethyl 7-(4-cyano-2-pyridinyl)-4-[(2S,5R)-2,5-dimethyl-4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]-5-methyl-6H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (14 mg, 11%, peak 1 (77A); 11 mg, 9%, peak 2 (77B)) as two separated non-mirror image isomers. Example 78 (2R,5S)-4-[7-(4- cyano -2 -pyridinyl )-5-( difluoromethyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

4- Chloro -7-(2,4 -dimethoxybenzyl )-5- methyl -6,7- dihydro - 5H - pyrrolo [2,3 -d ] pyrimidine -5- carbaldehyde: To a solution of (4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidin-5-yl)methanol (500 mg, 1.43 mmol) in DCM (10 mL) was added DMP (606 mg, 1.43 mmol) at 0°C. The mixture was stirred at 20°C for 2 h. The mixture was quenched by _H2O (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine-5-carbaldehyde (300 mg, 60%).

4- Chloro -5-( difluoromethyl )-7-(2,4 -dimethoxybenzyl )-5- methyl -6,7 -dihydro - 5H - pyrrolo [2,3- d ] pyrimidine: To a solution of 4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine-5-carbaldehyde (200 mg, 0.58 mmol) in DCM (2 mL) was added DAST (185 mg, 1.15 mmol) at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was poured into water (5 mL) and extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine (6 mL) and dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 2:1 to 1:1) to give 4-chloro-5-(difluoromethyl)-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine (130 mg, 61%).

4- Chloro-5-(difluoromethyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine: A mixture of 4-chloro-5-(difluoromethyl)-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidine (130 mg, 0.44 mmol) in TFA (2 mL) was degassed and purged with _N2 three times. The mixture was stirred at 70 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 1:1) to give 4-chloro-5-(difluoromethyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine (75 mg).

2-(4- Chloro -5-( difluoromethyl )-5- methyl - 5H - pyrrolo [2,3 -d ] pyrimidin -7( 6H ) -yl ) isonicotinecarbonitrile: General method 2 -Fluoropyridine-4-carbonitrile (83 mg, 0.68 mmol), 4-chloro-5-(difluoromethyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ] _pyrimidine (50 mg, 0.23 mmol), _K2CO3 (94 mg, 0.68 mmol) in DMF (1 mL) at 80 °C for 16 h. The residue was purified by flash silica gel column chromatography (PE:EtOAc = 2:1 to 1:1) to give 2-(4-chloro-5-(difluoromethyl)-5-methyl -5H -pyrrolo[2,3- d ]pyrimidin-7( 6H )-yl)isonicotinecarbonitrile (45 mg, 61%).

(2R,5S)-4-[7-(4- cyano -2 -pyridinyl )-5-( difluoromethyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester : General method 3-(2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (53 mg, 0.25 mmol), 2-(4-chloro-5-(difluoromethyl)-5-methyl- 5H -pyrrolo[2,3 -d ]pyrimidin-7( 6H )-yl)isocyanate (40 mg, 0.12 mmol), DIEA (80 mg, 0.62 mmol) in NMP (1 mL) at 140 °C for 16 h. The combined organic phases were washed with brine (5 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % of B in A: 52%-85%, 8 min) to obtain (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-5-(difluoromethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (10 mg, 14%) as a single unidentified stereoisomer. Example 79 (2R,5S)-4-((1s,3s)-7'-(4- cyanopyridin- 2- yl )-3- methoxy- 6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3-d] pyrimidine ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

2-((1r,3r)-4'- chloro -3- methoxyspiro [ cyclobutane -1,5' -pyrrolo [2,3-d] pyrimidin ]-7'(6'H) -yl ) isonicotinecarbonitrile: To a solution of _2- (4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'( 6'H )-yl)isonicotinecarbonitrile (160 mg, 0.51 mmol) and MeI (80 mg, 0.56 mmol) in DMF (3 mL) was added NaH (27 mg, 0.66 mmol, 60% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into NH ₄ Cl (15 mL) and extracted with EtOAc (3×5 mL).The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by p-TLC (PE:EtOAc = 3:1) to give 2-((1 s ,3 s )-4'-chloro-3-methoxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile (37 mg, 22%, peak 1) and 2-((1 r ,3 r )-4'-chloro-3-methoxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile (27 mg, 16%, peak 2).

(2 R ,5 S )-4-((1 s ,3 s )-7'-(4- cyanopyridin- 2-yl )-3- methoxy -6',7'- dihydrospiro [ cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester: General method 3- 2-((1 s ,3 s )-4'-chloro-3-methoxyspiro[cyclobutane -1,5' - pyrrolo[2,3- d ] pyrimidine ] -7' ( 6 ' H ) -yl )isocyanate (37 mg, 0.11 mmol), DIEA (117 mg, 0.9 mmol, 0.16 mL), (2 R ,5 S )-4-((1 s ,3 s )-7'-(4-cyanopyridin-2-yl)-3-methoxy-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester: General method 3- 2-((1 s ,3 s )-4'-chloro-3-methoxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6 ' H )-yl)isocyanate (37 mg, 0.11 mmol), DIEA (117 mg, 0.9 mmol, 0.16 mL ), )-tributyl 2,5-dimethylpiperazine-1-carboxylate (60 mg, 0.28 mmol) in NMP (1 mL). The residue was purified by p-HPLC (neutral) under the following conditions: (column: 2-Phenomenex Gemini C18 75 × 40 mm × 3 um; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % of B in A: 50%-80%, 8 min) to give (2 R ,5 S )-4-((1 s ,3 s )-7'-(4-cyanopyridin-2-yl)-3-methoxy-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (26 mg, 46%). Examples 82 and 83 (2R,5S)-4-((1r,3S)-3- cyano -7'-(4- cyanopyridin- 2- yl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3-d] pyrimidin ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester and (2R,5S)-4-((1s,3R)-3- cyano -7'-(4- cyanopyridin- 2- yl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3-d] pyrimidin ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

(2 R , 5 S )-4-(7'-(4- cyanopyridin- 2- yl )-3- hydroxy -6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tert-butyl ester : General method 3-2-(4'-chloro-3-hydroxyspiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'(6' H )-yl)isonicotinecarbonitrile (0.2 g, 0.64 mmol), DIEA (577 mg, 4.46 mmol), (2 R , 5 S )-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (328 mg, 1.53 mmol) were added to NMP (4 The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) to obtain (2 R ,5 S )-4-(7'-(4-cyanopyridin-2-yl)-3-hydroxy-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (0.3 g, 76%).

( 2R , 5S )-4-(7'-(4- cyanopyridin -2- yl )-3-(( methylsulfonyl ) oxy )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4'- yl )-2,5- dimethylpiperazine -1- carboxylic acid tributyl ester : To a solution of ( _2R , 5S )-4-(7'-(4- cyanopyridin -2-yl)-3-hydroxy-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (0.3 g, 0.61 mmol) in DCM (6 mL) at 20 °C under N2 was added TEA (93% HCl). 147 mg, 0.92 mmol), DMAP (7 mg, 0.06 mmol) and MsCl (105 mg, 0.92 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into water (18 mL) and extracted with DCM (3 x 6 mL). The combined organic phases were washed with brine (6 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) to give (2 R ,5 S )-4-(7'-(4-cyanopyridin-2-yl)-3-((methylsulfonyl)oxy)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (0.11 g, 32%).

(2 R ,5 S )-4-((1 s ,3 s )-3- cyano -7'-(4- cyanopyridin- 2- yl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4'- yl )-2,5 -dimethylpiperazine- 1- carboxylic acid tributyl ester and (2 R ,5 S )-4-((1 r ,3 r )-3- cyano -7'-(4- cyanopyridin- 2 - yl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4' - yl )-2,5 -dimethylpiperazine -1 - carboxylic acid tributyl ester : At 20°C, (2 R ,5 S To a solution of tributyl 4-(7'-(4-cyanopyridin-2-yl)-3-((methylsulfonyl)oxy)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (0.11 g, 0.19 mmol) in DMSO (2 mL) was added 18-crown-6 (5 mg, 0.02 mmol) and NaCN (47 mg, 0.97 mmol). The mixture was stirred at 140 °C for 4 h. The residue was poured into water (5 mL) and extracted with EtOAc (3 x 2 mL). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) and further separated by p-TLC (PE:EtOAc = 1:1) to give (2 R ,5 S )-4-( (1 s ,3 s )-3-cyano-7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin] -4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (7 mg, 7%, peak 1) and

( 2R , 5S )-4-(( 1r , 3r )-3-cyano-7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (9 mg, 10%, peak 2). Example 84 (2R, 5S)-4-[7-(4- cyanopyrimidin -2- yl ) spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4 - yl ]-2,5- dimethylpiperazine -1- carboxylic acid tributyl ester

2-(4'- Chlorospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-7'(6' H ) -yl ) pyrimidine -4 -carbonitrile : General Method 2- (4'-Chloro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine] (100 mg, 0.51 mmol), K ₂ CO ₃ (141 mg, 1.02 mmol), 2-chloropyrimidine-4-carbonitrile (107 mg, 0.77 mmol) in DMSO (1 mL). The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)pyrimidine-4-carbonitrile (60 mg, 39%).

(2R,5S)-tert-butyl 4-[7-(4- cyanopyrimidin -2- yl ) spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1 - carboxylate : General Method 3- 2-(4'-Chlorospiro[cyclobutane-1,5'-pyrrolo[2,3 -d ]pyrimidine]-7'( 6'H )-yl)pyrimidine-4-carbonitrile (60 mg, 0.20 mmol), DIEA (129 mg, 1.00 mmol), ( 2R , 5S )-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (64 mg, 0.30 mmol) in NMP (1 mL). The residue was purified by preparative HPLC (Phenomenex Luna C 18 100 × 30 mm × 3 μm; mobile phase: A: water containing 0.2% FA, B: MeCN; B% in A: B%: 50%-90%, 8 min) to give (2R,5S)-4-[7-(4-cyanopyrimidin-2-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (16 mg, 32%). Examples 85A and 85B (2R,5S)-4-[(5R)-7-(4- cyano -2 -pyridinyl )-5-( hydroxymethyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester and (2R,5S)-4-[(5S)-7-(4- cyano -2 -pyridinyl )-5-( hydroxymethyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5- dimethylpiperazine -1- carboxylic acid tributyl ester

Ethyl 4- chloro -7-(2,4 -dimethoxybenzyl )-6 -oxo -6,7- dihydro - 5H- pyrrolo [2,3-d] pyrimidine -5 -carboxylate : To a solution of 4-chloro-7-(2,4-dimethoxybenzyl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (35 g, 109.46 mmol) in THF (350 mL) was added dropwise LiHMDS (1 M in THF, 109 mL) at -20 °C. The mixture was stirred at -20 °C for 1 hour, followed by the addition of ethyl cyanoformate (14.10 g, 142.30 mmol) in THF (35 mL) at -20 °C. The resulting mixture was stirred at 20 °C for 3 hours. The reaction mixture was poured into aqueous NH ₄ Cl solution (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic phases were washed with 1M HCl (3 × 50 mL) and brine (3 × 50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography column (PE:EtOAc = 4:1 to 3:1) to give 4-chloro-7-(2,4-dimethoxybenzyl)-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (30 g, 69%).

4- Chloro -7-(2,4 -dimethoxybenzyl )-5- methyl -6 -oxo -6,7- dihydro -5H- pyrrolo [2,3-d] pyrimidine -5- carboxylic acid ethyl ester : To a solution of 4-chloro-7-(2,4-dimethoxybenzyl)-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (30 g, 76.57 mmol) in DMF (300 mL) was added Cs ₂ CO ₃ (49.90 g, 153.14 mmol) and MeI (13.04 g, 91.88 mmol). The mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography column (PE:EtOAc = 4:1 to 3:1) to give 4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (18 g, 58%).

4- Chloro -7-(2,4 -dimethoxybenzyl )-6- hydroxy -5- methyl -6,7- dihydro -5H- pyrrolo [2,3-d] pyrimidine -5- carboxylic acid ethyl ester : To a solution of 4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6-hydroxy-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (5 g, 12.32 mmol) in THF (110 mL) was added _LiBHEt3 (1 M in THF, 61.60 mL) dropwise at -70 °C. The mixture was stirred at -70 °C for 1 hour. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography column (PE:EtOAc = 4:1 to 3:1) to give 4-chloro-7-(2,4-dimethoxybenzyl)-6-hydroxy-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (3 g, 59%).

Ethyl 4- chloro -7-(2,4 -dimethoxybenzyl )-5- methyl -6,7- dihydro -5H- pyrrolo [2,3-d] pyrimidine -5 -carboxylate : To a solution of ethyl 4-chloro-7-(2,4-dimethoxybenzyl)-6-hydroxy-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (3 g, 7.36 mmol) in DCM (30 mL) was added TFA (25.16 g, 220.67 mmol, 16.39 mL) and _Et3SiH (11.97 g, 102.98 mmol, 16.45 mL) at 0°C. The mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into H ₂ O (50 mL) and extracted with DCM (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography column (PE:EtOAc = 4:1 to 3:1) to give 4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (2.5 g, 86%).

(4- Chloro -7-(2,4 -dimethoxybenzyl )-5- methyl -6,7- dihydro -5H- pyrrolo [2,3-d] pyrimidin -5- yl ) methanol : To a solution of ethyl 4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (7.1 g, 18.12 mmol) in THF (120 mL) was added _LiAlH4 (2.5 M in THF, 14.50 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into _H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography column (PE:EtOAc = 2:1 to 1:1) to give (4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol (4.7 g, 74%).

(4-Chloro-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl 2,2,2 -trifluoroacetate: A solution of (4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol (1 g, 2.86 mmol) in TFA (5 mL) was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give (4-chloro-5-methyl-6,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)methyl 2,2,2-trifluoroacetate (600 mg, 71%).

2-(4- Chloro -5-( hydroxymethyl )-5- methyl -5,6- dihydro -7H- pyrrolo [2,3-d] pyrimidin -7- yl ) isonicotinecarbonitrile: General method 2- (4-Chloro-5-methyl-6,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)methyl trifluoroacetate (400 mg, 1.35 mmol), _{K2CO3 (} 280 mg, 2.03 mmol), 2-fluoropyridine-4-carbonitrile (198 mg, 1.62 mmol) in DMF (4 mL) at 80 °C for 16 h. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give 2-(4-chloro-5-(hydroxymethyl)-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isonicotinecarbonitrile (50 mg, 12%).

(2R,5S)-4-[(5R)-7-(4- cyano -2 -pyridinyl )-5-( hydroxymethyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester and (2R,5S)-4-[(5S)-7-(4- cyano -2 -pyridinyl )-5-( hydroxymethyl )-5- methyl -6H- pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester : General method 3- 2-(4-chloro-5-(hydroxymethyl)-5-methyl-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)isocyanatocarbonitrile (30 mg, 0.1 mmol), DIEA (64.25 mg, 0.49 mmol), (2R,5S)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (64 mg, 0.29 mmol) in NMP (1.5 mL) at 140 °C for 48 hours. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30 mm×3 um; mobile phase: A: water containing 0.2% FA, B: MeCN; % B in A: 20%-60%, 8 min) to obtain (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-5-(hydroxymethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (5 mg, 10%, peak 1 (85A); 4 mg, 8%, peak 2 (85B)) as two separate non-mirror image isomers. Example 86 (2R)-4-[7-(4- cyano -2 -pyridinyl ) spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2- methyl -5 -oxopiperazine -1- carboxylic acid tributyl ester

( R )-2- methyl -5 -oxopiperazine -1- carboxylic acid tributyl ester: To a solution of ( R )-5-methylpiperazin-2-one (100 mg, 0.88 mmol) in ACN (2 mL) was added _Boc2O (201 mg, 0.92 mmol) at 20°C. The mixture was stirred at 20°C for 1.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give ( R )-2-methyl-5-oxopiperazine-1-carboxylic acid tributyl ester (230 mg, crude), which was used directly in the next step.

( R )-4-(7'-(4- cyanopyridin- 2- yl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4'- yl )-2- methyl -5 -oxopiperazine -1 - carboxylic acid tert-butyl ester : To a _solution of 2-(4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'( 6'H )-yl)isonicotinecarbonitrile (10 mg, 0.034 mmol) and ( R )-2-methyl-5-oxopiperazine-1-carboxylic acid tert-butyl ester (11 mg, 0.050 mmol) in toluene (0.5 mL) at 20 °C under N2 was added _Cs2CO3 ( ₂₂ mg, 0.067 mmol), Pd ₂ (dba) ₃ (3 mg, 0.0033 mmol), and Xantphos (4 mg, 0.0067 mmol). The mixture was stirred at 100 °C for 8 h. The reaction mixture was poured into H ₂ O (3 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 150 × 25 mm × 10 μm; mobile phase: A: water containing 0.05% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ , B: CH ₃ CN; % of B in A: 45%-70%, 8 min) to give (2R)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methyl-5-oxopiperazine-1-carboxylic acid tributyl ester (10 mg, 12%). Examples 92A and 92B (2R,5S)-4-[(5R)-5-( cyanomethyl )-7-(4- cyano -2 -pyridinyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester and (2R,5S)-4-[(5S)-5-( cyanomethyl )-7-(4- cyano -2 -pyridinyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5- dimethylpiperazine -1- carboxylic acid tributyl ester

Methanesulfonic acid (4- chloro -7-(2,4 -dimethoxybenzyl )-5- methyl -6,7- dihydro - 5H - pyrrolo [2,3- d ] pyrimidin -5- yl ) methyl ester: To _a solution of (4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidin-5-yl)methanol (2 g, 5.72 mmol) in DCM (30 mL) at 0 °C under N2 was added TEA (1.74 g, 17.15 mmol) and MsCl (1.31 g, 11.43 mmol). The mixture was stirred at 20 °C for 2 h. The mixture was quenched by _H2O (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL) and dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give methanesulfonic acid (4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidin-5-yl)methyl ester (1.9 g, 78%).

[0266 ] 2-(4- chloro -7-(2,4 -dimethoxybenzyl )-5- methyl -6,7 -dihydro - 5H - pyrrolo [2,3- d ] pyrimidin -5- yl ) acetonitrile: To a solution of (4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidin-5-yl)methyl methanesulfonate (1.7 g, 3.97 mmol) in DMSO (20 mL) was added NaCN (974 mg, 19.86 mmol). The mixture was stirred at 120 °C for 16 h. The mixture was quenched by _H2O (100 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (80 mL) and dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidin-5-yl)acetonitrile (780 mg, 55%).

2-(4- Chloro-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidin-5-yl)acetonitrile: A mixture of 2-(4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidin-5-yl)acetonitrile (570 mg, 1.59 mmol) in TFA (6 mL) was degassed and purged with _N2 three times. The mixture was stirred at 70 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4-chloro-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidin-5-yl)acetonitrile (330 mg, 99%).

2-(4- Chloro -5-( cyanomethyl )-5- methyl -5H - pyrrolo [2,3 _- d ] pyrimidin -7( 6H ) -yl ) isonicotinecarbonitrile: To a solution of 2-bromopyridine-4-carbonitrile (702 mg, 3.83 mmol) and 2-(4-chloro-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidin-5-yl)acetonitrile (400 mg, 1.92 mmol) in dioxane (10 mL) was added _Pd2 (dba) ₃ (176 mg, 0.19 mmol), Xantphos (222 mg, 0.38 mmol) and _Cs2CO3 (1.25 g, 3.83 mmol) at 20 °C under _N2 . The mixture was stirred at 100 °C for 16 h. The mixture was poured into water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (30 mL) and dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 2-(4-chloro-5-(cyanomethyl)-5-methyl- 5H -pyrrolo[2,3- d ]pyrimidin-7( 6H )-yl)isonicotinecarbonitrile (350 mg, 58%).

(2R,5S)-4-[(5R)-5-( cyanomethyl )-7-(4- cyano -2 -pyridinyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester and (2R,5S)-4-[(5S)-5-( cyanomethyl )-7-(4- cyano -2 -pyridinyl )-5- methyl -6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester : General method 3-2-(4-chloro-5-(cyanomethyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)isocyanatocarbonitrile (50 mg, 0.16 mmol), tributyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (69 mg, 0.32 mmol), DIEA (104 mg, 0.80 mmol) in NMP (1 mL) at 140 °C for 16 h. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 3 μm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % of B in A: 55%-85%, 8 min) to obtain (2R,5S)-4-[5-(cyanomethyl)-7-(4-cyano-2-pyridinyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (5 mg, 6%, peak 1 (92A); 5 mg, 6%, peak 2 (92B)) as two single stereoisomers. Example 93 (2R,5S)-4-[7-(4- cyano -2 -pyridinyl )-2' -fluorospiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclopropane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

4- Chloro -7-[(2,4 -dimethoxyphenyl ) methyl ] -5H - pyrrolo [2,3 -d ] pyrimidin -6- one : A mixture of methyl 2-(4,6-dichloropyrimidin-5-yl)acetate (20 g, 90.48 mmol), (2,4-dimethoxyphenyl)methanamine (15.13 g, 90.48 mmol), DIEA (23.39 g, 180.96 mmol) in EtOH (400 mL) was degassed and purged with _N2 three times at 20 °C. The mixture was stirred at 80 °C under _N2 atmosphere for 12 h. Two batches were combined. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with EtOAc (250 mL) and filtered to afford 4-chloro-7-[(2,4-dimethoxyphenyl)methyl] -5H -pyrrolo[2,3 -d ]pyrimidin-6-one (38 g, 66%).

( 2R , 5S )-tert-butyl 4-(7-(2,4 -dimethoxybenzyl )-6 -oxo -6,7- dihydro - 5H - pyrrolo [2,3- d ] pyrimidin -4- yl )-2,5 -dimethylpiperazine -1- carboxylate : General method 3-4-Chloro-7-(2,4-dimethoxybenzyl)-5,7-dihydro- 6H -pyrrolo[2,3- d ]pyrimidin-6-one (5 g, 15.64 mmol), ( 2R , 5S )-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (4.02 g, 18.77 mmol) in DIEA (40 mL) at 145 °C under _N2 atmosphere for 1 h. The residue was purified by silica gel column chromatography (PE:EtOAc = 2:1 to 1:1) to give ( 2R , 5S )-4-(7-(2,4-dimethoxybenzyl)-6-oxo-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (4 g, 51%).

( 2R , 5S )-4-(7-(2,4 -dimethoxybenzyl )-5- methylene -6 -oxo -6,7- dihydro - 5H - pyrrolo [2,3- d ] pyrimidin -4- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tert-butyl ester : To a solution of ( 2R , 5S )-4-(7-(2,4-dimethoxybenzyl)-6-oxo-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (4 g, 8.04 mmol) in DMSO (60 mL) were added N , N , N' , N' -tetramethylmethanediamine (1.23 g, 12.06 mmol), _Ac2O (2.71 g, 26.53 mmol). mmol). The mixture was stirred at 20 °C for 2 h. The mixture was poured into H ₂ O (180 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give ( 2R , 5S )-4-(7-(2,4-dimethoxybenzyl)-5-methylene-6-oxo-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (2.1 g, 51%).

(2 R ,5 S )-4-(7'-(2,4 -dimethoxybenzyl )-2 -fluoro -6'- oxo -6',7'- dihydrospiro [ cyclopropane -1,5' -pyrrolo [2,3- d ] pyrimidin -4' - yl )-2,5 -dimethylpiperazine- 1- carboxylic acid tert-butyl ester : (4-Chlorophenyl)-(fluoromethyl)-(2,3,4,5-tetramethylphenyl)phosphine tetrafluoroborate (2.65 g, 6.67 mmol) and (2 R ,5 S )-4-(7-(2,4-dimethoxybenzyl)-5-methylene-6-oxo-6,7-dihydro-5 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.7 g, 3.34 mmol) in THF (30 mL) was added NaH (480 mg, 12.01 mmol). The mixture was stirred at 0 °C for 2 h. The mixture was poured into NH ₄ Cl (60 mL) and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give (2 R ,5 S )-4-(7'-(2,4-dimethoxybenzyl)-2-fluoro-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (1.4 g, 77%).

(2 R ,5 S )-4-(7'-(2,4 -dimethoxybenzyl )-2 -fluoro -6',7'- dihydrospiro [ cyclopropane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester : General method 1- AlCl ₃ (1.18 mg, 8.86 mmol), LiAlH ₄ (2.5 M in THF, 8.86 mmol, 3.54 mL), (2 R ,5 S )-tributyl 4-(7'-(2,4-dimethoxybenzyl)-2-fluoro-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (1.6 g, 2.95 mmol) in THF (30 mL). The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give (2 R ,5 S )-4-(7'-(2,4-dimethoxybenzyl)-2-fluoro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (1.5 g, 48%).

4'-(( 2S , 5R )-2,5 -dimethylpiperazin- 1- yl )-2 -fluoro -6',7'- dihydrospiro [ cyclopropane -1,5' -pyrrolo [2,3- d ] pyrimidine ] : To a solution of tributyl ( 2R , 5S )-4-(7'-(2,4-dimethoxybenzyl)-2-fluoro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (650 mg, 1.23 mmol) in TFA (10 mL) was added trifluoromethanesulfonic acid (370 mg, 2.46 mmol). The mixture was stirred at 20 °C for 16 h. The mixture was concentrated, poured into H ₂ O (15 mL), and adjusted to neutral pH. The residue was poured into H ₂ O (10 mL) and extracted with DCM: i -PrOH (v:v = 3:1, 3 × 20 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give 4'-((2 S ,5 R )-2,5-dimethylpiperazin-1-yl)-2-fluoro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3- d ]pyrimidine] (300 mg, 87%).

( 2R , 5S )-4-(2- fluoro -6',7' -dihydrospiro [ cyclopropane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester : To a solution of 4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)-2-fluoro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3- d ]pyrimidine] (300 mg, 1.08 mmol) in DCM (5 mL) was added _Boc2O (142 mg, 0.65 mmol) and TEA (219 mg, 2.16 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was poured into H ₂ O (5 mL) and extracted with DCM (3 × 3 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 2:1 to 1:1) to give (2 R ,5 S )-4-(2-fluoro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (300 mg, 73%).

(2R,5S)-tert-butyl 4-[7-(4- cyano -2 -pyridinyl )-2' -fluorospiro [6H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclopropane ]-4- yl ]-2,5 -dimethylpiperazine -1 - carboxylate : General method 2-2-Fluoropyridine-4-carbonitrile (129 mg, 1.06 mmol), ( 2R , 5S )-tert-butyl 4-(2-fluoro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (200 mg, 0.53 mmol), _{K2CO3 (} 220 mg, 1.59 mmol) in DMSO (3 mL). The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 3 µm; mobile phase: A: water containing 0.2% FA, B: ACN; % B in A 45%-88%, 8.0 min). (2 R ,5 S )-4-(7'-(4-cyanopyridin-2-yl)-2-fluoro-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (21 mg, 8%, peak 1) was obtained as a single unknown isomer. Example 100 (2R,5S)-2,5 -dimethyl -4-[7-([1,2,4] triazolo [4,3-a] pyrazin -6- yl ) spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ] piperazine -1- carboxylic acid tributyl ester

(2R,5S)-2,5 -dimethyl -4-[7-([1,2,4] triazolo [4,3-a] pyrazin -6- yl ) spiro [6H -pyrrolo [2,3-d] pyrimidin -5,1'- cyclobutane ]-4- yl ] piperazine -1- carboxylic acid tributyl ester : To a solution of 6-chloro-[1,2,4]triazolo[4,3- a ]pyrazine (41 mg, 0.27 mmol) and ( 2R , 5S )-4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3 -d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (50 mg, 0.14 mmol) in dioxane (1 mL) was added Xantphos (15.49 mg, 0.03 mmol), Pd ₂ (dba) ₃ (12.26 mg, 0.01 mmol), and Cs ₂ CO ₃ (87 mg, 0.27 mmol). The mixture was stirred at 100 °C for 16 h. The mixture was quenched by H ₂ O (3 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (3 mL) and dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 3 μm; mobile phase: A: water containing 0.2% FA, B: MeCN; % B in A: 45%-75%, 8 min) to give (2R,5S)-2,5-dimethyl-4-[7-([1,2,4]triazolo[4,3-a]pyrazin-6-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]piperazine-1-carboxylic acid tert-butyl ester (6 mg, 5%). Example 107 (2R,5S)-4-[7-(4- cyano -2 -pyridinyl )-5- methyl -5-( methylaminoformyl )-6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

Ethyl 4- chloro-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine-5-carboxylate: _A solution of ethyl 4-chloro-7-(2,4-dimethoxybenzyl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine-5-carboxylate (1.5 g, 3.83 mmol) in TFA (5 mL) was stirred at 70 °C under N2 for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give ethyl 4-chloro-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidine-5-carboxylate (1.2 g, 65%).

Ethyl 4- chloro -7-(4- cyanopyridin- 2- yl )-5- methyl -6,7 -dihydro- 5H - pyrrolo [2,3- d ] pyrimidine -5 -carboxylate: General method 2 -Ethyl 4-chloro-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidine-5-carboxylate (1.2 g, 4.97 mmol), 2- _{fluoroisocyanatocarbonitrile} (1.82 g, 14.90 mmol), _K2CO3 (2.06 g, 14.90 mmol) in DMSO (20 mL). The residue was triturated with MTBE and filtered to give ethyl 4-chloro-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidine-5-carboxylate (1.3 g, 76%).

Ethyl 4-(( 2S , 5R )-4-(tributyloxycarbonyl)-2,5-dimethylpiperazin-1-yl)-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine-5-carboxylate: General procedure Tributyl 3-( 2R , 5S )-2,5-dimethylpiperazine-1-carboxylate (1.62 g, 7.56 mmol), ethyl 4-chloro-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine-5-carboxylate (1.3 g, 3.78 mmol) and DIEA (2.44 g, 18.91 mmol) in NMP (20 mL). The residue was purified by silica gel column chromatography (PE:EtOAc = 2:1 to 1:1) to give ethyl 4-(( 2S , 5R )-4-(tributyloxycarbonyl)-2,5-dimethylpiperazin-1-yl)-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidine-5-carboxylate (1.2 g, 61%).

4-(( 2S , 5R )-4-( tri-butyloxycarbonyl )-2,5 -dimethylpiperazin -1- yl )-7-(4- cyanopyridin- 2- yl )-5- methyl -6,7- dihydro - 5H - pyrrolo [2,3- d ] pyrimidine -5- carboxylic acid : To a solution of ethyl 4-(( 2S , 5R )-4-(tri-butyloxycarbonyl)-2,5-dimethylpiperazin-1-yl)-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3-d]pyrimidine-5-carboxylate (0.5 g, 0.96 mmol) in MeCN (10 mL) and _H2O (2 mL) was added 3,4,6,7,8,9-hexahydro- 2H -pyrimido[1,2-a]pyrimidine (267 mg, 1.92 mmol). The mixture was stirred at 20 °C for 6 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H ₂ O (20 mL), then adjusted to pH = 2 and extracted with EtOAc (3 × 8 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 1:2) to give 4-(( 2S , 5R )-4-(tributyloxycarbonyl)-2,5-dimethylpiperazin-1-yl)-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine-5-carboxylic acid (0.1 g, 21%).

(2R,5S)-4-[7-(4- cyano -2 -pyridinyl )-5- methyl -5-( methylaminocarbonyl )-6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester : 4-(( 2S , 5R )-4-(tributyloxycarbonyl)-2,5-dimethylpiperazin-1-yl)-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3- d ]pyrimidine-5-carboxylic acid (100 mg, 0.20 mmol), methylamine hydrochloride (41 mg, 0.61 mmol), DIEA (131 mg, 1.01 mmol), HATU (92 mg, 0.24 mmol) in DMF (2 The mixture in 50 mL) was degassed and purged with _N2 three times, then the mixture was stirred at 20 °C under _N2 atmosphere for 3 h. The mixture was poured into _H2O (5 mL) and extracted with EtOAc (3 x 3 mL). The combined organic phases were washed with brine (5 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by p-HPLC (column: Phenomenex Luna C18 100 × 30 mm × 3 µm; mobile phase: A: water containing 0.2% FA, B: MeCN; % B in A: 25%-55%, 8 min) to give a non-mirror isomeric mixture of (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-5-methyl-5-(methylaminocarbonyl)-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (19 mg, 18%). Example 116 (2R,5S)-4-[7-(4- cyano -2 -pyridinyl )-5- methyl -5-(5- methyl -1,3,4- oxadiazol -2- yl )-6H -pyrrolo [2,3-d] pyrimidin -4 - yl ]-2,5- dimethylpiperazine -1- carboxylic acid tributyl ester

( 2R , 5S )-4-(5-(2- acetylhydrazine -1- carbonyl )-7-(4- cyanopyridin -2- yl )-5- methyl -6,7- dihydro - 5H - pyrrolo [2,3- d ] pyrimidin -4 - yl )-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester : To a solution of 4-(( 2S , 5R )-4-(tributyloxycarbonyl)-2,5-dimethylpiperazin-1-yl)-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidine-5-carboxylic acid (70 mg, 0.14 mmol) in DMF (1 mL) were added HATU (54 mg, 0.14 mmol), acetylhydrazine (16 mg, 0.21 mmol) and DIEA. (18 mg, 0.14 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H ₂ O (3 mL) and extracted with EtOAc (3 x 2 mL). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , PE:EtOAc = 3:1 to 1:1) to give (2 R ,5 S )-4-(5-(2-acetylhydrazine-1-carbonyl)-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro-5 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (35 mg, 45%).

(2R,5S)-4-[7-(4- cyano -2 -pyridinyl )-5- methyl -5-(5- methyl -1,3,4- oxadiazol -2- yl )-6H -pyrrolo [2,3-d] pyrimidin -4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester : To a solution of ( _2R , 5S )-4-(5-(2-acetylhydrazine-1-carbonyl)-7-(4-cyanopyridin-2-yl)-5-methyl-6,7-dihydro- 5H -pyrrolo[2,3 -d ]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (20 mg, 0.04 mmol) in MeCN (1 mL) at 20 °C under N2 was added p-TsCl (8 mg, 0.04 mmol) and DIEA (17 mg, 0.13 mmol). The mixture was stirred at 70 °C for 16 h. The reaction was diluted with H ₂ O (3 mL) and extracted with EtOAc (3 × 2 mL). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 3 μm; mobile phase: [A: water containing 10 mM FA, B: CH ₃ CN; % of B in A: 50%-80%], 8 min) to give (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-5-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (14 mg, 74%). Example 133 6-[4-[(2S,5R)-4-(1- cyanocyclobutanecarbonyl )-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridazine -4- carbonitrile

( 2R , 5S )-4-(7'-(5- cyanopyridazin- 3- yl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tert-butyl ester : To a solution of ( _2R , 5S )-4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.34 mmol) in 1,4-dioxane (10 mL) at 20 °C under N2 was added 6-chloropyridazine-4-carbonitrile (374 mg, 2.68 mmol) _{, K2CO3} (370 mg, 2.68 mmol), XPhos (128 mg, 0.27 mmol) and Pd ₂ (dba) ₃ (123 mg, 0.13 mmol). The mixture was stirred at 110° C. for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give (2 R ,5 S )-4-(7'-(5-cyanopyridazin-3-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (600 mg, 78%).

6-(4'-(( 2S , 5R )-2,5 -dimethylpiperazin -1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-7'( 6'H ) -yl ) pyridazine -4 -carbonitrile hydrochloride : To a solution of tributyl ( 2R , 5S )-4-(7'-(5-cyanopyridazin-3-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (100 mg, 0.21 mmol) in MeOH (10 mL) was added HCl/MeOH (4 M, 3 mL) at 20°C. The mixture was stirred at 20°C for 3 h. The reaction mixture was concentrated under reduced pressure to give 6-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)pyridazine-4-carbonitrile hydrochloride (100 mg).

6-[4-[(2S,5R)-4-(1- cyanocyclobutanecarbonyl )-2,5 -dimethylpiperazin- 1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridazine -4 -carbonitrile : General method 6-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)pyridazine-4-carbonitrile hydrochloride (50 mg, 0.12 mmol), 1-cyanocyclobutane-1-carboxylic acid (30 mg, 0.24 mmol), DIEA (78 mg, 0.61 mmol), CMPI (46 mg, 0.18 mmol) in THF The residue was purified by preparative HPLC (Phenomenex Luna C 18 80 × 30 mm × 3 μm; mobile phase A: water containing 0.2% FA, B: MeCN; B% in A: 45%-75%, 8.0 min) to give 6-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile (10 mg, 17%). Example 171 (2R,5S)-4-[7-[4- cyano -6-( hydroxymethyl )-2 -pyridinyl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

( 2R , 5S )-tert-butyl 4-(7'-(6- chloro -4 -cyanopyridin -2- yl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4' - yl )-2,5 -dimethylpiperazine -1- carboxylate : To a solution of tert-butyl ( 2R , 5S )-4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (50 mg, 0.133 mmol) in DMF (0.5 mL) at 0 °C was added NaH (8 mg, 0.20 mmol, 60% dispersion in mineral oil). The mixture was stirred at 0 °C for 0.5 h, and 2,6-dichloropyridine-4-carbonitrile (35 mg, 0.200 mmol) in DMF (0.5 mL) was added dropwise. The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into H ₂ O (3 mL) and extracted with EtOAc (3×3 mL). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 2:1 to 1:1) to give (2 R ,5 S )-tert-butyl 4-(7'-(6-chloro-4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (50 mg, 60%).

(2R,5S)-4-[7-[4- cyano- 6-( hydroxymethyl )-2 -pyridinyl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester _: To a solution of ( 2R , 5S )-4-(7'-(6-chloro-4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (30 mg, 0.058 mmol) in dioxane (2 mL) was added Pd( _PPh3 ) ₄ (7.0 mg, 0.006 mmol) and tributyltinylmethanol (38 mg, 0.117 mmol). The mixture was stirred at 90 °C for 6 h. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30 mm×3 um; mobile phase: A: water containing 0.2% FA, B: MeCN; % of B in A: 55%-90%, 8 min) to give (2R,5S)-4-[7-[4-cyano-6-(hydroxymethyl)-2-pyridinyl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (7 mg, 25%). Example 189 (2R,5S)-4-[7-(2- cyano -5- fluoro- 4 -pyridinyl ) spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

( 2R , 5S )-4-(7'-(2- chloro -5 -fluoropyridin -4- yl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4'- yl )-2,5 -dimethylpiperazine- 1- carboxylic acid tributyl ester : To _a solution of ( 2R , 5S )-4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (200 mg, 0.535 mmol) in dioxane (4 mL) under N2 was added 4-bromo-2-chloro-5-fluoro-pyridine (169 mg, 0.803 mmol), _Pd2 (dba) ₃ (49 To the mixture was added ₄ % paraformaldehyde (5% paraformaldehyde) (2% paraformaldehyde, 1% paraformaldehyde) (3% paraformaldehyde, 1% _{paraformaldehyde} ) (4% paraformaldehyde, 1% paraformaldehyde) (5% paraformaldehyde, 1% paraformaldehyde) (6% paraformaldehyde, 1% paraformaldehyde) (7% paraformaldehyde, 1% paraformaldehyde) (8% paraformaldehyde, 1% paraformaldehyde) (9% paraformaldehyde, 1% paraformaldehyde) (10% paraformaldehyde, 1% paraformaldehyde) (20% paraformaldehyde _{, 1} % paraformaldehyde) (40% paraformaldehyde, 1% paraformaldehyde) (60% paraformaldehyde, 1% paraformaldehyde) (80% paraformaldehyde, ₁ % paraformaldehyde) (90% paraformaldehyde, 1% paraformaldehyde) (80% paraformaldehyde, 1% paraformaldehyde) (80% paraformaldehyde, 1% paraformaldehyde) ( The residue was purified by silica gel chromatography (PE:EtOAc = 4:1 to 3:1) to give ( 2R , 5S )-tert-butyl 4-(7'-(2-chloro-5-fluoropyridin-4-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3 -d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (150 mg, 55%).

(2R,5S)-4-[7-(2- cyano -5 -fluoro -4 -pyridinyl ) spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester _: To a solution of ( 2R , 5S )-4-(7'-(2-chloro-5-fluoropyridin-4-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (150 mg, 0.30 mmol) in DMA (1 mL) under N2 was added DPPF (8 mg, 0.015 mmol), Pd(OAc) ₂ (4 mg, 0.015 mmol) and Zn(CN) ₂ (24 mg, 0.21 mmol). The mixture was stirred at 120 °C for 16 h. The mixture was carefully poured into aqueous NaHCO ₃ solution (5 mL) and extracted with EtOAc (3 x 3 mL). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 80 × 30 mm × 3 um; mobile phase: [A: H ₂ O containing 0.2% FA; B: ACN; % B in A: 50%-80%], 8.0 min) to give (2R,5S)-4-[7-(2-cyano-5-fluoro-4-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (109 mg, 74%). Example 206 (2R,5S)-4-[7-(3- cyanocyclopentyl ) spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

(2R,5S)-tert-butyl 4-[7-(3- cyanocyclopentyl ) spiro [6H -pyrrolo [2,3-d] pyrimidin -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylate : To a solution of ( _2R , 5S ) -tert-butyl 4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (50 mg, 0.12 mmol) and 3-hydroxycyclopentane-1-carbonitrile (68 mg, 0.6 mmol) in toluene (1 mL) was added CMBP (147 mg, 0.6 mmol) at 20 °C under N2. The mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (5 mL) and then extracted with EtOAc (3 x 4 mL). The combined organic layers were washed with brine (5 mL), dried over _Na2SO4 , _filtered , and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % of B in A: 50%-88%, 8 min) to give (2R,5S)-4-[7-(3-cyanocyclopentyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (17 mg, 30%). Example 210 (2R,5S)-4-[7-(3- cyanocyclobutyl ) spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

3- Cyanocyclobutyl methanesulfonate: To a solution of 3-hydroxycyclobutanecarbonitrile (100 mg, 1.03 mmol) and methanesulfonic anhydride (179 mg, 2.06 mmol) in DCM (2 mL) was added TEA (417 mg, 4.12 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with _H2O (3 mL) and extracted with DCM (3 x 3 mL). The combined organic layers were washed with brine (3 _mL ), dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give 3-cyanocyclobutyl methanesulfonate (120 mg, crude).

(2R,5S)-tert-butyl 4-[7-(3- cyanocyclobutyl ) spiro [6H -pyrrolo [2,3-d] pyrimidin -5,1' -cyclobutane ]-4- yl ]-2,5 -dimethylpiperazine -1- carboxylate : To a solution of ( _2R , 5S ) -tert-butyl 4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (30 mg, 0.08 mmol) in DMF (1 mL) was added NaH (4.82 mg, 0.120 mmol, 60% dispersion in mineral oil) at 0 °C under N2. Then, 3-cyanocyclobutyl methanesulfonate (42 mg, 0.24 mmol) was added. The mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was quenched by aqueous _NH4Cl (5 mL ₎ and extracted with EtOAc (3 x 2 mL). The combined organic layers were washed with brine (2 mL), dried over _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % of B in A: 50%-80%, 8 min) to give (2R,5S)-4-[7-(3-cyanocyclobutyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (25 mg, 69%). Examples 213A and 213B 2-[4-[(2S,5R)-4-[(2R)-2- cyano -3- fluoro -2 -methylpropanoyl ]-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4 -carbonitrile and 2-[4-[(2S,5R)-4-[(2S)-2- cyano -3- fluoro -2 -methylpropanoyl ]-2,5 -dimethylpiperazin -1 - yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

Ethyl 2- cyano -3- hydroxy - 2-methylpropanoate : To a mixture of ethyl 2-cyanopropanoate (6.9 g, 54.27 mmol) in CH ₃ CN (100 mL), paraformaldehyde (4.9 g, 162.81 mmol), TEA (275 mg, 2.71 mmol) were added. The mixture was stirred at 50° C. under N ₂ for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 4:1 to 3:1) to give ethyl 2-cyano-3-hydroxy-2-methylpropanoate (7.9 g, 93%).

Ethyl 2- cyano -3 - fluoro - 2-methylpropanoate : To a solution of ethyl 2-cyano-3-hydroxy- _2- methyl-propanoate (3.5 g, 22.27 mmol) in DCM (30 mL) was added DAST (17.95 g, 111.35 mmol) at 0 °C. The mixture was stirred at 20 °C for 16 h. The mixture was quenched by NaHCO3 (100 mL) and extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 6:1 to 5:1) to give ethyl 2-cyano-3-fluoro-2-methylpropanoate (2.2 g, 62%).

2- Cyano -3- fluoro -2- methylpropanoic acid : To a solution of 2-cyano-3-fluoro-2-methyl-propionic acid ethyl ester (640 mg, 4.02 mmol) in THF (10 mL) and H ₂ O (2 mL) was added LiOH•H ₂ O (506 mg, 12.06 mmol) at 20° C. The mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with H ₂ O (10 mL), extracted with MTBE (10 mL) and the aqueous phase was adjusted to pH = 1 by 3N HCl and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried _{over Na2SO4} , filtered, and concentrated under reduced pressure to give 2-cyano-3-fluoro-2-methylpropanoic acid (0.5 g, 95%).

2-[4-[(2S,5R)-4-[(2R)-2- cyano - 3- fluoro -2-methylpropanoyl ]-2,5 -dimethylpiperazin- 1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4 -carbonitrile and 2-[4-[(2S,5R)-4-[(2S)-2- cyano -3- fluoro -2- methylpropanoyl ]-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile : General Method 6- 2-(4'-((2S,5R)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidin]-7'(6'H)-yl)isonicotinecarbonitrile hydrochloride (500 mg, 1.21 mmol), 2-cyano-3-fluoro-2-methyl-propionic acid (477 mg, 3.64 mmol), DIEA (1.10 g, 8.50 mmol), CMPI (930 mg, 3.64 mmol) in THF (7 mL) at 50 °C for 2 h. The mixture was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm×30 mm, 10 um); mobile phase: [CO ₂ -EtOH (0.1% NH ₃ H ₂ O)]; B%: 50%, isocratic elution mode) to obtain 2-[4-[(2S,5R)-4-[2-cyano-3-fluoro-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (104 mg, 5.4%, peak 1 (213A); 102 mg, 17.2%, peak 2 (213B)) as two separate non-mirror isomers. Examples 215A and 215B 2-[4-[(2S,5R)-4-[(2S)-2- cyano -3,3 -difluoro -2 -methylpropanoyl ]-2,5 -dimethylpiperazin- 1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4 -carbonitrile and 2-[4-[(2S,5R)-4-[(2R)-2- cyano -3,3 -difluoro -2 -methylpropanoyl ]-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine - 4-carbonitrile

2-(4'-(( 2S , 5R )-4-(2- cyanopropanoyl )-2,5 -dimethylpiperazin- 1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-7'( 6'H )-yl ) isonicotinecarbonitrile : General Method 6-2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6'H ) -yl)isonicotinecarbonitrile hydrochloride (0.5 g, 1.21 mmol), CMPI (465 mg, 1.82 mmol), DIEA (784 mg, 6.07 mmol, 1.06 mL), 2-cyanopropionic acid (180 mg, 1.82 mmol) in THF (10 mL) at 20°C. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) to give 2-(4'-(( 2S , 5R )-4-(2-cyanopropanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'( 6'H )-yl)isonicotinecarbonitrile (0.36 g, 64%).

2- [4-[(2S,5R)-4-[(2S)-2- cyano -3,3 -difluoro -2 -methylpropanoyl ]-2,5 -dimethylpiperazin- 1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7 -yl ] pyridine -4 -carbonitrile and 2-[4-[(2S,5R)-4-[(2R)-2- cyano -3,3 -difluoro -2 -methylpropanoyl ]-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile : 2-(4'-((2 S ,5 R To a solution of (4-(2-cyanopropanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'( 6'H )-yl)isonicotinecarbonitrile (0.4 g, 0.88 mmol) in THF (10 mL) was added LiHMDS (1 M, 0.88 mL). The mixture was stirred at -78 °C for 30 min. MeLi (1 M, 0.88 mL) was then added to the mixture and stirred for 10 min. TMSCF ₃ (623 mg, 4.38 mmol) was added at -78 °C. The mixture was stirred at 20 °C for 16 h. The mixture was quenched by saturated aqueous NH ₄ Cl solution (30 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) and then by chiral SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 um); mobile phase: [CO ₂ -EtOH (0.1% NH ₃ H ₂ O)]; B%: 35%, isocratic elution mode) to obtain 2-(4'-((2 S ,5 R )-4-(2-cyano-3,3-difluoro-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H ) as two separated non-mirror isomers. )-yl)isonicotinecarbonitrile (30 mg, 7%, peak 1 (215A); 35 mg, 8%, peak 2 (215B)). Example 216 2-[4-[(2S,5R)-4-[(2S)-2- amino - 3- methoxy -2- methylpropanoyl ]-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

( S )-methyl 2-(( tert-butyloxycarbonyl ) amino )-3- methoxy -2 -methylpropanoate: To a mixture of ( S )-2-((tert-butyloxycarbonyl)amino)-3-hydroxy-2-methylpropanoic acid (150 mg, 0.68 mmol) and MeI (971 mg, 6.84 mmol, 0.42 mL) in _CH3CN ( ₄ mL) was added _Ag2O (793 mg, 3.42 mmol) at 20°C under N2. The mixture was stirred at 20°C for 16 h. The mixture was filtered and concentrated under reduced pressure to give methyl ( S )-2-((tert-butyloxycarbonyl)amino)-3-methoxy-2-methylpropanoate (0.17 g, crude).

( S )-2-(( tert-Butyloxycarbonyl ) amino )-3- methoxy -2- methylpropanoic acid: To a solution of ( S )-2-((tert-Butyloxycarbonyl)amino)-3-methoxy-2-methylpropanoic acid methyl ester (0.2 g, 0.81 mmol) in THF (4 mL) and _H2O (0.8 mL) was added LiOH• _H2O (102 mg, 2.43 mmol) at 20°C. The mixture was stirred at 20°C for 3 h. The mixture was poured into water (10 mL) and extracted with MTBE (3 × 3 mL), and the aqueous phase was then adjusted to pH = 4 by 1 N HCl. The mixture was then extracted with EtOAc (3 × 3 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give ( S )-2-((tert-butyloxycarbonyl)amino)-3-methoxy-2-methylpropanoic acid (60 mg, 32%).

(( S )-1-(( 2R , 5S )-4-(7'-(4- cyanopyridin -2- yl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4' - yl )-2,5 -dimethylpiperazin -1- yl )-3- methoxy -2- methyl -1- oxopropan -2- yl ) carbamic acid tributyl ester : General method 6-2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (70 mg, 0.17 mmol), HATU (78 mg, 0.20 mmol), DIEA (110 mg, 0.85 mmol, 0.15 mL), ( S )-2-((tributyloxycarbonyl)amino)-3-methoxy-2-methylpropanoic acid (59 mg, 0.25 mmol) in DMF (1 mL) at 20 °C for 16 h. The residue was purified by preparative TLC (PE:EtOAc = 1:3) to give (( S )-1-(( 2R , 5S )-4-(7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazin-1-yl)-3-methoxy-2-methyl-1-oxopropan-2-yl)carbamic acid tributyl ester (56 mg, 56%).

2-[4-[(2S,5R)-4-[(2S)-2- amino -3- methoxy -2 -methylpropanoyl ]-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1' - cyclobutane ]-7- yl ] pyridine -4- carbonitrile : (( S )-1-(( 2R , 5S )-4-(7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazin-1-yl)-3-methoxy-2-methyl-1-oxopropan-2-yl)carbamic acid tributyl ester (56 mg, 0.09 mmol) in HCl/EtOAc (4 M, 1 mL) was stirred for 4 h. The mixture was then heated at 30 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: 3-Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: A: water containing 0.04% HCl, B: MeCN; % B in A: 20%-55%, 8 min) to give 2-[4-[(2S,5R)-4-[(2S)-2-amino-3-methoxy-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (31 mg, 63%). Example 217 2-[4-[(2S,5R)-4-(3- fluoro -2- methoxy -2 -methylpropanoyl )-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7- yl ] pyridine -4- carbonitrile

2- Methoxypropionic acid 2,4 -dimethoxybenzyl ester : To a mixture of (2,4-dimethoxyphenyl)methanol (646 mg, 3.84 mmol) and 2-methoxypropionic acid (400 mg, 3.84 mmol) in DCM (5 mL) at 0 °C was added DMAP (235 mg, 1.92 mmol), EDCI (1.47 g, 7.68 mmol). The mixture was stirred at 20 °C for 12 h. The mixture was poured into H ₂ O (10 mL) and extracted with DCM (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 3:1) to give 2,4-dimethoxybenzyl 2-methoxypropanoate (900 mg, 92%) .

2,4 - Dimethoxybenzyl 3 - fluoro - 2- methoxy -2-methylpropanoate : To a solution of 2,4-dimethoxybenzyl 2-methoxypropanoate (500 mg, 1.97 mmol) in THF (10 mL) at -78 °C under _N2 was added LDA (2 M in THF, 1.18 mL) and HMPA (247 mg, 1.38 mmol). The mixture was stirred at -78 °C for 0.5 h, followed by the addition of bromofluoromethane (555 mg, 4.92 mmol). The mixture was stirred at -78 °C for 1 h. The mixture was quenched by aqueous _NH4Cl solution (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 4:1) to give 2,4-dimethoxybenzyl 3-fluoro-2-methoxy-2-methylpropanoate (170 mg, 30%).

3- Fluoro -2- methoxy -2- methylpropanoic acid : To a solution of 2,4-dimethoxybenzyl 3-fluoro-2-methoxy-2-methylpropanoate (0.17 g, 0.59 mmol) in THF (2 mL) and H ₂ O (0.5 mL) was added LiOH • H ₂ O (74.75 mg, 1.78 mmol) at 20° C. The mixture was then stirred at 20° C. for 2 hours, followed by the addition of NaOH (1 M, 0.59 mL) and the mixture was stirred at 50° C. for 4 hours. The reaction mixture was diluted with H ₂ O (10 mL), extracted with MTBE (10 mL) and the aqueous phase was adjusted to pH = 1 by 3N HCl and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried _{over Na2SO4} , filtered, and concentrated under reduced pressure to give 3-fluoro-2-methoxy-2-methylpropanoic acid (50 mg, 62%).

2-[4-[(2S,5R)-4-(3- fluoro -2- methoxy -2 -methylpropanoyl )-2,5 -dimethylpiperazin- 1 -yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7 -yl ] pyridine -4 -carbonitrile : General method 6-2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isocyanate (30 mg, 0.08 mmol), 3-fluoro-2-methoxy-2-methylpropanoic acid (22 mg, 0.16 mmol), DIEA (52 mg, 0.40 mmol), CMPI (41 mg, 0.16 mmol) in THF (1 mL) at 50 °C for 2 h. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 µm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % B in A: 53%-85%, 8 min) to give 2-[4-[(2S,5R)-4-(3-fluoro-2-methoxy-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (6 mg, 15%). Example 218 2-[4-[(2S,5R)-4-[3- fluoro -2-( fluoromethyl )-2- methylpropanoyl ]-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

Benzyl 3- hydroxy -2-( hydroxymethyl )-2 -methylpropanoate: To a solution of 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (2 g, 14.91 mmol) in DMF (20 mL) at 0 °C under _N2 was _{added K2CO3} (3.09 g, 22.37 mmol) and (bromomethyl)benzene (3.83 g, 22.37 mmol). The mixture was stirred at 0 °C for 6 h. The reaction mixture was poured into _H2O (60 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) to give benzyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (3 g, 90%).

Benzyl 3- fluoro -2-( fluoromethyl )-2 -methylpropanoate: To a solution of benzyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (2.2 g, 9.81 mmol) in DCM (40 mL) at -20 °C under _N2 was added DAST (4.74 g, 29.43 mmol) dropwise. The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by saturated aqueous _NaHCO3 solution (50 mL) and extracted with DCM ( 3 x 20 mL). The combined organic layers were washed with brine ( 2 x 20 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 ) to give benzyl 3-fluoro-2-(fluoromethyl)-2-methylpropanoate (300 mg, 13%).

3- Fluoro -2-( fluoromethyl )-2- methylpropanoic acid: To a solution of benzyl 3-fluoro-2-(fluoromethyl)-2-methylpropanoate (150 mg, 0.66 mmol) in THF (1.5 mL) and H ₂ O (0.5 mL) was added LiOH•H ₂ O (83 mg, 1.97 mmol) at 20° C. The mixture was stirred at 20° C. for 12 h. The reaction mixture was concentrated to remove THF, and then the aqueous phase was adjusted to pH = 2 by 1N HCl and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine ( 3 x 5 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure to give 3-fluoro- _2- (fluoromethyl)-2-methylpropanoic acid (120 mg, crude).

2-[4-[(2S,5R)-4-[3- fluoro -2-( fluoromethyl )-2- methylpropanoyl ]-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7 -yl ] pyridine -4- carbonitrile : General Method 6-3-Fluoro-2-(fluoromethyl)-2-methylpropanoic acid (120 mg, 0.70 mmol), 2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isocyanate carbonitrile hydrochloride (286 mg, 0.70 mmol), CMPI (266 mg, 1.04 mmol) and DIEA (449 mg, 3.48 mmol) in THF (3 mL) at 50 °C for 2 h. The residue was purified by preparative HPLC (Phenomenex Luna C 18 100 × 30 mm × 3 μm; mobile phase A: water containing 0.2% FA, B: MeCN; B% in A: B%: 30%-70%, 8 min) to give 2-[4-[(2S,5R)-4-[3-fluoro-2-(fluoromethyl)-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (10 mg, 3%). Examples 222A and 222B 2-[4-[(2S,5R)-4-[(2R)-3- fluoro - 2- methyl -2- methylsulfonyl - propionyl ]-2,5 -dimethyl - piperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile and 2-[4-[(2S,5R)-4-[(2S)-3- fluoro -2- methyl -2- methylsulfonyl - propionyl ]-2,5 -dimethyl - piperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

Methyl 3- fluoro -2- methyl -2-( methylsulfonyl ) propanoate: To a solution of ethyl 2-methylsulfonylpropanoate (200 mg, 1.11 mmol) in DMF (2 mL) at 0 °C under _N2 was added NaH (88.77 mg, 2.22 mmol, 60% purity). The mixture was stirred at 0 °C for 0.5 h. Bromo(fluoro)methane (250 mg, 2.22 mmol) was added and the mixture was stirred at 20 °C for 11.5 h. The reaction mixture was poured into aqueous _NH4Cl solution (10 mL). The mixture was extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (3 x 3 mL), dried over anhydrous _{Na2SO4 ,} filtered, and concentrated under reduced pressure to give 3-fluoro-2-methyl-2-methylsulfonyl-propionic acid ethyl ester (170 mg, 72%).

3- Fluoro -2- methyl -2-( methylsulfonyl ) propanoic acid: To a solution of 3-fluoro-2-methyl-2-methylsulfonyl-propionic acid ethyl ester (120 mg, 0.57 mmol) in THF (2 mL) and H ₂ O (1 mL) was added LiOH-H ₂ O (59 mg, 1.41 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H ₂ O (2 mL) and extracted with MTBE (2 mL). The aqueous phase was adjusted to pH=1 by 3N HCl and extracted with EtOAc (3×1 mL). The combined organic layers were washed with brine (1 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give 3-fluoro-2-methyl-2-methylsulfonyl-propionic acid (50 mg, 48%).

6-[4-[(2S,5R)-4-[(2S)-2- cyano - 3- fluoro - 2-methylpropanoyl ]-2,5 -dimethylpiperazin- 1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridazine -4- carbonitrile and 6-[4-[(2S,5R)-4-[(2R)-2- cyano -3- fluoro -2- methylpropanoyl ]-2,5 -dimethylpiperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1' -cyclobutane ]-7- yl ] pyridazine -4 -carbonitrile : General Methods 6- 2-[4-[( 2S , 5R )-2,5-dimethylpiperazin-1-yl]spiro[ 6H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile hydrochloride (110 mg, 0.27 mmol), 3-fluoro-2-methyl-2-methylsulfonyl-propionic acid (50 mg, 0.27 mmol), DIEA (172.56 mg, 1.34 mmol), CMPI (81.87 mg, 0.32 mmol) in THF (5 mL) at 50 °C for 6 h. The chromatograms were analyzed by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % B in A: 50%-80%, 8.0 min), followed by SFC (column: ChiralPak IH, 250 × 30 mm, 10 um; mobile phase: [CO ₂ -EtOH (0.1% NH ₃ H ₂ O)]; B%: 45%, isocratic elution mode) to give 2-[4-[(2S,5R)-4-[3-fluoro-2-methyl-2-methylsulfonyl-propionyl]-2,5-dimethyl-piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (18 mg, 39%, peak 1 (222A); 15 mg, 32%, peak 2 (222B)) as two single stereoisomers. Example 225 2-(4'-((2S,5R)-4-(2- cyano -3- fluoro -2- ( fluoromethyl ) propanoyl )-2,5 -dimethylpiperazin -1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3-d] pyrimidine ]-7'(6'H) -yl ) isonicotinecarbonitrile

2-(4'-(( 2S , 5R )-4-(2- cyanoacetyl )-2,5 -dimethylpiperazin- 1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-7'( 6'H ) -yl ) isonicotinecarbonitrile : General method 6-2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (200 mg, 0.53 mmol), CMPI (204 mg, 0.80 mmol), DIEA (344 mg, 2.66 mmol), 2-cyanoacetic acid (68 mg, 0.80 mmol) in THF (6 mL) at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( PE:EtOAc = 1:2 ) to give 2-(4'-(( 2S , 5R )-4-(2-cyanoacetyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (150 mg, 64%).

2-(4'-(( 2S , 5R )-4-(2- cyano -3- hydroxy -2-( hydroxymethyl ) propanoyl )-2,5 -dimethylpiperazin- 1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-7'( 6'H ) -yl ) isonicotinecarbonitrile : 2-(4'-(( _2S , 5R ) -4-(2-cyanoacetyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3 -d ]pyrimidin]-7'( 6'H )-yl)isonicotinecarbonitrile (30 mg, 0.07 mmol) and 37% formaldehyde solution (7 mg, 0.09 To a solution of 4-(4-(2-[4-(2-[2-(4-(2-nitro-1-yl)-4-yl)-1-yl)-2-nitropropene (7-[2-nitro-1-yl)-1-nitropropene) (2-[2-nitro-1-yl)-1-nitropropene) (2-[2-nitro-1-yl)-1-nitropropene) (2-[2-nitro-1-yl)-1-nitropropene) ( 2- [ _2- nitro- 1 -yl)-1-nitropropene) (2-[2-nitro-1-yl)-1-nitropropene) (2-[2-nitro-1-yl)-1-nitropropene) ( 2- [2-nitro-1-yl)-1-nitropropene) (2-[2-nitro-1-yl)-1-nitropropene) (2-[2-nitro- 1 -yl)-1-nitropropene) ( _2- [ _2- nitro-1-yl)-1-nitropropene) (2-[2- nitro-1-yl)-1-nitropropene) The residue was purified by preparative TLC (silica gel, PE:EtOAc = 1:2 ) to give 2-(4'-(( 2S , 5R )-4-(2-cyano-3-hydroxy-2-(hydroxymethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (20 mg, 59%).

2-(4'-(( 2S , 5R )-4-(2- cyano -3- fluoro -2-( fluoromethyl ) propanoyl )-2,5 -dimethylpiperazin- 1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-7'( 6'H ) -yl ) isonicotinecarbonitrile : 2-(4'-(( _2S , 5R )-4-(2- cyano -3-hydroxy-2-(hydroxymethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'( 6'H )-yl)isonicotinecarbonitrile (20 mg, 0.04 mmol) in DCM was reacted at -40 °C under N2. To a solution of _{4-nitro-1-yl (4-nitro-1-yl)-2-nitropropene (1 mL) was added DAST (19 mg, 0.12 mmol) dropwise. The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by saturated NaHCO 3} (10 mL) and extracted with DCM (2 ×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 100 × 30 mm × 3 μm; mobile phase A: water containing 0.2% FA, B: MeCN; B% in A: B%: 40%-75%, 8 min) to give 2-(4'-(( 2S , 5R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3 -d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile (16 mg, 82%). Example 233 6-[4-[(2S,5R)-4-[2- cyano -2- methyl -3-( trifluoromethoxy ) propanoyl ]-2,5 -dimethyl - piperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridazine -4- carbonitrile

( R )-1- Phenylethyl 2- cyanopropanoate: To a solution of 2-cyanopropionic acid (6 g, 60.55 mmol) in DCM (60 mL) at 0 °C was added DMAP (3.70 g, 30.28 mmol) and EDCI (23.22 g, 121.10 mmol) and ( S )-1-phenylethanol (11.10 g, 90.83 mmol). The mixture was stirred at 20 °C for 16 h. The mixture was poured into water (100 mL). The aqueous phase was extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (30 mL), _dried over anhydrous _Na2SO4 , filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give ( R )-1-phenylethyl 2-cyanopropanoate (10.17 g, 82%).

( R )-1- phenylethyl 2- cyano- 3- hydroxy -2- methylpropanoate : To a solution of ( R )-1-phenylethyl 2-cyanopropanoate (10 g, 49.20 mmol) in MeCN (100 mL) was added TEA (249 mg, 2.46 mmol, 0.34 mL) and paraformaldehyde (4.43 g, 147.61 mmol) at 20°C. The mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give ( R )-1-phenylethyl 2-cyano-3-hydroxy-2-methylpropanoate (9.4 g, 81%).

( R )-1- phenylethyl 2- cyano - 2 -methyl-3-((( methylthio ) thiocarbonyl ) oxy ) propanoate : To a solution of ( R )-1-phenylethyl 2-cyano-3-hydroxy-2-methylpropanoate (2 g, 8.57 mmol) in THF (50 mL) was added NaH (412 mg, 10.29 mmol, 60% dispersion in mineral oil) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then _CS2 (3.26 g, 42.87 mmol, 2.58 mL) was added at 0 °C. After 30 min, MeI (2.43 g, 17.15 mmol, 1.07 mL) was added at 0 °C and the mixture was stirred at 20 °C for 12 h. The mixture was poured into NH ₄ Cl (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give ( R )-2-cyano-2-methyl-3-(((methylthio)thiocarbonyl)oxy)propanoic acid 1-phenylethyl ester (1.5 g, 54%).

( R )-1- Phenylethyl 2-cyano- 2 - methyl -3-( trifluoromethoxy ) propanoate : To a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (3.98 g, 13.91 mmol) in DCM (40 mL) at -78 °C under _N2 was added pyridine hydrofluoride (13.13 g, 92.76 mmol, 11.94 mL, 70% purity). The mixture was stirred at -78 °C for 30 min. Then, ( R )-1-Phenylethyl 2-cyano-2-methyl-3-(((methylthio)thiocarbonyl)oxy)propanoate (1.5 g, 4.64 mmol) in DCM (10 mL) was added at -78 °C. The mixture was stirred at 0 °C for 4 h. The mixture was poured into aqueous NaHCO ₃ solution (80 mL). The aqueous phase was extracted with DCM (3 × 20 mL), washed with 2N HCl (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give ( R )-2-cyano-2-methyl-3-(trifluoromethoxy)propionic acid 1-phenylethyl ester (0.75 g, 53%).

2- Cyano -2- methyl -3-( trifluoromethoxy ) propanoic acid: To a solution of ( R )-2-cyano-2-methyl-3-(trifluoromethoxy)propanoic acid 1-phenylethyl ester (0.8 g, 2.66 mmol) in THF (10 mL) and _H2O (2 mL) was added _LiOH.H2O (334 mg, 7.97 mmol) at 20°C. The mixture was stirred at 20°C for 2 h. The mixture was poured into water (30 mL), extracted with MTBE (3 x 10 mL), and the aqueous phase was adjusted to pH = 1 with 3M HCl. The mixture was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over _{anhydrous Na2SO4} , filtered, and concentrated to give 2-cyano-2-methyl-3-(trifluoromethoxy)propanoic acid (0.5 g, crude).

6-[4-[(2S,5R)-4-[2- cyano -2- methyl- 3-( trifluoromethoxy ) propanoyl ]-2,5 -dimethyl - piperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1' - cyclobutane ]-7- yl ] pyridazine -4- carbonitrile : To a solution of 2-cyano-2-methyl-3-(trifluoromethoxy)propanoic acid (0.2 g, 1.01 mmol) in DCM (4 mL) at 0°C were added DMF (7 mg, 0.10 mmol) and (COCl) ₂ (193 mg, 1.52 mmol, 0.13 mL). The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure and dissolved in DCM (0.5 mL). To this solution was added 6-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'(6'H) -yl )pyridazine-4-carbonitrile hydrochloride (0.1 g, 0.24 mmol) and DIEA (94 mg, 0.73 mmol, 0.13 mL) in DCM (1 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was poured into water (5 mL). The aqueous phase was extracted with DCM (3 x 2 mL). The combined organic phases were washed with brine (2 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 um; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: ACN, % B in A, gradient: 50%-90% B over 8.0 min) to give 6-[4-[(2S,5R)-4-[2-cyano-2-methyl-3-(trifluoromethoxy)propanoyl]-2,5-dimethyl-piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile (36 mg, 26%). Example 235 2-[4-[(2S,5R)-4-[3- fluoro -2- methyl -2-( triazol -2- yl ) propanoyl ]-2,5 -dimethyl - piperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7- yl ] pyridine -4- carbonitrile

Methyl 2-(2H - 1,2,3- triazol -2- yl ) propanoate: To a solution of 2H -1,2,3-triazole ( _3.3 g, 47.78 mmol) in acetonitrile (30 mL) was added methyl 2-bromopropanoate (8.78 g, 52.56 mmol) and _K2CO3 (9.91 g, 71.67 mmol). The mixture was stirred at 50 °C for 16 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 4:1 to 3:1) to give methyl 2-( 2H- 1,2,3-triazol-2-yl)propanoate (2.2 g, 29%).

Methyl 3- fluoro -2- methyl -2-(2H - 1,2,3- triazol -2- yl ) propanoate: To a solution of 2-( 2H- 1,2,3-triazol-2-yl)propanoate (2 g, 12.89 mmol) in THF (20 mL) was added LDA (2 M in THF, 13 mL) dropwise at -70 °C. After the addition, the mixture was stirred at -70 °C for 0.5 h, followed by the addition of fluoro(iodo)methane (3.09 g, 19.34 mmol) in THF (5 mL) dropwise at -70 °C. The resulting mixture was stirred at -20 °C for 16 h. The reaction mixture was poured into aqueous _NH4Cl solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EtOAc = 3:1) to give methyl 3-fluoro-2-methyl-2-(2 H -1,2,3-triazol-2-yl)propanoate (200 mg, 8%).

3- Fluoro -2- methyl -2-( 2H- 1,2,3- triazol -2- yl ) propanoic acid: To a solution of methyl 3-fluoro-2-methyl-2-( 2H -1,2,3-triazol-2-yl)propanoate (200 mg, 1.07 mmol) in THF (3 mL) and _H2O (0.6 mL) was added LiOH (128 mg, 5.34 mmol). The mixture was stirred at 50 °C for 2 h. The reaction mixture was poured into _H2O (3 mL) and extracted with MTBE (2 x 5 mL). The aqueous phase was then adjusted to pH = 3 with 3N HCl and extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (3 mL), dried over _{anhydrous Na2SO4} , filtered, and concentrated under reduced pressure to give 3-fluoro-2-methyl-2-(triazol-2-yl)propanoic acid (180 mg, 97%).

2-[4-[(2S,5R)-4-[3- fluoro -2- methyl -2-( triazol -2- yl ) propanoyl ]-2,5 -dimethyl - piperazin -1- yl ] spiro [6H -pyrrolo [2,3-d] pyrimidine -5,1'- cyclobutane ]-7 -yl ] pyridine -4 -carbonitrile : General method 6-2-(4'-(( 2S , 5R )-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile hydrochloride (150 mg, 0.364 mmol), 3-fluoro-2-methyl-2-(triazol-2-yl)propanoic acid (95 mg, 0.546 mmol), CMPI (111 4-[(2S,5R)-4-[3-fluoro-2-methyl-2-(triazol- ₂ -yl)propanoyl]-2,5-dimethyl-piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile (22 mg, 12%). Example 267 ( 2R , 5S )-4-(7'-( ethylaminocarbonyl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3 -d ] pyrimidin ]-4'- yl )-2,5 -dimethylpiperazine -1- carboxylic acid tributyl ester

4'- Chloro-7'-(phenylsulfonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]: To a solution of 4-chlorospiro[6,7- _{dihydropyrrolo} [2,3-d]pyrimidine-5,1'-cyclobutane] (500 mg, 2.56 mmol) in DMF (10 mL) was added NaH (133 mg, 3.32 mmol, 60% dispersion in mineral oil) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 30 min, followed by the addition of benzenesulfonyl chloride (496 mg, 2.81 mmol). The mixture was stirred at 20 °C for 4 h. The reaction mixture was poured into saturated aqueous NH ₄ Cl solution (30 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give 4'-chloro-7'-(phenylsulfonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine] (350 mg, 41%).

( 2R , 5S )-2,5-dimethyl-4-(7'-(phenylsulfonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3 -d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester: A mixture of 4'-chloro-7'-(phenylsulfonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin] (310 mg, 0.92 mmol), DIEA (597 mg, 4.62 mmol), ( 2R , 5S )-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (297 mg, 1.38 mmol) in NMP (4 mL) was degassed and purged with _N2 (3x). The mixture was stirred at 140 °C for 16 h. The mixture was poured into _H2O (15 mL) and extracted with EtOAc (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1 to 2:1) to give (2 R ,5 S )-2,5-dimethyl-4-(7'-(phenylsulfonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester (320 mg, 67%).

( 2R , 5S )-4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3 -d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester: To a solution of ( 2R , 5S )-2,5-dimethyl-4-(7'-(phenylsulfonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester (160 mg, 0.31 mmol) in MeOH (3 mL) and THF (1 mL) was added Mg (303 mg, 12.46 mmol). The mixture was stirred at 20 °C for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 0:1) to give (2 R ,5 S )-tert-butyl 4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (70 mg, 60% yield).

( 2R , 5S )-tert-butyl 4-(7'-(ethylaminocarbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate: To a solution of tert-butyl ( 2R , 5S )-4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (50 mg, 0.13 mmol) in EtOAc (1 mL) at 20 °C were added TEA (41 mg, 0.40 mmol) and bis(trichloromethyl) carbonate (40 mg, 0.13 mmol). After addition, the mixture was stirred at 80 °C for 5 min. The solvent was removed under reduced pressure and the residue was added to a solution of ethylamine hydrochloride (109 mg, 1.34 mmol) and TEA (135 mg, 1.34 mmol) in THF (1 mL). The mixture was stirred at 25 °C for 2 h. The mixture was poured into aqueous NaHCO ₃ solution (3 mL) and extracted with EtOAc (3 x 2 mL). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18 75 × 30 mm × 3 µm; mobile phase: A: water containing 0.2% FA, B: CH ₃ CN; % of B in A: 40%-80%, 8 min) to give (2 R ,5 S )-4-(7'-(ethylaminocarbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (3.82 mg, 6.4%). Example 268 (2 R , 5 S )-4-(7'-( cyclobutanecarbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester

(4'- Chlorospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidine ]-7'(6' H ) -yl )( cyclobutyl ) methanone : To a solution of 4'-chloro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine] (50 mg, 0.256 mmol) in DCM (1 mL) at 0 °C was added pyridine (61 mg, 0.77 mmol), cyclobutanecarbonyl chloride (61 mg, 0.77 mmol). After addition, the mixture was stirred at 20 °C for 2 h. The reaction was diluted with H ₂ O (5 mL) and extracted with DCM (3 x 4 mL). The combined organic layers were washed with brine (3 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography and preparative TLC (SiO ₂ , PE:EtOAc = 1:1 ) to give (4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-7'(6' H )-yl)(cyclobutyl)methanone (60 mg, 84%).

( 2R , 5S )-4-(7'-(cyclobutanecarbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester: A mixture of (4'-chlorospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidin]-7'(6'H)-yl)(cyclobutyl)methanone (59 mg, 0.212 mmol), ( 2R , 5S )-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.23 mmol) and DIEA (137 mg, 1.06 mmol) in NMP (1 mL) was degassed and heated with N ₂ was purged 3 times, then the mixture was stirred at 140 °C for 12 h. The reaction was diluted with H ₂ O (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 25 mm × 5 μm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: CH ₃ CN; % of B in A: 70%-98%, 8 min) to give (2 R ,5 S )-4-(7'-(cyclobutanecarbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (24.36 mg, 25%). Example 275 (2 R , 5 S )-4-(7'-(( cyclopropylmethyl)sulfonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester

( 2R , 5S )-tert-butyl 4-(7'-((cyclopropylmethyl)sulfonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate: To a solution of _tert-butyl ( 2R , 5S )-4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (30 mg, 0.08 mmol) was added NaH (4 mg, 0.10 mmol, 60% dispersion in oil) at 0 °C under N2. The mixture was stirred at 0 °C for 30 min, followed by the addition of cyclopropylmethanesulfonyl chloride (15 mg, 0.096 mmol) in DMF (1 mL). The mixture was stirred at 20 °C for 1 h. The mixture was poured into NH ₄ Cl (5 mL) and extracted with EtOAc (3×5 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 3 μm; mobile phase: A: water containing 10 mM FA, B: CH ₃ CN; % of B in A: 40%-70%, 8 min) to give (2 R ,5 S )-4-(7'-((cyclopropylmethyl)sulfonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (12.3 mg, 31%). Example 281 ( 2R , 5S )-4-(7'-(2-( dimethylamino)-2-oxoethyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester

( 2R , 5S )-tert-butyl 4-(7'-(2-(dimethylamino)-2-oxoethyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate: To a solution of tert-butyl ( 2R , 5S )-4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (30 mg, 0.08 mmol) and 2-chloro-N,N-dimethylacetamide (20 mg, 0.16 mmol ₎ in DMF (1 mL) was added _K2CO3 (23 mg, 0.16 mmol). The mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into water (2 mL) and extracted with EtOAc (3 x 2 mL). The organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm 10 um; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: CH ₃ CN; % of B in A: 50%-80%, 8 min) to give (2 R ,5 S )-4-(7'-(2-(dimethylamino)-2-oxoethyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester (5.6 mg, 15%). Example 284 4'-(( 2S , 5R )-4-( tert-butyloxycarbonyl )-2,5 -dimethylpiperazin- 1- yl ) spiro [ cyclobutane -1,5' -pyrrolo [2,3 -d ] pyrimidine ]-7'( 6'H ) -carboxylic acid cyclobutyl ester

Cyclobutyl 4'-(( 2S , 5R )-4-(tri-butyloxycarbonyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-carboxylate: To a solution of cyclobutanol (193 mg, 2.68 mmol) in THF (10 mL) were added bis(trichloromethyl) carbonate (795 mg, 2.68 mmol) and TEA (271 mg, 2.68 mmol) at 0°C. After the addition, the mixture was stirred at this temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was added to a solution of tributyl ( 2R , 5S )-4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylate (100 mg, 0.27 mmol) and t -BuOK (90 mg, 0.8 mmol) in THF (10 mL). The mixture was stirred at 20 °C for 16 h. The mixture was quenched with aqueous _NH4Cl solution (5 mL) and extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with brine (5 mL), dried over _Na2SO4 , _filtered , and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters xbridge 150 × 25 mm × 10 μm; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: MeCN; % of B in A: 60%-80%, 8 min) to give 4'-((2 S ,5 R )-4-(tert-butyloxycarbonyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3 -d ]pyrimidine]-7'(6' H )-carboxylic acid cyclobutyl ester (20.9 mg, 17%). Example 285 ( 2R , 5S )-2,5 -dimethyl -4-(7'-((1- methyl - 1H - pyrazol -4- yl ) methyl )-6',7'- dihydrospiro [ cyclobutane -1,5' -pyrrolo [2,3- d ] pyrimidin ]-4'- yl ) piperazine- 1- carboxylic acid tributyl ester

( 2R , 5S )-2,5-dimethyl-4-(7'-((1-methyl- 1H -pyrazol-4-yl)methyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tert-butyl ester: To a solution of ( 2R , 5S )-4-(6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.13 mmol) in THF (0.5 mL) at 0 °C was added NaH (12 mg, 0.28 mmol, 60% w/w, in oil) and 4-(chloromethyl)-1-methyl-pyrazole hydrochloride (25 mg, 0.15 mmol). The mixture was stirred at 25 °C for 12 h, then at 70 °C for 12 h. The reaction mixture was quenched by adding water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 um; mobile phase: A: water containing 10 mM NH ₄ HCO ₃ , B: CH ₃ CN; % of B in A: 40%-70%, 8 min) to give (2 R ,5 S )-2,5-dimethyl-4-(7'-((1-methyl-1 H -pyrazol-4-yl)methyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester (6.61 mg, 11%).

Unless otherwise specified in the Experimental Details, the following SFC and preparative HPLC separation methods were used to separate certain compounds disclosed herein into single isomers. In the following tables, peak numbers refer to elution order.

SFC method: column: DAICEL CHIRALPAK AD (250 mm × 30 mm × 10 µm); mobile phase: [CO ₂ -MeOH (0.1% NH ₃ H ₂ O)]; B%: 50%, isocratic elution mode.

Preparative HPLC method: Mobile phase: Solvent A: H2O (0.1% formic acid or TFA), Solvent B: MeCN (0.1% formic acid or TFA); Waters Xbridge Prep OBD 150 × 40 mm × 10 µm, Waters Xbridge BEH 100 × 30 mm × 10 µm, or Phenomenex Luna C18 100 × 40 mm × 3 µm.

The following compounds were prepared according to the examples provided herein using appropriate starting materials. The data of the selected compounds of Table 1 prepared by the above examples are shown in Table 3 below. surface 3 Examples IUPAC name MS 1 (2 R ,5 S )-4-[7-(4-cyano-2-pyridinyl)spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclopropane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z =462.2 [M+H] ⁺ 2 2-[4-[(2 S ,5 R )-4-(2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclopropane]-7-yl]pyridine-4-carbonitrile m/z = 446.2 [M+H] ⁺ 3 (2 R ,5 S )-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z =476.2 [M+H] ⁺ 4 (2 R ,5 S )-4-(7-(4-cyanopyridin-2-yl)-5,5-dimethyl-6,7-dihydro- 5H -pyrrolo[2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 464.2 [M +H] ⁺ 5 (2 R ,5 S )-4-[7-(4-cyano-2-pyridinyl)spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclopentane]-4-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tributyl ester m/z = 490.3 [M +H] ⁺ 6 ( 2R )-4-[7-(4-cyano-2-pyridinyl)spiro[ 6H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tributyl ester m/z = 462.3 [M+H] ⁺ 7 ( 3S )-4-[7-(4-cyano-2-pyridinyl)spiro[ 6H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-3-methylpiperazine-1-carboxylic acid tributyl ester m/z = 462.2 [M+H] ⁺ 8 2-[4-[(2 S )-4-(2,2-dimethylpropanoyl)-2-methylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 446.3 [M+H] ⁺ 9 2-[4-[(2 S ,5 R )-4-(2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z =460.2 [M +H] ⁺ 10 2-[4-[(3 R )-4-(2,2-dimethylpropanoyl)-3-methylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 446.2 [M+H] ⁺ 11 (2 R ,5 S )-4-[7-(4-cyano-2-pyridinyl)spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid 2,2,2-trifluoroethyl ester m/z = 488.2 [M+H] ⁺ 12 2-[4-[(2 S ,5 R )-4-(Bicyclo[2.1.1]hexane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z =484.2 [M +H] ⁺ 13 2-[4-[(2 S ,5 R )-4-(3-methoxy-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z =490.2 [M +H] ⁺ 14 2-[4-[(2 S ,5 R )-4-(2-methoxy-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z =476.2 [M +H] ⁺ 15 2-[4-[(2 S ,5 R )-4-(cyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 458.3 [M+H] ⁺ 16 2-[4-[(2 S ,5 R )-2,5-dimethyl-4-(1-methylcyclobutanecarbonyl)piperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 472.3 [M+H] ⁺ 17 2-[4-[(2 S ,5 R )-4-(3,3-difluoro-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 496.2 [M+H] ⁺ 18 2-[4-[(2 S ,5 R )-4-(3-fluoro-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 478.3 [M+H] ⁺ 19 2-[4-[(2 S ,5 R )-4-(2-cyclopropyl-2-methylpropionyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 486.3 [M+H] ⁺ 20 2-[4-[(2 S ,5 R )-4-(Bicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 470.3 [M+H] ⁺ twenty one 2-[4-[(2 S ,5 R )-2,5-dimethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z: 526.3 [M+H] ⁺ twenty two 2-[4-[(2 S ,5 R )-4-(2,2-difluoro-1-methylcyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z =494.3 [M +H] ⁺ twenty three 2-[4-[(2 S ,5 R )-4-(3,3-difluoro-2,2-dimethylbutyryl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z =510.3 [M +H] ⁺ twenty four 2-[4-[(2 S ,5 R )-4-(4,4-difluoro-2,2-dimethylbutyryl)-2,5-dimethylpiperazin-1-yl]spiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z =510.3 [M +H] ⁺ 25 (2 R ,5 S )-4-[7-(4-cyano-2-pyridinyl)-3'-hydroxyspiro[6 H -pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 492.3 [M+H] ⁺ 26 (3S)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-3-methylpiperazine-1-carboxylic acid 2,2,2-trifluoroethyl ester m/z = 488.2 [M+H] 27 (2R)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid 2,2,2-trifluoroethyl ester m/z = 488.2 [M+H] 28 2-[4-[(2S,5R)-2,5-dimethyl-4-(1-methylcyclopropanecarbonyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 458.2 [M+H] 29 6-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tributyl ester m/z = 460.3 [M+H] 30 2-[4-[(2S,5R)-4-(2-cyano-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 471.3 [M+H] 31 5-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tributyl ester m/z = 460.2 [M+H] 32 8-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tributyl ester m/z = 474.3 [M+H] 33 3-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester m/z = 474.2 [M+H] 34 2-[4-[(2S,5R)-2,5-dimethyl-4-(3,3,3-trifluoro-2,2-dimethylpropionyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 514.3 [M+H] 35 2-[4-[(2S,5R)-4-(1-methoxycyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 474.3 [M+H] 36 2-[4-[(2S,5R)-4-(3-hydroxy-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 476.3 [M+H] 37 2-[4-[(2S,5R)-4-(1-fluorocyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 462.2 [M+H] 38 (2R)-4-[7-(4-cyano-2-pyridinyl)-3'-fluorospiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methylpiperazine-1-carboxylic acid tributyl ester m/z = 480.3 [M+H] 39 2-[4-[(2S,5R)-4-(3-cyano-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 485.3 [M+H] 40 2-[4-[(2S,5R)-4-[1-(difluoromethyl)cyclobutanecarbonyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 508.3 [M+H] 41 (2R,5S)-2,5-Dimethyl-4-[7-(6-oxo-1H-pyrimidin-2-yl)spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]piperazine-1-carboxylic acid tributyl ester m/z = 468.3 [M+H] 42 2-[4-[(2S,5R)-4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 488.1 [M+H] 43 2-[4-[(2S,5R)-4-(2-cyclopropyl-2,2-difluoroacetyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 494.2 [M+H] 44 2-[4-[(2S,5R)-4-(3,3-difluorocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 494.1 [M+H] 45 2-[4-[(2S,5R)-4-(2,2-difluorocyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 480.1 [M+H] 46 2-[4-[(2S,5R)-2,5-dimethyl-4-[1-(trifluoromethyl)cyclopropanecarbonyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 512.2 [M+H] 47 2-[4-[(2S,5R)-4-(1-cyclopropylcyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 484.3 [M+H] 48 2-[4-[(2S,5R)-4-(3-cyanobicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 495.3 [M+H] 49 2-[4-[(2S,5R)-4-(1-cyanocyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 469.2 [M+H] 50 2-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 483.3 [M+H] 51 (2S)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-(trifluoromethyl)piperazine-1-carboxylic acid tributyl ester m/z = 516.1 [M+H] 52 (2R,5S)-4-[7-(6-cyanopyrimidin-4-yl)spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 477.2 [M+H] 53 2-[4-[(2S,5R)-2,5-dimethyl-4-[(1r,2r)-2-(trifluoromethyl)cyclopropanecarbonyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 512.3 [M+H] 54 2-[4-[(2S,5R)-2,5-dimethyl-4-[(1r,2s)-2-(trifluoromethyl)cyclopropanecarbonyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 512.2 [M+H] 55 (2S,5R)-4-[7-(4-cyano-2-pyridinyl)-1',1'-difluorospiro[6H-pyrrolo[2,3-d]pyrimidine-5,3'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 512.2 [M+H] 56 (2S,5R)-4-((1r,3s)-7'-(4-cyanopyridin-2-yl)-3-hydroxy-3-methyl-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3-d]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 506.3 [M+H] 57 2-[4-[2-(2,2-dimethylpropanoyl)-2,7-diazaspiro[3.5]non-7-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 472.2 [M+H] 58 2-[4-[7-(2,2-dimethylpropanoyl)-2,7-diazaspiro[3.5]non-2-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 472.3 [M+H] 59 2-[4-[2-(2,2-dimethylpropanoyl)-2,7-diazaspiro[3.4]octan-7-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 458.3 [M+H] 60 2-[4-[(2S,5R)-2,5-dimethyl-4-(2-methyl-2-pyrazol-1-ylpropionyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 512.3 [M+H] 61 2-(4'-((2S,5R)-2,5-dimethyl-4-(( 1s , 3S )-3-(trifluoromethoxy)cyclobutane-1-carbonyl)piperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)isonicotinecarbonitrile m/z = 542.3 [M+H] 62 (2R,5S)-4-[7-(6-cyanopyridazin-4-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 477.2 [M+H] 63 2-[4-[2-(2,2-dimethylpropanoyl)-2,6-diazaspiro[3.3]hept-6-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 444.2 [M+H] 64 2-[4-[2-(2,2-dimethylpropanoyl)-2,7-diazaspiro[4.4]nonan-7-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 472.2 [M+H] 65 2-[4-[8-(2,2-dimethylpropanoyl)-2,8-diazaspiro[4.5]dec-2-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 486.3 [M+H] 66 2-[4-[(2S,5R)-4-[(1s,2s)-2-cyanocyclopropanecarbonyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 469.2 [M+H] 67 2-[4-[(2S,5R)-4-[(1R,2S)-2-cyanocyclopropanecarbonyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 469.2 [M+H] 68A (2R,5S)-4-[(5R)-7-(4-cyano-2-pyridinyl)-5-(methoxymethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 494.3 [M+H] 68B (2R,5S)-4-[(5S)-7-(4-cyano-2-pyridinyl)-5-(methoxymethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 494.3 [M+H] 69 2-[4-[(2S,5R)-2,5-dimethyl-4-(2-methyl-2-methylsulfonylpropionyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 524.3 [M+H] 70 2-[4-[(2S,5R)-2,5-dimethyl-4-[2-methyl-2-(triazol-1-yl)propionyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 513.3 [M+H] 71 2-[4-[(2S,5R)-2,5-dimethyl-4-[2-methyl-2-(triazol-2-yl)propionyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 513.3 [M+H] 72 2-[4-[(2S,5R)-4-[2-(Azocyclobutan-1-yl)-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 501.3 [M+H] 73 2-[4-[(2S,5R)-4-[1-(Fluoromethyl)cyclopropanecarbonyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 476.2 [M+H] 74 (2R,5S)-4-(( 1s , 3R )-7'-(4-cyanopyridin-2-yl)-3-fluoro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 494.2 [M+H] 75 (2R,5S)-4-((1 r ,3 S )-7'-(4-cyanopyridin-2-yl)-3-fluoro-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 494.3 [M+H] 76 2-[4-[(2S,5R)-4-(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]-5,5-dimethyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 476.2 [M+H] 77A (5S)-7-(4-cyano-2-pyridinyl)-4-[(2S,5R)-2,5-dimethyl-4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]-5-methyl-6H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester m/z = 522.3 [M+H] 77B (5R)-7-(4-cyano-2-pyridinyl)-4-[(2S,5R)-2,5-dimethyl-4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]-5-methyl-6H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid ethyl ester m/z = 522.3 [M+H] 78 (2R,5S)-4-[(5S)-7-(4-cyano-2-pyridinyl)-5-(difluoromethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 500.3 [M+H] 79 (2R,5S)-4-(( 1s , 3R )-7'-(4-cyanopyridin-2-yl)-3-methoxy-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 506.3 [M+H] 80 (2R,5S)-4-((1 r ,3 S )-7'-(4-cyanopyridin-2-yl)-3-methoxy-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 506.3 [M+H] 81 6-[4-[(2S,5R)-4-(2-cyclopropyl-2,2-difluoroacetyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyrimidine-4-carbonitrile m/z = 495.2 [M+H] 82 (2R,5S)-4-(( 1s , 3R )-3-cyano-7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 501.3 [M+H] 83 (2R,5S)-4-((1 r ,3 S )-3-cyano-7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 501.3 [M+H] 84 (2R,5S)-4-[7-(4-cyanopyrimidin-2-yl)spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 477.2 [M+H] 85A (2R,5S)-4-[(5R)-7-(4-cyano-2-pyridinyl)-5-(hydroxymethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 480.2 [M+H] 85B (2R,5S)-4-[(5S)-7-(4-cyano-2-pyridinyl)-5-(hydroxymethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 480.2 [M+H] 86 (2R)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methyl-5-oxopiperazine-1-carboxylic acid tributyl ester m/z = 476.2 [M+H] 87 2-[4-[(2S,5R)-4-(1-cyano-2-fluorocyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 487.3 [M+H] 88 2-[4-[(2S,5R)-4-[(2S)-2-cyclopropyl-2-methoxyacetyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 488.2 [M+H] 89 2-[4-[(2S,5R)-4-[(2R)-2-cyclopropyl-2-methoxyacetyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 488.2 [M+H] 90 2-[4-[(2S,5R)-2,5-dimethyl-4-(2-methyl-2-oxolin-4-ylpropionyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 531.3 [M+H] 91A (2R,5S)-4-[(5R)-7-(4-cyano-2-pyridinyl)-5-(fluoromethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 482.2 [M+H] 91B (2R,5S)-4-[(5S)-7-(4-cyano-2-pyridinyl)-5-(fluoromethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 482.2 [M+H] 92A (2R,5S)-4-[(5R)-5-(cyanomethyl)-7-(4-cyano-2-pyridinyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 489.2 [M+H] 92B (2R,5S)-4-[(5S)-5-(cyanomethyl)-7-(4-cyano-2-pyridinyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 489.2 [M+H] 93 (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-2'-fluorospiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclopropane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 480.2 [M+H] 94 4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-1,4-diazacycloheptane-1-carboxylic acid tributyl ester m/z = 462.2 [M+H] 95 (2R,5S)-4-[7-(5-cyanopyridazin-3-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 477.3 [M+H] 96 (2S)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methyl-5-oxopiperazine-1-carboxylic acid tributyl ester m/z = 476.2 [M+H] 97 2-[4-[(2S,5R)-2,5-dimethyl-4-[2-(trifluoromethoxy)propionyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 516.2 [M+H] 98 2-[4-[(2S,5R)-2,5-dimethyl-4-[1-(triazol-2-yl)cyclopropanecarbonyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 511.3 [M+H] 99 2-[4-[(2S,5R)-2,5-dimethyl-4-[2-(triazol-2-yl)propionyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 499.2 [M+H] 100 (2R,5S)-2,5-Dimethyl-4-[7-([1,2,4]triazolo[4,3-a]pyrazin-6-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]piperazine-1-carboxylic acid tributyl ester m/z = 492.1 [M+H] 101 2-[4-[(2S,5R)-4-[2,2-difluoro-2-(triazol-2-yl)acetyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 521.2 [M+H] 102 2-[4-[(2S,5R)-4-(1-cyano-3,3-difluorocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 519.2 [M+H] 103 2-[4-[(2S,5R)-2,5-dimethyl-4-[1-(triazol-2-yl)cyclobutanecarbonyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 525.3 [M+H] 104 2-[4-[(2S,5R)-4-(2-cyano-2-cyclopropylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 497.3 [M+H] 105 2-[4-[(2S,5R)-2,5-dimethyl-4-[2-(triazol-2-yl)acetyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 485.3 [M+H] 106 2-[4-[4-(1-cyanocyclobutanecarbonyl)-3-(fluoromethyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 487.2 [M+H] 107 (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-5-methyl-5-(methylaminocarbonyl)-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 507.2 [M+H] 108 2-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyrimidine-4-carbonitrile m/z = 484.3 [M+H] 109 4-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-2-carbonitrile m/z = 483.2 [M+H] 110 6-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,6-diazabicyclo[3.2.1]octane-2-carboxylic acid tributyl ester m/z = 474.3 [M+H] 111 2-[4-[(3R)-4-(3-fluoro-2,2-dimethylpropanoyl)-3-methylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 464.2 [M+H] 112 2-[4-[(2S,5R)-4-[2-(3-methoxyazidocyclobutane-1-yl)-2-methylpropionyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 531.3 [M+H] 113 2-[4-[(2S,5R)-4-(2-cyano-3-methoxy-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 501.3 [M+H] 114 (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-5-(ethylaminocarbonyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 521.3 [M+H] 115 (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-5-(dimethylaminocarbonyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 521.3 [M+H] 116 (2R,5S)-4-[7-(4-cyano-2-pyridinyl)-5-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-6H-pyrrolo[2,3-d]pyrimidin-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 532.3 [M+H] 117 2-[4-[(2S)-4-(3-fluoro-2,2-dimethylpropanoyl)-2-methylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 464.2 [M+H] 118 4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-(hydroxymethyl)piperazine-1-carboxylic acid tributyl ester m/z = 478.3 [M+H] 119 (2R,5S)-2,5-Dimethyl-4-[7-([1,2,4]triazolo[1,5-c]pyrimidin-7-yl)spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]piperazine-1-carboxylic acid tributyl ester m/z = 492.3 [M+H] 120A 2-[4-[(2S,5R)-2,5-dimethyl-4-[(2R)-2-oxolin-4-ylpropionyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 517.3 [M+H] 120B 2-[4-[(2S,5R)-2,5-dimethyl-4-[(2S)-2-oxolin-4-ylpropionyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 517.3 [M+H] 121 (2S)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-(dimethylaminoformyl)piperazine-1-carboxylic acid tributyl ester m/z = 519.1 [M+H] 122 4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-(methoxymethyl)piperazine-1-carboxylic acid tributyl ester m/z = 492.3 [M+H] 123 2-[4-[4-(1-cyanocyclobutanecarbonyl)-1,4-diazacycloheptane-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 469.3 [M+H] 124 2-[4-[4-(3-fluoro-2,2-dimethylpropanoyl)-1,4-diazacycloheptan-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 464.3 [M+H] 125 2-[4-[4-(1-fluorocyclopropanecarbonyl)-1,4-diazocycloheptan-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 448.2 [M+H] 126 4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-6-methyl-1,4-diazacycloheptane-1-carboxylic acid tributyl ester m/z = 476.3 [M+H] 127 4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-7-methyl-1,4-diazocycloheptane-1-carboxylic acid tributyl ester m/z = 476.3 [M+H] 128 4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methyl-1,4-diazocycloheptane-1-carboxylic acid tributyl ester m/z = 476.3 [M+H] 129 (2R,5S)-4-(7-imidazo[1,2-c]pyrimidin-7-ylspiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 491.3 [M+H] 130 (2R,5S)-4-(7-imidazo[1,2-a]pyrazin-6-ylspiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 491.3 [M+H] 131 2-((1 r ,3 S )-3-fluoro-4'-((2R,5S)-4-(1-fluorocyclopropane-1-carbonyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile m/z = 480.2 [M+H] 132 2-((1 s ,3 R )-3-fluoro-4'-((2R,5S)-4-(1-fluorocyclopropane-1-carbonyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile m/z = 480.2 [M+H] 133 6-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 484.3 [M+H] 134 2-[4-[(2S,5R)-4-[2-(3-fluoroazidocyclobutan-1-yl)-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 519.3 [M+H] 135 2-[4-[(2S,5R)-2,5-dimethyl-4-(2-methyl-2-pyrrolidin-1-ylpropionyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 515.3 [M+H] 136A 2-[(5R)-4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]-5-(cyanomethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 496.2 [M+H] 136B 2-[(5S)-4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]-5-(cyanomethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 496.3 [M+H] 137 (2R)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methyl-3-oxopiperazine-1-carboxylic acid tributyl ester m/z = 476.2 [M+H] 138 (2S)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-methyl-3-oxopiperazine-1-carboxylic acid tributyl ester m/z = 476.2 [M+H] 139 2-[4-[(2S,5R)-2,5-dimethyl-4-[2-methyl-2-(2-oxopyrrolidin-1-yl)propionyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 529.3 [M+H] 140 2-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]-3'-fluorospiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 501.2 [M+H] 141 2-[4-[rac-(2R,5S)-4-[2-(2-azabicyclo[2.1.1]hex-2-yl)-2-methylpropionyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 527.3 [M+H] 142 2-[4-[(2S,5R)-4-[2-(dimethylamino)-2-methylpropionyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 489.3 [M+H] 143 (1 r ,3 S )-7'-(4-cyanopyridin-2-yl)-4'-((2S,5R)-4-(1-fluorocyclopropane-1-carbonyl)-2,5-dimethylpiperazin-1-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-3-carbonitrile m/z = 487.2 [M+H] 144A 2-[(5R)-5-(cyanomethyl)-4-[(2S,5R)-4-(3-fluoro-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 491.3 [M+H] 144B 2-[(5S)-5-(Cyanomethyl)-4-[(2S,5R)-4-(3-fluoro-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl]-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 491.3 [M+H] 145 4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-3-oxopiperazine-1-carboxylic acid tributyl ester m/z = 462.2 [M+H] 146 2-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]-5-fluoropyridine-4-carbonitrile m/z = 501.3 [M+H] 147 1-[(2R,5S)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carbonyl]-N,N-dimethylcyclopropane-1-carboxamide m/z = 515.3 [M+H] 148 1-[(2S,5R)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carbonyl]-N-methylcyclopropane-1-carboxamide m/z = 501.3 [M+H] 149 5-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-3-carbonitrile m/z = 483.3 [M+H] 150 (2R,5S)-4-[7-(5-aminopyrazin-2-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 467.3 [M+H] 151 (1 r ,3 S )-7'-(4-cyanopyridin-2-yl)-4'-((2R,5S)-4-(3,3-difluoro-2,2-dimethylpropionyl)-2,5-dimethylpiperazin-1-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-3-carbonitrile m/z = 521.2 [M+H] 152 (1 r ,3 S )-4'-((2R,5S)-4-(1-cyanocyclobutane-1-carbonyl)-2,5-dimethylpiperazin-1-yl)-7'-(4-cyanopyridin-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-3-carbonitrile m/z = 508.3 [M+H] 153 2-(Cyanomethyl)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]piperazine-1-carboxylic acid tributyl ester m/z = 487.2 [M+H] 154 2-[4-[(2S,5R)-2,5-dimethyl-4-[2-methyl-2-(methylamino)propionyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 475.3 [M+H] 155 2-[4-[(2S,5R)-4-(cubane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 506.3 [M+H] 156 3-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]-1-methylpyrazole-5-carbonitrile m/z = 486.3 [M+H] 157 (2R,5S)-4-[7-(3-cyano-5-fluorophenyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 493.3 [M+H] 158 (2R,5S)-4-[7-(3,5-Dicyanophenyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 500.3 [M+H] 159 (2R,5S)-2,5-dimethyl-4-[7-(1-methyl-2-oxo-4-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]piperazine-1-carboxylic acid tributyl ester m/z = 481.3 [M+H] 160 2-[4-[(2S,5R)-4-[1-(dimethylamino)cyclopropanecarbonyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 487.3 [M+H] 161 2-[4-[(2S,5R)-4-[1-(dimethylamino)cyclobutanecarbonyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 501.3 [M+H] 162 2-[4-[(2S,5R)-4-(1-aminocyclopropanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 459.2 [M+H] 163 2-[4-[(2S,5R)-4-(1-aminocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 473.2 [M+H] 164 (2R,5S)-4-[7-(6-aminopyrimidin-4-yl)spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 467.2 [M+H] 165 (2R,5S)-4-(( 1s , 3R )-7'-(4-cyanopyridin-2-yl)-3-( 2H- 1,2,3-triazol-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 543.3 [M+H] 166 (2R,5S)-4-((1 r ,3 S )-7'-(4-cyanopyridin-2-yl)-3-(2 H -1,2,3-triazol-2-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 543.3 [M+H] 167 (2R,5S)-4-(( 1s , 3R )-7'-(4-cyanopyridin-2-yl)-3-( 1H- 1,2,3-triazol-1-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 543.3 [M+H] 168 (2R,5S)-4-((1 r ,3 S )-7'-(4-cyanopyridin-2-yl)-3-(1 H -1,2,3-triazol-1-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 543.3 [M+H] 169 2-[4-[4-(1-cyanocyclobutanecarbonyl)-7-methyl-1,4-diazacycloheptan-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 483.2 [M+H] 170 2-[4-[4-(1-cyanocyclobutanecarbonyl)-2-methyl-1,4-diazacycloheptan-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 483.2 [M+H] 171 (2R,5S)-4-[7-[4-cyano-6-(hydroxymethyl)-2-pyridinyl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 506.2 [M+H] 172 (2R,5S)-4-[7-[6-cyano-2-(trifluoromethyl)pyrimidin-4-yl]spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 545.2 [M+H] 173 (2R,5S)-4-[7-(3-cyano-5-methylsulfonylphenyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 553.2 [M+H] 174 (2R,5S)-4-[7-(5-cyano-2-methoxy-3-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 506.2 [M+H] 175 6-[4-[(2S,5R)-4-[2-(3-fluoroazidocyclobutan-1-yl)-2-methylpropionyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 520.3 [M+H] 176 2-[4-[(2S,5R)-4-[2-(3-fluoroazidocyclobutan-1-yl)propanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 505.3 [M+H] 177 (2R,5S)-4-[7-(5-cyano-2-oxo-1H-pyridin-3-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 492.2 [M+H] 178 2-[4-[(2S,5R)-4-[2-(1,1-dioxo-1,4-thiazin-4-yl)-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 579.3 [M+H] 179 4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2-[(dimethylamino)methyl]piperazine-1-carboxylic acid tributyl ester m/z = 505.3 [M+H] 180 (2R,5S)-4-[7-(6-cyano-2-methoxypyrimidin-4-yl)spiro[6H-pyrrolo[2,3-d]pyrimidin-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 507.2 [M+H] 181 1-[(2R,5S)-4-[7-(4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carbonyl]-N,N-dimethylcyclobutane-1-carboxamide m/z = 529.3 [M+H] 182 6-[4-[(2S,5R)-4-(3-fluoro-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 479.3 [M+H] 183 6-[4-[(2S,5R)-4-(3,3-difluoro-2,2-dimethylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 497.3 [M+H] 184 6-[4-[(2S,5R)-4-(Bicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 471.3 [M+H] 185 (2R,5S)-4-[7-(6-chloro-4-cyano-2-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 510.2 [M+H] 186 (2R,5S)-4-[7-(3-cyano-5-methylsulfanylphenyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 521.2 [M+H] 187 2-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]-5,5-dimethyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 471.2 [M+H] 188 (2R,5S)-4-[7-(5-cyano-1-methyl-2-oxo-3-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 506.3 [M+H] 189 (2R,5S)-4-[7-(2-cyano-5-fluoro-4-pyridinyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 494.2 [M+H] 190 2-[4-[(2S,5R)-4-(2-cyano-3-hydroxy-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 487.2 [M+H] 191 6-[4-[(2R,5S)-2,5-dimethyl-4-[1-(triazol-2-yl)cyclobutanecarbonyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 526.3 [M+H] 192 6-[4-[(2S,5R)-4-[2-(dimethylamino)-2-methylpropionyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 490.3 [M+H] 193 2-[4-[4-(1-cyanocyclobutanecarbonyl)-3-(methoxymethyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 499.2 [M+H] 194 2-[4-[(2S,5R)-4-[2-(3-cyanoazidocyclobutane-1-yl)-2-methylpropionyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 526.3 [M+H] 195 4-[4-[(2S,5R)-4-(Bicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]-2-oxo-1H-pyrimidine-6-carbonitrile m/z = 487.2 [M+H] 196 6-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]-5,5-dimethyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridazine-4-carbonitrile m/z = 472.2 [M+H] 197 2-[4-[(2S,5R)-4-[1-(Azocyclobutane-1-yl)cyclobutanecarbonyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 513.3 [M+H] 198 6-[4-[(2S,5R)-2,5-dimethyl-4-[(1s,2s)-2-(triazol-2-yl)cyclobutanecarbonyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 526.3 [M+H] 199 2-[4-[(2S,5R)-2,5-dimethyl-4-[2-methyl-2-(1,2,4-triazol-1-yl)propionyl]piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 513.2 [M+H] 200 2-[4-[(2S,5R)-4-[1-(Azocyclobutane-1-yl)cyclopropanecarbonyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 499.2 [M+H] 201 6-[4-[(2S,5R)-4-(Bicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]-3-methyl-2-oxopyrimidine-4-carbonitrile m/z = 501.2 [M+H] 202 6-[4-[(2S,5R)-2,5-dimethyl-4-(1-methylsulfonylcyclobutanecarbonyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 537.3 [M+H] 203 1-[(2R,5S)-4-[7-(1-acetylpyrrolidin-3-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carbonyl]cyclobutane-1-carbonitrile m/z = 492.3 [M+H] 204A 2-[(5S)-4-[(2S,5R)-4-(Cubiane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]-5-(cyanomethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 519.2 [M+H] 204B 2-[(5R)-4-[(2S,5R)-4-(Cubiane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]-5-(cyanomethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 519.2 [M+H] 205A 2-[(5R)-4-[(2S,5R)-4-(Bicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]-5-(cyanomethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 483.2 [M+H] 205B 2-[(5S)-4-[(2S,5R)-4-(Bicyclo[1.1.1]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]-5-(cyanomethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 483.2 [M+H] 206 (2R,5S)-4-[7-(3-cyanocyclopentyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 467.3 [M+H] 207 2-(4'-((2R,5S)-4-(1-cyanocyclobutane-1-carbonyl)-2,5-dimethylpiperazin-1-yl)-2-fluorospiro[cyclopropane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)isonicotinecarbonitrile m/z = 487.3 [M+H] 208 (2R,5S)-2,5-Dimethyl-4-[7-(1H-pyrazolo[4,3-c]pyridin-6-yl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]piperazine-1-carboxylic acid tributyl ester m/z = 491.3 [M+H] 209 6-[4-[(2S,5R)-4-(2-cyano-3-methoxy-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 502.3 [M+H] 210 (2R,5S)-4-[7-(3-cyanocyclobutyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 453.3 [M+H] 211 6-[4-[(2S,5R)-2,5-dimethyl-4-(2-methyl-2-methylsulfonylpropionyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 525.3 [M+H] 212 2-Chloro-6-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyrimidine-4-carbonitrile m/z = 518.2 [M+H] 213A 2-[4-[(2S,5R)-4-[(2R)-2-cyano-3-fluoro-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 489.2 [M+H] 213B 2-[4-[(2S,5R)-4-[(2S)-2-cyano-3-fluoro-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 489.2 [M+H] 214A 6-[4-[(2S,5R)-4-[(2R)-2-cyano-3-fluoro-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 490.2 [M+H] 214B 6-[4-[(2S,5R)-4-[(2S)-2-cyano-3-fluoro-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 490.2 [M+H] 215A 2-[4-[(2S,5R)-4-[(2S)-2-cyano-3,3-difluoro-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 507.3 [M+H] 215B 2-[4-[(2S,5R)-4-[(2R)-2-cyano-3,3-difluoro-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 507.3 [M+H] 216 2-[4-[(2S,5R)-4-[(2S)-2-amino-3-methoxy-2-methylpropionyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 491.2 [M+H] 217 2-[4-[(2S,5R)-4-(3-fluoro-2-methoxy-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 494.2 [M+H] 218 2-[4-[(2S,5R)-4-[3-fluoro-2-(fluoromethyl)-2-methylpropanoyl]-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 496.3 [M+H] 219 2-[4-[(2S,5R)-4-(Bicyclo[2.1.0]pentane-1-carbonyl)-2,5-dimethylpiperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 470.3 [M+H] 220 (2S,5R)-4-[7-[(1R,3S)-3-cyanocyclohexyl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tributyl ester m/z = 481.3 [M+H] 221 (2R,5S)-4-[7-[(1S,3S)-3-cyanocyclohexyl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tributyl ester m/z = 481.3 [M+H] 222A 2-[4-[(2S,5R)-4-[(2R)-3-fluoro-2-methyl-2-methylsulfonyl-propionyl]-2,5-dimethyl-piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 542.2 [M+H] 222B 2-[4-[(2S,5R)-4-[(2S)-3-fluoro-2-methyl-2-methylsulfonyl-propionyl]-2,5-dimethyl-piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 542.2 [M+H] 223 2-[4-[(3R)-4-(1-cyanocyclobutanecarbonyl)-3-(cyanomethyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 494.3 [M+H] 224 2-[4-[(3S)-4-(1-cyanocyclobutanecarbonyl)-3-(cyanomethyl)piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 494.3 [M+H] 225 2-[4-[(2S,5R)-4-[2-cyano-3-fluoro-2-(fluoromethyl)propanoyl]-2,5-dimethyl-piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 507.2 [M+H] 226 (2R,5S)-4-(7'-((1 r ,3 S )-3-cyano-3-methylcyclobutyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 467.3 [M+H] 227 (2R,5S)-4-(7'-((1 r ,3 S )-3-cyano-3-methylcyclobutyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 467.3 [M+H] 228A 6-[4-[(2S,5R)-4-[(2R)-2-cyano-3-fluoro-2-methyl-propionyl]-2,5-dimethyl-piperazin-1-yl]-5,5-dimethyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridazine-4-carbonitrile m/z = 478.2 [M+H] 228B 6-[4-[(2S,5R)-4-[(2S)-2-cyano-3-fluoro-2-methyl-propionyl]-2,5-dimethyl-piperazin-1-yl]-5,5-dimethyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridazine-4-carbonitrile m/z = 478.2 [M+H] 229A 2-[4-[(2S,5R)-4-[(2R)-2-cyano-3-fluoro-2-methyl-propionyl]-2,5-dimethyl-piperazin-1-yl]-5,5-dimethyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 477.2 [M+H] 229B 2-[4-[(2S,5R)-4-[(2S)-2-cyano-3-fluoro-2-methyl-propionyl]-2,5-dimethyl-piperazin-1-yl]-5,5-dimethyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 477.2 [M+H] 230 2-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethyl-piperazin-1-yl]-5-methyl-5-(triazol-2-ylmethyl)-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 538.2 [M+H] 231A 2-[(5R)-4-[(2S,5R)-4-(2-cyano-3-fluoro-2-methyl-propionyl)-2,5-dimethyl-piperazin-1-yl]-5-(methoxymethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 507.2 [M+H] 231B 2-[(5S)-4-[(2S,5R)-4-(2-cyano-3-fluoro-2-methyl-propionyl)-2,5-dimethyl-piperazin-1-yl]-5-(methoxymethyl)-5-methyl-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 507.2 [M+H] 232 (2R,5S)-4-[7-(3-ethoxycarbonylcyclobutyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tributyl ester m/z = [M+H] 233 6-[4-[(2S,5R)-4-[2-cyano-2-methyl-3-(trifluoromethoxy)propanoyl]-2,5-dimethyl-piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridazine-4-carbonitrile m/z = 556.2 [M+H] 234A 4-[4-[(2S,5R)-4-[(2R)-2-cyano-3-fluoro-2-methyl-propionyl]-2,5-dimethyl-piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]-5-fluoro-pyridine-2-carbonitrile m/z = 507.2 [M+H] 234B 4-[4-[(2S,5R)-4-[(2S)-2-cyano-3-fluoro-2-methyl-propionyl]-2,5-dimethyl-piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]-5-fluoro-pyridine-2-carbonitrile m/z = 507.2 [M+H] 235 2-[4-[(2S,5R)-4-[3-fluoro-2-methyl-2-(triazol-2-yl)propionyl]-2,5-dimethyl-piperazin-1-yl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-7-yl]pyridine-4-carbonitrile m/z = 531.3 [M+H] 236 2-[4-[(2S,5R)-4-(1-cyanocyclobutanecarbonyl)-2,5-dimethyl-piperazin-1-yl]-5-methyl-5-(triazol-1-ylmethyl)-6H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-4-carbonitrile m/z = 538.2 [M+H] 237 (2R,5S)-4-(7-cyclobutylspiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl)-2,5-dimethyl-piperazine-1-carboxylic acid tributyl ester m/z = 428.2 [M+H] 238 (2R,5S)-4-[7-(3-Hydroxycyclobutyl)spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tributyl ester m/z = 444.4 [M+H] 239A (2R,5S)-4-[7-[3-(Hydroxymethyl)-3-methyl-cyclobutyl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tributyl ester m/z = 472.7 [M+H] 239B (2R,5S)-4-[7-[3-(Hydroxymethyl)-3-methyl-cyclobutyl]spiro[6H-pyrrolo[2,3-d]pyrimidine-5,1'-cyclobutane]-4-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tributyl ester m/z = 472.5 [M+H] 240 2-(4-((2R,5S)-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5,5-dimethyl-5,6-dihydro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)isocyanate m/z = 495.2 [M+H] 241 4-(4'-((2R,5S)-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)-5-fluoropicolinonitrile m/z = 525.2 [M+H] 242A 4-(( R )-4-((2R,5S)-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-(methoxymethyl)-5-methyl-5,6-dihydro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-5-fluoropicolinonitrile m/z = 543.3 [M+H] 242B 4-(( S )-4-((2R,5S)-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-(methoxymethyl)-5-methyl-5,6-dihydro- 7H -pyrrolo[2,3- d ]pyrimidin-7-yl)-5-fluoropicolinonitrile m/z = 543.3 [M+H] 243 (2 R ,5 S )-4-(7-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-6,7-dihydro-5 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 491.2 [M+H] 244A 4-(4'-(( 2S , 5R )-4-(( R )-2-cyano-3-fluoro-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)picolinonitrile m/z = 489.2 [M+H] 244B 4-(4'-((2 S ,5 R )-4-(( S )-2-cyano-3-fluoro-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)picolinonitrile m/z = 489.2 [M+H] 245 2-(( R )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-(methoxymethyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 525.2 [M+H] 246A 2-(( R )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-(fluoromethyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isocyanate m/z = 513.3 [M+H] 246B 2-(( S )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-(fluoromethyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 513.2 [M+H] 247A 4-(4-((2 S ,5 R )-4-(( R )-2-cyano-3-fluoro-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl)-5,5-dimethyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-5-fluoropicolinonitrile m/z = 495.2 [M+H] 247B 4-(4-((2 S ,5 R )-4-(( S )-2-cyano-3-fluoro-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl)-5,5-dimethyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-5-fluoropicolinonitrile m/z = 495.1 [M+H] 248A 2-(( R )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-((difluoromethoxy)methyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isocyanate m/z = 561.2 [M+H] 248B 2-(( S )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-((difluoromethoxy)methyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isocyanate m/z = 561.2 [M+H] 249 3-(4'-(( 2S , 5R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)-5-fluorobenzonitrile m/z = 524.2 [M+H] 250 5-(4'-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-yl)nicotinoid carbonitrile m/z = 507.3 [M+H] 251 (2 R ,5 S )-4-(7'-(6-chloropyridazin-4-yl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 486.2 [M+H] 252 4-(4'-(( 2S , 5R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)-5-fluoropyrimidine-2-carbonitrile m/z = 526.2 [M+H] 253 4-(4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5,5-dimethyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)-5-fluoropicolinonitrile m/z = 513.2 [M+H] 254 5-(4'-(( 2S , 5R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)pyridazine-3-carbonitrile m/z = 508.2 [M+H] 255A 2-(4-((2 S ,5 R )-4-(( R )-2-cyano-3-fluoro-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl)-5,5-bis(methyl- d 3 )-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 483.2 [M+H] 255B 2-(4-((2 S ,5 R )-4-(( S )-2-cyano-3-fluoro-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl)-5,5-bis(methyl- d 3 )-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 483.3 [M+H] 256A 2-(( R )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-(difluoromethyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isocyanate m/z = 531.2 [M+H] 256B 2-(( S )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-(difluoromethyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 531.2 [M+H] 257 2-(4-((2 S ,5 R )-2,5-dimethyl-4-(2-methyl-2-(oxacyclobutane-3-yl)propanoyl)piperazin-1-yl)-5,5-dimethyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 490.3 [M+H] 258A 2-(( R )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-(ethoxymethyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 539.3 [M+H] 258B 2-(( S )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-(ethoxymethyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 539.3 [M+H] 259 5-(4'-(( 2S , 5R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'( 6'H )-yl)-6-methylpyridazine-3-carbonitrile m/z = 522.2 [M+H] 260 2-(4-((2 S ,5 R )-4-(2-cyano-3,3-difluoro-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl)-5,5-dimethyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 495.3 [M+H] 261A 2-(( R )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-5-((trifluoromethoxy)methyl)-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isocyanate m/z = 579.3 [M+H] 261B 2-(( S )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-5-((trifluoromethoxy)methyl)-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isocyanate m/z = 579.2 [M+H] 262A 2-(( R )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-5-((methylsulfonyl)methyl)-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 573.2 [M+H] 262B 2-(( S )-4-((2 S ,5 R )-4-(2-cyano-3-fluoro-2-(fluoromethyl)propanoyl)-2,5-dimethylpiperazin-1-yl)-5-methyl-5-((methylsulfonyl)methyl)-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isocyanate m/z = 573.2 [M+H] 263 5-Fluoro-4-(4-((2 S ,5 R )-4-(3-fluoro-2-methyl-2-(methylsulfonyl)propionyl)-2,5-dimethylpiperazin-1-yl)-5,5-dimethyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)picolinonitrile m/z = 548.2 [M+H] 264A 5-Fluoro-4-(4-((2 S ,5 R )-4-(( R )-3-fluoro-2-methyl-2-(methylsulfonyl)propionyl)-2,5-dimethylpiperazin-1-yl)-5,5-dimethyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)picolinonitrile m/z = 530.3 [M+H] 264B 5-Fluoro-4-(4-((2 S ,5 R )-4-(( S )-3-fluoro-2-methyl-2-(methylsulfonyl)propionyl)-2,5-dimethylpiperazin-1-yl)-5,5-dimethyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)picolinonitrile m/z = 530.2 [M+H] 265A 2-(( R )-4-((2 S ,5 R )-4-(( S )-2-cyano-3-fluoro-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl)-5-((difluoromethoxy)methyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isocyanate m/z = 543.3 [M+H] 265B 2-(( S )-4-((2 S ,5 R )-4-(( S )-2-cyano-3-fluoro-2-methylpropanoyl)-2,5-dimethylpiperazin-1-yl)-5-((difluoromethoxy)methyl)-5-methyl-5,6-dihydro-7 H -pyrrolo[2,3- d ]pyrimidin-7-yl)isonicotinecarbonitrile m/z = 543.2 [M+H] 267 (2 R ,5 S )-4-(7'-(ethylaminocarbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 445.3 [M+H] ⁺ 268 (2 R ,5 S )-4-(7'-(cyclobutanecarbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 456.3 [M+H] ⁺ 269 rac- (2 R ,5 S )-4-(7'-((1 R ,2 R )-2-cyanocyclopropane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3 -d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 467.3 [M+H] ⁺ 270 rac- (2 R ,5 S )-4-(7'-((1 S ,2 R )-2-cyanocyclopropane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 467.3 [M+H] ⁺ 271 (2 R ,5 S )-4-(7'-((1 s ,3 R )-3-cyanocyclobutane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 481.3 [M+H] ⁺ 272 (2 R ,5 S )-4-(7'-((1 r ,3 S )-3-cyanocyclobutane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 481.3 [M+H] ⁺ 273 (2 R ,5 S )-2,5-dimethyl-4-(7'-(1-methylcyclobutane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 470.3 [M+H] ⁺ 274 (2 R ,5 S )-4-(7'-(3-cyanopropanoyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 455.3 [M+H] ⁺ 275 (2 R ,5 S )-4-(7'-((cyclopropylmethyl)sulfonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 492.3 [M +H] ⁺ 276 (2 R ,5 S )-4-(7'-((1 s ,3 R )-3-fluorocyclobutane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 474.3 [M +H] ⁺ 277 (2 R ,5 S )-4-(7'-((1 r ,3 S )-3-fluorocyclobutane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 474.3 [M +H] ⁺ 278 (2 R ,5 S )-4-(7'-(2,2-difluorocyclobutane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 492.3 [M +H] ⁺ 279 (2 R ,5 S )-4-(7'-(2,2-difluorocyclopropane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 478.3 [M +H] ⁺ 280 (2 R ,5 S )-4-(7'-(1-fluorocyclobutane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 474.3 [M +H] ⁺ 281 (2 R ,5 S )-4-(7'-(2-(dimethylamino)-2-oxoethyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 459.3 [M+H] ⁺ 282 (2 R ,5 S )-2,5-dimethyl-4-(7'-(2-(methylamino)-2-oxoethyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 445.3 [M+H] ⁺ 283 (2 R ,5 S )-4-(7'-(1-(cyanomethyl)cyclopropane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 481.3 [M+H] ⁺ 284 4'-((2 S ,5 R )-4-(tert-butyloxycarbonyl)-2,5-dimethylpiperazin-1-yl)spiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidine]-7'(6' H )-carboxylic acid cyclobutyl ester m/z = 472.3 [M+H] ⁺ 285 (2 R ,5 S )-2,5-dimethyl-4-(7'-((1-methyl-1 H -pyrazol-4-yl)methyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 468.3 [M+H] ⁺ 286 (2 R ,5 S )-2,5-dimethyl-4-(7'-((1-methyl-1 H -pyrazol-3-yl)methyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 468.3 [M+H] ⁺ 287 (2 S ,5 S )-1-(7'-(2-cyano-1-methylcyclopropane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperidine-4-carboxylic acid tributyl ester m/z = 481.2 [M+H] ⁺ 288 (2 R ,5 S )-4-(7'-((1 S ,2 R )-2-cyano-2-methylcyclopropane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 481.2 [M+H] ⁺ 289A (2 R ,5 S )-2,5-dimethyl-4-(7'-(( R )-tetrahydrofuran-2-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 472.2 [M+H] ⁺ 289B (2 R ,5 S )-2,5-dimethyl-4-(7'-(( S )-tetrahydrofuran-2-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 472.2 [M+H] ⁺ 290 (2 R ,5 S )-2,5-dimethyl-4-(7'-(tetrahydrofuran-3-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 472.3 [M+H] ⁺ 291 (2 R ,5 S )-4-(7'-(1-cyanocyclobutane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 481.2 [M+H] ⁺ 292 (2 R ,5 S )-4-(7'-((1 R ,2 R )-2-cyano-2-methylcyclopropane-1-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 481.2 [M+H] ⁺ 293 (2 R ,5 S )-2,5-dimethyl-4-(7'-(1-methyl-1 H -pyrazole-5-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 482.3 [M+H] ⁺ 294 (2 R ,5 S )-4-(7'-(2-(1 H -pyrazol-1-yl)acetyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 482.3 [M+H] ⁺ 295 (2 R ,5 S )-2,5-dimethyl-4-(7'-(3-(1-methyl-1 H -pyrazol-4-yl)propanoyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 510.3 [M+H] ⁺ 296 (2 R ,5 S )-2,5-dimethyl-4-(7'-(2-(pyrrolidin-1-yl)acetyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 485.3 [M+H] ⁺ 297 (2 R ,5 S )-4-(7'-( L -prolinyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 471.3 [M+H] ⁺ 298 (2 R ,5 S )-4-(7'-( D -prolinyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)-2,5-dimethylpiperazine-1-carboxylic acid tributyl ester m/z = 471.3 [M+H] ⁺ 299 (2 R ,5 S )-2,5-dimethyl-4-(7'-(( S )-pyrrolidine-3-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 471.3 [M+H] ⁺ 300 (2 R ,5 S )-2,5-dimethyl-4-(7'-(( R )-pyrrolidine-3-carbonyl)-6',7'-dihydrospiro[cyclobutane-1,5'-pyrrolo[2,3- d ]pyrimidin]-4'-yl)piperazine-1-carboxylic acid tributyl ester m/z = 471.3 [M+H] ⁺ Biological examples 1 Biochemical Assays of Compounds hTRPML1 FLIPR Verification

General Information: TRPML1 is a cation-permeable ion channel localized on the lysosomal membrane. The principle of the assay involves the measurement of fluorescence of a sensitive calcium dye as an indicator of changes in intracellular calcium concentrations in cells expressing mutant TRPML1 localized on the plasma membrane. Cellular calcium responses are measured in the presence or absence of test compounds to identify and characterize TRPML1-dependent calcium conductance modulators.

Cell culture: HEK293 cells stably expressing HA-bound human TRPML1 (HA-hTRPML1) were generated by lentiviral infection (using CMV promoter and puromycin selection). Mutations were introduced into the TRPML1 sequence (L15A L16A L577A L578A) to achieve plasma membrane expression of TRPML1. Cells were cultured at 37°C in a humidified and air-controlled (5% CO ₂ ) incubator. Cells were cultured in DMEM (Thermo Fisher) supplemented with fetal bovine serum (Thermo Fisher, 10% v/v), penicillin/streptomycin (Thermo Fisher, 1% v/v), and puromycin (Thermo Fisher, 4 mg/ml).

Assay protocol: One day before the assay, cells were lifted and lysed using TrypLE Express enzyme (Gibco) and seeded at 12k cells/well (30 µL) in growth medium in poly-D-lysine coated 384-well black-walled microplates (Greiner). The cell plates were placed in a cell culture incubator (5% CO ₂ at 37°C) until the next day.

On the day of the assay, the plates were centrifuged at 300 rpm for 7 s to remove the growth medium. FLIPR Calcium 6 Dye (Molecular Devices) was diluted in assay buffer and added to the plates at 20 µL/well. Assay buffer consisted of Hank's Balanced Salt Solution (Gibco) supplemented with 1% probenecid (Thermo Fisher) and 2% 1M HEPES (Gibco). The plates were then centrifuged at 300 rpm for 30 s and incubated at 37°C with 5% CO ₂ for 2 hours.

Compounds were dissolved in DMSO at 10 mM. Compound plates were prepared at 3X final concentration on the day of the experiment. Compound titrations were performed using an Echo acoustic dispenser (Beckman Coulter) in 384-well polypropylene plates (Greiner). Each compound plate included a high control (20 mM ML-SA5), a low control (1% DMSO), and up to 16 compounds at different doses. Each compound was titrated at 22 concentrations ranging from 300 μM to 143 pM, with final concentrations of 100 μM to 47.7 pM. The DMSO concentration throughout the plate was maintained at 1% as the final concentration.

The fluorescence signal from each well of the cell plate was determined using a FLIPR Tetra (Molecular Devices) at an excitation wavelength of 480 nm and an emission wavelength of 540 nm. The background fluorescence signal was first recorded for 60 seconds. Next, 10 µL of compound solution was transferred from the compound plate to each well of the cell plate using a FLIPR pipette. The solution was mixed three times using a pipette. The fluorescence signal was measured for 290 seconds.

Data Analysis: Cellular responses were calculated as the maximum signal minus background. Cellular responses to compound treatment were expressed as % of the assay window defined by the mean of the high control and the mean of the low control. % values were plotted as a function of test compound concentration in GraphPad Prism. Data were described by a 4-parameter logistic function that enabled the estimation of the _EC50 (potency) for each compound.

The activities of the test compounds are provided in Table 4 below as follows: A = EC ₅₀ < 0.1 µM; B = EC ₅₀ 0.1-0.5 µM; C = 0.5 µM < EC ₅₀ < 2 µM; D = EC ₅₀ > 2 µM. Table 4

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The disclosure described in this document in an illustrative manner may be suitably practiced in the absence of any one or more elements, one or more limitations that are not expressly disclosed herein. Thus, for example, the terms "comprising", "including", "containing", etc. should be interpreted broadly and without limitation. In addition, the terms and expressions used herein have been used as descriptive rather than limiting terms, and it is not intended to exclude any equivalent forms of the features shown and described or parts thereof by using such terms and expressions, but it should be recognized that various modifications are possible within the scope of the application scope.

All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each were individually incorporated by reference. In the event of a conflict, the present specification, including definitions, will control.

It should be understood that although the present disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate rather than limit the scope of the present disclosure. Other aspects, advantages and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure belongs.

Claims (39)

A compound of formula I, I or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a tautomer, a stereoisomer or a mixture of stereoisomers, wherein: X ¹ is N or CR ⁷ ; L is a bond, C _1-2 alkylene, C ₂ alkenylene, C ₂ alkynylene, -CH ₂ -C(O)NR ¹¹ -*, -C(O)-, -S(O)-, -S(O) ₂ -, -C(O)O-*, -C(O)NR ¹¹ -*, -S(O)NR ¹¹ -* or -S(O) ₂ NR ¹¹ -*; wherein the * bond is connected to R ⁴ ; R ¹ is a halogen, a cyano, a nitro, -CD ₃ , a C _1-6 alkyl, a C _2-6 alkenyl, a C _2-6 alkynyl, a C _3-10 Cycloalkyl, heterocyclic group, aryl group, heteroaryl group, -N(R ¹¹ ) ₂ , -OR ¹¹ , -SR ¹¹ , -C(O)R ¹¹ , -C(O)OR ¹¹ , -S(O)R ¹¹ , -S(O) ₂ R ¹¹ , -C(O)N(R ¹¹ ) ₂ , -NR ¹¹ C(O)R ¹¹ , -NR ¹¹ S(O)R ¹¹ , -NR ¹¹ S(O) ₂ R ¹¹ , -S(O)N(R ¹¹ ) ₂ , -S(O) ₂ N(R ¹¹ ) ₂ , -NR ¹¹ C(O)N(R ¹¹ ) ₂ , -NR ¹¹ S(O)N(R ¹¹ ) ₂ , -NR ¹¹ S(O) ₂ N(R ¹¹ ) ₂ , -OC(O)N(R ¹¹ ) ₂ or -NR ¹¹ C(O)OR ¹¹ ; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl group is independently substituted with one to five Z ^1a as appropriate; R ² is a halogen group, -CD ₃ , a C _1-6 alkyl, a C _2-6 alkenyl, a C _2-6 alkynyl, a C _3-10 cycloalkyl, a heterocyclic group, an aryl or a heteroaryl group; wherein the C _1-6 alkyl, the C _2-6 alkenyl, the C _2-6 alkynyl, the C 3-10 The C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted by one to five Z ^1a as appropriate; or R ¹ and R ² together with the carbon atom to which they are attached form a C _3-10 cycloalkyl or heterocyclic group; wherein the C _3-10 cycloalkyl or the heterocyclic group is independently substituted by one to five Z ^1a as appropriate; R ³ is: or ; R ⁴ is C _1-6 alkyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl; wherein the C _1-6 alkyl, the C _3-10 cycloalkyl, the heterocyclic group, the aryl or the heteroaryl is independently substituted by one to five Z ^1a as appropriate; each R ⁵ is independently halogen, cyano, C _1-6 alkyl, C _{1-6 halogenalkyl, C 2-6} alkenyl or C _2-6 alkynyl; or two R ⁵ together form a C 3-6 cycloalkyl or a _4-6 membered heterocyclic group; wherein the C _3-6 cycloalkyl or the 4-6 membered heterocyclic group is independently substituted by one to five Z ^1a as appropriate; or two R ⁵ together with the carbon atoms to which they are attached form a C _3-6 cycloalkyl or a 4-6 membered heterocyclic group; wherein the C _3-10 cycloalkyl or heterocyclic group is independently substituted by one to five Z ^1a as appropriate; or R ¹ and R ⁵ together with the carbon atom to which they are attached form a C _3-10 cycloalkyl or heterocyclic group; wherein the C _3-10 cycloalkyl or heterocyclic group is independently substituted by one to five Z ^1a as appropriate; or R ⁴ and R ⁵ together with the _atom to which they are attached form a heterocyclic group or heteroaryl; wherein the heterocyclic group or heteroaryl is independently substituted by one to five Z ^1a as appropriate; R ⁶ and R ⁷ are each independently hydrogen, hydroxyl, halogen, cyano, C _1-6 alkyl, C R ^a and ^{R b} are each independently hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, -(CH ₂ ⁾ _{0-2 -C 3-7} cycloalkyl and _3-7 membered heterocyclic group; each R ⁸ is independently -C(O)N(R ¹¹ ) ₂ , C _1-6 alkyl or C _1-6 haloalkyl; wherein the C _1-6 alkyl or _the C _1-6 haloalkyl is independently substituted with cyano, -N(R ¹³ ) ₂ , halo, hydroxyl or C _1-6 alkoxy; or two R ⁸ and _the carbon atom to which they are connected can form a pendant, fused or spiroC wherein the C _3-7 cycloalkyl or the 4-7 membered heterocyclic group is independently substituted by a halogen group, a hydroxyl group, _a C 1-6 alkyl group, a C _1-6 halogen group, a C _1-6 alkoxy group or a C _1-6 halogen alkoxy group; R ⁹ is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _3-10 cycloalkyl group or a -OC _3-10 cycloalkyl group; wherein the C _1-6 alkyl group, the C _1-6 alkoxy group, the C _3-10 cycloalkyl group or the -OC _3-10 cycloalkyl group is independently substituted by one to five Z ^1a ; each R ¹¹ is independently hydrogen, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C 1-6 alkoxy group or a -OC _3-10 cycloalkyl group; wherein each C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl is independently substituted with one to five Z ^1a as appropriate; t is 0, 1 or 2; m is ₁ or 2; n is 1, 2 or ₃ ; m1 is 0, 1 or 2; n1 is 0, 1, 2 or 3; m2 is 0, 1 or 2; n2 is 0, 1, 2 or 3; wherein m + n is 2, 3 or 4; m1 + n1 is 0, 1, 2, 3 or 4; m2 + n2 is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; each Z ^1a is independently halogen, cyano, -NO ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic, aryl, heteroaryl, -N(R ¹³ ) ₂ , -OR ¹³ , -SR ¹³ , -C(O)R 13 , -C(O)OR ¹³ , -S(O)R ¹³ , -S(O) ₂ R ¹³ , -C(O)N(R ¹³ ) ₂ , -NR ¹³ C(O)R ¹³ , -NR ¹³ S(O)R ¹³ , -NR ¹³ S(O) ₂ R ¹³ , -S(O)N( ^{R 13} ) ₂ , -S(O) ₂ N(R ¹³ ) _{2 wherein} ^each C 1-6 alkyl, ^{C 2-6} alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted _{with one} to five Z 1b as ^appropriate ; each R ¹³ is independently hydrogen, C ^1-6 alkyl, C ^{2-6 alkenyl, C 2-6} _{alkynyl ,} C ^3-10 cycloalkyl, heterocyclic group, aryl or ^heteroaryl group; wherein each C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to five Z ^1b as appropriate; each R ¹³ is independently hydrogen, C 1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C 3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group; wherein each C _1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C _3-10 cycloalkyl, heterocyclic group, aryl or heteroaryl group is independently substituted with one to _five Z 1b as appropriate; The group consisting of: -C _2-6 alkyl, -C _2-6 alkenyl, -C _2-6 alkynyl, -C ^3-10 cycloalkyl, -C 1-6 halogen, -C 3-10 cycloalkyl, -C _1-6 aryl, -C _2-6 alkylene group, -C ^2-6 alkynyl, -C _1-6 halogen _, -C _3-10 cycloalkyl, -C _1-6 aryl, -C _1-6 alkylene group, -C _{2-6 alkynyl} , ^{-C 2-6} _halogen , -C ^{3-10 cycloalkyl} , ^{-C 1-6} _{aryl ,} -C ^1-6 alkylene group ^... -aryl or -L ¹ -heteroaryl; and each L ¹ is independently -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -N(C _{1-6 alkyl)-, -N(C 2-6} alkenyl)-, -N(C _2-6 alkynyl)-, -N(C _1-6 halogenalkyl)-, -N(C _3-10 cycloalkyl)-, -N( _heterocyclo )-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C _1-6 alkyl)-, -C(O)N(C _2-6 alkenyl)-, -C(O)N(C _2-6 alkynyl)-, -C(O)N(C wherein each of Z 1b and L 1 is C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C 1-6 haloalkyl, C _3-10 cycloalkyl, _{heterocycloalkyl} , _aryl and _heteroaryl and is independently substituted with ^one to five independently selected substituents selected from halogen, cyano, -OH, _-SH , -NH _{2 , -NO} ² , -SF ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 halogenalkyl, C _1-6 alkoxy, C _1-6 halogenalkoxy, C _3-10 cycloalkyl, heterocyclo, aryl and heteroaryl. The compound of claim 1 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ¹ is -CD ₃ , C _1-6 alkyl, heteroaryl, -C(O)OR ¹¹ or -C(O)N(R ¹¹ ) ₂ , wherein the C _1-6 alkyl or heteroaryl is optionally substituted with one to three halogen groups, cyano groups, hydroxyl groups, C _1-6 alkyl groups, C _1-6 alkoxy groups, C _1-6 halogenalkoxy groups, -S(O) ₂ C _1-6 alkyl groups or heteroaryl groups. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ² is -CD ₃ or C _1-6 alkyl. The compound of claim 1 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ¹ and R ² together with the carbon atoms to which they are attached form a C _3-6 cycloalkyl or a 4-6 membered heterocyclic group; wherein the C _3-6 cycloalkyl or the 4-6 membered heterocyclic group is independently substituted with one to five Z ^1a as the case may be. The compound of claim 1 or its pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers, wherein R ¹ and R ² together with the carbon atom to which they are attached form a C _3-6 cycloalkyl group which is optionally substituted with one to five Z ^1a . The compound of claim 1 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein ^R1 and ^R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl group which is optionally substituted by one or two hydroxyl groups, halogen groups, cyano groups, _C1-6 alkyl groups, _C1-6 halogen groups, _C1-6 alkoxy groups or _heteroaryl groups. The compound of claim 1 or its pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers, wherein ^R1 and ^R2 together with the carbon atom to which they are attached form an unsubstituted _C3-5 cycloalkyl group. A compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ³ is . The compound of claim 8 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein m is 1 or 2. The compound of claim 8 or 9, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein n is 1. A compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein p is 0, 1, 2 or 3. A compound as claimed in any of the preceding claims or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein each R ⁸ is independently -C(O)N(R ¹¹ ) ₂ , C _1-6 alkyl or C _1-6 halogenalkyl; wherein the C _1-6 alkyl is independently substituted with cyano, -N(R ¹³ ) ₂ , halogen, hydroxyl or C _1-6 alkoxy as appropriate; or two R ⁸ together with the carbon atoms to which they are attached can form a pendoxy group or a bridged 4-7 membered heterocyclic group. A compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein p is 1 or 2; and each R ⁸ is methyl. A compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ⁹ is C _1-6 alkyl, C _1-6 alkoxy or C _3-10 cycloalkyl; wherein the C _1-6 alkyl, the C _1-6 alkoxy or the C _3-10 cycloalkyl is independently substituted with one to five halogen groups, cyano groups, hydroxyl groups, -S(O) ₂ C _1-6 alkyl, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , -C(O)NHC _1-6 alkyl ₂ , -C(O)N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C 1-6 alkoxy, C _1-6 halogen alkyl, C _3-10 cycloalkyl, The group may be substituted by a _{C 1-6} halogen alkoxy group, a C _3-7 cycloalkyl group, a heterocyclic group or a heteroaryl group; wherein the heterocyclic group may be further substituted by a halogen group or a C _1-6 alkoxy group. The compound of any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein ^X1 is N. A compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ⁶ is hydrogen. The compound of any of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein L is a bond, C _1-2 alkylene, -CH ₂ -C(O)NR ¹¹ -*, -C(O)-, -S(O) ₂ -, -C(O)O-* or -C(O)NR ¹¹ -*; wherein the * bond is connected to R ⁴ . The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ⁴ is C _1-6 alkyl optionally substituted with one to five Z ^1a . The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ⁴ is C _3-10 cycloalkyl optionally substituted with one to five Z ^1a . The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ⁴ is aryl which is optionally substituted with one to five Z ^1a . The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ⁴ is a heteroaryl group optionally substituted with one to five Z ^1a . The compound of claim 21 or its pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers, wherein R ⁴ is pyridinyl substituted by cyano. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein R ⁴ is 4-cyanopyridin-2-yl, 4-cyano-5-fluoro-pyridin-2-yl, 2-cyanopyridin-4-yl, 6-cyanopyrimidin-4-yl, 6-cyanopyrimidin-4-yl, 4-cyanopyrimidin-2-yl, 5-cyanopyrimidin-3-yl, [1,2,4]triazolo[4,3-a]pyrazin-6-yl, [1,2,4]triazolo[1,5-c]pyrimidin-7-yl, imidazo[1,2-c]pyrimidin-7-yl, imidazo[1,2-a]pyrazin-6-yl, 5-aminopyridin- oxazine-2-yl, 5-cyano-1-methyl-1H-pyrazol-3-yl, 3-cyano-5-fluorophenyl, 3,5-dicyanophenyl, 1-methyl-2-oxo-4-pyridyl, 6-aminopyrimidin-4-yl, 4-cyano-6-(hydroxymethyl)-2-pyridyl, 6-cyano-2-(trifluoromethyl)pyrimidin-4-yl, 7-(3-cyano-5-methylsulfonylphenyl), 5-cyano-2-methoxypyridin-3-yl, 5-cyano-2-oxo-1H-pyridin-3-yl, 7 -(6-cyano-2-methoxypyrimidin-4-yl), 6-chloro-4-cyanopyridin-2-yl, 7-(3-cyano-5-methylsulfanylphenyl), 5-cyano-1-methyl-2-oxo-3-pyridinyl, 2-cyano-5-fluoro-4-pyridinyl, 6-cyano-2-oxo-1,2-dihydropyrimidin-4-yl, 6-cyano-3-methyl-2-oxo-1,2-dihydropyrimidin-4-yl, 1-acetylpyrrolidin-3-yl, 7-(3-cyanocyclopentyl), 1H -pyrazolo[4,3-c]pyridin-6-yl, 3-cyanocyclobutyl, 2-chloro-6-cyanopyrimidin-4-yl, 3-cyanocyclohexyl, 3-cyano-3-methylcyclobutyl, 3-ethoxycarbonylcyclobutyl, 2-cyano-5-fluoropyridin-4-yl, cyclobutyl, 3-hydroxycyclobutyl, 3-(hydroxymethyl)-3-methyl-cyclobutyl, 2-chloro-5-fluoropyridin-4-yl, 6-chloropyridin-4-yl, 2-cyano-5-fluoropyridin-4-yl or 6-cyano-3-methylpyridin-4-yl. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein ^R4 is methyl, ethyl, cyclobutyl, 2-cyanocyclopropan-1-yl, 3-cyanocyclobutan-1-yl, 1-methylcyclobutan-1-yl, 3-cyanopropanoyl, cyclopropylmethyl, 3-fluorocyclobutan-1-yl, 2,2-difluorocyclobutan-1-yl, 2,2-difluorocyclopropan-1-yl, 1-fluorocyclobutan-1-yl, 1-(cyanomethyl)cyclopropan-1-yl, 1-methyl- 1H in the range of 1-4-nitro-2-nitropropan-1-yl, 1-nitro-2-nitropropan-1-yl, 1-nitro-1-nitropropan-2-yl, 1-nitro- 1 -nitropropan-5-yl, 1 - nitro-1-nitropropan-1-yl, 2-(1-methyl- 1H -pyrazol-4-yl)ethyl, pyrrolidin-1-ylmethyl, pyrrolidin-2-yl or pyrrolidin-3-yl. A compound as claimed in any preceding claim, or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein t is 0. The compound of claim 1, wherein the compound is represented by formula IA': IA' or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof. A compound selected from Table 1 or a pharmaceutically acceptable salt, isotopically enriched analog, tautomer, stereoisomer or mixture of stereoisomers thereof, or a compound selected from Table 2 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier. A method for activating TRPML1, comprising contacting cells with an effective amount of a compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers, or a pharmaceutical composition of claim 28. The method of claim 29, wherein the contacting is in vivo. A method for treating a disease or condition mediated at least in part by TRPML1, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers, or a pharmaceutical composition of claim 28. The method of claim 31, wherein the disease or condition is aging, bone disease, cardiovascular disease, congenital developmental disorder, eye disease, blood and solid malignancies, infectious diseases, inflammatory diseases, liver disease, metabolic disease, neurodegenerative or neurological disease or condition, pancreatitis, kidney disease, skeletal muscle disease, obesity, lysosomal storage disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, inclusion body myositis, Paget's disease, or lung disease. The method of claim 32, wherein the disease or disorder is fibrosis, fibrosis, neurodegenerative or neurological disease or disorder, lysosomal storage disease or disorder, lysosomal transport disease or disorder, glycogen storage disease or disorder, cholesterol ester storage disease or disorder, muscle disease, aging-related disease, macular degeneration, or cancer. The method of claim 33, wherein the neurodegenerative or neurological disease or disorder is selected from the group consisting of Parkinson's disease, GBA-Parkinson's disease, LRRK2 Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, FTDP-17, cortical basal degeneration, Lewy body dementia, Pick's disease, and multiple system atrophy. The method of claim 33, wherein the lysosomal storage disease or disorder is selected from the group consisting of Niemann-Pick disease, Gaucher's disease, neuropathic Gaucher's disease, sphingolipidosis, Farber disease, Krabbe disease, galactosialidosis, gangliosidosis, Gaucher's disease, lysosomal acid lipase deficiency, sulfatides, mucopolysaccharidosis, mucolipidosis, lipidosis, and oligosaccharidosis. In some embodiments, the lysosomal storage disease is selected from the group consisting of sphingolipidoses, Farber disease, Krabbe disease, galactosialidase, Fabry disease, Schindler disease, beta-galactosidase disorders, GM1 gangliosidosis, GM2 gangliosidosis AB variant, GM2 gangliosidosis activator deficiency, Sandhoff disease, Tay-Sachs disease, Gaucher disease, lysosomal acid lipase deficiency, Niemann-Pick disease, metachromatic leukodystrophy, saposin B deficiency, multiple sulfatase deficiency, Hurler syndrome, Scheie syndrome, syndrome, Hurler-Scheie syndrome, Hunter syndrome, Sanfilippo syndrome, Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, hyaluronidase deficiency, sialidosis, I cell disease, pseudo-Hurler polydystrophy, phosphotransferase deficiency, mucolipin 1 deficiency, Santavuori-Haltia disease, Jansky-Bielchowsky disease, Batten-Spielmeyer-Vogt disease, Kufs disease disease), Finnish variant neurocephaloid lipofuscinosis, late infantile variant neurocephaloid lipofuscinosis, neurocephaloid lipofuscinosis type 7, northern epileptic neurocephaloid lipofuscinosis, Turkish late infantile neurocephaloid lipofuscinosis, German/Serbian late infantile neurocephaloid lipofuscinosis, congenital histoplasmosis D deficiency, Wolman disease, alpha-mannosidosis, beta-mannosidosis, asparaginyl glucosaminuria, and fucosidosis. In some embodiments, the lysosomal storage disease is selected from the group consisting of Niemann-Pick disease, Gaucher disease, and neuropathic Gaucher disease. A use of a compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof, or a pharmaceutical composition of claim 28 for treating a disease or condition mediated at least in part by TRPML1. A compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof, or a pharmaceutical composition according to claim 28, for use in therapy. A compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof, or a pharmaceutical composition according to claim 28, for use in treating a disease or condition mediated at least in part by TRPML1. A use of a compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof, or a pharmaceutical composition of claim 28, for the manufacture of a medicament for treating a disease or condition mediated at least in part by TRPML1.