PHENYL mTORC INHIBITORS AND USES THEREOF

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to compounds and methods useful for modulating mTORCl activity. The invention also provides pharmaceutically acceptable compositions comprising provided compounds of the present invention and methods of using such compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

[0002] The mechanistic target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of cell metabolism, growth, proliferation and survival. Discoveries that have been made over the last decade show that the mTOR pathway is activated during various cellular processes (e.g. tumor formation and angiogenesis, insulin resistance, adipogenesis and T-lymphocyte activation) and is deregulated in human diseases such as cancer and type 2 diabetes. These observations have attracted broad scientific and clinical interest in mTOR. This is highlighted by the growing use of mTOR inhibitors [rapamycin and its analogues (rapalogues)] in pathological settings, including the treatment of solid tumors, organ transplantation, coronary restenosis and rheumatoid arthritis.

[0003] In particular, mTOR complex 1 (mTORCl) positively regulates cell growth and proliferation by promoting many anabolic processes, including biosynthesis of proteins, lipids and organelles, and by limiting catabolic processes such as autophagy. Much of the knowledge about mTORCl function comes from the use of the bacterial macrolide rapamycin. Upon entering the cell, rapamycin binds to FK506-binding protein of 12 kDa (FKBP12) and interacts with the FKBP12- rapamycin binding domain (FRB) of mTOR, thus inhibiting mTORCl functions (reviewed by Guertin and Sabatini, 2007). In contrast to its effect on mTORCl, FKBP12- rapamycin cannot physically interact with or acutely inhibit mTOR complex 2 (mTORC2)(Jacinto et al., 2004; Sarbassov et al., 2004). On the basis of these observations, mTORCl and mTORC2 have been respectively characterized as the rapamycin-sensitive and rapamycin-insensitive complexes. However, this paradigm might not be entirely accurate, as chronic rapamycin treatment can, in some cases, inhibit mTORC2 activity by blocking its assembly (Sarbassov et al., 2006). In addition, recent reports suggest that important mTORCl functions are resistant to inhibition by rapamycin (Choo et al., 2008; Feldman et al., 2009; Garcia-Martinez et al., 2009; Thoreen et al., 2009). Therefore, selective inhibition of mTORCl would enable the treatment of diseases that involve dysregulation of protein synthesis and cellular metabolism. Furthermore, this detailed understanding of regulating mTORCl activation pathways will permit the discovery of new strategies for regulating abnormal disease processes by modulating mTORCl activity across its spectrum of function.

[0004] Many diseases are associated with abnormal cellular responses triggered by events as described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone- related diseases.

[0005] The mechanistic target of rapamycin complex 1 (mTORCl) is a master growth regulator that senses diverse environmental cues, such as growth factors, cellular stresses, and nutrient and energy levels. When activated, mTORCl phosphorylates substrates that potentiate anabolic processes, such as mRNA translation and lipid synthesis, and limits catabolic ones, such as autophagy. mTORCl dysregulation occurs in a broad spectrum of diseases, including diabetes, epilepsy, neurodegeneration, immune response, suppressed skeletal muscle growth, and cancer among others (Howell et al., (2013) Biochemical Society transactions 41, 906-912; Kim et al., (2013) Molecules and cells 35, 463-473; Laplante and Sabatini, (2012) Cell 149, 274-293). Accordingly, there remains a need to find protein kinase inhibitors useful as therapeutic agents.

[0006] Additionally, Glucose transporters (GLUT) are a family of membrane proteins (GLUT1, 2, 3, 4, and 5) that facilitate the transport of glucose and other hexoses across cell membranes. The transport of glucose into cells is one of the most important cellular transport events because of the role in maintaining normal cellular respiration and metabolism (Gould and Holman, (1993) Biochem J., 295, 329-341). Dysfunction or dysregulation of glucose transporters may contribute to, or directly result in, disease states because of the central role the transporters play in cellular homeostasis and metabolism. For example, mutations in the GLUT1 gene are responsible for the rare autosomal disorder De Vivo disease, which is characterized by impaired glucose transport into the brain. Relatedly, elevated levels of GLUT1 in neutrophils has been found to contribute to the inflammatory response in cystic fibrosis (CF) patients (Laval et al., (2013) J. Immunol, 190(12), 6043-50). GLUT inhibition may normalize cellular metabolism and response in affected cells, including immune cells such as neutrophils. Therefore, GLUT inhibition would enable the treatment of cystic fibrosis, as well as autoimmune diseases characterized by abnormal GLUT expression or activity.

SUMMARY OF THE INVENTION

[0007] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors mTORCl inhibitors. Such compounds have the general Formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0008] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with mTORCl . Such diseases, disorders, or conditions include those described herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

1. General Description of Certain Embodiments of the Invention:

[0009] In certain embodiments, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A ¹ is N, N ⁺ -0 ^" , or CH;

A ² is N, N ⁺ -0 ^" , CH, or O;

A ³ is N, N ⁺ -0 ^" , CR', or C;

A ⁴ is N, N ⁺ -0 ^" , or CR', provided at least one of A ³ and A ⁴ comprises a nitrogen;

A ⁵ is CR" or N;

A ⁶ is CR" or N;

each R' is independently hydrogen, -C(0)N(R) ₂ , -N(R) ₂ , or -OR; or

an R' group on A ⁴ and Ring B are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R" is independently hydrogen, Ci-6 aliphatic, halogen, or -CN; or

an R group on A ⁵ and L ² are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of m, n, p, and q is independently 0, 1, or 2;

each of x, y, and z is independently 0, 1, 2, 3 or 4;

each of R ¹ and R ² is independently R; or:

two R ¹ groups are optionally taken together to form =0;

two R ² groups are optionally taken together to form =0;

two R ¹ groups are optionally taken together to form a covalent bond or a bivalent Ci-4 alkylene chain;

two R ² groups are optionally taken together to form a covalent bond or a bivalent Ci-4 alkylene chain; an R ¹ group and Ring A are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

an R ² group and Ring B are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

an R ² group and L ² are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

an R ² group and L ³ are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R ³ is independently R, halogen, -OR, -CN, or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

an R ³ group and L ² are optionally taken together with their intervening atoms to form a

5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring A is absent or an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring B is an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

L ¹ is a covalent bond or a C _1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -0-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S(0) ₂ - or -(C)=CH-; L ² is a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -0-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S(0) ₂ -, or -(C)=CH-; and

L ³ is a covalent bond, -N(R)-, or -S(0) ₂ -.

2. Compounds and Definitions:

[0010] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 ^th Ed., Ed. : Smith, M B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0011] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [0012] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), H (as in pyrrolidinyl) or R ⁺ (as in N-substituted pyrrolidinyl)).

[0013] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0014] As used herein, the term "bivalent Ci _-8 (or Ci-6) saturated or unsaturated, straight or branched, hydrocarbon chain", refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0015] The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH ₂ )n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0016] The term "alkenylene" refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0017] The term "halogen" means F, CI, Br, or I.

[0018] The term "aryl" used alone or as part of a larger moiety as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0019] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, e.g., "heteroaralkyl," or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyndazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyndinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0020] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro- 2H-pyrrolyl), H (as in pyrrolidinyl), or ⁺ R (as in N-substituted pyrrolidinyl).

[0021] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical," are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0022] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0023] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0024] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH ₂ )o-4R°; -(CH ₂ ) ₀ - ₄ OR°; -0(CH ₂ )o- ₄ R°, -O- (CH ₂ )o- ₄ C(0)OR°; -(CH ₂ ) ₀ - ₄ CH(OR°) ₂ ; -(CH ₂ ) ₀ ^SR°; -(CH ₂ ) ₀ ^Ph, which may be substituted with R°; which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH ₂ ) ₀ - ₄ O(CH ₂ ) ₀ -i-pyridyl which may be substituted with R°; -N0 ₂ ; -CN; -N ₃ ; -(CH ₂ )o- ₄ N(R°) ₂ ; -(CH ₂ ) ₀ - ₄ N(R ^o )C(O)R°; -N(R°)C(S)R°; -(CH ₂ ) ₀ - ₄ N(R°)C(0) R° ₂ ; -N(R°)C(S) R° ₂ ; -(CH ₂ ) ₀ - ₄ N(R°)C(O)OR°;

N(R°)N(R°)C(0)R°; -N(R°)N(R°)C(0) R° ₂ ; -N(R°)N(R°)C(0)OR°; -(CH ₂ ) ₀ - ₄ C(O)R°; - C(S)R°; -(CH ₂ )o^C(0)OR°; -(CH ₂ ) ₀ - ₄ C(O)SR°; -(CH ₂ ) ₀ - ₄ C(O)OSiR° ₃ ; -(CH ₂ ) ₀ - ₄ OC(O)R°; - OC(0)(CH ₂ )o- ₄ SR- SC(S)SR°; -(CH ₂ ) ₀ ^SC(O)R°; -(CH ₂ ) ₀ - ₄ C(O) R° ₂ ; -C(S) R° ₂ ; -C(S)SR°; -SC(S)SR°, -(CH ₂ )o-40C(0) R° ₂ ; -C(0)N(OR°)R°; -C(0)C(0)R°; -C(0)CH ₂ C(0)R°; - C(NOR°)R°; -(CH ₂ )o^SSR°; -(CH ₂ ) ₀ ^S(O) ₂ R°; -(CH ₂ ) ₀ ^S(O) ₂ OR°; -(CH ₂ ) ₀ - ₄ OS(O) ₂ R ^o ; - S(0) ₂ R° ₂ ; -S(0)( R°)R°; -S(0) ₂ N=C( R° ₂ ) ₂ ; -(CH ₂ ) ₀ ^S(O)R°; -N(R°)S(0) ₂ R° ₂ ; - N(R°)S(0) ₂ R°; -N(OR°)R°; -C( H) R° ₂ ; -P(0) ₂ R°; -P(0)R° ₂ ; -OP(0)R° ₂ ; -OP(0)(OR°) ₂ ; - SiR ⁰ ₃ ; -(Ci-4 straight or branched alkylene)0-N(R°) ₂ ; or -(Ci- ₄ straight or branched alkylene)C(0)0-N(R°) ₂ , wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, -CH ₂ -(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3—12— membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0025] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH ₂ )o- ₂ R*, -(haloR"), -(CH ₂ )o- ₂ OH, -(CH ₂ ) ₀ - ₂ OR", -(CH ₂ ) ₀ - ₂ CH(OR") ₂ ; -O(haloR'), -CN, -N ₃ , -(CH ₂ ) ₀ - ₂ C(0)R', -(CH ₂ )o- ₂ C(0)OH, -(CH ₂ )o- ₂ C(0)OR', -(CH ₂ ) ₀ - ₂ SR', -(CH ₂ ) ₀ - ₂ SH, -(CH ₂ ) ₀ - ₂ H ₂ , - (CH ₂ )o- ₂ HR ^e , -(CH ₂ )o- ₂ R' ₂ , -N0 ₂ , -SiR' ₃ , -OSiR' ₃ , -C(0)SR* -(Ci_ ₄ straight or branched alkylene)C(0)OR", or -SSR" wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from aliphatic, - CH ₂ Ph, -0(CH ₂ )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0026] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR ^* ₂ , =N HC(0)R ^* , =N HC(0)OR ^* , =N HS(0) ₂ R ^* , = R ^* , =NOR ^* , -0(C(R ^* ₂ )) ₂ - ₃ 0- or -S(C(R ^* ₂ )) ₂ - ₃ S- wherein each independent occurrence of R ^* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted" group include: -0(CR ^* ₂ ) ₂ - 3O-, wherein each independent occurrence of R is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0027] Suitable substituents on the aliphatic group of R* include halogen, -R", -(haloR"), -OH, -OR', -O(haloR'), -CN, -C(0)OH, -C(0)OR', - H ₂ , -NHR", -NR' ₂ , or -NO2, wherein each R" is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ^† , - R ^† ₂ , -C(0)R ^† , -C(0)OR ^† , -C(0)C(0)R ^† , C(0)CH ₂ C(0)R ^† , -S(0) ₂ R ^† , -S(0) ₂ R ^† ₂ , -C(S) R ^† ₂ , -C( H) R ^† ₂ , or -N(R ^† )S(0) ₂ R ^† ; wherein each R ^† is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ^† , taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] Suitable substituents on the aliphatic group of R ^† are independently halogen, - R', -(haloR*), -OH, -OR', -O(haloR'), -CN, -C(0)OH, -C(0)OR', -NH ₂ , -NHR', -NR' ₂ , or -NO2, wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH ₂ Ph, -0(CH ₂ )o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0030] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0031] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0032] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a C- or C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0033] The terms "measurable affinity" and "measurably inhibit," as used herein, means a measurable change in mTORCl activity between a sample comprising a compound of the present invention, or composition thereof, and mTORCl, and an equivalent sample comprising mTORCl in the absence of said compound, or composition thereof.

3. Description of Exemplary Embodiments:

[0034] As described above, in certain embodiments, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A ¹ is N, N ⁺ -0 ^" , or CH;

A ² is N, N ⁺ -0 ^" , CH, or O;

A ³ is N, N ⁺ -0 ^" , CR', or C;

A ⁴ is N, N ⁺ -0 ^" , or CR', provided at least one of A ³ and A ⁴ comprises a nitrogen;

A ⁵ is CR" or N;

A ⁶ is CR" or N;

each R' is independently hydrogen, -C(0)N(R) ₂ , -N(R) ₂ , or -OR; or

an R' group on A ⁴ and Ring B are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R" is independently hydrogen, Ci-6 aliphatic, halogen, or -CN; or an R group on A ⁵ and L ² are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R is independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of m, n, p, and q is independently 0, 1, or 2;

each of x, y, and z is independently 0, 1, 2, 3 or 4;

each of R ¹ and R ² is independently R; or:

two R ¹ groups are optionally taken together to form =0;

two R ² groups are optionally taken together to form =0;

two R ¹ groups are optionally taken together to form a covalent bond or a bivalent Ci-4 alkylene chain;

two R ² groups are optionally taken together to form a covalent bond or a bivalent Ci-4 alkylene chain;

an R ¹ group and Ring A are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

an R ² group and Ring B are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

an R ² group and L ² are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; or an R ² group and L ³ are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R ³ is independently R, halogen, -OR, -CN, or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

an R ³ group and L ² are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring A is absent or an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring B is an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

L ¹ is a covalent bond or a C _1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -0-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S(0) ₂ - or -(C)=CH-;

L ² is a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -0-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S(0) ₂ -, or -(C)=CH-; and L ³ is a covalent bond, -N(R)-, or -S(0) ₂ -.

[0035] As defined above and described herein, A ¹ is N, N ⁺ -0 ^" , or CH. In some embodiments, A ¹ is N. In some embodiments, A ¹ is CH. In some embodiments, A ¹ is N ⁺ -0 ^" .

[0036] In some embodiments, A ¹ is selected from those depicted in Table 1, below.

[0037] As defined above and described herein, A ² is N, N ⁺ -0 ^" , CH, or O. In some embodiments, A ² is N. In some embodiments, A ² is N ⁺ -0 ^" . In some embodiments, A ² is CH. In some embodiments, A ² is O.

[0038] In some embodiments, A ² is selected from those depicted in Table 1, below. [0039] As defined above and described herein, each of m, and n is independently 0, 1, or 2. In some embodiments, m is 0. In some embodiments, n is 0. In some embodiments, m is 1. In some embodiments, n is 1. In some embodiments, m is 2. In some embodiments, n is 2.

[0040] As defined above and described herein, A ³ is N, N ⁺ -0 ^" , CR', or C. In some embodiments, A ³ is N. In some embodiments, A ³ is N ⁺ -0 ^" . In some embodiments, A ³ is CR' . In some embodiments, A ³ is C.

[0041] In some embodiments, A ³ is selected from those depicted in Table 1, below.

[0042] As defined above and described herein, A ⁴ is N, N ⁺ -0 ^" , or CR', provided at least one of A ³ and A ⁴ comprises a nitrogen. In some embodiments, A ⁴ is N. In some embodiments, A ⁴ is N ⁺ -0 ^" . In some embodiments, A ⁴ is CR' . In some embodiments, at least one of A ³ and A ⁴ comprises a nitrogen.

[0043] In some embodiments, A ⁴ is selected from those depicted in Table 1, below.

[0044] As defined above and described herein, each of p, and q is independently 0, 1, or 2. In some embodiments, p is 0. In some embodiments, q is 0. In some embodiments, p is 1. In some embodiments, q is 1. In some embodiments, p is 2. In some embodiments, q is 2.

[0045] As defined above and described herein, each of x, y, and z is independently 0, 1, 2, 3 or 4. In some embodiments, x is 0. In some embodiments, y is 0. In some embodiments,z is 0.

In some embodiments, x is 1. In some embodiments, y is 1. In some embodiments,z is 1. In some embodiments, x is 2. In some embodiments, y is 2. In some embodiments,z is 2. In some embodiments, x is 3. In some embodiments, y is 3. In some embodiments,z is 3. In some embodiments, x is 4. In some embodiments, y is 4. In some embodiments,z is 4.

[0046] As defined above and described herein, A ⁵ is is CR or N. In some embodiments, A ⁵ is CR". In some embodiments, A ⁵ is N.

[0047] As defined above and described herein, A ⁶ is is CR or N. In some embodiments, A ⁶ is CR". In some embodiments, A ⁶ is N.

[0048] In some embodiments, A ⁶ is selected from those depicted in Table 1, below.

[0049] As defined above and described herein, each of R' is independently hydrogen, - C(0)N(R) ₂ , -N(R) ₂ , or -OR; or an R' group on A ⁴ and Ring B are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R' is hydrogen. In some embodiments, R' is -C(0)N(R) ₂ . In some embodiments, R' is -N(R) ₂ . In some embodiments, R' is -OR. In some embodiments, an R' group on A ⁴ and Ring B are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0050] In some embodiments, R' is -C(0) H ₂ . In some embodiments, R' is - H ₂ . In some embodiments, R' is -OH.

[0051] As defined above and described herein, each of R" is independently hydrogen, Ci- ₆ aliphatic, halogen, or -CN; or an R group on A ⁵ and L ² are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R" is hydrogen. In some embodiments, R" is Ci-6 aliphatic. In some embodiments, R" is halogen. In some embodiments, R" is -CN. In some embodiments, an R" group on A ⁵ and L ² are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0052] In some embodiments, R" is methyl. In some embodiments, R" is chloro. In some embodiments, R" is fluoro.

[0053] As defined above and described herein, each of R ¹ and R ² is independently R; or: two R ¹ groups are optionally taken together to form =0; two R ² groups are optionally taken together to form =0; two R ¹ groups are optionally taken together to form a covalent bond or a bivalent Ci- 4 alkylene chain; two R ² groups are optionally taken together to form a covalent bond or a bivalent Ci-4 alkylene chain; an R ¹ group and Ring A are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; an R ² group and Ring B are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; an R ² group and L ² are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; or an R ² group and L ³ are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. [0054] In some embodiments, each R ¹ is H. In some embodiments R ¹ is CH ₃ . In some embodiments, R ¹ is -CH2OH. In some embodiments, two R ¹ groups are optionally taken together to form =0. In some embodiments, two R ¹ groups are optionally taken together to form a covalent bond. In some embodiments, two R ¹ groups are optionally taken together to form a bivalent C _1-4 alkylene chain. In some embodiments, an R ¹ group and Ring A are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0- 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0055] In some embodiments, each R ² is H. In some embodiments, R ² is CH ₃ . In some embodiments, R ² is -CH2OH. In some embodiments, two R ² groups are optionally taken together to form =0. In some embodiments, two R ² groups are optionally taken together to form a covalent bond. In some embodiments, two R ² groups are optionally taken together to form a bivalent C _1-4 alkylene chain. In some embodiments, an R ² group and Ring B are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0- 2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, an R ² group and L ² are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, an R ² group and L ³ are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0056] In some embodiments, each of R ¹ and R ² is independently selected from those depicted in Table 1, below.

[0057] As defined above and described herein, each of R ³ is independently R, halogen, -OR, - CN, or two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an R ³ group and L ² are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R ³ is R. In some embodiments, R ³ is halogen. In some embodiments, R ³ is -OR. In some embodiments, R ³ is -CN. In some embodiments, two R ³ groups are optionally taken together to form a 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, an R ³ group and L ² are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated or aryl fused ring having 0- 2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0058] In some embodiments, R ³ is methyl. In some embodiments, R ³ is chloro. In some embodiments, R ³ is fluoro. In some embodiment In some embodiments,

R ³ is -OMe.

[0059] In some embodiments, each of R ³ is selected from those depicted in Table 1, below.

[0060] As defined above and described herein, Ring A is absent or an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0061] In some embodiments, Ring A is absent. In some embodiments, Ring A is phenyl, ridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, azaindolyl, indazolyl, or azaindazolyl. In

In some embodiments, Ring A is

0067] me embodiments, Ring A is

ome embodiments, Ring A is , or

[0070] In some embodiments, Ring A is selected from those depicted in Table 1, below.

[0071] As defined above and described herein, Ring B is an optionally substituted ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic aryl or heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0072] In some embodiments, Ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,

in lyl, azaindolyl, indazolyl, or azaindazolyl. In some embodiments, Ring B is In some embodiments, In some embodiments, Ring B is In some embodiments, Ring B is

B is

ome embodiments, Ring B is , or

[0081] In some embodiments, Ring B is selected from those depicted in Table 1, below.

[0082] As defined above and described herein, L ¹ is a covalent bond or a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -0-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, - N(R)-, -S(0) ₂ - or -(C)=CH-.

[0083] In some embodiments, L ¹ is a covalent bond. In some embodiments, L ¹ is -CH ₂ -.

[0084] In some embodiments, L ¹ is -0-. In some embodiments, L ¹ is In some

embodiments, L ¹ is . In some embodiments, L ¹ is -CH ₂ CH ₂ -. In some embodiments, L ¹

is . In some embodiments, L ¹ is In some embodiments, L ¹ is

In some embodiments, L ¹ is . In some In some embodiments,

[0085] In some embodiments, L ¹ is selected from those depicted in Table 1, below.

[0086] As defined above and described herein, L ² is a covalent bond or a C _1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -0-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, - N(R)-, -S(0) ₂ - or -(C)=CH-.

[0087] In some embodiments, L ¹ is a covalent bond. In some embodiments, L ¹ is -CH ₂ -. In

some embodiments, L ² is -0-. In some embodiments, L ² is in some embodiments, L ²

is In some embodiments, L ² is -CH ₂ CH ₂ -. In some embodiments, L ² is

In some embodiments, L ² is . In some

embodiments, L is . In some embodiments,

O H

L ² is O In some embodiments, L ² is O In some embodiments, L ² is

[0088] In some embodiments, L ² is selected from those depicted in Table 1, below.

[0089] As defined above and described herein, L ³ is a covalent bond, -N(R)-, or -S(0) ₂ -.

[0090] In some embodiments, L ³ is a covalent bond. In some embodiments, L ³ is -N(R)-. In some embodiments, L ³ is -S(0) ₂ -. [0091] In some embodiments, L ³ is - H-.

[0092] In some embodiments, L ³ is selected from those depicted in Table 1, below.

[0093] In some embodiments, the present invention provides a compound of Formulae Il-a,

Il-b, or II-c:

II-c

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , L ² , L ³ , A ³ , A ⁴ , Ring B, p, q, and z is defined above and described in embodiments herein.

[0094] In some embodiments, the present invention provides a compound of Formulae Ill-a, Ill-b, III-c, or !II-d:

III-c

Ill-d

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , L ¹ , L ³ , A ¹ , Ring B, m, n, and y is defined above and described in embodiments herein.

[0095] In some embodiments, the present invention provides a compound of Formula IV:

IV

or a pharmaceutically acceptable salt thereof, wherein each phenyl ring is substituted in the ortho position with a suitable monovalent substituent as described herein.

[0096] In some embodiments, the present invention provide a compound of formula I wherein each of Ring A and Ring B is phenyl substituted in the ortho position with a group independently selected

from -CN, -S(0) ₂ H ₂ , -S(0)( H)CH ₃ , -CF ₃ , -C(0) HCH ₃ , -C(0)N(CH ₃ ) ₂ , -S(0) ₂ CH ₃ , -C0 ₂ H,

-C(0) H ₂ , -CH ₃ , -OCH ₃ , -F, -CI,

[0097] In some embodiments, the present invention provides a compound of Formulae V-a or V-b:

V-a

described in embodiments herein.

[0098] In some embodiments, the present invention provides a compound of Formulae Vl-a, Vl-b, or VI-c:

-b

YI-c

or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R ¹ , R ² , R ³ , L ¹ , L ² , L ³ , A ¹ , A ² , A ³ , A ⁴ , Ring B, m, n, p, q, x, y, and z is defined above and described in embodiments herein. is defined above and described in embodiments herein.

[0099] Exemplary compounds of the invention are set forth in Table 1, below.

Table 1: Exemplary Compounds

1-4

-133 1-134

-147 1-148

-157 1-158

-169 1-170

-179 1-180

-189 1-190

-217 1-218

-227 1-228

-235 1-236

-253 1-254

-263 1-264

1-273 1-274

-285 1-286

-297 1-298

-307 1-308

-317 1-318

-327 1-328

1-359 1-360

1-369 [00100] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. It will be appreciated that the present invention also provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof.

5. Uses, Formulation and Administration

Pharmaceutically acceptable compositions

[00101] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit mTORCl, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit mTORCl, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[00102] The term "patient," as used herein, means an animal, preferably a mammal, and most preferably a human.

[00103] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[00104] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[00105] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethyl ated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[00106] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[00107] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[00108] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[00109] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[00110] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00111] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[00112] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [00113] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[00114] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

[00115] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

[00116] Compounds and compositions described herein are generally useful for the inhibition of mTORCl .

[00117] The activity of a compound utilized in this invention as an inhibitor of mTORCl, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine the inhibition of mTORCl . Detailed conditions for assaying a compound utilized in this invention as an inhibitor of mTORCl are well known to one of ordinary skill in the art. Such methods are described in detail by Liu et al., Cancer Research, 73(8), April 15, 2013 and Liu et al., J. Biological Chemistry, vol 287, no. 13, pp 9742-9752 (2012).

[00118] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[00119] Provided compounds are inhibitors of mTORCl and are therefore useful for treating one or more disorders associated with activity of mTORCl . Thus, in certain embodiments, the present invention provides a method for treating an mTORCl -mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.

[00120] As used herein, the terms "mTORCl -mediated" disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which mTORCl, is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which mTORCl is known to play a role. In certain embodiments, an mTORCl -mediated disorder, disease, and/or condition is selected from those described by Matt Kaeberlin, Scientifica, vol. 2013, Article ID 849186.

[00121] The methods described herein include methods for the treatment of cancer in a subject. As used in this context, to "treat" means to ameliorate or improve at least one symptom or clinical parameter of the cancer. For example, a treatment can result in a reduction in tumor size or growth rate. A treatment need not cure the cancer or cause remission 100% of the time, in all subjects.

[00122] As used herein, the term "cancer" refers to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. The term "tumor" as used herein refers to cancerous cells, e.g., a mass of cancer cells.

[00123] Cancers that can be treated or diagnoses using the methods described herein include malignancies of the various organ systems, such as affecting lung, breast, thyroid, lymphoid, gastrointestinal, and genito-urinary tract, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non- small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus.

[00124] In some embodiments, the methods described herein are used for treating or diagnosing a carcinoma in a subject. The term "carcinoma" is art recognized and refers to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas. In some embodiments, the cancer is renal carcinoma or melanoma. Exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, breast, head and neck, colon and ovary. The term also includes carcinosarcomas, e.g., which include malignant tumors composed of carcinomatous and sarcomatous tissues. An "adenocarcinoma" refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures.

[00125] The term "sarcoma" is art recognized and refers to malignant tumors of mesenchymal derivation.

[00126] In some embodiments, the cancers that are treated by the methods described herein are cancers that have increased levels of mTORC 1 or an increased expression or activity of a mTORC 1 relative to normal tissues or to other cancers of the same tissues; methods known in the art and described herein can be used to identify those cancers. In some embodiments, the methods include obtaining a sample comprising cells of the cancer, determining the mTORC 1 activity in the sample, and administering a treatment as described herein (e.g., a provided inhibitor of of mTORCl). In some embodiments, the cancer is one that is shown herein to have increased levels of mTORC 1 activity

[00127] In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder.

Cellular Proliferative Disorders

[00128] The present invention features methods and compositions for the diagnosis and prognosis of cellular proliferative disorders (e.g., cancer) and the treatment of these disorders by inhibiting mTORCl activity. Cellular proliferative disorders described herein include, e.g., cancer, obesity, and proliferation-dependent diseases. Such disorders may be diagnosed using methods known in the art.

Cancer

[00129] Cancers include, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocyte leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). In some embodiments, the cancer is melanoma or breast cancer.

Other Proliferative Diseases

[00130] Other proliferative diseases include, e.g., obesity, benign prostatic hyperplasia, psoriasis, abnormal keratinization, lymphoproliferative disorders (e.g., a disorder in which there is abnormal proliferation of cells of the lymphatic system), chronic rheumatoid arthritis, arteriosclerosis, restenosis, and diabetic retinopathy. Proliferative diseases that are hereby incorporated by reference include those described in U.S. Pat. Nos. 5,639,600 and 7,087,648. Fibrotic Diseases

[00131] Idiopathic Pulmonary Fibrosis (IPF). The PI3K pathway is activated in fibrotic foci, the cardinal lesions in IPF. mTOR kinase inhibitor GSK2126458 reduces PI3K pathway signaling and functional responses in IPF-derived lung fibroblasts and mTOR inhibition reduces collagen expression in models of IPF patients. In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of a-smooth muscle actin and fibronectin by fibroblasts in vitro.

[00132] In some embodiments, the method of inhibiting mTORCl activity is used to treat idiopathic pulmonary fibrosis (IPF). (See Thorax. 2016, 71(8), pp. 701-11; PLoS One. 2012, 7(7)). Accordingly, in some embodiments, the present invention provides a method of treating idiopathic pulmonary fibrosis (TPF), in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00133] Kidney Fibrosis. mTORCl is activated in myofibroblasts, a major pathogenic cell type in kidney fibrosis. Inhibition of mTOR with rapamycin in a murine model of kidney fibrosis (UUO), attenuated expression of markers of fibrosis and tubulointerstitial damage.

[00134] In some embodiments, the method of inhibiting mTORCl activity is used to treat kidney fibrosis. (See J Am Soc Nephrol 2013, 24, pp. 1114-1126; Kidney International 2006, 69, pp. 2029-2036; PLoS 2012,7, Issue 3, e33626; Clin Invest Med 2014, Vol 37, no 3, E142). Accordingly, in some embodiments, the present invention provides a method of treating kidney fibrosis, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00135] In some embodiments, the method of inhibiting mTORCl activity is used to treat scleroderma. (See J Invest Dermatol. 2015 Nov; 135(11): 2873-6). Accordingly, in some embodiments, the present invention provides a method of treating scleroderma, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00136] In some embodiments, the method of inhibiting mTORCl activity is used to treat hypertrophic scarring and keloid disease. (See Am J Pathol. 2012 Nov; 181(5): 1642-58). Accordingly, in some embodiments, the present invention provides a method of treating hypertrophic scarring and keloid disease, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00137] In some embodiments, the method of inhibiting mTORCl activity is used to treat cardiac fibrosis. (See J Mol Cell Cardiol. 2016 Feb; 91 : 6-9). Accordingly, in some embodiments, the present invention provides a method of treating cardiac fibrosis, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

Other Disorders

[00138] Other disorders include lysosomal storage diseases, including but not limited to Pompe disease, Gaucher disease, mucopolysaccharidosis, multiple sulfatase deficiency; neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, alphal -anti -trypsin deficiency, and spinal bulbar muscular atrophy. The present invention provides compounds that were shown to cause translocation of TFEB to the nucleus. TFEB translocation to the nucleus promotes exocytosis and/or cellular clearance of accumulating substrates in the above-mentioned diseases.

[00139] In some embodiments, the method of inhibiting mTORCl activity is used to treat asthma. (See Respirology 2015 Oct; 20(7): 1055-65). Accordingly, in some embodiments, the present invention provides a method of treating asthma, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00140] In some embodiments, the method of inhibiting mTORCl activity is used to treat a lysosomal storage disease. {See Annals of the New York Academy of Sciences, 2016, Volume 1371, Issue 1, pp. 3-14; Hum Mol Genet. 2015, 24(20), pp. 5775-88; EMBO Mol Med. 2013, 5(5), pp. 691-706; Medina, D.L., et al., Dev Cell. 2011 Sep 13, 21(3), pp. 421-30). Accordingly, in some embodiments, the present invention provides a method of treating a lysosomal storage disease, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00141] In some embodiments, the method of inhibiting mTORCl activity is used to treat Parkinson's disease. (See Proc Natl Acad Sci U S A. 2013, 110(19):E1817-26). Accordingly, in some embodiments, the present invention provides a method of treating Parkinson's disease, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00142] In some embodiments, the method of inhibiting mTORCl activity is used to treat Alzheimer's disease. {See EMBO Mol Med. 2014, 6(9), pp. 1142-60). Accordingly, in some embodiments, the present invention provides a method of treating Alzheimer's disease, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00143] In some embodiments, the method of inhibiting mTORCl activity is used to treat Huntington's disease. {See Sci Transl Med. 2012, 4(142): 142ra97). Accordingly, in some embodiments, the present invention provides a method of treating Huntingtons's disease, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00144] In some embodiments, the method of inhibiting mTORCl activity is used to treat alphal -anti -trypsin deficiency. (See EMBO Mol Med. 2013, 5(3), pp.397-412). Accordingly, in some embodiments, the present invention provides a method of treating alphal -anti -trypsin deficiency, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00145] In some embodiments, the method of inhibiting mTORC 1 activity is used to treat spinal bulbar muscular atrophy. (See Nat Neurosci. 2014, 17(9), pp. 1180-9). Accordingly, in some embodiments, the present invention provides a method of treating spinal bulbar muscular atrophy, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00146] The present invention provides compounds that are inhibitors of mTORCl activity and were shown to selectively inhibit mTORCl over mTORC2 as measured by pS6K inhibition (a measure of mTORCl activity) and pAKT activation (a measure of mTORC2 activity). In some embodiments, a provided compound inhibits mTORCl selectively over mTORC2. In some embodiments, a provided compound does not measurably inhibit mTORC2. In some embodiments, a provided compound has a pAKT activation IC50 of >10μΜ. In some embodiments, a provided compound inhibits mTORCl with >10-fold selectivity over mTORC2. In some embodiments, a provided compound inhibits mTORCl with >20-fold selectivity over mTORC2. In some embodiments, a provided compound inhibits mTORCl with >50-fold selectivity over mTORC2. In some embodiments, a provided compound inhibits mTORCl with >100-fold selectivity over mTORC2. In some embodiments, a provided compound inhibits mTORCl with >150-fold selectivity over mTORC2. In some embodiments, a provided compound inhibits mTORCl with >200-fold selectivity over mTORC2. In some embodiments, a provided compound inhibits mTORCl with >500-fold selectivity over mTORC2. In some embodiments, a provided compound inhibits mTORCl with >1, 000-fold selectivity over mTORC2. Accordingly, in some embodiments, the present invention provides a method of treating a disorder associate with mTORCl comprising administering to patient a compound that inhibits mTORCl wherein said compound does not inhibit mTORC2. Such compounds may be employed for indications where rapamycin and rapalogs demonstrated a benefit either in animal models or in a human disease setting. Such indications include:

[00147] Treatment of Metabolic Disease (Obesity and Insulin Resistance in Type 2 Diabetes). Inhibition of mTORCl pathway leads to extension of life span in yeast, fly and mouse, and caloric restriction improves longevity and insulin sensitivity. The underlying mechanism has been proposed to function by regulation of mTORCl activation. Rapamycin-induced insulin resistance has been shown to be mediated by inhibition of mTORC2 and selective mTORCl inhibitor is predicted to improve insulin sensitivity and glucose homeostasis.

[00148] In some embodiments, the method of inhibiting mTORCl activity is used to treat metabolic disease (obesity and insulin resistance in type 2 diabetes). {See J Gerontol A Biol Sci Med Sci 2015, 70 (4), pp. 410-20; Aging Cell 2014, 13 (2), pp. 311-9; Diabetologia 2016, 59(3), pp. 592-603; Science 2012, 335, pp. 1638-1643). Accordingly, in some embodiments, the present invention provides a method of treating metabolic disease (obesity and insulin resistance in type 2 diabetes), in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00149] Neurofibromatosis. Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. Its protein product, neurofibromin, functions as a tumor suppressor and ultimately produces constitutive upregulation of mTOR. mTOR inhibitors have been shown to reduce tumor size and induce anti-proliferative effect in NF1 -associated plexiform neurofibroma.

[00150] In some embodiments, the method of inhibiting mTORCl activity is used to treat neurofibromatosis. {See Curr Neurol Neurosci Rep. 2012 Jun 12(3), pp. 294-301; Oncotarget. 2016 Jan 31). Accordingly, in some embodiments, the present invention provides a method of treating neurofibromatosis, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00151] Cardiomyopathy and skeletal muscle dystrophy, Emery-Dreifuss muscular dystrophy model (LMNA ^"/_ ). Mutations in LMNA result in several human diseases including limb-girdle muscular dystrophy (LGMDIB), Emery-Dreifuss muscular dystrophy (EDMD2/3), dilated cardiomyopathy (DCM) and conduction-system disease (CMDIA), lipodystrophy, Charcot- Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome (HGPS). Lmna ^_/" mice have elevated mTORCl activity and short-term treatment with rapamycin in Lmna ^_/" mice results in reduced mTORCl signaling, improved cardiac and skeletal muscle function and enhanced survival by -50%.

[00152] In some embodiments, the method of inhibiting mTORCl activity is used to treat cardiomyopathy and skeletal muscle dystrophy. {See Sci Transl Med. 2012, 4(144): 144ral03; Handb Clin Neurol. 2013, 113, pp. 1367-76). Accordingly, in some embodiments, the present invention provides a method of treating cardiomyopathy and skeletal muscle dystrophy, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00153] Leigh syndrome. Ndufs4 knockout (KO) mice are used as a model of Leigh syndrome and exhibit hyperactivation of mTORCl and metabolic defects. Treatment of Ndufs4 KO mice with rapamycin extended lifespan, improve metabolic and neurological defect associated with this disease.

[00154] In some embodiments, the method of inhibiting mTORCl activity is used to treat Leigh syndrome. {See Science 2013, 342(6165), pp. 1524-8). Accordingly, in some embodiments, the present invention provides a method of treating Leigh syndrome, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00155] Oncology. Inhibition of mTOR with rapalogs has been shown to have antitumor activity in murine cancer models and in cancer patients. Examples of sensitive cancer types include, but are not limited to, hepatocellular carcinoma, breast cancers, mantle cell lymphomas, lung carcinoma, tuberous sclerosis and lymphangioleiomyomatosis.

[00156] In some embodiments, the method of inhibiting mTORCl activity is used to treat cancer and oncologic disorders. {See Trends Cancer 2016; In press). Accordingly, in some embodiments, the present invention provides a method of treating cancer and oncologic disorders, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00157] Non-alcoholic steatohepatitis (NASH). The present invention provides inhibitors that induce autophagy to clear degraded cytoplasmic proteins, and NASH disease is characterized by lipid deposits, inflammation and fibrosis in the liver. The inhibition of mTORCl pathway induce autophagy and down regulate SREBP-1 to decrease lipid biosynthesis to reduce lipid storage.

[00158] In some embodiments, the method of inhibiting mTORC 1 activity is used to treat nonalcoholic steatohepatitis (NASH). {See J Clin Exp Hepatol 2014;4(1), pp. 51-9). Accordingly, in some embodiments, the present invention provides a method of treating non-alcoholic steatohepatitis (NASH), in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00159] Tuberous sclerosis (TSC) and lymphangioleiomyomatosis (LAM). Failure in the regulation of mTOR is critical to the pathogenesis of the inherited disorder tuberous sclerosis complex (TSC) and the related lung disease, lymphangioleiomyomatosis (LAM). Both diseases are caused by mutations of TSC1 or TSC2 leading to inappropriate activity of signaling downstream of mTORCl . TSC patients develop nonmalignant tumors in many organs, including the brain, while LAM patients, mostly women, accumulate abnormal, muscle-like cells in certain organs or tissues, especially the lungs, lymph nodes, and kidneys. The rapalogs, Everolimus and Sirolimus, are currently approved for the treatment of both TSC and LAM, respectively, by the US FDA.

[00160] In some embodiments, the method of inhibiting mTORCl activity is used to treat tuberous sclerosis and lymphangioleiomyomatosis. (See J. Clin. Invest. 2011, 121, pp. 1231- 1241; J. Clin Epidemiol. 2015, 7, pp. 249-57). Accordingly, in some embodiments, the present invention provides a method of treating tuberous sclerosis and lymphangioleiomyomatosis, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00161] Senescence and diseases of aging. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. Rapamycin was shown to inhibit the pro-inflammatory phenotype of senescent cells. As senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. Inhibition of mTOR suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced cytokine levels including IL6 and suppressed translation of the membrane-bound cytokine ILIA. Reduced ILIA diminishes F-κΒ transcriptional activity, which controls the SASP. Thus, mTORCl inhibitors might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence- associated inflammation.

[00162] In some embodiments, the method of inhibiting mTORCl activity is used to treat senescence and diseases of aging. (See Nature Cell Biology 17, 2015, pp. 1049-1061; Free Radic Biol Med. 2016 Jun;95: 133-54). Accordingly, in some embodiments, the present invention provides a method of treating senescence and diseases of aging, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00163] Additional therapeutic indications where mTORC inhibition may be beneficial are: cardiovascular disease (acute coronary syndrome), coronary occlusions with eluting stents, polycystic kidney disease, neurofibromatosis, epilepsy assoc. with TSC1 and/or TSC2 mutations, polycystic liver, pachyonychia congenital, fragile x syndrome, Friedrich ataxia, Peutz-Jeghers syndrome, eye disease including neovascular age-related macular degeneration, uveitis, diabetic macular edema, fibroblast growth including pulmonary fibrosis, renal insufficiency/fibrosis, metabolic syndrome, diseases of the immune system including immune senescence, lupus nephritis, chronic immune thrombocytopenia, multiple sclerosis, cancer including lymphoma, tumors associated with TSCl/2 mutations, angiomyolipoma assoc. with TSCl/2 mutations, breast cancer, hepatocellular cancer, leukemia, glioma, adenoid cystic carcinoma, senescence, autism, and vascular rheumatoid arthritis.

[00164] In some embodiments, the method of inhibiting mTORCl activity is used to treat cardiovascular disease (acute coronary syndrome), coronary occlusions with eluting stents, polycystic kidney disease, neurofibromatosis, epilepsy assoc. with TSC1 and/or TSC2 mutations, polycystic liver, pachyonychia congenital, fragile x syndrome, Friedrich ataxia, Peutz-Jeghers syndrome, eye disease including neovascular age-related macular degeneration, uveitis, diabetic macular edema, fibroblast growth including pulmonary fibrosis, renal insufficiency/fibrosis, metabolic syndrome, diseases of the immune system including immune senescence, lupus nephritis, chronic immune thrombocytopenia, multiple sclerosis, cancer including lymphoma, tumors associated with TSCl/2 mutations, angiomyolipoma assoc. with TSCl/2 mutations, breast cancer, hepatocellular cancer, leukemia, glioma, adenoid cystic carcinoma, senescence, autism, and vascular rheumatoid arthritis. Accordingly, in some embodiments, the present invention provides a method of treating cardiovascular disease (acute coronary syndrome), coronary occlusions with eluting stents, polycystic kidney disease, neurofibromatosis, epilepsy assoc. with TSC1 and/or TSC2 mutations, polycystic liver, pachyonychia congenital, fragile x syndrome, Friedrich ataxia, Peutz-Jeghers syndrome, eye disease including neovascular age-related macular degeneration, uveitis, diabetic macular edema, fibroblast growth including pulmonary fibrosis, renal insufficiency/fibrosis, metabolic syndrome, diseases of the immune system including immune senescence, lupus nephritis, chronic immune thrombocytopenia, multiple sclerosis, cancer including lymphoma, tumors associated with TSCl/2 mutations, angiomyolipoma assoc. with TSCl/2 mutations, breast cancer, hepatocellular cancer, leukemia, glioma, adenoid cystic carcinoma, senescence, autism, and vascular rheumatoid arthritis, in a patient in need thereof, comprising the step of administering to said patient a provided compound or pharmaceutically acceptable salt thereof.

[00165] In some embodiments, the present invention is an inhibitor of members of the glucose transporter (GLUT) family. In some embodiments, the present invention is a pan-glucose inhibitor, inhibiting GLUT subtypes 1, 2, 3, 4, and 5. In some embodiments, the present invention is an inhibitor of one or more GLUT subtypes, individually or severally.

[00166] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[00167] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00168] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[00169] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00170] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[00171] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00172] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00173] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[00174] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[00175] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[00176] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[00177] In other embodiments, the present invention provides a method for treating a disorder mediated by mTORCl in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[00178] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[00179] A compound of the current invention may also be used to advantage in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17- allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17- demethoxy-geldanamycin, NSC707545), IPI-504, CNF 1010, CNF2024, CNF 1010 from Conforma Therapeutics; temozolomide (Temodal ^® ); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin. The term "aromatase inhibitor" as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, tnlostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[00180] The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

[00181] The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™. [00182] The term "topoisom erase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[00183] The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as Caelyx™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed, under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

[00184] The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin R.P™. Vincristine sulfate is marketed under the trade name Farmistin™.

[00185] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[00186] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[00187] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[00188] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Eloxatin™.

[00189] The term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB- 111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor- receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD 180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin- dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD 184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23/RG- 50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, El . l, E2.4, E2.5, E6.2, E6.4, E2. l l, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT-062070, SB- 1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[00190] The term "PI3K inhibitor" as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to ΡΒΚα, ΡΒΚγ, ΡΒΚδ, ΡΒΚβ, PBK-C2a, PBK-C2p, PBK- C2y, Vps34, pi 10-a, pi 10-β, pi 10-γ, pi 10-δ, p85-a, ρ85-β, ρ55-γ, pl50, plOl, and p87. Examples of PBK inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[00191] The term "Bcl-2 inhibitor" as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), H-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.

[00192] The term "BTK inhibitor" as used herein includes, but is not limited to compounds having inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.

[00193] The term "SYK inhibitor" as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT- 062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib

[00194] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.

[00195] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference. [00196] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.

[00197] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.

[00198] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and T P-470.

[00199] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[00200] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[00201] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, α- γ- or δ- tocopherol or a- γ- or δ-tocotrienol.

[00202] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.

[00203] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[00204] The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons.

[00205] The term "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor" such as L-744832, DK8G557 or Rl 15777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.

[00206] The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[00207] The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (Velcade™) and MLN 341.

[00208] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251 , BAY 12-9566, TAA211 , MMI270B or AAJ996.

[00209] The term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, Ι-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase. [00210] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.

[00211] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.

[00212] The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DMl, erbitux, bevacizumab (Avastin™), rituximab (Rituxan ^® ), PR064553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.

[00213] For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

[00214] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of hi stone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl){2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2 E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 ^th Edition, Vol. 1 , pp. 248-275 (1993).

[00215] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binders" as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.

[00216] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

[00217] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.

[00218] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortex ol one, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone. [00219] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.

[00220] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.

[00221] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications).

[00222] A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[00223] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[00224] Those additional agents may be administered separately from an inventive compound- containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another. [00225] As used herein, the term "combination," "combined," and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[00226] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.

[00227] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 μg/kg body weight/day of the additional therapeutic agent can be administered.

[00228] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[00229] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.

EXEMPLIFICATION

[00230] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[00231] List of common abbreviations used in the experimental section.

4 A MS: 4 A molecular sieves

AcOH. acetic acid

Anhyd: anhydrous

aq: aqueous

BH3-THF: borane tetrahydrofuran complex

BINAP : (2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl)

Bn: benzyl

Boc: tert-butoxycarbonyl

(Boc)20: di-tert-butyl dicarbonate

BrettPhos : 2-(Dicyclohexylphosphino)3 ,6-dimethoxy-2 ',4 ', 6 '-trii sopropyl -1, 1 '- biphenyl

CbzCl: benzyl chloroformate

Cbz-0 SU : N-(Benzyl oxy carbonyl oxy)succinimi de

CHIRAL-HPLC: chiral high performance liquid chromatography

CMBP: (cyanom ethyl ene)tributylphosphorane

Cone: concentrated

CuCN: copper cyanide

d: days

DAST: diethylaminosulfur trifluoride

DavePhos: 2-Dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl

dba: dibenzylideneacetone

DBU: l,8-diazobicyclo[5.4.0]undec-7-ene

DCE: 1,2-dichloroethane

DCM: dichloromethane

DEA: diethylamine

DIBAL-H: diisobutyl aluminium hydride

DIPEA: N,N-diisopropylethylamine

DMA: N,N-dimethylacetamide

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide DMPU: l,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone

DMSO: dimethyl sulfoxide

DPPA: diphenylphosphoryl azide

dppf : 1 , 1 '-bis(diphenylphosphino)ferrocene

EA: ethyl acetate

EDCI: l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

EDTA: ethylenediaminetetraacetic acid

ee: enantiomeric excess

ESI: electrospray ionization

Et3N: triethylamine

Et20: diethyl ether

EtOAc: ethyl acetate

EtOH: ethanol

Fmoc: fluorenylmethyloxycarbonyl

Fmoc-OSu: N-(9-fluorenylmethoxycarbonyloxy)succinimide

h: hours

HATU: Ν,Ν,Ν' ,Ν' -tetramethyl-0-(7-azabenzotriazol- 1 -yl)uranium

hexafluorophosphate

HOBT: Hydroxybenzotriazole

F PLC: high performance liquid chromatography

HC1: hydrochloric acid

IBX: 2-iodoxybenzoic acid

IPA: isopropyl alcohol

JackiePhos: 2-{Bis[3,5-bis(trifluoromethyl)phenyl]phosphino}-3,6-dimetho xy - 2',4',6'-triisopropyl-l, l '-biphenyl, Bis(3,5-bis(trifluoromethyl)phenyl)(2',4',6'- triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine

LDA: lithium diisopropylamide

M: molar

mCPBA: meta-chloroperoxybenzoic acid

Me: methyl

MeCN: acetonitrile

MeOH: methanol

MgO: magnesium oxide

min: minutes

mL: milliliters

mM: millimolar

mmol: millimoles

MOM: methoxymethyl

MsCl: Mesyl Chloride

MTBE: methyl tert-butyl ether

NMP: N-methyl-2-pyrrolidone

n-BuLi: n-butyl lithium

BS: N-bromosuccinimide

NIS: N-iodosuccinimide

MO: 4-methylmorpholine N-oxide

NMP: N-methylpyrrolidine NMR: Nuclear Magnetic Resonance

oC: degrees Celsius

PBS: phosphate buffered saline

Pd/C: palladium on carbon

Pd2(dba)3 : tris(dibenzylideneacetone)dipalladium(0)

PE: petroleum ether

prep-HPLC: preparative high performance liquid chromatography

P(o-tol)3 : tri(o-tolyl)phosphine

PTFE: polytetrafluoroethylene

Rel: relative

rt: room temperature

RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

sat: saturated

SFC: supercritical fluid chromatography

SGC: silica gel chromatography

STAB: sodium triacetoxyborohydride

TBAB: Tetra-n-butylammonium bromide

TBAF: Tetra-n-butylammonium fluoride

TBSC1: tert-Butyldimethylsilyl chloride

tBuOK: potassium tert-butoxide

tBuONa: sodium tert-butoxide

TEA: triethylamine

TEBAC: Benzyltriethylammonium chloride

Tf: trifluoromethanesulfonate

TfAA: trifluoromethanesulfonic anhydride

TFA: trifluoracetic acid

TIPS: triisopropylsilyl

TLC: thin layer chromatography

THF: tetrahydrofuran

TMSCN: trimethylsilyl cyanide

pTSA: para-toluenesulfonic acid

TsOH: p-Toluenesulfonic acid

XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

LCMS Methods

[00232] Samples were analyzed by LCMS ELSD using the following methods:

Method A: SunFire C18, 4.6*50mm, 3.5um column Xbridge C18 3.5μιη 4.6x50mm column.. The elution system used was a gradient of 5%-95% over 1.5 min at 2ml/min and the solvent was MeCN/0.01% aqueous TFA.

Method B: Xbridge C18 3.5μηι 4.6x50mm column, the elution system used was a gradient of 5%-95% over 1.5 min at 2 ml/min and the solvent was MeCN/10 mM ammonium acetate aqueous solution.

1.6 100

1.61 5

Flow rate 1 ml/min

Injection Vol 3 μΐ

Detection

Signal UV215

PDA Spectrum Range: 210-420nm step: lnm

MSD Signal ScanPos (Shimadzu): 100-1000

settings ScanPos (MS14): 130-850

ScanPos (MSll):150-850

PDA Spectrum Range: 210-420nm step: lnm

MSD Signal Scan Pos (MS 14): 130-850 settings

Table 5: LCMS Method 4

settings Scan Pos (MS 14): 130-850

Table 6: LCMS Method 5

5.40 100

5.42 5

7.00 5

Flow rate 0.6 ml/min

Injection Vol 3 μΐ

Detection

Signal UV 215

PDA Spectrum Range: 210-420nm step: lnm

MSD Signal Scan Pos (Shimadzu): 100-1000

settings Scan Pos (MSl l): 150-850

Table 7: LCMS Method 6

Phenomenex Gemini -NX CI 8

Column Part No. 00D-4453-B0

2.0 xlOOmm, 3 πι column

Column Temp 40°C

A, 2mM amm. bicarbonate, buffered to pHIO

Mobile Phase

B, Acetonitrile

Gradient Time (mins) % organic

0.00 5

5.50 100

5.90 100

5.92 5

7.00 5

Flow rate 0.5 ml/min

Injection Vol 3 μΐ

Detection

Signal UV 215 PDA Spectrum Range: 210-420nm step: lnm

MSD Signal Scan Pos (MS 10): 150-850 settings Scan Pos (MS 14): 130-850

Table 8: LCMS Method 7

settings

Table 9: LCMS Method 8

2.20 100

2.70 100

2.71 5

Flow rate 1 nil/min

Injection Vol 3 μΐ

Detection

Signal UV 215

PDA Spectrum Range: 210-420nm step: lnm

MSD Signal Scan Pos: 100-1000

settings

Purification Methods

[00233] Samples were purified by prep-HPLC using the following methods :

Method C: unless otherwise noted, the crude samples were dissolved in DMF before purification.

Boston C18 21 *250mm ΙΟμιη column. The mobile phase was MeCN/0.01% aqueous TFA.

Method D: unless otherwise noted, the crude samples were dissolved in DMF before purification. Boston C18 21 *250mm ΙΟμπι column. The mobile phase was MeCN/10 mM ammonium acetate aqueous solution.

Table 10: Generic UV-Directed Hi h H re method

Injection Vol 1500μ1

Detection

Signal UV 215

Table 11: Generic UV-Directed low pH prep method

Amine Intermediates

[Amine 1] - Commercially available

[Amine 2] - Commercially available

[Amine 3] - Commercially available

[Amine 4] - Commercially available

[Amine 5] - 5-Fluoro-2-(piperazin-l-yl)benzonitrile

[00234] 2,5-Difluorobenzonitrile (400 mg, 2.88 mmol) and piperazine (2.48 g, 28.8 mmol) were added to a reaction tube under nitrogen. The tube was sealed and the reaction stirred at 140 °C for 2 hours. The reaction was diluted with water (20 ml) and DCM (20 ml). The organics were separated and the aqueous phase extracted with DCM (2 x 20 ml). The combined organics were dried over MgS0 ₄ , filtered and concentrated in vacuo to yield the title compound as a yellow solid (550 mg, 93%).

1H MR (250 MHz, Chloroform-i ) δ 7.32 - 7.27 (m, 1H), 7.25 - 7.17 (m, 1H), 7.04 - 6.97 (m,

1H), 3.17 - 3.03 (m, 8H), 2.87 (s, 1H)

LCMS Method 8 - Tr = 1.45 min (ES+) (M+H) ⁺ 206.2 -

[Amine 6] - 4,5-Difluoro-2-(piperazin-l-yl)benzonitrile

[00235] tert-Butyl 4-(2-cyano-4,5-difluorophenyl)piperazine-l-carboxylate [Intermediate 1]

(600 mg, 1.86 mmol) was dissolved in trifluoroacetic acid (20% in DCM) (2.5 ml) then the reaction was agitated at ambient temperature for 4 hours and left standing overnight. The reaction was concentrated in vacuo then the residue was partitioned between DCM (15 ml) and sat aq NaHCCb (15 ml) then the organics were dried over Na ₂ S04, filtered and concentrated in vacuo to yield the title compound as a pale tan crystalline solid (361 mg, 87%)

1H MR (500 MHz, DMSO-d6) δ 8.00 (dd, J = 10.4, 8.8 Hz, 1H), 7.26 (dd, J = 12.9, 7.2 Hz, 1H),

3.05 - 3.01 (m, 4H), 2.87 - 2.82 (m, 4H).

LCMS Method 2 - Tr = 0.70 min (ES+) (M+H ⁺ ) 224.20 [Amine 7] - Methyl [2-(phenylamino)ethyl] amine

[00236] tert-Butyl 4-(2-cyanophenyl)-3-oxopiperazine-l-carboxylate [Intermediate 2] (98%, 513 mg, 1.67 mmol) was suspended in HC1 (4M in 1,4-dioxane, 8.4 ml) and stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and the residue was loaded onto a Biotage SCX-2 column (10 g) and eluted with 1 : 1 DCM / MeOH (40 ml). The product was then eluted with 7N H ₃ in MeOH (40 ml) and concentrated in vacuo to give a green solid which was purified via flash column chromatography (DCM/MeOH, gradient from 10% MeOH to 100%) MeOH). The fractions containing product were combined and the solvents removed in vacuo to yield the title compound as a dark brown solid (252 mg, 71 %).

1H MR (250 MHz, Chloroform-d) δ 8.33 (dd, J = 7.9, 1.5 Hz, 1H), 7.76 - 7.66 (m, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.38 (d, J = 8.6 Hz, 1H), 4.12 (s, 2H), 4.01 (t, J = 5.7 Hz, 2H), 3.43 (t, J = 5.7 Hz, 2H)

LCMS Method 1 - Tr = 0.81 min (ES+) (M+H)+ 202.0

[Amine 8] - Commercially available

[Amine 9] - 2-[(3S)-3-Methylpiperazin-l-yl]benzonitrile

[00237] tert-Butyl (2S)-4-(2-cyanophenyl)-2-methylpiperazine-l-carboxylate [Intermediate 3] (247 mg, 0.82 mmol) was taken up in trifluoroacetic acid [20%> in DCM] (2 ml) and agitated for 18 hours at ambient temperature. The reaction was diluted with DCM (10 ml) and sat aq NaHC0 ₃ (5 ml) then the organics were separated, dried over Na ₂ S04, filtered and concentrated in vacuo to to yield the title compound as a light yellow viscous oil (152 mg, 92%).

LCMS Method 2 - Tr = 0.67 min (ES+) (M+H ⁺ ) 202.2

[Amine 10] - Commercially available

[Amine 11] - 3-(Piperazin-l-yl)pyridazine-4-carbonitrile hydrochloride

[00238] tert-Butyl 4-(4-cyanopyridazin-3-yl)piperazine-l-carboxylate [Intermediate 4] (1.1 g, 3.0 mmol) was dissolved in HC1 (4M in 1,4-dioxane, 5ml) then the reaction was stirred at room temperature overnight. The reaction was filtered; the solid was filtered off and washed with further 1,4-dioxane. The solid was then dried in a vacuum oven in vacuo at 40°C to afford the title compound as a yellow solid (447 mg, 63 %).

1H NMR (500 MHz, DMSO-d6) δ 9.50 (s, 2H), 9.02 (d, J = 4.9 Hz, 1H), 8.09 (d, J = 4.9 Hz, 1H),

3.96 - 3.88 (m, 4H), 3.27 (s, 4H)

LCMS Method 4 - Tr = 1.1 min (ES+) (M+H)+ 190.2

[Amine 12] - 3-(Piperazin-l-yl)pyridine-2-carbonitrile

[00239] 3-Fluoropyridine-2-carbonitrile (216 μΐ, 2.05 mmol) and piperazine (1.75 g, 20.0 mmol) were suspended in toluene (1 ml) in a sealed reaction tube. The reaction was heated at 110 °C for 3 hours. The reaction was then partitioned between DCM and water. The DCM was washed with water (x 2). The organics were dried (MgS0 ₄ ), filtered and concentrated in vacuo to afford the title compound as a light brown solid (421 mg, 79 %).

1H MR (250 MHz, Chloroform-d) δ 8.40 (dd, J = 4.0, 1.8 Hz, 1H), 7.50 - 7.41 (m, 2H), 3.97 (d, J = 23.5 Hz, 1H), 3.59 - 3.36 (m, 8H).

LCMS Method 2 - Tr = 2.81 min (ES+) (M+H)+ 189.0

[Amine 13] - 4-Phenylpiperidine-4-carboxamide

in Bioorganic and Medicinal Chemistry Letters (2010) vol. 20, #20 p. 6088

- 6092. [Amine 14] Commercially available [Amine 15] Commercially available [Amine 16] Commercially available [Amine 17] Commercially available [Amine 18] Commercially available [Amine 19] Commercially available [Amine 20] 2-Methyl-5-(piperazin-l-yl)-l,3-oxazole-4-carbonitrile

[00240] tert-Butyl 4-(4-cyano-2-methyl-l,3-oxazol-5-yl)piperazine-l-carboxylate [Intermediate 6] (100 mg, 0.342 mmol) was dissolved in HC1 (4N in dioxane, 6 mL) and was stirred at room temperature for 3 hours. The reaction was concentrated in vacuo then the residue was loaded onto a SCX-2 column (2 g) and the column was washed with 1 : 1 DCM / methanol (30 ml). The product was eluted with 7N H ₃ in MeOH (30 ml) which was concentrated in vacuo to yield the title compound as a viscous yellow oil (60 mg, 87%).

1H MR (500 MHz, Chloroform-d) δ 3.51 - 3.47 (m, 4H), 3.00 - 2.94 (m, 4H), 2.31 (s, 3H). LCMS Method 2 - Tr = 1.19 min (ES+) (M+H ⁺ ) 193.2

[Amine 21] - 2-Cyclopropyl-5-(piperazin-l-yl)-l,3-oxazole-4-carbonitrile

[00241] Prepared from Intermediate 8 analogously to the method for Amine 20 to yield the title compound as a yellow viscous oil (80 mg, 43%).

1H MR (500 MHz, Chloroform-d) δ 3.49 - 3.44 (m, 4H), 3.00 - 2.92 (m, 4H), 1.89 - 1.82 (m, 2H), 1.10 - 1.05 (m, 1H), 0.97 - 0.89 (m, 2H).

LCMS Method 2 - Tr = 1.32 min (ES+) (M+H ⁺ ) 219.2

[Amine 22] - Commercially available

[Amine 23] - 2-(Piperazin-l-yl)benzamide

Prepared via the method of Lagu et. al. Journal of Medicinal Chemistry (1999) 42, 23, 4794 - 4803.

[Amine 24] - Commercially available [Amine 25] - N-Methyl-2-(piperazin-l-yl)benzamide

[00242] Prepared from Intermediate 9 analogously to the method for Amine 20 to yield the title compound as a viscous yellow oil (80 mg, 43%).

LCMS Method 4 - Tr = 1.29 min (ES+) (M+H)+ 220.2 inline 26] - Commercial (oxalate

[Amine 27] - Commercially available

[Amine 28] - Commercially available

[Amine 29] - Commercially available

[Amine 30] - Imino(methyl){2-[(3S)-3-methylpiperazin-l-yl]phenyl}- ⁶ -sulfanone

[00243] Prepared from Intermediate 12 analogously to the method for Amine 20 to yield the title compound as a yellow / brown viscous oil (200 mg, 65%).

1H MR (500 MHz, Chloroform-d) δ 8.02 (d, J = 7.9 Hz, 1H), 7.59 - 7.54 (m, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 3.43 (s, 3H), 3.22 - 3.01 (m, 6H), 2.50 (td, J = 10.2, 4.1 Hz, 1H), 1.10 (d, J = 6.3 Hz, 3H).

LCMS Method 6 - Tr = 1.64 min (ES+) (M+H)+ 254 [Amine 31] - l-(2-Methanesulfonylpyridin-3-yl)piperazine dihydrochloride

[00244] To a solution of tert-butyl 4-(2-methanesulfonylpyridin-3-yl)piperazine-l- carboxylate [Intermediate 15] (230 mg, 0.674 mmol) in DCM (4 ml) was added concentrated HC1 (0.1 ml) and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo to yield the title compound as a tan solid (200 mg, 94%).

lH MR (500 MHz, Methanol -^4) δ 8.64 (dd, 7= 4.8, 1.8 Hz, 1H), 8.41 (dd, 7= 7.9, 1.8 Hz, 1H), 7.48 - 7.42 (m, 1H), 3.54 - 3.50 (m, 4H), 3.47 - 3.43 (m, 4H), 3.35 (s, 3H).

LCMS Method 4 - Tr = 1.15 min (ES+) (M+H)+ 240

[Amine 32] - Imino(methyl)[3-(piperazin-l-yl)pyridin-2-yl]- ⁶ -sulfanone dihydrochloride

[00245] Prepared from Intermediate 16 analogously to the method for Amine 31 to yield the title compound as a tan solid (150 mg, 55%).

lH MR (500 MHz, Methanol-d4) δ 8.87 (dd, J = 4.8, 1.7 Hz, 1H), 8.54 (dd, J = 8.1, 1.7 Hz, 1H), 7.65 (dd, J = 8.1, 4.8 Hz, 1H), 4.07 (s, 3H), 3.49 (qd, J = 8.7, 3.0 Hz, 8H)

LCMS Method 4 - Tr = 1.01 min (ES+) (M+H)+ 241

[Amine 33] - Imino(methyl)[2-(piperazin-l-yl)pyridin-3-yl]- ⁶ -sulfanone dihydrochloride

[00246] Prepared from Intermediate 20 analogously to the method of Amine 31 to yield the title compound as a tan solid (40 mg, 58%).

1H NMR (500 MHz, Chloroform-d) δ 8.53 (dd, J = 4.7, 1.8 Hz, 1H), 8.36 - 8.29 (m, 1H), 7.21 (dd, J = 7.8, 4.7 Hz, 1H), 3.41 (s, 3H), 3.33 - 3.24 (m, 4H), 3.10 - 3.07 (m, 4H).

LCMS Method 4 - Tr = 1.01 min (ES+) (M+H)+ 241

[Amine 34] - (S or R)-Imino(methyl)[2-(piperazin-l-yl)phenyl]- ⁶ -sulfanone

[Amine 35] - (R or S)-imino(methyl)[2-(piperazin-l-yl)phenyl]- ⁶ -sulfanone

[00247] (RS)-Imino(methyl)[2-(piperazin-l-yl)phenyl]- ⁶ -sulfanone (208 mg, 0.87 mmol) was dissolved to 35 mg/mL in methanol and was then purified by SFC. The second eluting peak 2.33 min fractions were then evaporated to near dryness using a rotary evaporator, transferred into final vessels with DCM, which was removed under a stream of nitrogen at 40 °C before being stored in a vacuum oven at 40 °C and 5 mbar for 16 hours to afford the title compound as a yellow oil (58.7 mg, 29%).

Column Details: Lux Al (21.2mm x 250mm, 5um)

Column Temperature: 40 C

Flow Rate: 50 ml/min

Detector Wavelength: 210 nm

Isocratic Conditions: 25:75 MeOH:C02 (0.1% v/v H3)

The stereochemistry was arbitrarily assigned

1H NMR (500 MHz, Chloroform-d) δ 8.02 (dd, J = 7.9, 1.5 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.42 (dd, J = 8.0, 1.0 Hz, 1H), 7.38 - 7.28 (m, 1H), 3.43 (s, 3H), 3.13 - 3.01 (m, 8H).

LCMS (Lux Al (4.6mm x 250mm, 5um), 4 ml/min) Tr = 2.326

Imino(methyl)[2-(piperazin-l-yl)phenyl]- ⁶ -sulfanone peak 1 1.98 min

The stereochemistry was arbitrarily assigned

1H NMR (500 MHz, Chloroform-d) δ 8.02 (dd, J = 7.9, 1.5 Hz, 1H), 7.57 (td, J = 7.8, 1.6 Hz, 1H), 7.42 (dd, J = 8.0, 1.1 Hz, 1H), 7.33 - 7.29 (m, 1H), 3.44 (s, 3H), 3.06 (m, J = 9.4, 6.2 Hz, 8H). LCMS (Lux Al (4.6mm x 250mm, 5um), 4 ml/min) Tr = 1.975 [Amine 36] - l-(5-Fluoro-6-methylpyridin-2-yl)piperazine

[00248] 2-Chloro-5-fluoro-3-methylpyridine (l .Og, 6.9 mmol) was added under nitrogen at 20 °C to piperazine (3.0 g, 34 mmol) in ethanol (30 ml). The ethanol was partially distilled off and the solution heated at 155 °C (130 °C internal) using an air condenser for one hour and allowed to cool. The reaction was heated for a further 2 hours at 145 °C for complete conversion. The cooled residue was stirred with water (10 ml) to give an orange solution and pale crystalline solid. The product was partitioned between DCM (30 ml) and water (10 ml). The layers were separated and the aqueous was extracted with DCM (4 x 10 ml). The combined organics were concentrated in vacuo and purified via flash column chromatography: elution with 5 column volumes of MTBE removed the starting halide; further elution with 10:4: 1 MTBE / MeOH / H ₃ (35% aq) afforded fractions containing product. The fractions were reduced in vacuo to afford the title compound as a yellow oil which crystallised on standing (706 mg, 53 %).

1H MR (500 MHz, Methanol-d4) δ 7.26 (t, J = 9.0 Hz, 1H), 6.59 (dd, J = 9.0, 2.6 Hz, 1H), 3.44 - 3.38 (m, 4H), 2.93 - 2.89 (m, 4H), 2.33 (d, J = 3.0 Hz, 3H).

LCMS Method 2 - Tr = 0.98 min (ES+) (M+H)+ 196

[Amine 37] - 6-[(3S)-3-Methylpiperazin-l-yl]pyridine-2-carbonitrile

[00249] tert-Butyl (2S)-4-(6-cyanopyridin-2-yl)-2-methylpiperazine-l -carboxylate

[Intermediate 21] (321 mg, 1.06 mmol) was dissolved in HC1 (4M in 1,4-dioxane, 10 ml). The reaction was then stirred at room temperature for 5 hours. The reaction was concentrated in vacuo and the residue was loaded onto a SCX-2 Column (5 g). The column was washed with 1 : 1 DCM / MeOH (30 ml) and then eluted with 7N H ₃ in MeOH (30 ml). The 7N H ₃ in MeOH (30 ml) fraction was concentrated in vacuo to give the title compound as a yellow oil (155 mg, 71 %). 1H MR (500 MHz, Chloroform-d) δ 7.49 (dd, J = 8.8, 7.2 Hz, 1H), 6.94 (d, J = 7.1 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.21 - 4.11 (m, 2H), 3.14 - 3.06 (m, 1H), 2.94 - 2.81 (m, 3H), 2.55 - 2.46 (m, 1H), 1.14 (d, J =6.3 Hz, 3H).

LCMS Method 8 - Tr = 1.42 min (ES+) (M+H)+ 203.3

[Amine 38] - Commercially available

[Amine 39] - 5-Fluoro-2-(piperazin-l-yl)pyrimidine

[00250] 2-Bromo-5-fluoropyrimidine (250 mg, 1.41 mmol) and piperazine (1217 mg, 14.13 mmol) were added to a reaction tube. The tube was sealed and the mixture stirred at 100 °C for 15 min. The temperature was then increased to 130 °C and the reaction stirred for 1 hour. The reaction was cooled and DMF (5 ml) was added, forming an orange solution. The reaction was then stirred at 130 °C for an additional 3 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was then partitioned between EtOAc (20 ml) and sat aq NaHC0 ₃ (20 ml). The organics were separated and the aqueous phase extracted with EtOAc (2 x 20 ml). The combined organics were washed with water (20 ml), brine (20 ml), dried over MgS0 ₄ , filtered and concentrated in vacuo. The residue was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give the title compound as a yellow solid (94 mg, 37 %).

1H MR (250 MHz, Chloroform-d) δ 8.19 (s, 2H), 3.80 - 3.74 (m, 4H), 3.00 - 2.92 (m, 4H) LCMS Method 8 - Tr = 1.28 min (ES+) (M+H)+ 365.3

[Amine 40] - Commercially available [Amine 41] - Commercially available

[Amine 42] - Commercially available

[Amine 43] - l-(4-Methyl-l,3-oxazol-2-yl)piperazine and piperazine-l-carbonitrile

[00251] tert-Butyl 4-(4-methyl-l,3-oxazol-2-yl)piperazine-l-carboxylate [Intermediate 22] (118 mg, 0.44 mmol) was suspended in HC1 (4M in 1,4-dioxane, 8 ml) and stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and the residue was loaded onto a Biotage SCX-2 Column (5 g). The column was washed with 1 : 1 DCM / MeOH (40 ml) then the product was eluted with 7N H ₃ in MeOH (40 ml) which was concentrated in vacuo to give the title compound as a white solid (50 mg, 68 %).

1H MR (500 MHz, Chloroform-d) δ 6.94 - 6.91 (m, 1H), 3.51 - 3.47 (m, 4H), 3.22 - 3.18 (m, 3H), 3.01 - 2.96 (m, 4H), 2.93 - 2.90 (m, 3H), 2.04 (s, 3H).

LCMS Method 8 - Tr = 1.18 min (ES+) (M+H)+ 168.1

[Amine 44] - 6-Methyl-2-(piperazin-l-yl)pyridine-3-carbonitrile

[00252] 2-Chloro-6-methylpyridine-3-carbonitrile (250 mg, 1.64 mmol) and piperazine (1.4 g, 16 mmol) were added to a reaction tube under nitrogen. The tube was sealed and the reaction was stirred at 110 °C for 30 min, at which point the piperazine had melted to form an orange solution. The reaction mixture was then heated at 140 °C for 1 hour. The reaction was diluted with water (30 ml) and extracted with EtOAc (3 x 30ml). The combined organics were dried over MgS0 ₄ , filtered and concentrated in vacuo. The residue was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give the title compound as a white solid (248 mg, 75%).

1H NMR (250 MHz, Chloroform-d) δ 7.63 (d, J = 7.8 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H), 3.74 - 3.65 (m, 4H), 3.04 - 2.97 (m, 4H), 2.43 (s, 3H).

LCMS Method 8 - Tr = 1.42 min (ES+) (M+H)+ 203.3

[Amine 45]- 5-Fluoro-6-methyl-2-(piperazin-l-yl)pyridine-3-carbonitrile

[00253] 2-Chloro-5-fluoro-6-methylpyridine-3-carbonitrile [Intermediate 23] (48 mg, 0.28 mmol) and piperazine (242 mg, 2.81 mmol) were added to a reaction tube under nitrogen. The tube was sealed and the mixture was stirred at 140 °C for 16 hours. The reaction was diluted with water (20 ml) and extracted with EtOAc (4 x 20ml). The combined organics were washed with brine (20 ml), dried over MgS0 ₄ , filtered and concentrated in vacuo. The residue was then purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give the title compound as a white solid (22 mg, 71 %).

H NMR (250 MHz, Chloroform-d) δ 7.43 (s, 1H), 3.59 (s, 4H), 3.04 - 3.01 (m, 4H), 2.43 (s, 3H). LCMS Method 8 - Tr = 1.49 min (ES+) (M+H)+ 221.3

[Amine 46] - 5-Fluoro-2-(piperazin-l-yl)pyridine-3-carbonitrile

[00254] 2-Chloro-5-fluoropyridine-3-carbonitrile (250 mg, 1.6 mmol) and piperazine (1.4 g, 16 mmol) were added to a reaction tube. The tube was sealed and the mixture stirred at 135 °C for 2 hours. The reaction was then diluted with water (20 ml) and extracted with EtOAc (4 x 20 ml). The combined organics were then washed with brine (40 ml), dried over MgS0 ₄ , filtered and concentrated in vacuo. The residue was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give the title compound as a yellow solid (180 mg, 55 %).

1H MR (250 MHz, Chloroform-d) δ 8.26 (d, J = 3.0 Hz, 1H), 7.55 (dd, J = 7.2, 3.0 Hz, 1H), 3.75

- 3.61 (m, 4H), 3.18 - 3.09 (m, 4H).

LCMS Method 8 - Tr = 1.35 min (ES+) (M+H)+ 207.2

[Amine 47] - Commercially available

[Amine 48] - 4-Chloro-5-fluoro-2-(piperazin-l-yl)benzonitrile hydrochloride

[00255] tert-Butyl 4-(5-chloro-2-cyano-4-fluorophenyl)piperazine-l-carboxylate

[Intermediate 24] (96%, 115 mg, 0.32 mmol) was suspended in HC1 (4M in 1,4-dioxane, 5 ml) and the mixture was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo to yield the title compound as the hydrochloride salt and as a white solid (86 mg, 94 %).

1H MR (250 MHz, Chloroform-d) δ 7.40 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 6.2 Hz, 1H), 3.70 (s, 4H), 3.48 (s, 6H)

LCMS Method 8 - Tr = 1.55 min (ES+) (M+H)+ 240.1 [Amine 49] - 4,5-Difluoro-2-(2-oxopiperazin-l-yl)benzonitrile

[00256] tert-Butyl 4-(3,4-difluorophenyl)-3-oxopiperazine-l-carboxylate [Intermediate 25] (30 mg, 0.1 mmol) was suspended in HC1 (4M in 1,4-dioxane, 1 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was loaded onto a Biotage SCX-2 Column (5 g). The column was washed with 1 : 1 DCM/MeOH (40 ml) then the product was eluted with 7N NH ₃ in MeOH (40 ml) which was concentrated in vacuo to give the title compound as a pale brown solid (15 mg, 68 %).

1H MR (250 MHz, Chloroform-d) δ 7.24 - 7.07 (m, 3H), 3.69 (s, 2H), 3.66 (t, J = 5.4 Hz, 2H),

3.23 (t, J = 5.4 Hz, 2H), 2.35 (s, 1H).

LCMS Method 8 - Tr = 1.21 min (ES+) (M+H)+ 213.1

[Amine 50] - Commercially available

[Amine 51] - 2-{Octahydropyrrolo[3,4-c]pyrrol-2-yl}benzonitrile dihydrochloride

[00257] tert-Butyl 5-(2-cyanophenyl)-octahydropyrrolo[3,4-c]pyrrole-2-carboxyla te [Intermediate 26] (27 mg, 0.09 mmol) was suspended in HC1 (4M in 1,4-dioxane, 0.43 ml) and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo to yield the title compound as brown solid (19 mg, 71 %).

1H NMR (250 MHz, Methanol-d4) δ 7.54 - 7.40 (m, 2H), 7.05 - 6.86 (m, 2H), 3.71 - 3.56 (m, 4H), 3.42 - 3.14 (m, 6H).

LCMS Method 1 - Tr = 1.59 min (ES+) (M+H)+ 244.0 [Amine 52] - 2-[(Pyrrolidin-3-yl)amino]benzonitrile dihydrochloride

[00258] Prepared from Intermediate 27 analogously to the method for Amine 51 to yield the title compound as an orange oil (123 mg, 96 %).

1H MR (250 MHz, Methanol-d4) δ 7.54 - 7.44 (m, 2H), 6.94 - 6.75 (m, 2H), 4.46 - 4.36 (m, 1H), 3.69 - 3.38 (m, 3H), 3.35 (s, 2H), 2.55 - 2.36 (m, 1H), 2.23 - 2.04 (m, 1H).

LCMS Method 1 - Tr = 1.43 min (ES+) (M+H)+ 188.0

[Amine 53] - 2-[(Azetidin-3-yl)amino]benzonitrile dihydrochloride

[00259] Prepared from Intermediate 28 analogously to the method for Amine 51 to yield the title compound as as an orange oil (128 mg, 96 %).

1H MR (250 MHz, Methanol-d4) δ 7.53 - 7.42 (m, 2H), 6.84 (td, J = 7.6, 0.9 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 4.67 (p, J = 6.9 Hz, 1H), 4.51 - 4.39 (m, 2H), 4.19 - 4.06 (m, 2H)

LCMS Method 1 - Tr = 1.33 min (ES+) (M+H)+ 173.9

[Amine 54] - 5-Fluoro-4-methyl-2-(piperazin-l-yl)pyrimidine

[00260] 2-Chloro-5-fluoro-4-methylpyrimidine (183.55 μΐ, 1.71 mmol) and piperazine (1469.43 mg, 17.06 mmol) were suspended in ethanol (2.5 ml) then the sealed reaction was heated at 120 °C for 18 hours to give a light yellow solution. The reaction was partitioned between DCM (20 ml) and water (10 ml) then the organics were separated, dried over Na ₂ S04, filtered and concentrated in vacuo to yield the title compound as a pale yellow powder (465 mg, 138%). 1H MR (500 MHz, DMSO-d6) δ 8.26 (d, J = 1.8 Hz, 1H), 3.60 - 3.56 (m, 4H), 2.73 - 2.69 (m, 4H), 2.30 (d, J = 2.5 Hz, 3H).

LCMS Method 4 - Tr = 1.41 min (ES+) (M+H ⁺ ) 197.3 [Amine 55] - Commercially available

[Amine 56] - (l-Phenylpiperazin-2-yl)methanol

[00261] l-Phenylpiperazine-2-carboxylic acid dihydrochloride (250 mg, 0.9 mmol) was suspended in tetrahydrofuran (anhydrous) (5 ml) under nitrogen. The reaction was placed in a chilled waterbath for the slow addition of lithium aluminium hydride solution (4M in Et ₂ 0, 672 μΐ) then the reaction was stirred at ambient temperature for 2 hours. The reaction was diluted with DCM (15ml) then 2: 1 sat aq H ₄ C1 / water (30ml) was added dropwise to the stirring reaction with a waterbath applied (effervescence). The biphasic suspension was filtered, then the organics were separated and concentrated in vacuo to yield the title compound as a tan oil (179 mg, 100%). 1H MR (500 MHz, DMSO-d6) δ 7.17 (ddt, J = 9.7, 7.3, 2.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 7.2 Hz, 1H), 3.74 (t, J = 9.8 Hz, 1H), 3.21 (dt, J = 6.4, 4.3 Hz, 2H), 3.14 (d, J = 12.0 Hz, 1H), 3.02 (dd, J = 6.0, 4.0 Hz, 1H), 2.94 (d, J = 11.7 Hz, 1H), 2.82 (ddt, J = 11.6, 7.8, 3.4 Hz, 2H), 2.74 (dd, J = 11.7, 3.3 Hz, 1H), 2.66 (td, J = 11.6, 3.5 Hz, 1H).

[Amine 57] - Commercial

[Amine 58] - Commercially available

[Amine 59] - l-(5-Methoxypyridin-2-yl)piperazine

[00262] Piperazine (4.6 g, 53.19 mmol) and 2-bromo-5-methoxypyridine (826 μΐ, 5.32 mmol) were added to a pressure tube and stirred at 100 °C for 1 hour, forming a yellow solution. The mixture was then heated at 140 °C for 18 h. The reaction was cooled, diluted with water (25 ml) and extracted with DCM (4 x 15 ml). The combined organics were concentrated in vacuo to give the title compound as a yellow solid (670 mg, 62 %).

lH MR (500 MHz, Chloroform-d) δ 7.93 (d, J = 3.0 Hz, 1H), 7.15 (dd, J = 9.1, 3.1 Hz, 1H), 6.63 (d, J = 9.1 Hz, 1H), 3.79 (s, 3H), 3.40 - 3.37 (m, 4H), 3.02 - 2.99 (m, 4H), 2.12 (s, 1H)

LCMS Method 8 - Tr = 1.26 min (ES+) (M+H)+ 194.2

[Amine 60] - Commercially available

[Amine 61] - Commercially available

[Amine 62] - Commercially available

[Amine 63] - Commercially available

[Amine 64] - l-[6-(Propan-2-yl)pyridin-2-yl] piperazine

[00263] 2-Bromo-6-(propan-2-yl)pyridine (183.55 μΐ, 1.25 mmol) and piperazine (1.076 g, 12.5 mmol) were suspended in ethanol (2.5 ml) then the sealed reaction was heated at 160 °C for 6 hours. The reaction was cooled then diluted with water (10 ml) and DCM (20 ml) then the organics were separated, dried over Na ₂ S04, filtered and concentrated in vacuo to yield the title compound as a pale yellow oil (283 mg, 100%).

1H NMR (500 MHz, DMSO-d6) δ 7.44 - 7.39 (m, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 7.3 Hz, 1H), 3.39 - 3.35 (m, 4H), 2.84 - 2.78 (m, 1H), 2.78 - 2.74 (m, 4H), 1.18 (d, J = 6.9 Hz, 6H). LCMS Method 2 - Tr = 0.38 min (ES+) (M+H ⁺ ) 206.3

[Amine 65] - (3S)-3-Methyl-l-(pyridin-2-yl)piperazine

[00264] A mixture of 2-bromopyridine (1.43 mL, 14.98 mmol) and tert-butyl (2S)-2- methylpiperazine-l-carboxylate (300 mg, 1.498 mmol) was heated at 120 °C for 6 hours. The reaction mixture was cooled and partitioned between EtOAc (30 ml) and water (30 ml). The aqueous was extracted with EtOAc (3 x 30 ml) and the combined organics were washed with brine, dried (MgS0 ₄ ), filtered and concentrated in vacuo. The residue was loaded onto an SCX-2 cartridge. The column was washed with 1 : 1 DCM / MeOH (30 ml) then the product was eluted with 7N NH ₃ in MeOH (30 ml) which was concentrated in vacuo to yield the title compound as a brown viscous oil (200 mg, 63%).

1H NMR (500 MHz, Chloroform-d) δ 8.65 (s, 1H), 8.14 (d, 1H), 7.53 - 7.46 (m, 1H), 6.71 - 6.62 (m, 2H), 4.38 - 4.19 (m, 2H), 3.63 - 3.49 (m, 2H), 3.49 - 3.39 (m, 1H), 3.31 - 3.23 (m, 1H), 3.12 (td, J = 3.5 Hz, 1H), 1.57 (d, J = 6.6 Hz, 3H).

LCMS Method 2 - Tr = 1.33 min (ES+) (M+H ⁺ ) 178.2

[Amine 66] - (3S)-3-Methyl-l-phenylpiperazine

[00265] tert-Butyl (2S)-2-methylpiperazine-l-carboxylate (500 mg, 2.497 mmol), bromobenzene (261 uL, 2.497 mmol), NaO'Bu (360 mg, 3.745 mmol), (±)-BINAP (155 mg, 0.250 mmol) and Pd(OAc) ₂ (56 mg, 0.250 mmol) were suspended in nitrogen-degassed toluene (6 mL) and heated at 100 °C for 18 hours. The reaction was filtered through a sintered funnel, using EtOAc (50 ml) then the filtrate was concentrated in vacuo. The residue was dissolved in HC1 (4M in 1,4- dioxane, 10 mL) and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and the residue was loaded onto an SCX-2 column. The column was washed with 1 : 1 DCM / MeOH (30 ml) then the product was eluted with 7N H ₃ in MeOH (30 ml) which was concentrated in vacuo to yield the crude title compound as a yellow oil (210 mg, 38%).

1H NMR (500 MHz, Chloroform-d) δ 7.26 (t, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.85 (t, J = 7.3 Hz, 1H), 3.52 (d, J = 12.2 Hz, 2H), 3.16 - 3.11 (m, 1H), 3.08 - 2.97 (m, 2H), 2.75 (td, J = 11.7, 3.2 Hz, 1H), 2.42 - 2.35 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H).

[Amine 67] - 6-(Piperazin-l-yl)pyridine-2-carbonitrile

[00266] tert-Butyl 4-(6-cyanopyridin-2-yl)piperazine-l-carboxylate [Intermediate 29] (251 mg, 0.87 mmol) was dissolved in trifluoroacetic acid (20% in DCM) (2 ml) then the reaction was agitated for 2 hours. The reaction was diluted with DCM (10 ml) and sat aq NaHC0 ₃ (10 ml) then the organics were separated, dried over Na ₂ S04, filtered and concentrated in vacuo to yield the title compound as a pale yellow glass (96 mg, 59%).

1H NMR (500 MHz, DMSO-d6) δ 7.69 (dd, J = 8.9, 7.2 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 9.0 Hz, 1H), 3.50 - 3.46 (m, 4H), 2.83 - 2.76 (m, 4H).

LCMS Method 4 - Tr = 1.35 min (ES+) (M+H ⁺ ) 189.2

[Amine 68] - Commercially available

[Amine 69] - Commercially available

[Amine 70] - Commercially available

[Amine 71] - Commercially available [Amine 72] - Commercially available

[Amine 73] - Commercially available

[Amine 74] - 2-(3-Oxopiperazin-l-yl)benzonitrile

[00267] 2-Fluorobenzonitrile (1.0 g, 896.06 μΐ, 8.26 mmol) and piperazin-2-one (2.48 g, 24.77 mmol) were suspended together in a sealed tube then heated to 145 °C for 18 hours. The reaction was cooled, then partitioned between DCM (50 ml) and water (50 ml). The organics were separated and dried over Na ₂ S04, then filtered and concentrated in vacuo to yield the title compound as a tan powder (1.326 g, 67%).

1H MR (500 MHz, DMSO-d6) δ 7.71 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.27 - 7.18 (m, 1H), 6.95 - 6.89 (m, 1H), 5.54 (s, 2H), 4.06 - 3.98 (m, 2H), 3.56 - 3.53 (m, 2H). LCMS Method 2 - Tr = 0.76 min (ES+) (M+H ⁺ ) 202.25

[Amine 75] - 2-(3-Aminopyrrolidin-l-yl)benzonitrile dihydrochloride

[00268] Prepared from Intermediate 30 analogously to the method for Amine 51 to yield the title compound as a white solid (33 mg, 93 %).

1H MR (250 MHz, Methanol-d4) δ 7.57 - 7.45 (m, 2H), 6.94 - 6.82 (m, 2H), 4.18 - 3.59 (m, 6H), 3.41 - 3.29 (m, 1H), 2.61 - 2.42 (m, 1H), 2.32 - 2.15 (m, 1H).

LCMS Mehtod 1 - Tr = 1.39 min (ES+) (M+H)+ 188.0 [Amine 76] - Commercially available

[Amine 77] - Commercially available

[Amine 78] - Commercially available

[Amine 79] - Commercially available

[Amine 80] - Imino(methyl)[2-(piperazin-l-yl)phenyl]- ⁶ -sulfanone dihydrochloride

[00269] tert-Butyl 4- { 2- [imino(methyl)oxo- ⁶ - sulfanyljphenyl } piperazine- 1 - carboxylate [Intermediate 31] (230 mg, 0.678 mmol) was suspended in HC1 (4M in 1,4-dioxane, 4 ml) and was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to yield the title compound as a tan solid (200 mg, 95%).

IH MR (500 MHz, Methanol-d4) δ 8.17 (dd, J = 8.2, 1.5 Hz, 1H), 8.02 (td, J = 7.8, 1.5 Hz, 1H), 7.89 (dd, J = 8.1, 1.0 Hz, 1H), 7.74 - 7.68 (m, 1H), 4.07 (s, 3H), 3.53 - 3.45 (m, 4H), 3.40 - 3.34 (m, 2H), 3.33 (s, 1H), 3.29 (s, 1H).

LCMS Method 4 - Tr = 1.13 min (ES+) (M+H)+ 240 [Amine 81] - Commercially available [Amine 82] - Commercially available [Amine 83] - Commercial

Intermediates [Intermediate A] - 5-{[4-(2-Cyanophenyl)piperazin-l-yl]methyl}-2-methylbenzoic

[00270] 5-formyl-2-methylbenzoic acid (1 g, 6.09 mmol) and 2-(piperazin-l-yl)benzonitrile [Amine 72] (1.25 g, 6.7 mmol) were suspended in dichloromethane (10 ml) then NaBH(OAc) ₃ (2.58 g, 12.18 mmol) was added and the reaction was stirred at ambient temperature overnight. The reaction was diluted with DCM (30 ml) and water (30 ml) then the organics were separated, dried over Na ₂ S04, filtered and concentrated in vacuo. The residue was triturated under MTBE and filtered, washing with further MTBE then dried in vacuo to afford the title compound as a pale yellow solid (1.43 g, 70%).

1H MR (500 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.69 (dd, J = 7.7, 1.6 Hz, 1H), 7.59 (ddd, J = 9.0, 7.5, 1.7 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.09 (td, J = 7.6, 0.9 Hz,

1H), 3.55 (s, 2H), 3.17 - 3.12 (m, 4H), 2.58 - 2.54 (m, 4H).

LCMS Method 2 - Tr = 0.82 min (ES+) (M+H)+ 336.5

[Intermediate B] - 5-{[4-(2-Chlorophenyl)piperazin-l-yl]methyl}-2-methylbenzoic acid

[00271] 5-Formyl-2-methylbenzoic acid (400 mg, 2.4 mmol)) and l-(2- chlorophenyl)piperazine hydrochloride [Amine 82] (750 mg, 3.2 mmol) were dissolved in DCM (20 ml). NaBH(OAc) ₃ (1.5 g, 7.1 mmol) was added and the reaction was stirred for 2 hours. The reaction was quenched with sat aq NaHC0 ₃ then partitioned between DCM and water. The DCM was then reduced down in vacuo to yield crude product (1.4g, 73% purity by LCMS). The crude product was sonicated in 10ml EtOAc (white solid appeared). The solid was filtered off and dried in vacuo to yield the title compound as a white solid (530mg, 76%). 1H NMR (500 MHz, DMSO-d6) δ 7.76 (d, J = 1.4 Hz, 1H), 7.38 (ddd, J = 7.6, 4.0, 1.5 Hz, 2H), 7.32 - 7.22 (m, 2H), 7.15 (dd, J = 8.1, 1.4 Hz, 1H), 7.02 (td, J = 7.8, 1.5 Hz, 1H), 3.53 (s, 2H), 2.95 (d, J = 19.0 Hz, 4H), 2.57 - 2.51 (m, 4H).

LCMS Method 2 - Tr = 1.26 min (ES+) (M+H)+ 345.2 / 347.2

[Intermediate C] - 5-{[4-(2-Cyanophenyl)piperazin-l-yl]methyl}-2,4-dimethylbenz oic acid

[00272] 5-Formyl-2,4-dimethylbenzoic acid (2 g, 11.2 mmol) and 2-(piperazin-l- yl)benzonitrile [Amine 72] (2.21 g, 11.79 mmol) were suspended in DCM (40 ml) and stirred at room temperature for 3 hours. NaBH(OAc) ₃ (5.95 g, 28.1 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with water (50 ml). The organics were separated and the aqueous extracted with DCM (2 x 50 ml). The combined organics were concentrated in vacuo and the solid obtained was purified via flash column chromatography (DCM / MeOH: Gradient from 0% MeOH to 10% MeOH in DCM). The fractions containing product were combined and concentrated in vacuo to afford the title compound as a white solid

(3.06 g, 77 %).

1H NMR (250 MHz, Chloroform-d) δ 8.45 (s, 1H), 8.13 (s, 1H), 7.56 (dd, J = 7.9, 1.6 Hz, 1H), 7.52 - 7.41 (m, 1H), 7.03 (dd, J = 9.4, 1.6 Hz, 3H), 3.77 (s, 2H), 3.43 - 3.27 (m, 4H), 2.94 (s, 4H), 2.58 (s, 3H), 2.40 (s, 3H). LCMS Method 2 - Tr = 0.93 min (ES+) (M+H)+ 350.0

[Intermediate D] - 5-{[4-(2-Chlorophenyl)piperazin-l-yl]methyl}-2,4-dimethylben zoic acid

[00273] 5-Formyl-2,4-dimethylbenzoic acid (125 mg, 0.7 mmol) and NaBH(OAc) ₃ (297.4 mg, 1.4 mmol), were suspended in DCM (2 ml) then DIPEA (147 μΐ, 0.84 mmol) was added followed by l-(2-chlorophenyl)piperazine hydrochloride [Amine 82] (180 mg, 0.77 mmol). The reaction mixture was then stirred at room temperature for 4 hours. The mixture was diluted with water (10 ml) and DCM (10 ml) then the organics were separated and concentrated in vacuo. The residue was dissolved in minimal DCM and purified via flash column chromatography using gradients from heptane to EtOAc then from EtOAc to MeOH. Fractions containing product were combined to afford the title compound as a solid (221 mg, 86 %).

1H MR (500 MHz, Chloroform-d) 8.21 (s, 1H), 7.38 (dd, J = 7.9, 1.4 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.10 (s, 1H), 7.08 (d, J = 6.9 Hz, 1H), 7.04 - 6.99 (m, 1H), 3.92 (s, 2H), 3.30 (s, 4H), 3.06 (s, 4H), 2.61 (s, 3H), 2.45 (s, 3H).

LCMS Method 2 - Tr = 0.96 min (ES+) (M+H)+ 359.5 / 361.05

[Intermediate E] - 5-{[4-(3-Chloropyridin-2-yl)piperazin-l-yl]methyl}-2-methylb enzoic acid.

[00274] To a suspension of 5-formyl-2-methylbenzoic acid (257 mg, 1.57 mmol) and l-(3- chloropyridin-2-yl)piperazine [Amine 78] (310 mg, 1.568 mmol) in DCM (10 ml) was added NaBH(OAc) ₃ (665 mg, 3.14 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was partitioned between sat aq NaHC0 ₃ (20 ml) and DCM (20 ml). The organics were separated then the aqueous was extracted with DCM (3 x 20 ml) and the combined organics were washed with brine (30 ml), dried (MgS0 ₄ ) filtered and concentrated in vacuo to afford the title compound as an off-white solid (185 mg, 34 %).

1H MR (500 MHz, DMSO-d6) δ 8.20 (dd, J = 4.7, 1.4 Hz, 1H), 7.79 - 7.75 (m, 2H), 7.38 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.00 - 6.95 (m, 1H), 3.53 (s, 2H), 3.25 (s, 8H), 2.52 (s, 3H).

LCMS Method 2 - Tr = 0.86 min (ES+) (M+H)+ 346.0

[Intermediate F] - 5-{[4-(3-Cyanopyridin-2-yl)piperazin-l-yl]methyl}-2-methylbe nzoic acid.

[00275] 5-Formyl-2-methylbenzoic acid (1 g, 6.1 mmol) and 2-(piperazin-l-yl)pyridine-3- carbonitrile [Amine 73] (1.26 g, 6.7 mmol) were suspended in DCM (10 ml). NaBH(OAc) ₃ (2.58 g, 12.2 mmol) was added and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with DCM (10 ml) to give a mobile slurry, which was filtered and dried over airflow then the retained solid was sequentially washed with water (2 x 20ml) and MeOH (2 x 10ml) then dried in vacuo to afford the title compound as a white solid (1.98 g, 93 %).

1H MR (500 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.40 (dd, J = 4.8, 1.9 Hz, 1H), 8.06 (dd, J = 7.6, 1.9 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.40 (dd, J = 7.7, 1.6 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.92 (dd, J = 7.6, 4.8 Hz, 1H), 3.64 - 3.56 (m, 4H), 3.54 (s, 2H), 2.53 (s, 4H).

LCMS Method 2 - Tr = 0.78 min (ES+) (M+H)+ 337.5

[Intermediate G] - 5-{[4-(3-Chloropyridin-2-yl)piperazin-l-yl]methyl}-2,4-dimet hylbenzoic acid

[00276] 5-Formyl-2,4-dimethylbenzoic acid (365 mg, 2.1 mmol) and l-(3-chloropyridin-2- yl)piperazine [Amine 78] (405 mg, 2.1 mmol) were suspended in DCM (5 ml) and stirred at room temperature for 30 min. NaBH(OAc) ₃ (1.08 g, 5.1 mmol) was then added and the reaction stirred for 4 hours at room temperature. The reaction was then partitioned between DCM (20 ml) and water (30 ml). The organics were separated and the aqueous phase extracted with DCM (2 x 30 ml). The combined organics were washed with sat aq NaHC0 ₃ and concentrated in vacuo to afford the title compound as a white solid (622 mg, 83%).

1H MR (250 MHz, Chloroform-d) δ 8.14 (dd, J = 4.8, 1.6 Hz, 1H), 8.03 (s, 1H), 7.55 (dd, J = 7.7, 1.6 Hz, 1H), 6.97 (s, 1H), 6.81 (dd, J = 7.7, 4.8 Hz, 1H), 4.79 (s, 1H), 3.64 (s, 2H), 3.52 - 3.39 (m, 4H), 2.87 - 2.70 (m, 4H), 2.52 (s, 3H), 2.35 (s, 3H).

LCMS Method 2 - Tr = 0.94 min (ES+) (M+H)+ 360.0 / 362.0

[Intermediate H] - 2-[4-(5-Formyl-2,4-dimethylbenzoyl)piperazin-l-yl]benzonitri le.

[00277] 5-Formyl-2,4-dimethylbenzoic acid (500 mg, 2.8 mmol) and HATU (1.28 g, 3.4 mmol) were suspended in DMF (5 ml) and stirred at room temperature for 1 hour. A solution of 2- (piperazin-l-yl)benzonitrile [Amine 72] (578 mg, 3.1 mmol) in DMF (5 ml) was added, DIPEA (1.47 ml, 8.4 mmol) was added, then the reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between DCM (20 ml) and water (20 ml). The organics were separated and the aqueous extracted with DCM (2 x 20 ml). The combined organics were concentrated in vacuo. The resultant oil was purified via flash column chromatography using gradients from heptane to EtOAc then EtOAc to MeOH. The product- containing fractions were combined and the solvents removed in vacuo to afford the title compound (1.0 g, 99%).

1H MR (250 MHz, Chloroform-d) δ 10.22 (s, 1H), 7.65 (s, 1H), 7.59 (dd, J = 7.7, 1.6 Hz, 1H), 7.56 - 7.47 (m, 1H), 7.16 (s, 1H), 7.12 - 7.04 (m, 1H), 7.02 (d, J = 8.2 Hz, 1H), 4.01 (d, J = 31.5 Hz, 2H), 3.48 (s, 2H),3.27 (s, 2H), 3.12 (d, J = 4.5 Hz, 2H), 2.66 (s, 3H), 2.38 (s, 3H)

LCMS Method 2 - Tr = 1.11 min (ES+) (M+H)+ 348

[Intermediate I] - 5-{[4-(3-Chloropyridin-2-yl)piperazin-l-yl]methyl}-2,4-dimet hylbenzoic acid.

[00278] 5-Formyl-2,4-dimethylbenzoic acid (365 mg, 2.1 mmol) and l-(3-chloropyridin-2- yl)piperazine [Amine 78] (404.9 mg, 2.05 mmol) were suspended in DCM (5 ml) and stirred at room temperature for 30 min. NaBH(OAc) ₃ (1.08 g, 5.1 mmol) was then added and the reaction stirred for 4 hours at room temperature. The reaction mixture was partitioned between DCM (20 ml) and water (30 ml). The DCM was separated and the aqueous phase extracted with DCM (2 x 30 ml). The combined organics were washed with sat aq NaHC0 ₃ and concentrated in vacuo to afford the title compound as white solid (622 mg, 84%).

1H MR (250 MHz, Chloroform-d) δ 8.14 (dd, J = 4.8, 1.6 Hz, 1H), 8.03 (s, 1H), 7.55 (dd, J = 7.7, 1.6 Hz, 1H), 6.97 (s, 1H), 6.81 (dd, J = 7.7, 4.8 Hz, 1H), 4.79 (s, 1H), 3.64 (s, 2H), 3.52 - 3.39 (m, 4H), 2.87 - 2.70 (m, 4H), 2.52 (s, 3H), 2.35 (s, 3H).

LCMS Method 2 - Tr = 0.94 min (ES+) (M+H)+ 360.0/362.0

[Intermediate J] 3-[4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl]-4- methylbenzaldehyde.

[00279] 5-Formyl-2-methylbenzoic acid (450 mg, 2.7 mmol) and l-(5-fluoropyridin-2- yl)piperazine trihydrochloride [Amine 57] (836 mg, 2.9 mmol) were added to a flask under nitrogen and dissolved in DMF (5 ml). DIPEA (1.7 ml) was added followed by HATU (1.25 mg, 3.3 mmol) then the reaction was stirred at room temperature for 16 hours. The reaction was partitioned between DCM (20 ml) and water (20 ml). The organics were separated, dried over Na ₂ S04, filtered and concentrated in vacuo. The residue was purified via flash column chromatography using gradients from heptane to EtOAc and then EtOAc to MeOH. The product- containing fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow viscous oil (863mg, 93 %).

lH MR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.11 (d, J = 3.1 Hz, 1H), 7.86 (dd, J = 7.9, 1.7 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.57 - 7.51 (m, 2H), 6.90 (dd, J = 9.3, 3.4 Hz, 1H), 3.78 (s, 2H), 3.57 (t, J = 5.2 Hz, 2H), 3.40 (s, 2H), 3.25 (d, J = 4.6 Hz, 2H), 2.33 (s, 3H).

LCMS Method 2 - Tr = 1.02 min (ES+) (M+H)+ 328.4 [Intermediate K] - 2-[4-(5-Formyl-2,4-dimethylbenzoyl)piperazin-l-yl]benzene-l- sulfonamide

[00280] 5-Formyl-2,4-dimethylbenzoic acid (600 mg, 3.4 mmol) and 2-(piperazin-l- yl)benzene-l -sulfonamide [Amine 2] (894 mg, 3.7 mmol) were dissolved in DMF (10 ml) then HATU (1.4 g, 3.7 mmol) was added and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with water and the resultant suspension was left for 1 hour to give a sticky residue around the glass and a pale yellow supernatant. The supernatant was decanted and the residue was taken up in DCM. The organic solution was dried over Na ₂ S04, then filtered and concentrated in vacuo. The residue was purified via flash column chromatography using gradients from heptane to EtOAc then from EtOAc to MeOH. The peaks containing product were combined and reduced in vacuo to afford the title compound as pale tan glass (623 mg, 28 %).

LCMS Method 2 - Tr = 1.01 min (ES+) (M+H)+ 402.4

[Intermediate L] - 2-[4-(5-Formyl-2,4-dimethylbenzoyl)piperazin-l-yl]pyridine-3 - carbonitrile

[00281] 5-Formyl-2,4-dimethylbenzoic acid (200 mg, 1.1 mmol) and HATU (500 mg, 1.3 mmol) were dissolved in DMF (5 ml). DIPEA (500 μΐ, 2.9 mmol) was added and the reaction mixture was stirred for 30 mins. 2-(piperazin-l-yl)pyridine-3-carbonitrile [Amine 73] (225 mg, 1.2 mmol) was added and the reaction mixture was stirred overnight. The reaction was partitioned between DCM and citric acid (10% aq). The organics were washed sequentially with H ₂ 0, sat aq NaHC0 ₃ , H ₂ 0, then dried (MgS0 ₄ ), filtered and concentrated in vacuo to afford the title compound as a brown oil (425 mg, 98 %). 1H MR (250 MHz, Chloroform-d) δ 10.24 (s, 1H), 8.39 (dd, J = 4.9, 1.9 Hz, 1H), 7.84 (dd, J = 7.6, 2.0 Hz, 1H), 7.66 (s, 1H), 7.18 (s, 1H), 6.88 (dd, J = 7.6, 4.9 Hz, 1H), 4.01 (s, 2H), 3.92 - 3.54 (m, 5H), 3.45 (s, 2H), 3.27 - 3.02 (m, 2H), 2.68 (s, 3H), 2.39 (s, 3H).

LCMS Method 4 - Tr = 1.59 min (ES+) (M+H)+ 349

[Intermediate 1] - tert-Butyl 4-(2-cyano-4,5-difluorophenyl)piperazine-l-carboxylate

[00282] 2-Bromo-4,5-difluorobenzonitrile (1.0 g, 4.59 mmol), tert-butyl piperazine-1- carboxylate (0.9 g, 4.82 mmol), Pd ₂ (dba) ₃ (0.21 g, 0.23 mmol), Xantphos (0.27 g, 0.46 mmol) and sodium tert-butoxide (1.32 g, 13.76 mmol) were suspended in 1,4-dioxane (20 ml, degassed with nitrogen for 5 minutes) then the reaction was heated at 100 °C for 6 hours. The reaction was cooled then filtered through Celite. The filtrate was partitioned between DCM (50 ml) and water (30 ml) then the organics were separated; the aqueous layer was re-extracted with further DCM (30 ml) then the combined organics were dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified via flash chromatography using gradients from heptane to EtOAc followed by EtOAc to methanol to yield the title compound as a pale yellow crystalline solid (757 mg, 51%). 1H MR (500 MHz, DMSO-d6) δ 8.04 (dd, J = 10.4, 8.8 Hz, 1H), 7.33 (dd, J = 12.7, 7.2 Hz, 1H), 3.48 (d, J = 4.7 Hz, 4H), 3.08 (t, J = 5.0 Hz, 4H), 1.42 (s, 9H).

LCMS Method 2 - Tr = 1.24 min (ES+) (M+Na ⁺ ) 346.2

[Intermediate 2] - tert-Butyl 4-(2-cyanophenyl)-3-oxopiperazine-l-carboxylate

[00283] 2-Bromobenzonitrile (500 mg, 2.75 mmol), tert-butyl 3-oxopiperazine-l-carboxylate (191.42 mg, 0.96 mmol), 'N,N-dimethylethylenediamine (30.01 μΐ, 0.27 mmol), copper(I)iodide (26.16 mg, 0.14 mmol) and K2CO3 (759.3 mg, 5.49 mmol) were suspended in toluene (10 ml) under nitrogen and heated at 110 °C for 18 hours. The reaction was diluted with EtOAc and filtered through Celite. The filtrate was concentrated in vacuo and the resultant beige solid was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The product-containing fractions were combined and concentrated in vacuo to yield the title compound as a cream solid (513 mg, 61 %).

1H MR (250 MHz, Chloroform-d) δ 7.78 - 7.64 (m, 2H), 7.50 - 7.34 (m, 2H), 4.31 (s, 2H), 3.91 - 3.83 (m, 2H), 3.79 - 3.71 (m, 2H), 1.51 (s, 9H)

LCMS Method 1 - Tr = 1.52 min (ES+) (M+H)+ 302

[Intermediate 3] - tert-Butyl (2S)-4-(2-cyanophenyl)-2-methylpiperazine-l-carboxylate

[00284] tert-Butyl (2S)-2-methylpiperazine-l-carboxylate (200 mg, 1 mmol), 2- bromobenzonitrile (199.94 mg, 1.1 mmol), Pd ₂ (dba) ₃ CHCl ₃ (10.34 mg, 0.01 mmol), RuPhos (11.65 mg, 0.02 mmol) and cesium carbonate (406.7 mg, 1.25 mmol) were suspended in toluene (anhydrous, 5 ml) then the reaction was heated to 1 10 °C for 18 hours. The reaction was partitioned between DCM (20ml) and water (20 ml) then the organics were separated, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified via flash chromatography using gradients from heptane to EtOAc followed by EtOAc to methanol to yield the title compound as a brown glass (247 mg, 82%).

LCMS Method 2 - Tr = 1.27 min (ES+) (M+Na ⁺ ) 324.05

[Intermediate 4] - tert-Butyl 4-(4-cyanopyridazin-3-yl)piperazine-l-carboxylate

[00285] tert-Butyl piperazine-l-carboxylate (734 mg, 3.9 mmol), 3-chloropyridazine-4- carbonitrile (500 mg, 3.6 mmol) and NaHC0 ₃ (602 mg, 7.2 mmol) were dissolved in DMF (5 ml). The reaction mixture was heated for 3 hours. The reaction was partitioned between DCM and citric acid (10% aq). The organics were washed with water, sat aq NaHC0 ₃ , dried (MgS0 ₄ ), filtered and concentrated in vacuo to afford the title compound as an orange oil. (1.1 g, 70%).

1H MR (250 MHz, Chloroform-d) δ 8.86 (d, J = 4.9 Hz, 1H), 7.51 (d, J = 4.9 Hz, 1H), 3.91 - 3.59 (m, 8H), 1.52 (s, 9H).

[Intermediate 5] - 5-Bromo-2-methyl-l,3-oxazole-4-carbonitrile

[00286] To a solution of copper (II) dibromide (544 mg, 2.437 mmol) in anhydrous acetonitrile (5 ml) was added tert-butyl nitrite (90%, 112 μΐ, 1.340 mmol) then the reaction was stirred for 5 min at ambient temperature. A suspension of 5-amino-2-methyl-l,3-oxazole-4-carbonitrile (150 mg, 1.218 mmol) in anhydrous acetonitrile (2 ml) was added (gas evolution noted) and the deep blue/black reaction mixture was then stirred at ambient temperature for 1 hour. Water (15 ml) was added to give a sky blue solution then EtOAc (15 ml) was added and briefly stirred then the organics were separated, washed with brine, dried over MgS0 ₄ , filtered and concentrated in vacuo to yield the title compound as an orange viscous oil (100 mg, 44%).

1H NMR (500 MHz, Chloroform-d) δ 2.52 (s, 3H).

[Intermediate 6] - tert-Butyl 4-(4-cyano-2-methyl-l,3-oxazol-5-yl)piperazine-l-carboxylate

[00287] 5-Bromo-2-methyl-l,3-oxazole-4-carbonitrile [Intermediate 5] (100 mg, 0.588 mmol) and sodium hydrogen carbonate (135 mg, 1.604 mmol) were suspended in DMF then tert-butyl piperazine-l-carboxylate (100 mg, 0.535 mmol) was added and the reaction was heated at 80 °C for 1 hour. The reaction was partitioned between EtOAc (20 ml) and water (20 ml) then the organics were separated. The aqueous was further extracted with EtOAc (3 x 20 ml) then the combined organics were washed with brine (30 ml), dried over MgS0 ₄ , filtered and concentrated in vacuo to yield the crude title compound as an orange viscous oil (100 mg, 30%).

1H MR (500 MHz, Chloroform-d) δ 3.56 - 3.52 (m, 4H), 3.49 - 3.46 (m, 4H), 2.31 (s, 3H), 1.47 (s, 9H).

LCMS Method 2 - Tr = 1.62 min (ES+) (M+H ⁺ ) 293.3

[Intermediate 7] - 5-Bromo-2-cyclopropyl-l,3-oxazole-4-carbonitrile

[00288] To a solution of copper (II) bromide (809 mg, 3.621 mmol) in anhydrous acetonitrile (5 ml) was added tert-butyl nitrite (90%, 167 μΐ, 1.991 mmol) then the reaction was stirred for 5 min at ambient temperature. A suspension of 5-amino-2-cyclopropyl-l,3-oxazole-4-carbonitrile (270 mg, 1.810 mmol) in anhydrous acetonitrile (2 ml) was added (gas evolution noted) and the deep blue/black reaction was then stirred at ambient temperature for 1 hour. Water (15 ml) was added to give a sky blue solution then EtOAc (15 ml) was added and briefly stirred then the organics were separated, washed with brine, dried over MgS0 ₄ , filtered and concentrated in vacuo to yield the title compound as a viscous orange oil (220 mg, 51%).

1H MR (500 MHz, Chloroform-d) δ 2.11 - 2.05 (m, 2H), 1.29 - 1.20 (m, 2H), 1.09 - 1.03 (m, 1H). [Intermediate 8] - tert-Butyl 4-(4-cyano-2-cyclopropyl-l,3-oxazol-5-yl)piperazine-l- carboxylate

[00289] To a suspension of 5-bromo-2-cyclopropyl-l,3-oxazole-4-carbonitrile [Intermediate

7] (220 mg, 1.033 mmol) and sodium hydrogen carbonate (260 mg, 3.098 mmol) in DMF was added tert-butyl piperazine-l-carboxylate (212 mg, 1.136 mmol) and the reaction mixture heated at 80 °C for 1 hour. The reaction was partitioned between EtOAc (30 ml) and water (30 ml) then the organics were separated. The aqueous was further extracted with EtOAc (3 x 20 ml) then the combined organics were washed with brine (30 ml), dried over MgS0 ₄ , filtered and concentrated in vacuo to yield the crude title compound as a viscous orange oil (150 mg, 12%).

LCMS Method 2 - Tr = 1.72 min (ES+) (M+H ⁺ ) 319.2

[Intermediate 9] - tert-Butyl 4- [2-(methylcarbamoyl)phenyl] piperazine-l-carboxylate.

[00290] 2-{4-[(tert-Butoxy)carbonyl]piperazin-l-yl}benzoic acid (626 mg, 1.98 mmol) and DIPEA (1243 μΐ, 7.14 mmol) were suspended in DCM (10 ml). Thionyl chloride (173 μΐ, 2.38 mmol) in DCM (5 ml) was then added dropwise with stirring at 0 °C. The mixture was allowed to warm to room temperature over 1 hour. The mixture was cooled to 0 °C and methylamine hydrochloride (121 mg, 1.79 mmol) was added. The reaction mixture was then allowed to warm to room temperature and stirred for 18 hours. The reaction was concentrated in vacuo and the residue was partitioned between DCM (30 ml) and sat aq NaHCCb (30 ml). The organics were separated and the aqueous extracted with DCM (2 x 30 ml). The combined organics were washed with NaOH (0.1M aq, 2 x 50 ml), dried (MgS0 ₄ ) and concentrated in vacuo to yield the title compound as a brown solid (286 mg, 55 %).

lH NMR (250 MHz, Chloroform-d) δ 9.32 (s, 1H), 8.14 (dd, J = 7.8, 1.7 Hz, 1H), 7.42 (td, J = 7.8, 1.7 Hz, 1H), 7.25 - 7.17 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 3.64 - 3.54 (m, 4H), 3.00 (d, J = 4.9 Hz, 3H), 2.98 - 2.90 (m, 4H), 1.49 (s, 9H).

LCMS Method 2 - Tr = 1.16 min (ES+) (M+H)+ 320

[Intermediate 10] - l-Fluoro-2-methanesulfinylbenzene

[00291] l-Fluoro-2-(methylsulfanyl)benzene (5 g, 35.16 mmol) was suspended in THF (10 ml) at 0 °C then wCPBA (6.675 g, 38.68 mmol) was added portionwise and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with sodium bisulfite (10% aq, 20 ml) and DCM (30 ml) and the phases separated. The aqueous layer was extracted with DCM (3 x 20 ml) and the combined organics were concentrated in vacuo to afford a white solid. The white solid (containing 3-chlorobenzoic acid) was partitioned between NaOH (2M aq) (30 ml) and DCM (30 ml). The organics were washed with NaOH (2M aq) (2 x 20 ml), followed by brine (30 ml), dried (MgS0 ₄ ), filtered and the filtrate concentrated in vacuo to yield the title compound as a yellow oil

(5.0 g, 69%).

1H NMR (500 MHz, Chloroform-d) δ 7.84 - 7.77 (m, 1H), 7.48 - 7.42 (m, 1H), 7.35 (t, J = 7.0 Hz, 1H), 7.08 (t, J = 8.7 Hz, 1H), 2.80 - 2.76 (m, 3H).

LCMS Method 3 - Tr = 0.82 min (ES+) (M+H)+ 159

[Intermediate 11] - (2-Fluorophenyl)(imino)methyl- ⁶ -sulfanone

[00292] To a suspension of l-fluoro-2-methanesulfinylbenzene [Intermediate 10] (5 g, 31.61 mmol), trifluoroacetamide (7.15 g, 63.21 mmol), magnesium oxide (5.1 g, 124.43 mmol) and rhodium (II) acetate (419 mg, 0.948 mmol) in dry DCM (20 ml) under nitrogen was added portionwise (diacetoxyiodo)benzene (20.4 g, 63.21 mmol) and the reaction was stirred at room temperature for 72 hours. The reaction was filtered through a sintered glass funnel using DCM (-10 ml) and the filtrate was concentrated in vacuo. The residue was dissolved in methanol, then K2CO3 (13.1 g, 94.82 mmol) was added and the resultant suspension stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between DCM (10 ml) and water (10 ml) and subjected to sonication. The aqueous phase was concentrated in vacuo and the residue was suspended in water (5 ml). The suspension was subjected to sonication, filtered and the filtrate was concentrated in vacuo to afford the title compound as a viscous brown oil (1.3 g, 21%).

1H MR (500 MHz, Chloroform-d) δ 7.97 (td, J = 7.6, 1.8 Hz, 1H), 7.61 (dddd, J = 8.2, 7.3, 4.9, 1.8 Hz, 1H), 7.33 (dd, J = 7.7, 1.0 Hz, 1H), 7.24 (ddd, J = 9.6, 8.3, 1.0 Hz, 1H), 3.28 (s, 3H).

LCMS Method 4 - Tr = 1.03 min (ES+) (M+H)+ 174

[Intermediate 12] - tert-Butyl (2S)-4-{2-[imino(methyl)oxo- ⁶ -sulfanyl]phenyl}-2- methylpiperazine-l-carboxylate

[00293] (2-Fluorophenyl)(imino)methyl- ⁶ -sulfanone [Intermediate 11] (500 mg, 2.887 mmol) and tert-butyl (2S)-2-methylpiperazine-l-carboxylate (1.16 g, 5.773 mmol) in toluene (2 ml) were heated at 130 °C within a sealed tube for 3 hours. The reaction was cooled to room temperature and then partitioned between water (10 ml) and EtOAc (20 ml). The phases were separated and the aqueous was extracted with EtOAc (3 x 10 ml), then the combined organics were washed with brine (20 ml), dried (MgS0 ₄ ) and filtered. The filtrate was concentrated in vacuo and the crude residue was purified by flash column chromatography eluting with methanol in MeOH- DCM (0% with gradient towards 50%). The product-containing fractions were concentrated in vacuo to yield the title compound as a brown viscous oil (400 mg, 25%). 1H NMR (500 MHz, Chloroform-d) δ 8.05 (ddd, J = 11.3, 7.9, 1.6 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.33 (t, J = 7.6 Hz, 1H), 4.39 (s, 1H), 3.95 (q, J = 13.6, 12.6 Hz, 1H), 3.44 (s, 2H), 3.38 (s, 1H), 3.35 - 3.19 (m, 3H), 3.15 - 2.92 (m, 4H), 1.48 (s, 9H), 1.38 (dd, J = 6.8, 3.8 Hz, 3H).

LCMS Method 4 - Tr = 0.56 min (ES+) (M+H)+ 354

[Intermediate 13] - tert-Butyl 4-[2-(methylsulfanyl)pyridin-3-yl]piperazine-l-carboxylate

[00294] tert-Butyl piperazine-l-carboxylate (456 mg, 2.450 mmol), 3-bromo-2- (methylsulfanyl)pyridine (500 mg, 2.450 mmol) and cesium carbonate (1 197 mg, 3.675 mmol) were suspended in anhydrous toluene (5 ml) within a pressure tube and nitrogen degassed for 20 min. Pd ₂ (dba) ₃ (22 mg, 0.024 mmol) and (±)-BINAP (38 mg, 0.061) were added and the suspension degassed for a further 10 min; the pressure tube was sealed and heated at 110 °C overnight. The reaction mixture was cooled to room temperature and filtered through a sintered glass funnel, washing the solid filter cake with EtOAc (-10 ml). The filtrate was concentrated in vacuo to afford a brown oily liquid. The crude material was purified by flash column chromatography eluting with EtOAc in heptane (0% with gradient towards 100%). The product- containing fractions were combined and concentrated in vacuo to afford to the title compound as a viscous brownish-yellow oil (660 mg, 84%).

1H NMR (500 MHz, Chloroform-d) δ 8.09 (dd, J = 4.8, 1.6 Hz, 1H), 7.39 (dd, J = 7.7, 1.4 Hz, 1H), 6.96 (dd, J = 7.7, 4.8 Hz, 1H), 3.63 - 3.56 (m, 4H), 3.22 - 3.16 (m, 4H), 2.43 (s, 3H), 1.48 (s, 9H).

LCMS Method 4 - Tr = 1.82 min (ES+) (M+H)+ 310

[Intermediate 14] - tert-Butyl 4-(2-methanesulfinylpyridin-3-yl)piperazine-l-carboxylate

[00295] tert-Butyl 4-[2-(methylsulfanyl)pyridin-3-yl]piperazine-l-carboxylate [Intermediate 13] (650 mg, 2.101 mmol) was suspended in THF (6 ml) at 0 °C then wCPBA (399 mg, 2.311 mmol) was added portionwise and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with sodium bisulfite (10% aq, 20 ml) and DCM (30 ml) and the phases separated. The aqueous layer was extracted with DCM (3 x 20 ml) and the combined organics were washed with brine (30 ml), dried (MgS0 ₄ ) and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography eluting with EtOAc in heptane (0% with gradient towards 100%). The fractions containing product were combined and concentrated in vacuo to afford the title compound as a yellow oil (360 mg, 44%).

1H NMR (250 MHz, Chloroform-i ) δ 8.39 (dd, J = 4.8, 1.8 Hz, 1H), 8.24 (dd, J = 7.7, 1.8 Hz, 1H), 7.20 (dd, J = 7.7, 4.9 Hz, 1H), 3.67 - 3.34 (m, 6H), 3.20 - 3.02 (m, 2H), 2.81 (s, 3H), 1.48 (s, 9H).

LCMS Method 4 - Tr = 1.51 min (ES+) (M+H)+ 326

[Intermediate 15] - tert-Butyl 4-(2-methanesulfonylpyridin-3-yl)piperazine-l-carboxylate

[00296] tert-Butyl 4-[2-(methylsulfanyl)pyridin-3-yl]piperazine-l-carboxylate [Intermediate 14] (650 mg, 2.101 mmol) was suspended in THF (6 ml) at 0 °C then wCPBA (399 mg, 2.311 mmol) was added portionwise and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with sodium bisulfite (10% aq) (20 ml) and DCM (30 ml) and the phases separated. The aqueous layer was extracted with DCM (3 x 20 ml) and the combined organics were washed with brine (30 ml), dried (MgS0 ₄ ) and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography eluting with EtOAc in heptane (0% with gradient towards 100%). The fractions containing product were combined and concentrated in vacuo to afford the title compound as a yellow oily liquid (250 mg, 35%).

1H NMR (250 MHz, Chloroform-d) δ 8.57 (dd, J = 4.8, 1.9 Hz, 1H), 8.37 (dd, J = 7.8, 1.9 Hz,

1H), 7.26 (dd, 1H), 3.67 - 3.57 (m, 4H), 3.27 (m, J = 9.7 Hz, 7H), 1.48 (s, 9H).

LCMS Method 4 - Tr = 1.62 min (ES+) (M+H)+ 342

[Intermediate 16] - iert-Buiyi 4-{2~[imiEo(nieiliyI)oso- ⁶ -sisIfiiiiyI]pyridiii~3-yI}piperaziiie~l~ carboxylase

[00297] Prepared analogously to the preparation of [Amine 31] from 3-bromo-2- (methylsulfanyl)pyridine with purification by flash column chromatography using a gradient of EtOAc in heptane (0% to 100%) to yield the title compound as a yellow oil (230 mg, 34%). 1H NMR (500 MHz, Chloroform-d) δ 8.52 (dd, J = 4.7, 1.8 Hz, 1H), 8.35 (dd, J = 7.8, 1.8 Hz, 1H), 7.23 (dd, J = 7.8, 4.7 Hz, 1H), 3.65 - 3.60 (m, 4H), 3.38 (s, 3H), 3.27 - 3.24 (m, 4H), 3.04 (s, J = 4.5 Hz, 1H), 1.48 (s, 9H).

LCMS Method 4 - Tr = 1.45 min (ES+) (M+H)+ 341

[Intermediate 17] - tert-Butyl 4-(3-iodopyridin-2-yl)piperazine-l-carboxylate

[00298] To a solution of 2-fluoro-3-iodopyridine (1.0 g, 4.485 mmol) and tert-butyl piperazine- 1-carboxylate (877 mg, 4.709 mmol) in DMF (3 ml) was added DIPEA (937 μΐ, 5.381 mmol) then the reaction was heated at 100 °C for 18 hours. The reaction was cooled and partitioned between water (20 ml) and EtOAc (30 ml). The phases were separated and the aqueous was extracted with EtOAc (3 x 20 ml). The combined organics were washed with water (2 x 10 ml), brine (2 x 20 ml) and then concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of EtOAc in heptane (0% to 100%). The product-containing fractions were combined and concentrated in vacuo to afford to the title compound as a viscous yellow oil (440 mg, 20%).

1H NMR (500 MHz, Chloroform-d) δ 8.26 (dd, J = 4.7, 1.6 Hz, 1H), 8.07 (dd, J = 7.7, 1.6 Hz, 1H), 6.67 (dd, J = 7.7, 4.7 Hz, 1H), 3.65 - 3.57 (m, 4H), 3.26 - 3.16 (m, 4H), 1.48 (s, 9H).

LCMS Method 4 - Tr = 1.92 min (ES+) (M+H)+ 390

[Intermediate 18] - tert-Butyl 4-[3-(methylsulfanyl)pyridin-2-yl]piperazine-l-carboxylate

[00299] tert-Butyl 4-(3-iodopyridin-2-yl)piperazine-l-carboxylate [Intermediate 17] (440 mg, 1.130 mmol), sodium thiomethoxide (111 mg, 1.583 mmol) and copper powder (24 mg, 0.377 mmol) were suspended in methanol (3 ml) and heated at 100 °C under microwave irradiation for 1 hour. The reaction mixture was retreated with sodium thiomethoxide (111 mg, 1.583 mmol) and copper powder (24 mg, 0.377 mmol) and again heated under microwave irradiation at 100 °C for 75 min. The solids were filtered off, washing the filter cake with methanol (-20 ml) then the filtrate was concentrated in vacuo. The solids were dissolved in EtOAc (10 ml) and water (10 ml), then the phases were separated. The aqueous phase was extracted with EtOAc (3 x 10 ml) and the combined organics were washed with brine (10 ml), dried over MgS0 ₄ , filtered and concentrated in vacuo to yield the title compound as a viscous yellow oil (220 mg, 60%).

1H NMR (500 MHz, Chloroform-d) δ 8.09 (dd, J = 4.8, 1.6 Hz, 1H), 7.39 (dd, J = 7.7, 1.6 Hz, 1H), 6.96 (dd, J = 7.7, 4.8 Hz, 1H), 3.61 - 3.57 (m, 4H), 3.23 - 3.16 (m, 4H), 2.43 (s, 3H), 1.48 (s, 9H).

LCMS Method 4 - Tr = 1.84 min (ES+) (M+H)+ 310

[Intermediate 19] - tert-Butyl 4-(3-methanesulfinylpyridin-2-yl)piperazine-l-carboxylate

[00300] Prepared analogously to the method of [Intermediate 14] from [Intermediate 18] to yield the title compound as a viscous yellow oil (230 mg, 67%).

1H NMR (500 MHz, Chloroform-d) δ 8.38 (dd, J = 4.8, 1.8 Hz, 1H), 8.26 - 8.22 (m, 1H), 7.20 (dd, J = 7.7, 4.8 Hz, 1H), 3.64 - 3.56 (m, 2H), 3.52 - 3.46 (m, 2H), 3.38 (ddd, J = 10.4, 7.0, 3.0 Hz, 2H), 3.11 - 3.05 (m, 2H), 2.81 (s, 3H), 1.48 (s, 9H).

LCMS Method 4 - Tr = 1.50 min (ES+) (M+H)+ 326

[Intermediate 20] - tert-Butyl 4-{3-[imino(methyl)oxo- ⁶ -sulfanyl]pyridin-2-yl}piperazine-l- carboxylate

[00301] Prepared analogously to the method of [Intermediate 11] from [Intermediate 19] to yield the title compound as a yellow oil (80 mg, 26%).

1H NMR (250 MHz, Chloroform-d) δ 8.52 (dd, J = 4.8, 1.9 Hz, 1H), 8.35 (dd, J = 7.9, 1.9 Hz, 1H), 7.26 - 7.20 (m, 1H), 3.64 - 3.57 (m, 4H), 3.38 (s, 3H), 3.28 - 3.22 (m, 4H), 3.04 (s, 1H), 1.48 (s, 9H).

LCMS Method 4 - Tr = 1.46 min (ES+) (M+H)+ 341

[Intermediate 21] - tert-Butyl 4-(6-cyanopyridin-2-yl)piperazine-l-carboxylate

[00302] 6-Chloropyridine-2-carbonitrile (250 mg, 1.8 mmol) and tert-butyl (2S)-2- methylpiperazine-l-carboxylate (433 mg, 2.17 mmol) were added to a reaction tube with DIPEA (377 μΐ, 2.17 mmol) in DMF (2.5 ml). The tube was then sealed and the reaction stirred at 80 °C for 20 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (25 ml) and sat aq NaHCCb (25 ml). The organics were separated and the aqueous phase extracted with EtOAc (2 x 20 ml). The combined organics were washed with water (20 ml), brine (20 ml), dried over MgS0 ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a yellow oil (321 mg, 51 %).

1H MR (500 MHz, Chloroform-d) δ 7.51 (dd, J = 8.8, 7.2 Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.32 (s, 1H), 4.11 (s, 1H), 4.03 - 3.88 (m, 2H), 3.36 - 3.19 (m, 2H), 3.11 - 2.98 (m, 1H), 1.48 (s,9H), 1.17 (d, J = 6.7 Hz, 3H).

LCMS Method 2 - Tr = 1.23 min (ES+) (M+H)+ 288.0

[Intermediate 22] - tert-Butyl 4-(4-methyl-l,3-oxazol-2-yl)piperazine-l-carboxylate

[00303] tert-Butyl 4-cyanopiperazine-l-carboxylate (515 mg, 2.44 mmol) and K2CO3 (371 mg, 2.68 mmol) were suspended in anhydrous l-hydroxypropan-2-one (5 ml) under nitrogen and heated at 75 °C via microwave irradiation for 3 min. The reaction was then concentrated in vacuo and the residue was purified via flash column chromatography (heptane / MTBE, 0% to 100%) MTBE). The fractions containing product were combined and concentrated in vacuo. The residue obtained was repurified via column chromatography (DCM / MeOH, gradient from 0% to 1%> MeOH). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a white solid (210 mg, 20 %).

1H MR (500 MHz, Chloroform-d) δ 6.95 (d, J = 1.4 Hz, 1H), 3.54 - 3.42 (m, 11H), 3.21 - 3.17 (m, 3H), 2.06 (d, J = 1.3 Hz, 3H), 1.47 (s, 9H), 1.46 (s, 8H).

LCMS Method 8 - Tr = 1.59 min (ES+) (M+H)+ 268.2

[Intermediate 23] - 2-Chloro-5-fluoro-6-methylpyridine-3-carbonitrile

[00304] 2,6-Dichloro-5-fluoropyridine-3-carbonitrile (250 mg, 1.31 mmol), methylboronic acid (78 mg, 1.31 mmol), PdCl2(dppf) (48 mg, 0.07 mmol) and sodium carbonate (416 mg, 3.93 mmol) were suspended in 2: 1 DMF / H ₂ 0 (6 ml) and the mixture was stirred at 80 °C for 4 hours. The reaction was filtered through Celite and washed with EtOAc (20 ml). To the filtrate was added water (30 ml). The organics were separated and the aqueous phase extracted with EtOAc (3 x 30 ml). The combined organics were washed with brine (30 ml), dried over MgS0 ₄ , filtered and concentrated in vacuo. The residue was then purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a white solid (24 mg, 11 %).

1H MR (250 MHz, Chloroform-d) δ 7.65 (s, 1H), 2.60 (s, 3H).

LCMS Method 2 - Tr = 0.99 min (ES+) (M+H)+ 143.5

[Intermediate 24] - Tert-Butyl 4-(4-chloro-2-cyano-5-fluorophenyl)piperazine-l-carboxylate

[00305] 4-Chloro-2,5-difluorobenzonitrile (250 mg, 1.44 mmol) and tert-butyl piperazine-1- carboxylate (268 mg, 1.44 mmol) were suspended in DMF (10 ml) under a nitrogen atmosphere. The mixture was stirred and heated at 100 °C via microwave irradiation for 2 hours. The reaction was concentrated in vacuo. The residue was partitioned between water (10 ml) and DCM (10 ml) then the organics were separated and the aqueous phase extracted with DCM (2 x 10 ml). The combined organics were concentrated in vacuo. The residue was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a white solid (69 mg, 14 %).

1H MR (500 MHz, Chloroform-d) δ 7.36 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 6.3 Hz, 1H), 3.65 - 3.61 (m, 4H), 3.11 - 3.07 (m, 4H), 1.48 (s, 9H).

LCMS Method 1 - Tr = 1.38 min (ES+) (M+H)+ 281.3

[Intermediate 25] - tert-Butyl 4-(3,4-difluorophenyl)-3-oxopiperazine-l-carboxylate

[00306] 4-Bromo-l,2-difluorobenzene (146 μΐ, 1.3 mmol), tert-butyl 3-oxopiperazine-l- carboxylate (259 mg, 1.3 mmol), [Pd(allyl)Cl] ₂ (5 mg, 0.01 mmol), JackiePhos (52 mg, 0.06 mmol) and K ₂ C0 ₃ (358 mg, 2.59 mmol) were suspended in nitrogen degassed toluene (10 ml) under a nitrogen atmosphere. 250 mg of 4A molecular sieves were added and the reaction was heated at 125 °C via microwave irradiation for 12 hours. The reaction was diluted with DCM (20 ml) and 10% citric acid (20 ml). The organics were separated and the aqueous phase extracted with DCM (20 ml). The combined organics were washed with sat aq NaHC0 ₃ (20 ml) then concentrated in vacuo to give a yellow solid, which was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give the title compound as a yellow glass (32 mg, 8 %).

1H MR (500 MHz, Chloroform-d) δ 7.17 - 7.01 (m, 2H), 4.25 (s, 2H), 3.81 - 3.76 (m, 2H), 3.73 - 3.68 (m, 2H), 1.50 (s, 9H).

LCMS Method 8 - Tr = 1.62 min (ES+) (M+H)+ 313.2 [Intermediate 26] - Tert-butyl 5-(2-cyanophenyl)-octahydropyrrolo[3,4-c]pyrrole-2- carboxylate

[00307] 2-Fluorobenzonitrile (100 mg, 0.83 mmol) and tert-butyl octahydropyrrolo[3,4- c]pyrrole-2-carboxylate (210 mg, 0.99 mmol) were suspended in DMF (5 ml). DIPEA (172 μΐ, 0.99 mmol) was added and the reaction was stirred and heated at 100 °C via microwave irradiation for 6 hours. The reaction was concentrated in vacuo. The residue was partitioned between DCM (20 ml) and water (20 ml). The organics were separated and the aqueous phase extracted with DCM (2 x 20 ml). The combined organics were concentrated in vacuo to give an orange oil. The oil was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give the title compound as an orange oil (27 mg, 10 %).

1H MR (250 MHz, Chloroform-d) δ 7.44 (dd, J = 7.8, 1.6 Hz, 1H), 7.33 (ddd, J = 8.8, 7.2, 1.7 Hz, 1H), 6.75 - 6.65 (m, 1H), 6.62 (d, J = 8.6 Hz, 1H), 3.79 (d, J = 23.7 Hz, 2H), 3.72 - 3.41 (m, 4H), 3.31 (s, 2H), 3.01 (d, J = 14.5 Hz, 2H), 1.45 (s, 9H).

LCMS Method 1 - Tr = 1.78 min (ES+) (M+H)+ 314.0

[Intermediate 27] - Tert-butyl 3-{[(2-cyanophenyl)methyl]amino}pyrrolidine-l-carboxylate

[00308] 2-Bromobenzonitrile (200 mg, 1.1 mmol), tert-butyl 3-aminopyrrolidine-l-carboxylate (225 mg, 1.21 mmol), Pd ₂ (dba) ₃ (50 mg, 0.05 mmol), XantPhos (64 mg, 0.11 mmol) and NaOtBu (211 mg, 2.2 mmol) were suspended in nitrogen degassed toluene (8 ml) in a reaction tube under nitrogen. The tube was sealed and the stirred mixture was heated at 110 °C for 16 hours. The reaction was filtered through Celite, washed with EtOAc (20 ml), and the filtrate was concentrated in vacuo. The resultant oil was purified via column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give the title compound as a yellow oil (147 mg, 43 %). 1H NMR (250 MHz, Chloroform-d) δ 7.46 - 7.36 (m, 2H), 6.77 - 6.65 (m, 2H), 4.55 (d, J = 6.1 Hz, 1H), 4.18 - 4.02 (m, 1H), 3.84 - 3.69 (m, 1H), 3.64 - 3.41 (m, 2H), 3.27 (s, 1H), 2.35 - 2.17 (m, 1H), 1.93 (s, 1H),1.47 (s, 9H).

LCMS Method 2 - Tr = 1.17 min (ES+) (M+H)+ 188.4

[Intermediate 28] - Tert-butyl 3-[(2-cyanophenyl)amino]azetidine-l-carboxylate

[00309] 2-Bromobenzonitrile (200 mg, 1.1 mmol), tert-butyl 3-aminoazetidine-l-carboxylate (189 mg, 1.1 mmol), Pd ₂ (dba) ₃ (50 mg, 0.05 mmol), XantPhos (64 mg, 0.11 mmol) and NaOtBu (211 mg, 2.2 mmol) were suspended in nitrogen degassed toluene (8 ml) under a nitrogen atmosphere. The mixture was stirred at 110 °C for 16 hours. The reaction mixture was filtered through Celite using EtOAc (20 ml) then the filtrate was concentrated in vacuo. The resultant oil was purified via flash column chromatography (gradient of 0 - 100%) EtOAc in heptane followed by 0-100%) MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give the title compound as a yellow oil (148 mg, 48 %).

1H NMR (250 MHz, Chloroform-d) δ 7.47 - 7.35 (m, 2H), 6.77 (td, J = 7.6, 0.9 Hz, 1H), 6.43 (d, J = 8.4 Hz, 1H), 4.82 (d, J = 4.3 Hz, 1H), 4.39 - 4.20 (m, 3H), 3.87 - 3.75 (m, 2H), 1.46 (s, 9H). LCMS Method 2 - Tr = 1.14 min (ES+) (M+H)+ 174.4

[Intermediate 29] - tert-butyl 4-(6-cyanopyridin-2-yl)piperazine-l-carboxylate

[00310] 6-Bromopyridine-2-carbonitrile (183.55 μΐ, 1.37 mmol), tert-butyl piperazine-1- carboxylate (279.88 mg, 1.5 mmol) and DIPEA (285.54 μΐ, 1.64 mmol) were dissolved in DMF (2.5 ml) then the sealed reaction was heated to 60 °C for 2 hours. The reaction was further heated at 80 °C for 18 hours. The reaction was cooled then diluted with water (10 ml) and 4: 1 EtOAc / heptane (10 ml) then the organics were separated, washed with further water, dried over Na ₂ S04, filtered and concentrated in vacuo to give a yellow powdery residue. The residue was triturated under MTBE and filtered, washing with further MTBE then dried in vacuo to yield the title compound as a pale yellow powder (231 mg, 59%).

1H MR (500 MHz, DMSO-d6) δ 7.72 (dd, J = 8.8, 7.2 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 3.57 - 3.51 (m, 4H), 3.42 (d, J = 5.5 Hz, 4H), 1.42 (s, 9H).

LCMS Method 2 - Tr = 1.18 min (ES+) (M+H ⁺ -*Bu) 233.1

[Intermediate 30] - Tert-butyl N-[l-(2-cyanophenyl)pyrrolidin-3-yl] carbamate

[00311] tert-Butyl N-(pyrrolidin-3-yl)carbamate (185 mg, 0.99 mmol) and 2-fluorobenzonitrile (90 μΐ, 0.83 mmol) were suspended in DMF (5 ml) and DIPEA (173 μΐ, 0.99 mmol). The reaction mixture was heated at 100 °C via microwave irradiation and stirred for 4 hours. The reaction was concentrated in vacuo. The residue was partitioned between DCM (20 ml) and water (20 ml) then the organics were separated and the aqueous phase extracted with DCM (2 x 20 ml). The combined organics were concentrated in vacuo to give an orange oil. The oil was then purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give the title compound as a clear oil (39 mg, 16 %).

1H NMR (250 MHz, Chloroform-d) δ 7.44 (dd, J = 7.8, 1.6 Hz, 1H), 7.33 (ddd, J = 8.8, 7.3, 1.7 Hz, 1H), 6.75 - 6.65 (m, 1H), 6.62 (d, J = 8.7 Hz, 1H), 4.76 (d, J = 6.8 Hz, 1H), 4.33 (s, 1H), 3.79 (dt, J = 10.4, 5.5 Hz,2H), 3.63 (ddd, J = 9.8, 8.0, 5.6 Hz, 1H), 3.43 (dd, J = 10.1, 4.2 Hz, 1H), 2.11 (dtd, J = 69.6, 12.7, 6.3 Hz, 2H), 1.45 (s, 9H).

LCMS Method 1 - Tr = 1.71 min (ES+) (M+H)+ 231.9 tert-Butyl 4-{2-[imino(methyl)oxo- ⁶ -sulfanyl]phenyl}piperazine-l-

[00312] tert-Butyl piperazine-l-carboxylate (516 mg 2.771 mmol) and (2- fluorophenyl)(imino)methyl- -sulfanone [Intermediate 11] (400 mg, 2.309 mmol) were heated at 130 °C within a sealed tube for 3 hours. The cooled reaction was partitioned between water (10 ml) and EtOAc (10 ml). The aqueous phase was extracted with EtOAc (3 x 20 ml) and the combined organics were concentrated in vacuo. The crude brown residue was purified by flash column chromatography eluting with EtOAc in heptane (0% with gradient towards 100%). The desired product was obtained in a methanol flush of the column and these fractions were concentrated in vacuo to afford the title compound as a brown / yellow viscous oil (400 mg, 51%). 1H MR (500 MHz, Chloroform-d) δ 8.04 (dd, J = 7.9, 1.6 Hz, 1H), 7.57 (td, J = 7.7, 1.6 Hz, 1H), 7.38 - 7.32 (m, 2H), 3.49 (s, 4H), 3.42 (s, 3H), 2.99 (d, J = 22.9 Hz, 4H), 1.49 (s, 9H).

LCMS Method 4 - Tr = 1.52 min (ES+) (M+H)+ 340

[Intermediate 32] - Methyl 5-amino-2,4-dimethylbenzoate

[00313] Methyl 2,4-dimethyl-5-nitrobenzoate (2 g, 9.56 mmol) was suspended in a mixture of 4: 1 ethanol / water (60 ml) then ammonium chloride (0.56 g, 10.52 mmol) and iron powder (1.87 g, 33.46 mmol) were added and the reaction was stirred at 80 °C for 1 hour. The mixture was cooled to room temperature and filtered through Celite, using EtOAc. The filtrate was concentrated in vacuo to yield crude title compound as a cream solid (2.171 g, 127%).

1H NMR (250 MHz, DMSO-d6) δ 7.15 (s, 1H), 6.85 (s, 1H), 4.89 (s, 2H), 3.76 (s, 3H), 2.32 (s, 3H), 2.06 (s, 3H).

LCMS Method 2 - Tr = 0.88 min (ES+) (M+H)+ 180.0

[Intermediate 33] - Methyl 2-cyano-3-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}benzoate

[00314] Methyl 3-(bromomethyl)-2-cyanobenzoate (250 mg, 0.98 mmol) and 2-(piperazin-l- yl)benzonitrile [Amine 72] (203 mg, 1.08 mmol) were dissolved in acetone (5 ml) then K2CO3 (163 mg, 1.18 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction was diluted with water (20 ml) which caused a precipitate to form. The suspension was filtered and the precipitate collected and purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and the solvents removed in vacuo to yield the title compound as a white solid (341 mg, 89 %).

1H NMR (500 MHz, DMSO-d6) δ 7.77 (t, J = 7.7 Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.62 - 7.57 (m, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.45 (t, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 3.78 (s, 4H), 3.61 (s, 2H), 3.48 (s, 2H), 3.17 (s, 4H), 2.67 - 2.64 (m, 4H), 2.53 - 2.52 (m, 2H), 2.30 (s, 3H). LCMS Method 1 - Tr = 0.91 min (ES+) (M+H)+ 361.5

[Intermediate 34] - 2-Cyano-3-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}benzoic acid

[00315] To a solution of methyl 2-cyano-3-{[4-(2-cyanophenyl)piperazin-l- yl]methyl}benzoate [Intermediate 33] (340 mg, 0.93 mmol) in THF (5 ml) was added lithium hydroxide (2M aq) (0.71 ml). The reaction mixture was stirred at 65 °C for 30 min.

The reaction was cooled to room temperature then an equivolume of hydrochloric acid (2M, 0.71ml) was added followed by water (5 ml). DCM (10 ml) was then added, causing a precipitate to form. The mixture was triturated and filtered to yield the title compound as a white solid (193 mg, 59 %).

1H MR (500 MHz, Methanol-d4) δ 8.35 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H), 7.71 (dd, J = 7.7, 1.4 Hz, 1H), 7.69 - 7.62 (m, 1H), 7.30 - 7.19 (m, 2H), 4.73 (s, 2H), 3.62 (s, 4H), 3.57 - 3.37 (m, 4H).

LCMS Method 1 - Tr = 0.79 min (ES+) (M+H)+ 347.4

[Intermediate 35] - Methyl 5-formyl-2-methylbenzoate

[00316] 5-Formyl-2-methylbenzoic acid (500 mg, 3.05 mmol) was suspended in methanol (5 ml) then sulfuric acid (162.34 μΐ, 3.05 mmol) was added and the sealed reaction was heated to 100 °C for 2 hours. The bulk of the methanol was removed in vacuo then the residue was taken up in 3 :2 acetone / HC1 (1M aq) (20 ml) and agitated for 1 hour. The reaction mixture was extracted with DCM (20 ml) then the organics were dried over Na ₂ S04, filtered and concentrated in vacuo to yield the title compound as a pale yellow powder (536 mg, 99%).

1H NMR (500 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.00 (dd, J = 7.9, 1.8 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 3.88 (s, 3H), 2.62 (s, 3H).

LCMS Method 2 - Tr = 1.00 min (ES+) (M+H ⁺ ) 179.25

[Intermediate 36] - 3-(Methoxycarbonyl)-4-methylbenzoic acid

[00317] Methyl 5-formyl-2-methylbenzoate [Intermediate 35] (268 mg, 1.5 mmol) was dissolved in DMF (5 ml) then Oxone (1.110 g, 1.8 mmol) was added and the reaction was stirred at ambient temperature for 18 hours. The reaction was diluted with EtOAc (10 ml) followed by aq HC1 (0.5 M, 20 ml) then the organics were separated, dried over Na ₂ S04, filtered and concentrated in vacuo to give the title compound as an off-white powder (247 mg, 85%).

1H NMR (500 MHz, DMSO-d6) δ 8.38 (d, J

(d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 2.59 (s, 3H).

[Intermediate 37] 4-Methyl-3-[4-(6-methylpyridin-2-yl)piperazine-l- carbonyljbenzaldehyde

[00318] 3-(Methoxycarbonyl)-4-methylbenzoic acid [Intermediate 36] (247 mg, 1.27 mmol), 2-(piperazin-l-yl)benzonitrile [Amine 72] (234.97 μΐ, 1.4 mmol) and HATU (580.38 mg, 1.53 mmol) were suspended in DMF (5 ml) then the reaction was stirred at ambient temperature for 3 hours. Further HATU (100 mg, 0.26 mmol) was added and the reaction was stirred for a further 1 hour. The reaction was then partitioned between 4: 1 EtOAC / heptane (30 ml) and water (30 ml) then the organic layer was separated, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified via flash chromatography using gradients from heptane to EtOAc followed by EtOAc to methanol to yield the title compound as a white powder (285 mg, 44%).

LCMS Method 2 - Tr = 1.12 min (ES+) (M+H ⁺ ) 364.1

[Intermediate 38] - 5-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-2-methylbenzoic acid

[00319] Methyl 5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2-methylbenzoate [Intermediate 37] (285 mg, 0.78 mmol) was dissolved in tetrahydrofuran (2.5 ml) then lithium hydroxide (2M aq) (529.35 μΐ) was added and the reaction was heated to 65 °C for 18 hours. The reaction was diluted with water (20 ml) and an equivolume of hydrochloric acid (2M, 529.35 μΐ) then briefly stirred before extraction with DCM (20 ml). The organics were dried over Na ₂ S04, filtered and concentrated in vacuo. The residue was purified via flash chromatography using gradients from heptane to EtOAc followed by EtOAc to methanol to yield the title compound as a white powdery solid (170 mg, 58%).

LCMS Method 2 - Tr = 1.07 min (ES+) (M+H ⁺ ) 350.1

[Intermdiate 39] - Methyl 4-methyl-3-(4-phenylpiperazine-l-carbonyl)benzoate

[00320] To a suspension of 5-(methoxycarbonyl)-2-methylbenzoic acid (48 mg, 0.247 mmol) and HATU (103 mg, 0.271 mmol) in DMF (1 ml) was added DIPEA (132 μΐ, 0.740 mmol) and the resultant solution was stirred at room temperature for 1 hour. 1-Phenylpiperazine [Amine 71] (40 mg, 0.247 mmol) was then added and the reaction was stirred at room temperature for 3 hours. The crude reaction mixture was loaded onto an SCX-2 cartridge. The column was washed with 1 : 1 DCM / MeOH (30 ml) then the product was eluted with 7N NH ₃ in MeOH (30 ml) which was concentrated in vacuo to afford the title compound as a yellow oil (88 mg, 82%).

1H MR (500 MHz, Chloroform-d) δ 8.01 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 7.8, 1.9 Hz, 1H), 7.34 - 7.27 (m, 3H), 6.96 - 6.90 (m, 3H), 4.00 - 3.84 (m, 5H), 3.72 - 3.51 (m, 2H), 3.33 - 3.06 (m, 4H), 2.64 (s, 3H).

LCMS Method 2 - Tr = 1.15 min (ES+) (M+H)+ 339.5

[Intermediate 40] - Methyl 3-[4-(2-cyanophenyl)piperazine-l-carbonyl]-4-methylbenzoate

[00321] The title compound was synthesised from [Amine 72] using the method described above for [Intermediate 39] to yield the title compound as a yellow oil (90 mg, 87%).

LCMS Method 2 - Tr = 1.13 min (ES+) (M+H)+ 364

[Intermediate 41] - 4-Methyl-3-(4-phenylpiperazine-l-carbonyl)benzoic acid

[00322] A suspension of methyl 4-methyl-3-(4-phenylpiperazine-l-carbonyl)benzoate [Intermediate 39] (90 mg, 0.27 mmol) and lithium hydroxide monohydrate (156 mg, 3.72 mmol) in 3 : 1 methanol and water (10 ml) was heated at 50 °C for 30 min. The cooled reaction was acidified to pH 4 using citric acid (2M aq) (-20 ml). EtOAc (20 ml) was added and the phases were separated. The aqueous was extracted with EtOAc (3 x 20 ml) and the combined organics were washed with brine, dried (MgS0 ₄ ) and filtered. The filtrate was concentrated in vacuo to afford the title compound as a tan solid (100 mg, 96 %).

lH MR (500 MHz, Chloroform-i ) δ 8.13 (d, J= 1.8 Hz, 1H), 7.55 (dd, J= 7.8, 1.9 Hz, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.31 - 7.27 (m, 2H), 6.97 - 6.90 (m, 3H), 4.10 - 3.81 (m, 2H), 3.72 - 3.52 (m,

2H), 3.35 - 3.06 (m, 4H), 2.68 (s, 3H).

LCMS Method 2 - Tr = 1.02 min (ES+) (M+H)+ 325.5

[Intermediate 42] - 3-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-4-methylbenzoic acid

[00323] The title compound was synthesised from [Intermediate 40] using the method described above for [Intermediate 41] to yield the crude title compound as a tan solid (180 mg, 141%).

1H MR (500 MHz, Chloroform-i ) δ 8.12 (d, J = 1.9 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.57 - 7.50 (m, 2H), 7.35 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 0.9 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 4.04 (d, J = 26.7 Hz, 2H), 3.70 (s, 2H), 3.30 - 3.13 (m, 4H), 2.68 (s, 3H).

LCMS Method 2 - Tr = 1.02 min (ES+) (M+H)+ 350

[Intermediate 43] (5-{[4-(2-Chlorophenyl)piperazin-l-yl]methyl}-2- methylphenyl)methanol

[00324] 5-{[4-(2-Chlorophenyl)piperazin-l-yl]methyl}-2-methylbenzoic acid (150 mg, 0.43 mmol) [Intermediate B] was suspended in anhydrous tetrahydrofuran (2.5 ml) in a sealed tube, then borane (1M in THF, 870 μΐ) was added and the reaction was stirred at ambient temperature for 5 minutes, pressure equalised then heated to 65 °C for 3 hours. A further aliquot of borane (1M in THF, 1.5 ml) was added then the reaction was stirred at ambient temperature for 10 mins, pressure equalised then heated to 70 °C for 3 hours. The reaction was added to 1 : 1 sat aq H ₄ C1 / water (30 ml) then the solution was extracted with DCM (30 ml). The organics were dried over Na ₂ S04, filtered and concentrated in vacuo then purified via flash chromatography eluting using gradients from heptane to EtOAc and then from EtOAc to methanol to yield the title compound as a pale tan gel (50 mg, 35%).

1H NMR (500 MHz, DMSO-d6) δ 7.39 (dd, J = 7.9, 1.4 Hz, 1H), 7.32 (s, 1H), 7.30 - 7.26 (m, 1H), 7.15 (dd, J = 8.1, 1.4 Hz, 1H), 7.08 (s, 2H), 7.04 - 7.00 (m, 1H), 5.07 (t, J = 5.3 Hz, 1H), 4.48 (d, J = 5.1 Hz, 2H), 3.49 (s, 2H), 2.96 (s, 4H), 2.52 (d, J = 1.8 Hz, 4H), 2.21 (s, 3H).

[Intermediate 44] - l-{[3-(Chloromethyl)-4-methylphenyl]methyl}-4-(2- chlorophenyl)piperazine

[00325] (5-{[4-(2-Chlorophenyl)piperazin-l-yl]methyl}-2-methylphenyl )methanol

[Intermediate 43] (50 mg, 0.15 mmol) was dissolved in thionyl chloride (500 μΐ) within a sealed tube then the reaction was heated to 70 °C for 2 hours. The reaction was diluted with DCM (10 ml) then added slowly to sat aq NaHC0 ₃ (20 ml) (effervescence) then the biphasic solution was agitated for 10 mins. The organics were separated and concentrated in vacuo to yield the crude title compound. (59 mg, 110%).

1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.58 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.44 (dd, J = 7.9, 1.4 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.19 (dd, J = 8.1, 1.4 Hz, 1H), 7.13 - 7.08 (m, 1H), 4.81 (s, 2H), 4.39 (d, J = 5.1 Hz, 2H), 3.42 (d, J = 11.3 Hz, 4H), 3.21 (q, J = 9.6 Hz, 2H), 3.06 (t, J = 11.5 Hz, 2H), 2.41 (s, 3H).

[Intermediate 45] - Methyl l-hydroxy-2,3-dihydro-lH-indene-4-carboxylate

[00326] Methyl l-oxo-2,3-dihydro-lH-indene-4-carboxylate (600 mg, 3.15 mmol) was dissolved in EtOH (25ml). The reaction mixture was cooled to 0 °C. Sodium borohydride (240 mg, 6.34 mmol) was added and the reaction mixture was stirred at 0 °C for 30 min. The reaction was warmed to room temperature and stirred for 2 hours. The reaction mixture was added dropwise to sat aq NaHCCb. The quenched reaction was extracted with EtOAc (2 x 20 ml). The organics were washed with brine, dried (MgS0 ₄ ) filtered and concentrated in vacuo to yield the title compound as an orange oil (600 mg, 84 %).

1H NMR (500 MHz, Chloroform-d) δ 7.98 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 5.35 - 5.22 (m, 1H), 3.93 (s, 3H), 3.56 - 3.42 (m, 1H), 3.26 - 3.08 (m, 1H), 2.62 - 2.47 (m, 1H), 2.03 - 1.94 (m, 1H), 1.71 (s, 1H).

LCMS Method 4 - Tr = 3.59 min (ES+) (M+H)+ 192.2

[Intermediate 46] - Methyl l-chloro-2,3-dihydro-lH-indene-4-carboxylate

[00327] Methyl l-hydroxy-2,3-dihydro-lH-indene-4-carboxylate [Intermediate 45] (600 mg, 3.1 mmol) was dissolved in CHCh. The reaction was cooled to 0 °C. Thionyl dichloride (340 μΐ, 4.7 mmol) was added dropwise over 1 min then the reaction mixture was stirred at 0 °C for 2 hours. The reaction was reduced in vacuo and loaded onto a pre-packed silica gel column (10 g) then the column was eluted with CHCb. The fractions containing product were combined and reduced in vacuo to yield the title compound as a straw coloured oil. (550 mg, 75 %)

1H NMR (250 MHz, Chloroform-d) δ 8.00 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.7 Hz, 1H), 5.46 (dd, J = 6.8, 3.5 Hz, 1H), 3.94 (s, 3H), 3.66 - 3.20 (m, 2H), 2.76 - 2.55 (m, 1H), 2.54 - 2.34 (m, 1H).

[Intermediate 47] - Methyl l-[4-(2-chlorophenyl)piperazin-l-yl]-2,3-dihydro-lH-indene-4 - carboxylate

[00328] Methyl l-chloro-2,3-dihydro-lH-indene-4-carboxylate [Intermediate 46] (250 mg, 1.2 mmol), l-(2-chlorophenyl)piperazine hydrochloride [Amine 82] (304 mg, 1.3 mmol) and DIPEA (1000 μΐ, 5.7 mmol) were suspended in DMF (1 ml). The reaction mixture was heated at 50 °C for 4 hours. The reaction mixture was stirred at room temperature over the weekend. The reaction was loaded onto a silica gel pre-packed column (lOg) and was eluted from 0% EtOAc to 100% EtOAc in heptane. The fractions containing product were combined and reduced in vacuo to yield the title compound as an orange oil. (260 mg, 56 %).

1H MR (500 MHz, Chloroform-d) δ 7.85 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.27 (dd, J = 7.9, 1.5 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.17 - 7.11 (m, 1H), 6.97 (dd, J = 8.1, 1.5 Hz, 1H), 6.88 (td, J = 7.6, 1.5 Hz, 1H), 4.37 - 4.30 (m, 1H), 3.83 (s, 3H), 3.34 - 3.23 (m, 1H), 3.17 - 3.07 (m, 1H), 3.04 - 2.95 (m, 4H), 2.70 - 2.51 (m, 4H), 2.21 - 2.00 (m, 2H).

LCMS Method 4 - Tr = 2.12 min (ES+) (M+H)+ 371.2

[Intermediate 48] - Methyl l-[4-(2-cyanophenyl)piperazin-l-yl]-2,3-dihydro-lH-indene-4- carboxylate

[00329] The title compound was synthesised from 2-(piperazin-l-yl)benzonitrile [Amine 72] and methyl l-chloro-2,3-dihydro-lH-indene-4-carboxylate [Intermediate 46] using the method described for [Intermediate 47] to yield the title compound as a yellow solid (260 mg, 55 %). 1H MR (500 MHz, Chloroform-d) δ 7.85 (d, J = 7.7 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.40 (td, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.95 - 6.88 (m, 2H), 4.34 (dd, 1H), 3.83 (s, 3H), 3.34 - 3.22 (m, 1H), 3.19 - 3.13 (m, 4H), 3.13 - 3.06 (m, 1H), 2.72 - 2.51 (m, 4H), 2.18 - 1.98 (m, 2H).

LCMS Method 4 - Tr = 1.88 min (ES+) (M+H)+ 362.3 l-[4-(2-Chlorophenyl)piperazin-l-yl]-2,3-dihydro-lH-indene-4 -

[00330] Methyl l-[4-(2-chlorophenyl)piperazin-l-yl]-2,3-dihydro-lH-indene-4 -carboxylate [Intermediate 47] (260 mg, 0.67 mmol) was suspended in MeOH (5 ml). Li OH (2M aq, 2 ml) was added and the reaction mixture was heated at 40 °C for 3 hours. The reaction mixture was left to stand overnight then the reaction was acidified to pH 1-2 with HCl (2M aq) and extracted with DCM (x 2). The organics were dried (MgS0 ₄ ) filtered and reduced in vacuo to yield the title compound as an off white solid (220 mg, 88 %).

lH MR (500 MHz, Chloroform-d)□ 13.10 (s, 1H), 8.58 (d, J = 7.7 Hz, 1H), 8.19 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.40 (dd, J = 7.9, 1.4 Hz, 1H), 7.28 (td, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.09 (td, 1H), 5.13 - 5.07 (m, 1H), 4.11 - 4.00 (m, 1H), 3.80 - 3.70 (m, 1H), 3.64 - 3.58 (m, 1H), 3.57 - 3.50 (m, 2H), 3.47 - 3.36 (m, 2H), 3.36 - 3.27 (m, 1H), 3.24 - 3.12 (m, 2H), 2.73 - 2.53 (m, 2H).

LCMS Method 4 - Tr = 1.21 min (ES+) (M+H)+ 357.2 l-[4-(2-Cyanophenyl)piperazin-l-yl]-2,3-dihydro-lH-indene-4-

[00331] The title compound was synthesised from methyl l-[4-(2-cyanophenyl)piperazin-l-yl]- 2,3-dihydro-lH-indene-4-carboxylate [Intermediate 48] using the method described for [Intermediate 49] to yield the title compound as an off-white solid (220 mg, 93%) .

1H MR (500 MHz, Chloroform-d) δ 13.17 (s, 1H), 8.55 (d, J = 7.7 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.62 (dd, J = 7.7, 1.5 Hz, 1H), 7.59 - 7.51 (m, 2H), 7.20 - 7.12 (m, 2H), 5.13 - 5.05 (m, 1H), 4.16 - 4.07 (m, 1H), 3.88 - 3.79 (m, 1H), 3.69 - 3.59 (m, 1H), 3.57 - 3.47 (m, 4H), 3.31 - 3.10 (m, 3H), 2.71 - 2.54 (m, 2H).

LCMS Method 4 - Tr = 1.16 min (ES+) (M+H)+ 348.3

2-(4-{[3-(Hydroxymethyl)-4-methylphenyl]methyl}piperazin- l-

[00332] Step 1. 5-{[4-(2-Cyanophenyl)piperazin-l-yl]methyl}-2-methylbenzoic acid (250 mg, 0.75 mmol) [Intermediate A] was suspended in tetrahydrofuran (anhydrous) (5 ml) with DIPEA (155.8 μΐ, 0.89 mmol) and cooled with an ice-bath for the addition of thionyl chloride (59.8 μΐ, 0.82 mmol) then stirred for 30 mins at ambient temperature. A further aliquot of thionyl chloride (20 μΐ, 0.54 mmol) was added and the reaction mixture was stirred for a further 30 mins to yield 5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2-methylbenzoyl chloride in solution.

Step 2. To the solution of 5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2-methylbenzoyl chloride, LiBH ₄ was sequentially added until the acid chloride was consumed (in total 121.75 mg, 5.6 mmol). The reaction mixture was partitioned between DCM (10 ml) and water (10 ml) and stirred for 5 mins, then the organics were separated, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was purified via flash chromatography using gradients from heptane to EtOAc followed by EtOAc to methanol to yield the title compound as a pale yellow glass (84 mg, 28 %).

1H NMR (500 MHz, DMSO-d6) δ 7.68 (dd, J = 7.6, 1.5 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.32 (s, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.12 - 7.06 (m, 3H), 5.07 (t, J = 5.3 Hz, 1H), 4.49 (d, J = 5.1 Hz, 2H), 3.50 (s, 2H), 3.16 - 3.10 (m, 4H), 2.55 (d, J = 4.4 Hz, 4H), 2.22 (s, 3H).

LCMS Method 2 - Tr = 0.85 min (ES+) (M+H ⁺ ) 322.2

[Intermediate 52] - 2-(4-{[3-(Chloromethyl)-4-methylphenyl]methyl}piperazin-l- yl)benzonitrile

[00333] 2-(4-{[3-(Hydroxymethyl)-4-methylphenyl]methyl}piperazin-l-y l)benzonitrile

[Intermediate 51] (84 mg, 0.26 mmol) was dissolved in dichloromethane (2.5 ml) then DIPEA (59.18 μΐ, 0.34 mmol) was added followed by the addition of thionyl chloride (22.75 μΐ, 0.31 mmol) then the reaction was stirred at ambient temperature for 3 hours. Further dichloromethane (3 ml) and thionyl chloride (10 μΐ, 0.15 mmol) were required to push the reaction to completion. The reaction mixture was diluted with water (5 ml) and sat aq NaHCCb (2 ml) then the organics were separated and concentrated in vacuo to yield the title compound as a pale yellow glass (54 mg, 61%).

LCMS Method 2 - Tr = 0.95 min (ES+) (M+H ⁺ ) 340.15 / 342.15

[Intermediate 53] - 2-{4-[3-(Hydroxymethyl)-4-methylbenzoyl]piperazin-l-yl}benzo nitrile

[00334] 5-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-2-methylbenzoic acid [Intermediate 38]

(150 mg, 0.43 mmol) was dissolved in anhydrous tetrahydrofuran (3 ml) then carbonyl diimidazole (83.54 mg, 0.52 mmol) was added and the reaction was stirred for 2 hours. LiBH ₄ (28.05 mg, 1.29 mmol) was added and the reaction was stirred for 30 minutes. The reaction was partitioned between DCM (5 ml) and sat aq H4CI (3 ml) then the organics were separated and concentrated in vacuo. The residue was purified via flash chromatography using gradients from heptane to EtOAc followed by EtOAc to methanol to yield the title compound as a white crystalline solid (58 mg, 40%).

LCMS Method 2 - Tr = 1.01 min (ES+) (M+H ⁺ ) 336.15 [Intermediate 54] - Methyl 5-(hydroxymethyl)-2-methylbenzoate

[00335] Methyl 5-formyl-2-methylbenzoate [Intermediate 35] (367 mg, 2.06 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) then borane (1M in THF, 4.32 ml) was added and the reaction was stirred at ambient temperature for 4 hours. The reaction was partitioned between 1 : 1 sat aq H4CI / water (10 ml) and DCM (10 ml) then the organics were separated, dried over Na ₂ S04, filtered and concentrated in vacuo to yield the title compound as a light yellow oil (387 mg, 95%).

1H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J = 1.5 Hz, 1H), 7.40 (dd, J = 7.8, 1.7 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 5.26 (t, J = 5.7 Hz, 1H), 4.49 (d, J = 5.7 Hz, 2H), 3.82 (s, 3H), 2.48 (s, 3H). LCMS Method 2 - Tr = 0.90 min (ES+) (M+H ⁺ ) 163.35

[Intermediate 55] - Methyl 5-(chloromethyl)-2-methylbenzoate

[00336] Methyl 5-(hydroxymethyl)-2-methylbenzoate [Intermediate 54] (387 mg, 2.15 mmol) was dissolved in thionyl chloride (2.5 ml) (effervescence) then the reaction was heated to 70 °C for 1 hour. The reaction was concentrated in vacuo then the residue was diluted with DCM (5 ml) and sat aq NaHC0 ₃ (5 ml) and the reaction mixture was agitated for 10 mins. The organics were separated and concentrated in vacuo to yield the title compound as a yellow oil (384 mg, 90%). 1H NMR (500 MHz, DMSO-d6) δ 7.88 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 7.8, 1.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 4.78 (s, 2H), 3.83 (s, 3H), 2.50 (s, 3H).

LCMS Method 2 - Tr = 1.20 min (ES+) (M+H ⁺ ) 198.9 / 200.9

[Intermediate 56] - Methyl 5-{[4-(2-cyanophenyl)-2-oxopiperazin-l-yl]methyl}-2- methylbenzoate

[00337] Methyl 5-(chloromethyl)-2-methylbenzoate [Intermediate 55] (384 mg, 1.93 mmol) and 2-(3-oxopiperazin-l-yl)benzonitrile [Amine 74] (466.78 mg, 2.32 mmol) were dissolved in DMF (4 ml) then sodium hydride (60% dispersion in mineral oil) (104.38 mg, 2.61 mmol) was added and the reaction was stirred at ambient temperature for 1.5 hours. The reaction was partitioned between 4: 1 EtOAc / heptane (20 ml) and water (20 ml) then the organics were separated, washed with further water then dried over Na ₂ S04, filtered and concentrated in vacuo. The residue was purified via flash chromatography using gradients from heptane to EtOAc followed by EtOAc to methanol to yield the title compound as a pale yellow glass (327 mg, 43%). 1H MR (500 MHz, DMSO-d6) δ 7.78 (d, J = 1.8 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 7.9, 1.8 Hz, 1H), 7.31 (dd, J = 8.1, 5.8 Hz, 2H), 7.27 - 7.22 (m, 1H), 6.98 - 6.92 (m, 1H), 5.68 (s, 2H), 4.70 (s, 2H), 4.09 - 4.04 (m, 2H), 3.81 (s, 3H), 3.66 - 3.59 (m, 2H).

LCMS Method 2 - Tr = 1.15 min (ES+) (M+H ⁺ ) 364.45

[Intermediate 57] - 5-{[4-(2-Cyanophenyl)-2-oxopiperazin-l-yl]methyl}-2-methylbe nzoic acid

[00338] Methyl 5-{[4-(2-cyanophenyl)-2-oxopiperazin-l-yl]methyl}-2-methylbe nzoate [Intermediate 56] (327 mg, 0.9 mmol) was suspended in tetrahydrofuran (5 ml) then lithium hydroxide (2M aq, 607 μΐ) was added along with methanol 200.0 μΐ) and the reaction was heated for 18 hours. Further lithium hydroxide (2M aq, 350 μΐ) was required for complete conversion after heating for a further 8 hours. The reaction was cooled then an equivolume of hydrochloric acid (2M, 957 μΐ) was added followed by water (10 ml) and DCM (10 ml). The organics were separated, dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to yield the title compound as a brown glass (376 mg, 111%).

LCMS Method 2 - Tr = 1.02 min (ES+) (M+H ⁺ ) 350.05

[Intermediate 5-{[4-(2-Cyano-4-fluorophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoic

[00339] 5-Formyl-2,4-dimethylbenzoic acid (40 mg, 0.22 mmol) and 5-fluoro-2-(piperazin-l- yl)benzonitrile [Amine 5] (50 mg, 0.25 mmol) were suspended in DCM (1 ml) and stirred at room temperature for 1 hour. NaBH(OAc) ₃ (119 mg, 0.56 mmol) was then added and the reaction was stirred for 18 hours. The reaction mixture was then diluted with water (10 ml) and DCM (10 ml). The organics were separated and the aqueous phase extracted with DCM (10 ml). The combined organics were dried over MgS0 ₄ , filtered and concentrated in vacuo. The resultant residue was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and the solvents removed in vacuo to yield the title compound as a white solid (55 mg, 66%).

1H MR (250 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.31 - 7.26 (m, 1H), 7.25 - 7.16 (m, 1H), 7.09 - 6.98 (m, 2H), 3.73 (s, 2H), 3.32 - 3.23 (m, 4H), 2.94 - 2.84 (m, 4H), 2.59 (s, 3H), 2.40 (s, 3H). LCMS Method 1 - Tr = 0.91 min (ES+) (M+H)+ 368.1

[Intermediate 59] - 2-(4-Hydroxypiperidin-l-yl)benzonitrile

[00340] A suspension of 2-fluorobenzonitrile (1.00 g, 8.257 mmol), piperidin-4-ol (1.25 g, 12.39 mmol) and K ₂ C0 ₃ (2.28 g, 16.51 mmol) in DMF (10 ml) was heated at 130 °C for 18 hours. The cooled reaction mixture was diluted with water (30 ml) and EtOAc (30 ml) then the phases were separated. The aqueous phase was extracted with EtOAc (3 x 30 ml) and the combined organics were washed with brine (3 x 20 ml), dried (MgS0 ₄ ) and filtered. The filtrate was concentrated in vacuo to yield the title compound as a brown viscous oil (1.80 g, 97%).

1H MR (500 MHz, Chloroform-d) δ 7.54 (dd, J = 7.7, 1.5 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 3.90 (tt, J = 8.0, 3.9 Hz, 1H), 3.46 (dt, J = 10.4, 4.2 Hz, 2H), 3.01 (ddd, J = 12.1, 9.0, 3.0 Hz, 2H), 2.07 (ddt, J = 12.3, 6.3, 3.2 Hz, 2H), 1.80 (dtd, J = 12.6, 8.6, 3.6 Hz, 2H).

LCMS Method 3 - Tr = 1.39 min (ES+) (M+H)+ 203

[Intermediate 60] - {[4-(2-Cyanophenyl)piperazin-l-ium-l-yl]methyl}trifluorobora te

[00341] Potassium bromomethyltrifluoroborate (1.61 g, 8 mmol) was added to a solution of 2- (piperazin-l-yl)benzonitrile [Amine 72] (1.57g, 8.4 mmol) in THF (12 ml) at 20 °C under nitrogen, and the mixture heated and stirred at 80 °C in a sealed tube for 6 hours. The resulting reaction mixture was concentrated in vacuo. The product was dissolved in a solution of dry acetone (250 ml), K2CO3 (1.11 g, 8 mmol) was added and the reaction was stirred for 30 min. The solution was filtered through a pad of Celite to remove the insoluble salts, and the filtrate was concentrated in vacuo. The crude solid was dissolved in a minimal amount of hot acetone (30 ml) and MTBE (90 ml) was slowly added; crystallisation of the product occurred very slowly and was left overnight. The suspension was filtered, washing with minimal MTBE and the retained solid was dried in vacuo to yield the title compound as a white crystalline powder (1.56 g, 67%).

1H MR (250 MHz, DMSO-d6) δ 7.85 - 7.65 (m, 1H), 7.68 - 7.58 (m, 1H), 7.27 - 7.09 (m, 2H), 3.24 (s, 8H), 2.03 (q, J = 4.8 Hz, 2H).

LCMS Method 2 - Tr = 1.11 min (ES+) (M+H)+ 248.05

[Intermediate 61] - Ethyl 6-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-3,5- dimethylpyrazine-2-carboxylate

[00342] Ethyl 6-chloro-3,5-dimethylpyrazine-2-carboxylate was prepared by the method of P. Johannesson et al (J. Med. Chem. 2012, 55, 10610-10629)

A solution of {[4-(2-cyanophenyl)piperazin-l-ium-l-yl]methyl}trifluorobora te [Intermediate 60] (148 mg, 0.55 mmol), Cs ₂ C0 ₃ (489 mg, 1.5 mmol), XPhos (14 mg, 0.06 mmol) and ethyl 6-chloro- 3,5-dimethylpyrazine-2-carboxylate (107 mg, 0.5 mmol) in cyclopentyl methyl ether (2.5 ml) and H ₂ 0 (0.5 ml) was stirred and degassed with nitrogen. The yellow mixture was treated with Pd(OAc) ₂ (4 mg, 0.03 mmol) and further degassed with nitrogen to give a red organic layer. The mixture was heated under a nitrogen atmosphere in a sealed tube at 100 °C for 17 hours. The mixture was diluted with MTBE, washed with water, dried (Na ₂ S0 ₄ ), concentrated in vacuo and the residue triturated with 2: 1 cyclohexane / MTBE to yield the title compound as a cream solid (185 mg, 88%).

LCMS Method 2 - Tr = 0.86 min (ES+) (M+H)+ 380.60

1H MR (250 MHz, Chloroform-d) δ 7.69 - 7.43 (m, 2H), 7.16 - 6.95 (m, 2H), 4.48 (q, J = 7.2 Hz, 2H), 3.82 (s, 2H), 3.58 - 3.39 (m, 2H), 3.29 - 3.19 (m, 4H), 3.16 - 2.94 (m, 2H), 2.79 (s, 3H), 2.72 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H).

[Intermediate 62] - Lithium 6-{[4-(2-Cyanophenyl)piperazin-l-yl]methyl}-3,5- dimethylpyrazine-2-carboxylate

[00343] To a mixture of ethyl 6-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-3,5- dimethylpyrazine-2-carboxylate [Intermediate 61] (185 mg, 0.49 mmol) in 1 :4 H ₂ 0 / MeOH (10 ml) was added LiOH H ₂ 0 (51 mg, 1.22 mmol). The reaction was stirred at 50 °C for 1 hour and evaporated to dryness to yield the title compound as a white solid (186 mg, 96%).

LCMS Method 2 - Tr = 0.79 min (ES+) (M+H)+ 352.55

[Intermediate 63] - 5-{[4-(2-Cyano-4,5-difluorophenyl)piperazin-l-yl]methyl}-2,4 - dimethylbenzoic acid

[00344] 4,5-Difluoro-2-(piperazin-l-yl)benzonitrile hydrochloride [Amine 6] (80 mg, 0.31 mmol), 5-formyl-2,4-dimethylbenzoic acid (50 mg, 0.28 mmol) and DIPEA (147 μΐ, 0.84 mmol) were suspended in DCM (1 ml) and stirred at room temperature for 30 min. NaBH(OAc) ₃ (148.68 mg, 0.7 mmol) was then added and the reaction was stirred for 5 further hours. The reaction was partitioned between DCM (20 ml) and citric acid (10% aq, 20 ml). The organics were separated and the aqueous extracted with DCM (20 ml). The combined organics were washed with sat aq NaHC0 ₃ (20 ml), dried over MgS0 ₄ and concentrated in vacuo to yield the title compound as a yellow solid (104 mg, 96%).

1H MR (250 MHz, Chloroform-d) δ 7.78 (s, 1H), 7.36 - 7.27 (m, 2H), 6.90 (s, 1H), 6.70 (dd, J = 12.0, 7.0 Hz, 1H), 3.39 (s, 2H), 3.04 (s, 4H), 2.58 (s, 4H), 2.41 (s, 3H), 2.28 (s, 3H).

LCMS Method 2 - Tr = 1.27 min (ES+) (M+H ⁺ ) 386.2

[Intermediate 64] - Methyl 5-hydroxy-2-methylbenzoate

[00345] To a solution of 5-hydroxy-2-methylbenzoic acid (750 mg, 4.93 mmol) in methanol (20 ml) at room temperature was dropwise added acetyl chloride (1.94 g, 24.65 mmol) and the reaction was heated at 80 °C for 2 hours. The reaction mixture was cooled to room temperature and then concentrated in vacuo to afford the title compound as a brown solid (750 mg, 91%). 1H MR (250 MHz, Chloroform-i ) δ 7.41 (d, J= 2.8 Hz, 1H), 7.10 (d, J= 8.3 Hz, 1H), 6.91 (dd, J= 8.3, 2.8 Hz, 1H), 3.88 (s, 3H), 2.50 (s, 3H).

LCMS Method 2 - Tr = 0.94 min (ES+) (M+H)+ 166.9

[Intermediate 65] - 5-Hydroxy-2,4-dimethylbenzoic acid

Prepared by the method of Adediran Cabaret et al. Journal of Organic Chemistry (1999) 64, 3,

713-720.

[00346] To a stirred solution of methyl 5-amino-2,4-dimethylbenzoate [Intermediate 32] (250 mg, 1.39 mmol) in 20% sulfuric acid (aq) (10 ml) at 0 °C was added a solution of NaN0 ₂ (115 mg, 1.67 mmol) in water (5 ml). Cone sulfuric acid (8 ml) was then added. The resultant solution was then added to boiling 50% aq sulfuric acid (30 ml) at 100 °C. The reaction mixture was stirred for 10 min then poured over ice and extracted with EtOAc. The organics were concentrated in vacuo then purified via flash column chromatography using 9: 1 DCM/MeOH. The fractions containing product were combined and the solvents removed in vacuo to yield the title compound (151 mg, 65%).

1H MR (250 MHz, Methanol-d4) δ 7.36 (s, 1H), 6.98 (s, 1H), 2.46 (s, 3H), 2.21 (s, 3H). [Intermediate 66] - 2-[4-(5-Hydroxy-2,4-dimethylbenzoyl)piperazin-l-yl]benzonitr ile

[00347] 5-Hydroxy-2,4-dimethylbenzoic acid [Intermediate 65] (151 mg, 0.91 mmol) and HATU (414 mg, 1.09 mmol) were suspended in DMF (5 ml) and stirred at room temperature for 20 min. 2-(Piperazin-l-yl)benzonitrile [Amine 72] (187 mg, 1 mmol) and DIPEA (475 μΐ, 2.7 mmol) were then added and the reaction was stirred for 16 hours. The reaction was concentrated in vacuo. The residue was partitioned between DCM (20 ml) and water (20 ml) then the organics were separated and the aqueous phase extracted with DCM (2 x 20 ml). The combined organics were concentrated in vacuo then the residue was purified via flash column chromatography (gradient of 0 - 100% EtOAc in heptane followed by 0-100% MeOH in EtOAc). The fractions containing product were combined and concentrated in vacuo to give a yellow solid. The solid was then loaded onto the UV Direct High pH preparative HPLC system. The fractions containing product were collected and the solvents removed in vacuo to yield the title compound as a yellow solid (56 mg, 18%).

1H MR (250 MHz, Chloroform-d) δ 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.56 - 7.47 (m, 1H), 7.07 (t, J = 7.2 Hz, 1H), 7.01 (s, 1H), 6.89 (s, 1H), 6.64 - 6.56 (m, 2H), 4.02 (d, J = 40.6 Hz, 2H), 3.48 (t, J = 4.9 Hz, 2H),3.32 - 3.17 (m, 2H), 3.13 - 3.01 (m, 2H), 2.19 (s, 3H), 2.15 (s, 3H).

LCMS Method 8 - Tr = 1.61 min (ES+) (M+H)+ 336.2

[Intermediate 67] - 2-{4-[l,3-Dioxo-2-(triphenylmethyl)-2,3-dihydro-lH-isoindole -5- carbonyl]piperazin-l-yl}benzonitrile

[00348] l,3-Dioxo-2-(triphenylmethyl)-2,3-dihydro-lH-isoindole-5-car boxylic acid (prepared by the method of H. Glatz, W. Bannwarth et al. (Tetrahedron Letters 44 (2003) 149-152), 433 mg, 1 mmol) was dissolved in dry DMF (10 ml) under nitrogen. DIPEA (536 μΐ, 3 mmol), 2- (piperazin-l-yl)benzonitrile [Amine 72] (187 mg, 1 mmol) and HATU (418 mg, 1.1 mmol) were then added and the reaction was stirred at room temperature for 2 hours then heated at 50 °C overnight. The reaction mixture was concentrated in vacuo. The residue was suspended in DCM (10 ml) and filtered. The filtrate was concentrated in vacuo and purified via flash column chromatography using a gradient from DCM to 35% MTBE in DCM to yield the title product as a white solid (299 mg, 50%). 1H NMR (500 MHz, Chloroform-d) δ 7.82 (dd, J = 7.6, 0.6 Hz, 1H), 7.79 - 7.76 (m, 1H), 7.74 (dd, J = 7.6, 1.3 Hz, 1H), 7.60 (dd, J = 7.7, 1.5 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.49 - 7.43 (m, 6H), 7.33 - 7.25 (m, 6H), 7.24 - 7.18 (m, 3H), 7.09 (td, J = 7.6, 0.8 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 4.03 - 3.81 (m, 2H), 3.64 - 3.41 (m, 2H), 3.29 - 2.95 (m, 4H).

LCMS Method 2 - Tr = 1.42 min (ES+) (M+Na)+ 625.20

2-[4-(l,3-Dioxo-2,3-dihydro-lH-isoindole-5-carbonyl)piper azin-l-

[00349] 2-{4-[l,3-Dioxo-2-(triphenylmethyl)-2,3-dihydro-lH-isoindole -5-carbonyl]piperazin- l-yl}benzonitrile [Intermediate 67] (240 mg, 0.4 mmol) was dissolved in DCM (1 ml) under nitrogen. Triethylsilane (70 μΐ, 0.55 mmol) was added followed by TFA (1 ml) then the reaction was stirred for 2 minutes and the clear, very pale yellow solution allowed to stand for 4 days. The reaction was concentrated in vacuo gave a residue which was diigested with 2 x 3 ml cyclohexane at 80 °C. The gummy insolubles were warmed with 2 ml EtOAc to give a white solid which was collected and washed with the same solvent then dried under vacuum to yield the title compound as a white solid (69 mg, 48%).

1H NMR (500 MHz, DMSO-d6) δ 11.49 (s, 1H), 7.99 - 7.83 (m, 3H), 7.74 (dd, J = 7.7, 1.5 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.95 - 3.75 (m, 2H), 3.60 - 3.45 (m, 2H), 3.30 - 3.04 (m, 4H).

LCMS Method 2 - Tr = 1.02 min (ES+) (M+H)+ 361.1

[Intermediate 69] - 2-[4-(3-Hydroxy-l-oxo-2,3-dihydro-lH-isoindole-5-carbonyl)pi perazin- l-yl]benzonitrile

[00350] 2-[4-(l,3-Dioxo-2,3-dihydro-lH-isoindole-5-carbonyl)piperazi n-l-yl]benzonitrile [Intermediate 68] (60 mg, 0.17 mmol) was added in six portions over 30 minutes to a stirred suspension of zinc powder (14.2 mg, 0.22 mmol) and copper (II) sulfate pentahydrate (60 mg, 0.25 mmol) in NaOH (2M aq, 0.42 ml) at 0°C. The mixture was stirred at 0 °C for an additional 30 minutes, diluted with ethanol (0.42 ml) and stirred at room temperature for 2.5 hours. The reaction was neutralized to pH 7 with hydrochloric acid (1M aq), diluted with methanol (2 ml) and filtered. The solids were washed with EtOAc and the combined organics were concentrated in vacuo to yield the crude title compound as a pale yellow gum (68 mg, 90%). Product was a mixture of regioisomers.

LCMS Method 2 - Tr = 0.90 min (ES+) (M+H)+ 363.05

[Intermediate 70] - 2-[4-(3-Chloro-l-oxo-2,3-dihydro-lH-isoindole-5-carbonyl)pip erazin-l- yljbenzonitrile

[00351] 2-[4-(3-Hydroxy-l-oxo-2,3-dihydro-lH-isoindole-5-carbonyl)pi perazin-l- yljbenzonitrile [Intermediate 69] (60 mg, 0.17 mmol) was suspended in DCM (1 ml) then thionyl chloride (0.2 ml) was added at 0 °C. After stirring overnight at 20 °C the cream suspension was evaporated in vacuo below 30 °C to yield the crude title compound as a white solid (60 mg, 95%) as a mixture of its regioisomer. The product was used immediately without further purification or characterisation.

[Intermediate 71] - 5-[4-(2-Cyanophenyl)piperazine-l-carbothioyl]-2,4-dimethylbe nzoic acid

[00352] 5-Formyl-2,4-dimethylbenzoic acid (150 mg, 0.84 mmol), 2-(piperazin-l- yl)benzonitrile [Amine 72] (282 μΐ, 1.68 mmol) and sulfur (216 mg, 0.84 mmol) were suspended in N-methyl pyrrolidine (2.5 ml) then the reaction was subjected to microwave irradiation (120 °C, 20 mins, 100W, 200PSI). The reaction was poured into water (20 ml) then the reaction was filtered, washing with further water. The retained solid was taken up in 9: 1 DCM/MeOH then filtered. The filtrate was concentrated in vacuo then the residue was taken up in MeCN and the resultant suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified via flash column chromatography using a gradient of MeOH in DCM (0% to 10%) to yield the title compound as a dark purple oil (113 mg, 25%).

LCMS Method 2 - Tr = 1.13 min (ES+) (M+H+) 380.05

[Intermediate 72] - Tert-butyl N-[(2-fluorophenyl)(methyl)oxo- ⁶ -sulfanylidene] carbamate

[00353] l-Fluoro-2-methanesulfinylbenzene [Intermediate 10] (5 g, 31.61 mmol), tert-butyl carbamate (7.4 g, 63.21 mmol), magnesium oxide (5.1 g, 126.4 mmol) and rhodium (II) acetate (419 mg, 0.95 mmol) were suspended in DCM (20 ml) then (diacetoxyiodo)benzene (20.4 g, 63.2 mmol) was added portionwise and the reaction was stirred at room temperature for 18 hours. The reaction was filtered through a sintered glass funnel and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography eluting with EtOAc in heptane (0% with a gradient towards 100%). The fractions containing product were concentrated in vacuo to yield the title compound as a pale yellow oil (6.5 g, 60%).

1H NMR (250 MHz, Chloroform-d) δ 8.12 - 7.87 (m, 1H), 7.74 - 7.60 (m, 1H), 7.42 - 7.33 (m, 1H), 7.30 - 7.19 (m, 1H), 3.40 - 3.31 (m, 3H), 1.37 - 1.30 (m, 9H).

LCMS Method 4 - Tr = 2.14 min (ES+) (M+H)+ 274

[Intermediate 73] - tert-butyl N-[methyl(oxo)[2-(piperazin-l-yl)phj sulfanylidene] carbamate

[00354] Tert-butyl N-[(2-fluorophenyl)(methyl)oxo- ⁶ -sulfanylidene]carbamate

[Intermediate 72] (6.5 g, 19.0 mmol) and piperazine (6.55 g, 76.1 mmol) were heated neat in a pressure tube at 110 °C for 18 hours. The reaction mixture was cooled to room temperature and then dissolved in water (20 ml) and EtOAc (20 ml). The phases were separated and the aqueous phase was extracted with EtOAc (3 x 20 ml). The combined organics were washed with brine (2 x 30 ml) and then concentrated in vacuo to afford a viscous pale brown oil. The crude material was purified by flash column chromatography eluting first with EtOAc in heptane (0% with gradient towards 100%), then methanol in EtOAc, (0% with gradient towards 100%). The fractions containing product were combined and concentrated in vacuo to afford a pale yellow viscous oil. DCM (5 ml) was added and the mixture subjected to sonication. Traces of residual piperazine were filtered off and the filtrate was concentrated in vacuo to give a clear pale yellow viscous oil. The material was dried in a vacuum oven to yield the title compound as a pale yellow glass (4.5 g, 68%).

1H NMR (500 MHz, Chloroform-d) δ 8.14 (dd, J = 8.0, 1.5 Hz, 1H), 7.64 (td, J = 7.9, 1.5 Hz, 1H), 7.45 (dd, J = 8.0, 0.9 Hz, 1H), 7.42 - 7.37 (m, 1H), 3.56 (s, 3H), 3.16 - 3.07 (m, 4H), 3.07 - 3.01 (m, 2H), 2.92 - 2.81 (m, 2H), 1.39 (s, 9H).

LCMS Method 2 - Tr = 0.77 min (ES+) (M+H)+ 340 [Intermediate 74] - tert-Butyl N-({2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]phenyl}(methyl)oxo- ⁶ -sulfanylidene)carbamate

[00355] To a suspension of 5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4-dimethylbenz oic acid [Intermediate C] (204 mg, 0.58 mmol) and HATU (306 mg, 0.80 mmol) in DMF (2 ml) was added DIPEA (391 μΐ, 2.19 mmol) and the resultant solution was stirred at 50 °C for 1 hour. tert- Butyl N-[methyl(oxo)[2-(piperazin-l-yl)phenyl]- ⁶ -sulfanylidene]carbamate [Intermediate 73] (310 mg, 0.91 mmol) was then added and the reaction was stirred at 50 °C for 18 hours. The reaction was directly submitted for open access preparative HPLC (basic pH). The fractions containing product were concentrated in vacuo and the residue was oven-dried under vacuum to afford the title compound as an off-white glass (190 mg, 39%, 100% purity by 7 min LCMS). lH MR (500 MHz, Chloroform-d) δ 8.15 (dd, J = 8.2, 1.4 Hz, 1H), 7.66 (td, J = 7.8, 1.5 Hz, 1H), 7.56 - 7.52 (m, 1H), 7.49 - 7.40 (m, 3H), 7.12 (s, 1H), 7.04 (s, 1H), 7.01 - 6.96 (m, 2H), 3.63 - 3.24 (m, 8H), 3.24 - 2.71 (m, 9H), 2.70 - 2.62 (m, 4H), 2.36 (s, 3H), 2.30 (s, 3H), 1.37 (s, 9H). LCMS Method 6 - Tr = 4.32 min (ES+) (M+H)+ 671

[Intermediate 75] - 2-(4-Oxopiperidin-l-yl)benzonitrile

[00356] To a solution of 2-(4-hydroxypiperidin-l-yl)benzonitrile [Intermediate 59] (300 mg, 1.48 mmol) in DCM (5 ml) at 0 °C was added Dess-Martin periodinane (944 mg, 2.23 mmol) and the reaction was stirred at room temperature for 2 hours. NaOH (2M aq, 10 ml) was added to the reaction mixture with stirring for 10 min. DCM (10 ml) was added and the phases separated. The aqueous phase was extracted with DCM (3 x 15 ml) and the combined organic extracts were washed with brine (30 ml) and then concentrated in vacuo to yield the title compound as a brown viscous oil (300 mg, 72%).

1H MR (500 MHz, Chloroform-d) δ 7.61 (dd, J = 7.7, 1.6 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.09 - 7.04 (m, 2H), 3.52 (t, J = 6.1 Hz, 4H), 2.69 (t, J = 6.1 Hz, 4H).

LCMS Method 4 - Tr = 1.49 min (ES+) (M+H)+ 201

[Intermediate 76] - 2,4-Dimethyl-5-{[(2S)-2-methyl-4-phenylpiperazin-l-yl]methyl }benzoic acid

[00357] To a suspension of 5-formyl-2,4-dimethylbenzoic acid (250 mg, 1.403 mmol) and 2- [(3S)-3-methylpiperazin-l-yl]benzonitrile [Amine 9] (282 mg, 1.40 mmol) in DCM (3 ml) was added NaBH(OAc) ₃ (892 mg, 4.21 mmol) and the reaction was stirred at room temperature for 18 hours. Water (5 ml) and DCM (5 ml) were added and the phases were separated. The aqueous phase was extracted with DCM (3 x 10 ml) and the combined organics were concentrated in vacuo. The residue was purified by flash column chromatography eluting with a gradient of EtOAc in heptane (0% to 100%). The fractions containing product were combined and concentrated in vacuo, followed by oven drying to afford to the title compound as a white solid (100 mg, 10%). lH MR (500 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.46 (td, J = 8.1, 1.6 Hz, 1H), 7.06 (s, 1H), 7.03 - 6.95 (m, 2H), 4.12 (d, J = 13.1 Hz, 1H), 3.42 (d, J = 11.2 Hz, 1H), 3.31 - 3.25 (m, 2H), 3.09 (d, J = 9.2 Hz, 1H), 3.01 (dd, J = 11.5, 8.3 Hz, 1H), 2.96 - 2.88 (m, 1H), 2.85 (ddd, J = 11.3, 4.6, 2.7 Hz, 1H), 2.59 (s, 3H), 2.51 - 2.44 (m, 1H), 2.41 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H).

LCMS Method 2 - Tr = 1.31 min (ES+) (M+H)+ 364

[Intermediate 77] - 2-{4-[(3-Hydroxy-4-methylphenyl)methyl]piperazin-l-yl}benzon itrile

[00358] 3-Hydroxy-4-methylbenzaldehyde (204.2 mg, 1.500 mmol) and 2-(piperazin-l- yl)benzonitrile [Amine 72] (294.9 mg, 1.575 mmol) were dissolved in DCM (12 ml) and stirred at room temperature for 30 min. NaBH(OAc) ₃ (636 mg, 3.0 mmol) was then added and the mixture stirred for 18 hours. The reaction mixture was stirred with water (10 ml) and NaHC0 ₃ added until pH 8.4 was achieved then the aqueous was extracted with DCM (2 x 10 ml). The organic layer was dried (MgS0 ₄ ) and concentrated in vacuo to yield the title compound as a cream solid (531 mg, 98%).

1H MR (500 MHz, Chloroform-d) δ 7.48 (dd, J = 7.9, 1.6 Hz, 1H), 7.42 - 7.37 (m, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.92 (dd, J = 7.7, 6.0 Hz, 2H), 6.81 - 6.68 (m, 2H), 3.45 (s, 2H), 3.20 - 3.15 (m, 4H), 2.65 - 2.52 (m, 4H), 2.16 (s, 3H).

LCMS Method 2 - Tr = 0.85 min (ES+) (M+H ⁺ ) 308

[Intermediate 78] - Methyl 5-formyl-2,4-dimethylbenzoate

[00359] The title compound was prepared analogously to the method of [Intermediate 35] from 5-formyl-2,4-dimethylbenzoic acid (250 mg, 1.4 mmol) to yield the title compound as a pale yellow solid (234 mg, 87%).

1H MR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.29 (s, 1H), 7.34 (s, 1H), 3.85 (s, 3H), 2.63 (s, 4H), 2.57 (s, 3H).

LCMS Method 2 - Tr = 1.08 min (ES+) (M+H ⁺ ) 193

[Intermediate 79] - Methyl 5-(hydroxymethyl)-2,4-dimethylbenzoate

[00360] Methyl 5-formyl-2,4-dimethylbenzoate [Intermediate 78] (234 mg, 1.22 mmol) was dissolved in anhydrous tetrahydrofuran (4 ml) then borane (1M in THF, 2.56 ml) was added and the reaction was heated to 60 °C for 1 hour. Further addition of borane (1M in THF, 0.50 ml) and heating for 1 further hour was required for complete conversion. The reaction was partitioned between DCM (20 ml) and sat aq H4CI (20 ml) then the organics were separated, dried over Na ₂ S04, filtered and concentrated in vacuo. The residue was purified via flash column chromatography using gradients from heptane to EtOAc then from EtOAc to MeOH. The fractions containing product were concentrated in vacuo to yield the title compound as a white crystalline solid (162 mg, 69%).

1H MR (500 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.10 (s, 1H), 5.15 (t, J = 5.4 Hz, 1H), 4.48 (d, J = 5.3 Hz, 2H), 3.81 (s, 3H), 2.47 (s, 3H), 2.24 (s, 3H).

LCMS Method 2 - Tr = 1.00 min (ES+) (M+H+) 177

[Intermediate 80] - Methyl 5-(chloromethyl)-2,4-dimethylbenzoate

[00361] Methyl 5-(hydroxymethyl)-2,4-dimethylbenzoate [Intermediate 79] (162 mg, 0.83 mmol) was dissolved in tetrahydrofuran (2 ml) then DIPEA (218 μΐ, 1.25 mmol) was added followed by the addition of thionyl chloride (72.6 μΐ, 1 mmol) then the reaction was stirred at ambient temperature for 1 hour. The reaction was diluted with DCM (20 ml) and sat aq NaHCCb (15 ml) then the organics were separated and concentrated in vacuo to yield the title compound as a brown oil (180 mg, 93%).

1H MR (500 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.22 (s, 1H), 4.83 (s, 2H), 3.82 (s, 3H), 2.50 (s, 3H), 2.40 (s, 3H).

LCMS Method 2 - Tr = 1.21 min (ES+) (M+H+) 213 / 215 Methyl 5-{[4-(2-cyanophenyl)-2-oxopiperazin-l-yl]methyl}

[00362] Methyl 5-(chloromethyl)-2,4-dimethylbenzoate [Intermediate 80] (180 mg, 0.85 mmol) and 2-(3-oxopiperazin-l-yl)benzonitrile [Amine 74] (187 mg, 0.93 mmol) were dissolved in DMF (5 ml) then sodium hydride (60% dispersion in mineral oil) (40.62 mg, 1.02 mmol) was added and the reaction was stirred for 1 hour. The reaction was partitioned between DCM (20 ml) and water (10 ml) then the organics were separated and concentrated in vacuo. The residue was purified via reverse phase flash column chromatography using a gradient of MeCN in water (5%> to 100%)). The fractions containing product were combined and concentrated in vacuo to remove the bulk of the organics then the aqueous was extracted with DCM (30 ml) which was dried (Na ₂ S04), filtered and concentrated in vacuo yield the title compound as a light orange crystalline solid (124 mg, 39%).

1H MR (500 MHz, DMSO-d6) δ 7.75 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.28 - 7.22 (m, 1H), 7.18 (s, 1H), 6.96 (t, J = 7.5 Hz, 1H), 5.69 (s, 2H), 4.70 (s, 2H), 4.09 - 4.01 (m, 2H), 3.77 (s, 3H), 3.61 - 3.51 (m, 2H), 2.48 (s, 3H), 2.32 (s, 3H).

LCMS Method 2 - Tr = 1.14 min (ES+) (M+H+) 378

[Intermediate 82] - 5-{[4-(2-Cyanophenyl)-2-oxopiperazin-l-yl]methyl}-2,4-dimeth ylbenzoic acid

[00363] Methyl 5-{[4-(2-cyanophenyl)-2-oxopiperazin-l-yl]methyl}-2,4-dimeth ylbenzoate [Intermediate 81] (124 mg, 0.33 mmol) was dissolved in tetrahydrofuran (5 ml) then lithium hydroxide (2M aq, 222 μΐ) was added and the reaction was heated at 65 °C for 3 hours. A few drops of MeOH and further lithium hydroxide (2M aq) (221.75 μΐ) were added then the reaction was heated at 70 °C for 24 hours. The reaction was cooled then diluted with hydrochloric acid (2M aq, 444 μΐ) and left to stand for 15 minutes, then DCM (15 ml) was added and the organics were separated and dried with Na ₂ S04, then filtered and concentrated in vacuo to yield the title compound as an orange solid (143 mg, 93%).

1H MR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.15 (s, 1H), 6.96 (t, J = 7.4 Hz, 1H), 5.69 (s, 2H), 4.70 (s, 2H), 4.10 - 4.01 (m, 2H), 3.60 - 3.53 (m, 2H), 2.49 (s, 3H), 2.32 (s, 3H).

LCMS Method 2 - Tr = 1.06 min (ES+) (M+H+) 364

[Intermediate 83] - 5-((4-(2-Cyano henyl)piperazin-l-yl)methyl)-2,4-dimethylbenzoic acid

Syn hetic scheme:

Procedures and characterization:

Step 1: 5-Bromo-2,4-dimethylbenzoic acid:

[00364] A mixture of 2,4-dimethylbenzoic acid (4.5 g, 30 mmol) and BS (5.34 g, 30 mmol) in TFA (100 mL) was stirred at 50 °C for 16 h. The solvent was removed in vacuo and the resulting residue was purified by recrystallization using EtOAc twice to afford 5-bromo-2,4- dimethylbenzoic acid (5.36 g, 23.4 mmol, 78%) as a white solid. ESI-MS (EI ⁺ , m/z): 229 [M+H] ⁺ . ¹ H MR (500 MHz, CDCb): 8.23 (s, 1H), 7.15 (s, 1H), 2.57 (s, 3H), 2.42 (s, 3H).

Step 2: 5-Formyl-2,4-dimethylbenzoic acid:

[00365] To a solution of 5-bromo-2,4-dimethylbenzoic acid (5.34 g, 23.4 mmol) in THF (200 mL) was added «-BuLi (hexane, 2.5 M) (23.4 mL, 58.5 mmol) dropwise at -78 °C. After 1 h, DMF (6.49 g, 88.92 mmol) was added to the mixture and the reaction mixture was allowed to stir for another 3 h. H ₂ 0 (5 mL) was added to quench the reaction. The pH was adjusted to 3-4 using aq. HC1 (6 M). The mixture was extracted with EtOAc (3 x 400 mL), and the organic layers were concentrated then purified by chromatography (silica, EtOAc/PE = 1/1) to afford 5-formyl-2,4- dimethylbenzoic acid (2.13 g, 11.9 mmol, 51%) as a white solid. ESI-MS (EI ⁺ , m/z): 179.1 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb): δ 10.21 (s, 1H), 8.50 (s, 1H), 7.20 (s, 1H), 2.71 (s, 3H), 2.70 (s, 3H).

Step 3: 5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid:

[00366] To a solution of 5-formyl-2,4-dimethyl-benzoic acid (6.00 g, 33.67 mmol) and 2- piperazin-l-ylbenzonitrile (7.57 g, 40.41 mmol) in AcOH (0.3 mL) and EtOH (50 mL) was added NaC BH ₃ (3.17 g, 50.51 mmol) with ice-bath. After 20 h stirring at 20 °C, the reaction mixture was filtered. The filter cake was washed with EtOAc (50 mL) and dried to afford 5-[[4-(2- cyanophenyl)piperazin-l-yl]methyl]-2,4-dimethyl-benzoic acid (6.00 g, 17.19 mmol, 51%) as a white solid.

[00367] ESI-MS (EI ⁺ , m/z): 350.3 [M+H] ⁺ . ¾ MR (500 MHz, DMSO-^e) δ 7.74 (s, 1H), 7.70 (dd, J= 7.7, 1.5 Hz, 1H), 7.63-7.56 (t, 1H), 7.16 (d, J= 8.2 Hz, 1H), 7.13-7.06 (m, 2H), 3.51 (s, 2H), 3.13 (s, 4H), 2.56 (s, 4H), 2.48 (s, 3H), 2.36 (s, 3H).

[Intermediate 84] - 5-(Chlorosulfonyl)-2,4-dimethylbenzoic acid

[00368] 2,4-Dimethylbenzoic acid (1.50 g 1 mmol) was added in portions with stirring to chlorosulfonic acid (5 ml) at 20 °C . The reaction was stirred at 70-75 °C overnight. The reaction was added dropwise with stirring to ~200g ice / water. The beige precipitate was collected and washed well with water with filtration. The solid was taken up in ethyl acetate, dried over Na ₂ S04, filtered and concentrated in vacuo to yield the title compound as a pale grey solid (2.36g, 90%). 1H MR (500 MHz, Chloroform-d) δ 8.76 (s, 1H), 7.38 (s, 1H), 2.83 (s, 3H), 2.76 (s, 3H).

[Intermediate 85] - 2,4-Dimethyl-5-sulfinobenzoic acid

[00369] 5-(Chlorosulfonyl)-2,4-dimethylbenzoic acid (248 mg) was added in portions to a stirred suspension of sodium sulphite (277 mg) in water (1 ml). 2M. aq. Sodium hydroxide (1 ml) was then added dropwise till the reaction mixture was pH ~9. The reaction mixture was stirred for 18 h at rt to give a very pale brown solution. The solution was acidified to pH 1 by addition of 4M. aq. HC1 and after 10 minutes the suspension was cooled in ice and the solid collected by filtration to yield the title compound as a white solid. (232 mg, 99%)

LCMS Method 2 - Tr = 0.73 min (ES ⁺ ) (M+H ⁺ ) 215

[Intermediate 86] - l-(2-Cyanophenyl)piperidin-4-yl methanesulfonate

[00370] 2-(4-Hydroxypiperidin-l-yl)benzonitrile (1.01 g, 5 mmol) was dissolved in anhydrous DCM (5 ml) under nitrogen atmosphere. DIPEA (1.05 ml, 6 mmol) was added and the reaction was cooled to 0 °C. Methanesulfonyl chloride (0.387 mL, 2.635 mmol) was added dropwise. The reaction was stirred at 20 °C overnight, then the reaction was partitioned with water (60 ml), then extracted with MTBE (3 x 40 ml), washed with water, brine, dried over Na ₂ S0 ₄ filtered and concentrated in vacuo to yield the title compound as a pale grey oil (1.38 g, 91%). 1H NMR (500 MHz, Chloroform-d) δ 7.62 - 7.53 (m, 1H), 7.53 - 7.44 (m, 1H), 7.07 - 6.99 (m, 2H), 4.98 - 4.92 (m, 1H), 3.44 - 3.37 (m, 2H), 3.19 - 3.11 (m, 2H), 3.06 (s, 3H), 2.26 - 2.17 (m, 2H), 2.17 - 2.09 (m, 2H).

LCMS Method 2 - Tr = 1.10 min (ES ⁺ ) (M+H ⁺ ) 281

[Intermediate 87] - 5-{[l-(2-Cyanophenyl)piperidin-4-yl]sulfonyl}-2,4-dimethylbe nzoic acid

[00371] 2,4-Dimethyl-5-sulfinobenzoic acid [Intermediate 85] (177 mg, 0.82 mmol) and l-(2- cyanophenyl)piperidin-4-yl methanesulfonate [Intermediate 86] (232 mg, 0.83 mmol) were suspended in anhydrous DMF (5 ml) and stirred under nitrogen atmosphere and DIPEA (0.17 mL, 0.99 mmol) was added. The reaction was then stirred at 100 °C for 17 h. The reaction was concentrated in vacuo then purified by preparative HPLC [Generic UV-Directed low pH prep method] to yield the title compound (6.6 mg, 2%).

LCMS Method 7 - Tr = 3.45 min (ES ⁺ ) (M+H ⁺ ) 399

Final Compounds

Example 1. Synthesis of (S)-2-(4-(5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l- carbonyl)-2,4-dimethylbenz l)piperazin-l-yl)benzonitrile, 1-264

1-264

Synthetic scheme:

Procedures and characterization:

[00372] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- Cyanophenyl)piperazin-l -yl)methyl)-2,4-dimethylbenzoic acid.

The analysis was performed following Method A. Separation was performed following Method D.

Step 1 : (S)-2-(4-(5-(4-(5-Fluoropyridin-2-yl)-2-methylpiperazine-l-c arbonyl)-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile [1-264]

[00373] A mixture of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (100 mg, 0.29 mmol), (<S)-l-(5-fluoropyridin-2-yl)-3-methylpiperazine (67 mg, 0.34 mmol), HATU (163 mg, 0.43 mmol) and DIPEA (111 mg, 0.86 mmol) in DMF (4.00 mL) was stirred at 20 °C for 16 h. The mixture was purified by prep-HPLC to afford (S)-2-(4-(5-(4-(5-fluoropyridin- 2-yl)-2-methylpiperazine- 1 -carbonyl)-2,4-dimethylbenzyl)piperazin- 1 -yl)benzonitrile [1-264] (47 mg, 0.089 mmol, 31%) as product.

[00374] ¾ MR (500 MHz, CDCb) 5 8.03 (d, J= 3.0 Hz, 1H), 7.55 (dd, J= 7.6, 1.3 Hz, 1H), 7.51-7.44 (m, 1H), 7.31-7.23 (m, 1H), 7.21-6.91 (m, 4H), 6.62 (s, 1H), 4.89 (m, 1H), 4.33-2.72 (m, 13H), 2.66 (s, 4H), 2.37 (s, 3H), 2.27 (d, J= 29.2 Hz, 3H), 1.36 (t, J= 14.5 Hz, 2H).

Example 2. Synthesis of 6-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)piperaz -l-yl)-2,3,4-trifluorobenzonitrile, 1-112

1-112

Synthetic scheme:

Procedures and characterization:

[00375] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- Cyanophenyl)piperazin-l -yl)methyl)-2,4-dimethylbenzoic acid.

The analysis was performed following Method A. The separation was performed following Method C.

Step 1: tert-Butyl 4-(3,4,5-trifluorophenyl)piperazine-l-carboxylate

[00376] A solution of 5-bromo-l,2,3-trifluorobenzene (5.0 g, 23.7 mmol), tert-butyl piperazine- 1-carboxylate (5.3 g, 28.4 mmol), t-BuONa (3.4 g, 35.5 mmol), BINAP (300 mg, 0.5 mmol), Pd ₂ (dba)3 (458 mg, 0.5 mmol) in dry toluene (100 mL) was stirred for 17 h at 80 °C. The crude product was purified by chromatography (silica, EtOAc/PE = 1/10) to afford ter/-butyl-4-(3,4,5- trifluorophenyl)piperazine-l-carboxylate (6.0 g, 18.9 mmol, 80%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 261.1 [M-56] ⁺ .

Step 2: tert-Butyl 4-(3,4,5-trifluoro-2-iodophenyl)piperazine-l-carboxylate

[00377] To a solution of tert-butyl-4-(3,4,5-trifluorophenyl)piperazine-l-carboxylate (2.0 g, 6.3 mmol) in EtOH (30 mL) was added Ag ₂ S0 ₄ (1.97 g, 6.3 mmol) and stirred for 5 min at rt. Then I ₂ (1.6 g, 6.3 mmol) was added and stirred for 4 h at rt. The solid was filtered and the filtrate was concentrated. The residue was diluted with EtOAc (20 mL) and washed with aq. Na ₂ S ₂ 0 ₄ . The organic layer was concentrated and then purified by chromatography (silica, EtOAc/PE =1/10) to afford tert-butyl 4-(3,4,5-trifluoro-2-iodophenyl)piperazine-l-carboxylate as a yellow solid (600 mg, 1.35 mmol, 21%). ESI-MS (EI ⁺ , m/z): 387.0 [M-56] ⁺ . Step 3: ieri-Butyl-4-(2-cyano-3,4,5-trifluorophenyl)piperazine-l-car boxylate

[00378] To a solution of tert-butyl-4-(3,4,5-trifluoro-2-iodophenyl)piperazine-l-carb oxylate

(700 mg, 1.58 mmol) in MP (10 mL) was added CuCN (285 mg, 3.1 mmol). The mixture was stirred for 5 h at 160 °C. The mixture was cooled down to rt and extracted with EtOAc. The organic layer was concentrated and the crude product was purified by chromatography (silica,

EtOAc/PE = 1/6) to afford tert-butyl 4-(2-cyano-3,4,5-trifluorophenyl)piperazine-l-carboxylate as a white solid (200 mg, 0.58 mmol, 36%). ESI-MS (EI ⁺ , m/z): 242.1 [M-100] ⁺ .

Step 4: 2,3,4-Trifluoro-6-(piperazin-l-yl)benzonitrile hydrochloride salt

[00379] To a solution of ter/-butyl-4-(2-cyano-3,4,5-trifluorophenyl)piperazine-l-car boxylate

(200 mg, 0.58 mmol) was added 4 M HCl/dioxane (10 mL), then the mixture was stirred for 17 h at rt. The solvent was concentrated to afford to afford crude 2,3,4-trifluoro-6-(piperazin-l- yl)benzonitrile hydrochloride salt (200 mg, 100%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 242.0

[M+H] ⁺ .

Step 5: 6-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4-dimeth ylbenzoyl)piperazin- l-yl)-2,3,4-trifluorobenzonitrile, 1-112

[00380] To a solution of crude 2,3,4-trifluoro-6-(piperazin-l-yl)benzonitrile hydrochloride salt (60 mg, 0.25 mmol), 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (60 mg, 0.17 mmol) in DMF (3 mL) was added HATU (78 mg, 0.2 mmol), and TEA (0.3 mL, 2.0 mmol). The mixture was stirred at rt for 17 h. The solution was purified by prep-HPLC (Method C) to afford 6-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimeth ylbenzoyl)piperazin- l-yl)-2,3,4-trifluorobenzonitrile 1-112 (42.8 mg, 0.07 mmol, 44%) as a white solid.

[00381] ESI-MS (EI ⁺ , m/z): 573.0 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.55 (d, J= 7.5 Hz, 1H), 7.47 (m, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 6.99 (m, 2H), 6.61 (m, 1H), 4.03 (m, 2H), 3.50 (m, 4H), 3.23 (m, 6H), 3.10 (s, 2H), 2.65 (m, 4H), 2.36 (s, 3H), 2.28 (s, 3H).

Example 3. Synthesis of (S)-2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)benzenesulfonamide, 1-39

1-39

Synthetic scheme:

Procedures and characterization:

[00382] General procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

The analysis was performed following Method B. Separation was performed following Method D.

Step 1 : (S)-2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-di methylbenzoyl)-3- methylpiperazin-l-yl)benzenesulfonamide, 1-39

[00383] A mixture of (<S)-2-(3-methylpiperazin-l-yl)benzenesulfonamide hydrochloride (60 mg, 0.206 mmol), 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid hydrochloride (86 mg, 0.247 mmol), EDCIHCl (48 mg, 0.247 mmol), HOBt (34 mg, 0.247 mmol), DIPEA (133 mg, 1.03 mmol), and DMF (3 mL) was stirred at 30 °C for 17 h. The reaction mixture was purified by prep-HPLC to afford (,S)-2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)benzenesulfonamide 1-39 (20.3 mg, 0.035 mmol, 17%) as a white solid. MS (EI ⁺ , m/z): 587.3 [M+H] ⁺ . ¾NMR (500 MHz, CDCb) δ 8.05-8.04 (m, 1H), 7.62-7.59 (m, 1H), 7.56-7.54 (m, 1H), 7.47-7.41 (m, 2H), 7.36-7.34 (m, 1H), 7.12-6.95 (m, 4H), 5.53 (s, 2H), 3.51-3.48 (m, 3H), 3.32-3.27 (m, 2H), 3.19-3.13 (m, 5H), 3.00-2.91 (m, 1H), 2.66 (s, 5H), 2.36-2.17 (m, 6H), 1.30-1.24 (m, 3H). Example 4. Synthesis of (S)-2-(4-(5-(4-(lH-indazol-7-yl)-2-methylpiperazine-l-carbon yl)- 2,4-dimethylbenzyl)piperazin-l- l)benzonitrile, 1-118

1-118

Synthetic scheme:

Procedures and characterization:

[00384] General procedure for Intermediate 83 was followed to obtain 5-((4-(2- Cyanophenyl)piperazin-l -yl)methyl)-2,4-dimethylbenzoic acid (Intermediate 83).

Analysis was performed following Method B. Separation was performed following Method D. Step 1: 7-Bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole

[00385] A mixture of 7-bromo-lH-indazole (400 mg, 2.03 mmol), SEMC1 (404 mg, 2.44 mmol), and K ₂ C0 ₃ (420 mg, 3.05 mmol) in DMF (20 mL) was stirred at 50 °C for 16 h. The mixture was extracted with EtOAc and the organic layer was concentrated to afford 7-bromo-l- ((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole (531 mg, 1.62 mmol, 80%) as product. ESI-MS (EI ⁺ , m/z): 327.1 [M+H] ⁺ . Step 2: (S)-teri-butyl-2-methyl-4-(l-((2-(trimethylsilyl)ethoxy)meth yl)-lH-indazol-7- yl)piperazine-l-carboxylate

[00386] A mixture of 7-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indazole (365 mg, 1.12 mmol), (S)-tert-buty\ 2-methylpiperazine-l-carboxylate (224 mg, 1.12 mmol), t-BuONa (161 mg, 1.68 mmol) BINAP (15 mg, 0.02 mmol), and Pd ₂ (dba) ₃ (8 mg,0.01 mmol) in DMF (10 mL) was stirred at 80 °C for 4 h. The mixture was purified by chromatography (silica, EtOAc/PE = 1/8) to afford (5)-tert-butyl-2-methyl-4-(l-((2-(trimethylsilyl)ethoxy)meth yl)-lH-indazol-7- yl)piperazine-l-carboxylate (135 mg, 0.3 mmol, 27%) as product. ESI-MS (EI ⁺ , m/z): 447.3 [M+H] ⁺ .

Step 3: (S)-ieri-butyl-4-(lH-indazol-7-yl)-2-methylpiperazine-l-carb oxylate

[00387] A mixture of (S)-tert-butyl-2-methyl-4-(l-((2-(trimethylsilyl)ethoxy)meth yl)-lH- indazol-7-yl)piperazine-l -carboxylate (135 mg, 0.3 mmol) in TBAF (1 M, THF) (2 mmol, 2 mL) was stirred at 80 °C for 4 h. The mixture was purified by prep-HPLC to afford (S)-tert-butyl 4- (lH-indazol-7-yl)-2-methylpiperazine-l-carboxylate (80 mg, 0.25 mmol, 85%) as product. ESI- MS (EI ⁺ , m/z): 317.3 [M+H] ⁺ .

Step 4: (S)-7-(3-methylpiperazin-l-yl)-lH-indazole

[00388] To a solution of HC1 (4 N, dioxane) (15 mL) was added (5)-tert-butyl-4-(lH-indazol- 7-yl)-2-methylpiperazine-l-carboxylate (80 mg, 0.25 mmol) with ice-bath cooling. After stirring 16 h at 20 °C, the mixture was concentrated to afford (5)-7-(3-methylpiperazin-l-yl)-lH-indazole (49 mg, 0.23 mmol, 90%). ESI-MS (EI ⁺ , m/z): 217.2 [M+H] ⁺ .

The synthesis of (S)-2-(4-(5-(4-(lH-indazol-7-yl)-2-methylpiperazine-l-carbon yl)-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile 1-118 was the same as Example 35: ESI-MS (EI ⁺ , m/z): 548.3 [M+H] ⁺ . ¾ MR (500 MHz, CDC1 ₃ ) δ 8.08 (s, 1H), 7.56 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.22-7.02 (m, 3H), 6.99 (d, J= 6.7 Hz, 2H), 6.90 (d, J = 8.1 Hz, 1H), 5.00 (m, 1H), 3.46 (m, 5H), 3.20 (m, 5H), 3.00 (m, 2H), 2.67 (s, 4H), 2.37 (s, 3H), 2.30 (s, 3H), 1.51 (s, 3H).

Example 5. Synthesis of 2-(4-(5-(4-(lH-pyrazolo[4,3-c]pyridin-7-yl)piperazine-l-carb onyl)- 2,4-dimethylbenzyl)piperazin-l-yl)benzonitrile 2,2,2-trifluoroacetate, 1-61

1-61

Procedures and characterization:

[00389] General procedure for Intermediate 83 was followed to obtain 5-((4-(2- Cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenzoic acid (Intermediate 83).

Analysis was performed following Method B. Separation was performed following Method C. The procedure was same as Example 4.

2-(4-(5-(4-(lH-pyrazolo[4,3-c]pyridin-7-yl)piperazine-l-carb onyl)-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile 2,2,2-trifluoroacetate, 1-61: ESI-MS (EI ⁺ , m/z):

535.3 [M+H] ⁺ . ¾ NMR (500 MHz, CD ₃ OD) δ 9.17 (s, 1H), 8.62 (s, 1H), 7.88 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.66 (t, J= 7.9 Hz, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.24 (dd, J= 15.4, 7.9 Hz, 2H), 4.51 (s, 2H), 4.11 (m, 2H), 3.58 (m, 15H), 2.54 (s, 3H), 2.39 (s, 3H).

Example 6. Synthesis of (S)-2-(4-(2,4-dimethyl-5-(2-methyl-4-(l-methyl-lH-indazol-7- yl)piperazine-l-carbonyl)benz l)piperazin-l-yl)benzonitrile, 1-119

1-119

Synthetic scheme:

Procedures and characterization:

[00390] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenzoic acid ( Intermediate 83).

Analysis was performed following Method B. Separation was performed following Method D.

Step 1: (S)-ieri-butyl-2-methyl-4-(l-methyl-lH-indazol-7-yl)piperazi ne-l-carboxylate

[00391] A mixture of 7-bromo-l -methyl- lH-indazole (500 mg, 2.37 mmol), (S)-fert-butyl-2- methylpiperazine-l-carboxylate (474 mg, 2.37 mmol), t-BuONa (341 mg, 3.55 mmol) BINAP (19 mg, 0.03 mmol), and Pd ₂ (dba)3 (9 mg, 0.01 mmol) in toluene (15 mL) was stirred at 80 °C for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE = 1/8) to afford (^-tert-butyl-

2-methyl-4-(l -methyl- lH-indazol-7-yl)piperazine-l-carboxylate (353 mg, 1.07 mmol, 45%) as product. ESI-MS (EI ⁺ , m/z): 331.4 [M+H] ⁺ .

Step 2: (S)-l-methyl-7-(3-methylpiperazin-l-yl)-lH-indazole

[00392] To a solution of HC1 (4 N, dioxane) (15 mL) was added (S)-fer/-butyl-2-methyl-4-(l- methyl-lH-indazol-7-yl)piperazine-l-carboxylate (280 mg, 0.89 mmol) with ice-bath. After 16 h of stirring at 20°C, the mixture was concentrated to afford (,S)-l-methyl-7-(3-methylpiperazin-l- yl)-lH-indazole (184 mg, 0.80 mmol, 90%). ESI-MS (EI ⁺ , m/z): 231.3 [M+H] ⁺ .

The synthesis of (S)-2-(4-(2,4-dimethyl-5-(2-methyl-4-(l-methyl-lH-indazol-7- yl)piperazine- l-carbonyl)benzyl)piperazin-l-yl)benzonitrile 1-119 was same as Example 35: ESI-MS (EI ⁺ , m/z): 562.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.96 (d, J= 5.5 Hz, 1H), 7.55 (t, J = 8.7 Hz, 1H), 7.48 (d, J = 7.0 Hz, 2H), 7.23-6.89 (m, 6H), 5.44-4.62 (m, 1H), 4.40 (d, J = 26.1 Hz, 3H), 4.15-3.35 (m, 4H), 3.33-2.86 (m, 7H), 2.68 (s, 5H), 2.40-2.19 (m, 6H), 1.46 (m, 3H).

Example 7. Synthesis of 2-(4-(2,4-dimethyl-5-(4-(l-methyl-lH-indol-7-yl)piperazine-l - carbonyl)benzyl)piperazin- l- l)benzonitrile, I- 111

1-111

Synthetic scheme:

Procedures and characterization:

[00393] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- Cyanophenyl)piperazin-l -yl)methyl)-2,4-dimethylbenzoic acid.

Analysis was performed following Method A. Separation was performed following Method D. Step 1: 7-Bromo-l-methyl-lH-indole [00394] A mixture of 7-bromo-lH-indole (3.0 g, 14.29 mmol) and NaH (700 mg, 17.14 mmol) in THF (50 mL) was stirred at 0 °C for 1 h, iodomethane (3.04 g, 21.43 mmol) was added and stirring was continued for an additional 5 h. The mixture was extracted with EtOAc and concentrated to yield 7-bromo-l-methyl-lH-indole (2.55 g, 12.1 mmol, 85%) as a solid. ¾ NMR (500 MHz, CDCb) δ 7.52 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 3.1 Hz, 1H), 6.89 (t, J= 7.7 Hz, 1H), 6.44 (d, J = 3.1 Hz, 1H), 4.13 (s, 3H).

Step 2: ieri-Butyl-4-(l-methyl-lH-indol-7-yl)piperazine-l-carboxylat e

[00395] A mixture of 7-bromo-l -methyl- lH-indole (500 mg, 2.38 mmol), tert-butyl piperazine- 1-carboxylate (487 mg, 2.62 mmol), t-BuONa (457 mg, 4.76 mmol), BINAP (30 mg, 0.05 mmol), and Pd ₂ (dba)3 (22 mg, 0.03 mmol) in toluene (15 mL) was stirred at 80 °C for 3 h. The mixture was purified by chromatography (silica, EtOAc/PE = 1/8) to afford ter/-butyl-4-(l -methyl- 1H- indol-7-yl)piperazine-l-carboxylate (262 mg, 0.83 mmol, 35%) as product. ESI-MS (EI ⁺ , m/z): 316.3 [M+H] ⁺ .

Step 3: l-Methyl-7-(piperazin-l-yl)-lH-indole

[00396] To a solution of TFA (10 mL) and DCM (10 mL) was added fert-butyl-4-(l -methyl - lH-indol-7-yl)piperazine-l-carboxylate (360 mg, 1.14 mmol). After 2 h of stirring at 20 °C, the mixture was concentrated to afford l-methyl-7-(piperazin-l-yl)-lH-indole (221 mg, 1.03 mmol, 90%). ESI-MS (EI ⁺ , m/z): 216.3 [M+H] ⁺ .

The synthesis of 2-(4-(2,4-Dimethyl-5-(4-(l-methyl-lH-indol-7-yl)piperazine-l - carbonyl)benzyl)piperazin-l-yl)benzonitrile I-lll was same as Example 35: ESI-MS (EI ⁺ , m/z): 547.2 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.55 (d, J = 7.4 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J= 7.8 Hz, 1H), 7.15-6.83 (m, 7H), 6.46 (d, J = 3.0 Hz, 1H), 4.89 (s, 1H), 4.14 (d, J = 4.4 Hz, 3H), 3.73-3.26 (m, 5H), 3.14 (m, 6H), 2.89 (m, 2H), 2.67 (s, 4H), 2.52-2.24 (m, 6H).

Example 8. Synthesis of (S)-2-(4-(5-(4-(lH-indol-5-yl)-2-methylpiperazine-l-carbonyl )-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile 2,2,2-trifluoroacetate salt, 1-229

1-229

Synthetic scheme:

Procedures and characterization:

[00397] The procedure for (5)-2-(4-(5-(4-(lH-indol-5-yl)-2-methylpiperazine-l-carbonyl )-2,4- di-methylbenzyl)piperazin-l-yl)benzonitrile tnfluoroacetate salt 1-229 was the same as Examples 1 and 4.

Analysis was performed following Method A. Separation was performed following Method C. ESI-MS (EI ⁺ , m/z): 569.2 [M+Na] ⁺ . ¾- MR (500 MHz, DMSO-^)5: 10.88 (s, 1H), 9.66-9.69 (m, 1H), 7.77 (d, J= 7.5 Hz, 1H), 7.65 (d, J= 7.0 Hz, 1H), 7.42 (s, 1H), 7.25-7.29 (m, 4H), 7.17- 7.20 (t, J = 7.5 Hz, 2H), 7.06 (s, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.29 (s, 1H), 4.43-4.87 (m, 4H), 3.13-3.71 (m, 10H), 2.55-2.81 (m, 2H), 2.43 (s, 3H), 2.20-2.26 (m, 4H), 1.28-1.43(m, 3H).

Example 9. Synthesis of (S)-2-(4-(5-(4-(lH-indol-6-yl)-2-methylpiperazine-l-carbonyl )-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile trifluoroacetate salt, 1-367

1-367

Synthetic scheme:

Procedures and characterization:

[00398] The procedure for (5)-2-(4-(5-(4-(lH-indol-5-yl)-2-methylpiperazine-l-carbonyl )-2,4- di-methylbenzyl)piperazin-l-yl)benzonitrile trifluoroacetate salt 1-367 was the same as Examples 1 and 4.

Analysis was performed following Method A. Separation was performed following Method C.

[00399] ESI-MS (EI ⁺ , m/z): 569.3 [M+Na] ⁺ . ¾- MR (500 MHz, DMSO)5: 10.80 (s, 1H), 9.64-9.68 (m, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.65 (s, 1H), 7.38-7.41 (m, 2H), 7.16-7.26 (m, 4H), 6.85 (s, 1H), 6.77 (d, J = 7.0 Hz, 1H), 6.28 (s, 1H), 4.48-4.88 (m, 4H), 3.19-3.64 (m, 10H), 2.61- 2.82 (m, 2H), 2.43 (s, 3H), 2.20-2.26 (m, 4H), 1.26-1.42(m, 3H).

Example 10. Synthesis of (S)-2-(4-(2,4-dimethyl-5-(2-methyl-4-(li -pyrrolo[2,3-c]pyridin-7- yl)piperazine-l-carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-115

1-115

Synthetic scheme:

Procedures and characterization:

[00400] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

The procedure for (S)-2-(4-(2,4-dimethyl-5-(2-methyl-4-(lH-pyrrolo[2,3-c]pyrid in-7- yl)piperazine-l-carbonyl)benzyl)piperazin-l-yl)benzonitrile was the same as Examples 1 and 4.

Analysis was performed following Method A. Separation was performed following Method D.

Step 5: (S)-2-(4-(2,4-dimethyl-5-(2-methyl-4-(lH-pyrrolo[2,3-c]pyrid in-7-yl)piperazine-l- carbonyl)benzyl)piperazin-l-yl)benzonitrile

[00401] To a solution of (,S)-7-(3-methylpiperazin-l-yl)-lH-pyrrolo[2,3-c]pyridine trifluoroacetate (11 mg, crude) and 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoic acid (12 mg, 0.035 mmol) in DMF (2mL) was added HATU (13 mg, 0.035 mmol) and DIPEA (26 uL, 0.16 mmol). The mixture was stirred at rt for 2 h. The resulting reaction mixture was purified by prep-HPLC to afford (S)-2-(4-(2,4-dimethyl-5-(2-methyl-4-(lH- pyrrolo[2,3-c]pyridin-7-yl)piperazine-l-carbonyl)benzyl)pipe razin-l-yl)benzonitrile 1-115 (5 mg, 0.01 mmol, 28% for two steps). ESI-MS (EI ⁺ , m/z): 548.3 [M+H] ⁺ . ¹ H-NMR (500 MHz, MeOD)5: 7.70 (d, J= 8.0 Hz, 1H), 7.85-7.89 (m, 1H), 7.59-7.73 (m, 3H), 7.37-7.51 (m, 3H), 7.23- 7.26 (m, 2H), 6.83 (s, 1H), 4.56-5.09 (m, 3H), 3.37-4.13 (m, 14H), 2.35-2.61 (m, 6H), 1.33-1.51 (m, 3H).

Example 11. Synthesis of 7-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)piperazin-l-yl)-lH-indole-6-carbonitrile trifluoroacetate salt, 1-109

1-109

Synthetic scheme:

51 % for two steps

Procedures and characterization:

[00402] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

Analysis was performed following Method A. Separation was performedfollowing Method C. Step 1: l-Bromo-2-fluoro-3-nitrobenzene

[00403] A solution of l-bromo-2-fluoro-3 -nitrobenzene (1 g, 4.54 mmol) and piperazine (1.56 g, 18.16 mmol) in CH3CN (50 mL) was stirred at 80 °C for 5 h. The resulting mixture was concentrated and the residue was diluted with EtOAc (200 mL), washed with water (50mL x 2) and brine (50mL). The organic phase was dried and concentrated to give l-bromo-2-fluoro-3- nitrobenzene (1.2 g, crude) as a yellow liquid which was used for next step directly. ESI-MS (EI ⁺ , m/z): 286.1 [M+H] ⁺ .

Step 2: ieri-Butyl-4-(2-bromo-6-nitrophenyl)piperazine-l-carboxylate

[00404] A mixture of l-bromo-2-fluoro-3 -nitrobenzene (1 g, crude), Boc ₂ 0 (1.53g, 7.0 mmol) and NaHCCb (588 mg, 7.0 mmol) in THF (40 mL), and water (8 mL) was stirred at room temperature for 6 h. The resulting mixture was concentrated and the residue was diluted with EtOAc (200 mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried and concentrated. The residue was purified by column chromatography on silica to give tert- butyl 4-(2-bromo-6-nitrophenyl)piperazine-l-carboxylate (1.3 g, 3.36 mmol, 80% for two steps) as a yellow solid. ESI-MS (EI ⁺ , m/z): 386.1 [M+H] ⁺ .

Step 3: terf-Butyl 4-(6-bromo-lH-indol-7-yl)piperazine-l-carboxylate

[00405] To a solution of tert-butyl 4-(2-bromo-6-nitrophenyl)piperazine-l-carboxylate (500 mg, 1.3 mmol) in dry THF (50 mL) at -40 °C was added vinylmagnesium bromide (1 in THF, 5.2 mL) dropwise, then the mixture was stirred at -40 °C for 2 h. The resulting solution was quenched with saturated aqueous H ₄ C1 solution (5 mL), then poured into water and extracted with EtOAc (100 mL x 2). The combined organic phase was dried and concentrated. The residue was purified by column chromatography on silica to give tert-butyl 4-(6-bromo-lH-indol-7- yl)piperazine-l-carboxylate (80 mg, 0.21 mmol, 13%) as a white solid. ESI-MS (EI ⁺ , m/z): 380.0 [M+H] ⁺ .

Step 4: terf-Butyl 4-(6-cyano-lH-indol-7-yl)piperazine-l-carboxylate

[00406] To a solution of tert-butyl 4-(6-bromo-lH-indol-7-yl)piperazine-l-carboxylate (40 mg, 0.1 mmol) in DMF (5 mL) was added Zn(CN) ₂ (23 mg, 0.2 mmol) and Pd[P(t-Bu) ₃ ] ₂ (5 mg, 0.01 mmol). The mixture was stirred at 120 °C overnight. The reaction mixture was diluted with EtOAc (100 mL), and washed with water (50 mL x 2 ) and brine (20 mL). The organic phase was dried and concentrated. The residue was purified by column chromatography on silica to give tert-butyl 4-(6-cyano-lH-indol-7-yl)piperazine-l-carboxylate (35 mg, 0.11 mmol, 81%) as a white solid. ESI-MS (EI ⁺ , m/z): 394.2 [M+H] ⁺ .

Step 6: 7-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4-dimeth ylbenzoyl)piperazin- l-yl)-lH-indole-6-carbonitrile trifluoroacetate, 1-109 [00407] To a solution of 7-(piperazin-l-yl)-lH-indole-6-carbonitrile trifluoroacetate (22 mg, crude) and 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (26 mg, 0.075 mmol) in DMF (2mL) was added HATU (29 mg, 0.075 mmol) and DIPEA (56 uL, 0.35 mmol). The mixture was stirred at rt for 2 h. The resulting reaction mixture was purified by prep-HPLC to afford 7-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimeth ylbenzoyl)piperazin-l- yl)-lH-indole-6-carbonitrile trifluoroacetate salt 1-109(28.3 mg, 0.042 mmol, 51% for two steps). ESI-MS (EI ⁺ , m/z): 558.0 [M+H] ⁺ . ¹ H- MR (500 MHz, MeOD)5: 7.71 (d, J= 7.5 Hz, 1H), 7.64- 7.67 (t, J= 7.0 Hz, 1H), 7.45-7.49 (m, 3H), 7.37 (s, 1H), 7.18-7.27 (m, 3H), 6.60 (d, J= 3.0 Hz, 1H), 4.52-4.59 (m, 2H), 4.05-4.17 (m, 2H), 3.35-3.75 (m, 14H), 2.53 (s, 3H), 2.41 (s, 3H).

Example 12. Synthesis of 2-(4-(5-(4-(4,5-Difluoro-lH-indol-7-yl)piperazine-l-carbonyl )- 2,4-dimethylbenzyl)piperazin-l-yl)benzonitrile, 1-60

1-60

Synthetic scheme:

Procedures and characterization:

[00408] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid. The procedure for 4,5-difluoro-7-(piperazin-l-yl)-lH-indole trifluoroacetate was the same as Example 7.

Analysis was performed following Method A. Separation was performed following Method D. Step 4: 2-(4-(5-(4-(4,5-Difluoro-lH-indol-7-yl)piperazine-l-carbonyl )-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile, 1-60

[00409] To a solution of 4,5-difluoro-7-(piperazin-l-yl)-lH-indole trifluoroacetate (5.6 mg, crude) and 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (9.2 mg, 0.026 mmol) in DMF (2mL) was added HATU (10 mg, 0.026 mmol) and DIPEA (20 uL, 0.12 mmol). The mixture was stirred at rt for 2h. The resulting reaction mixture was purified by prep-HPLC to afford 2-(4-(5-(4-(4,5-difluoro-lH-indol-7-yl)piperazine-l-carbonyl )-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile 1-60 (4.3 mg, 7.57 umol, 32% for two steps). ESI-MS (EI ⁺ , m/z): 569.3 [M+H] ⁺ . ¾- MR (500 MHz, CDC1 ₃ )5: 8.23-8.41 (m, 1H), 7.47-7.56 (m, 2H), 6.98-7.14 (m, 5H), 6.73-6.83 (m, 1H), 4.73-4.85 (m, 1H), 3.38-3.58 (m, 4H), 3.10-3.19 (m, 5H), 2.80-2.97 (m, 2H), 2.47-2.66 (m, 4H), 2.20-2.36 (m, 7H), 2.00-2.01 (m, 1H).

Example 13. Synthesis of 4-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)piperaz -l-yl)-2,5-difluorobenzenesulfonamide, 1-344

1-344

Synthetic scheme:

Procedures and characterization:

[00410] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 2,4,5-trifluorobenzenesulfonamide

[00411] To a solution of 2,4,5-trifluorobenzene-l-sulfonyl chloride (3.0 g, 13 mmol), in THF(30 mL) was added H4OH (910 mg, 26 mmol) and the solution was stirred for 14 h at rt. The solution was concentrated in vacuo to afford 2,4,5-trifluorobenzenesulfonamide (2.7 g, 13 mmol, 98%) as a yellow solid. ESI-MS (EI+, m/z): 211.9 [M+H] ⁺ .

Step 2: 2,5-difluoro-4-(piperazin-l-yl)benzenesulfonamide

[00412] A mixture of 2,4,5-trifluorobenzenesulfonamide (1 g, 4.74 mmol) and piperazine (4.08g, 47.35 mmol) was dissolved in CH3CN (10 mL). The mixture was stirred at 100 °C for 1 h under microwave radiation. The solution was purified by prep-HPLC (Boston C18 21 *250mm ΙΟμπι, Mobile phase: A: 0.1 % trifluoroacetic acid; B: acetonitrile) to afford 2,5-difluoro-4- (piperazin-l-yl)benzenesulfonamide (800 mg, 2.88 mmol) as a white solid. MS (EI+, m/z): 278.2 [M+H] ⁺ .

¾ MR (400 MHz, DMSO) δ 7.41 (dd, J = 12.7, 6.8 Hz, 1H), 7.00 (dd, J = 12.3, 7.0 Hz, 1H), 3.14-2.93 (m, 4H), 2.89-2.68 (m, 4H).

Step 3: 4-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimeth ylbenzoyl)piperazin-l- yl)-2,5-difluorobenzenesulfonamide, 1-344 [00413] To a solution of 2,5-difluoro-4-(piperazin-l-yl)benzenesulfonamide (100 mg, 0.36 mmol) in 10 mL of DMF was added 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoic acid (113 mg, 0.32 mmol) at rt, followed by DIPEA (456 mg, 0.36 mmol), then HATU (139 mg, 0.36 mmol). The mixture was stirred at rt for 17 h then purified by prep-HPLC (Boston CI 8 21 *250mm ΙΟμπι, Mobile phase: A: 0.1 % trifluoroacetic acid; B: acetonitrile) to afford 4-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimeth ylbenzoyl)piperazin-l-yl)- 2,5-difluorobenzenesulfonamide 1-344 (60 mg, 0.10 mmol) as a white solid. MS (EI+, m/z): 609.3 [M+H] ⁺ .

[00414] ¾ MR (500 MHz, DMSO) δ 7.69 (d, J = 7.9 Hz, 1H), 7.65-7.53 (m, 3H), 7.44 (dd, J = 12.3, 6.6 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.12-7.03 (m, 4H), 3.80 (s, 2H), 3.50 (s, 2H), 3.31 (s, 2H), 3.25 (s, 2H), 3.13 (s, 6H), 2.56 (s, 4H).

Example 14. Synthesis of 2-(4-(5-(4-(lH-pyrazolo[3,4-c]pyridin-7-yl)piperazine-l- carbonyl)-2,4-dimethylbenz l)piperazin-l-yl)benzonitrile, 1-21

1-21

Synthetic scheme:

Procedures and characterization:

[00415] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

Analysis was performed following Method A. Separation was performed following Method C. Step 1: 7-(Piperazin-l-yl)-lH-pyrazolo[3,4-c]pyridine [00416] Amixture of 7-chloro-lH-pyrazolo[3,4-c]pyridine (200 mg, 1.30 mmol) and piperazine (1.12g, 13.02 mmol) was dissolved in EtOH (20 mL). The mixture was stirred at 80 °C for 8 h under microwave radiation. The solution was purified by prep-HPLC (Boston C18 21 *250mm ΙΟμπι, Mobile phase: A: 0.1 % trifiuoroacetic acid; B: acetonitrile) to afford 7-(piperazin-l-yl)- lH-pyrazolo[3,4-c]pyridine (100 mg, 0.493 mmol) as a white solid. MS (EI ⁺ , m/z): 204.2 [M+H] ⁺ . ¾ NMR (500 MHz, OMSO-d ₆ ) δ 13.72 (s, 1H), 8.15 (s, 1H), 7.64 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 5.4 Hz, 1H), 3.64 (s, 4H), 2.75 (d, J= 108.1 Hz, 4H).

Step 2: 2-(4-(5-(4-(lH-pyrazolo[3,4-c]pyridin-7-yl)piperazine-l-carb onyl)-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile, 1-21

[00417] To a solution of 7-(piperazin-l-yl)-lH-pyrazolo[3,4-c]pyridine (80 mg, 0.39 mmol) in 10 mL of DMF was added 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (123 mg, 0.35 mmol) at rt, followed by DIPEA (494 mg, 0.39 mmol), then HATU (151 mg, 0.39 mmol) was added. The mixture was stirred at 30 °C for 17 h then purified by prep-HPLC (Boston C18 21 *250mm ΙΟμιη, Mobile phase: A: 0.1 % trifiuoroacetic acid; B: acetonitrile) to afford 4,5- difluoro-2-(piperazin-l-yl)benzenesulfonamide 1-21 (50 mg, 0.09 mmol) as a white solid. MS (EI ⁺ , m/z): 534.8 [M+H] ⁺ .

¾ MR (500 MHz, OMSO-d ₆ ) δ 15.21 (s, 1H), 13.06 (d, J = 3.5 Hz, 1H), 11.11 (dd, J = 13.5,14Hz, 1H), 8.62 (s, 1H), 7.78-7.63 (m, 3H), 7.33-7.17 (m, 5H), 4.57-3.42 (m, 18H), 2.51 (d, J= 3.5 Hz, 3H), 2.31 (m, 3H).

Example 15. Synthesis of (S)-2-(4-(2,4-dimethyl-5-(2-methyl-4-(lH-pyrazolo[3,4-c]pyri din- 7-yl)piperazine-l-carbonyl)benzyl)piperazin-l-yl)benzonitril e, I-l

I-l

Synthetic scheme:

Procedures and characterization:

[00418] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- Cyanophenyl)piperazin-l -yl)methyl)-2,4-dimethylbenzoic acid.

Analysis was performed following Method A. Separation was performed following Method C. Step 1: (S)-7-(3-Methylpiperazin-l-yl)-lH-pyrazolo[3,4-c]pyridine

[00419] A mixture of 7-chloro-lH-pyrazolo[3,4-c]pyridine (200 mg, 1.30 mmol) and (S)-2- methylpiperazine (1.30g, 13.02 mmol) was dissolved in CH3CH2OH (20 mL). The mixture was stirred at 80 °C for 8 h in microwave radiation. The solution was purified by prep-HPLC (Boston CI 8 21 *250mm ΙΟμηι, Mobile phase: A: 0.1 % trifluoroacetic acid; B: acetonitrile) to afford (S 7-(3-methylpiperazin-l-yl)-lH-pyrazolo[3,4-c]pyridine (80 mg, 0.37 mmol) as a white solid. MS (EI+ m/z): 218.2 [M+H] ⁺ . ¾ NMR (400 MHz, OMSO-d ₆ ) δ 8.15 (s, 1H), 7.63 (d, J = 5.7 Hz, 1H), 7.02 (d, J = 5.7 Hz, 1H), 4.39 (s, 2H), 3.04-2.68 (m, 4H), 2.46 (s, 2H), 1.03 (d, J = 6.3 Hz, 3H).

Step 2: (S)-2-(4-(2,4-dimethyl-5-(2-methyl-4-(lH-pyrazolo[3,4-c]pyri din-7-yl)piperazine-l- carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-1

[00420] To a solution of (,S)-7-(3-methylpiperazin-l-yl)-lH-pyrazolo[3,4-c]pyridine (58 mg, 0.27 mmol) in 10 mL of DMF was added 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoic acid ( 84 mg, 0.24 mmol) at rt, followed by DIPEA (342 mg, 0.27 mmol), then HATU (105 mg, 0.27 mmol). The mixture was stirred at 30 °C for 17 h then purified by prep- HPLC (Boston CI 8 21 *250mm ΙΟμιη, Mobile phase: A: 0.1 % trifluoroacetic acid; B: acetonitrile) to afford 4,5-difluoro-2-(piperazin-l-yl)benzenesulfonamide 1-1 (30 mg, 0.05 mmol) as a white solid. MS (EI ⁺ , m/z): 550.0 [M+H] ⁺ . ¾ NMR (500 MHz, MeOD) δ 8.46 (s, 1H), 7.76-7.61 (m, 3H), 7.29 (ddd, J = 26.5, 22.7, 15.4 Hz, 6H), 4.57 (s, 3H), 3.71 (s, 6H), 3.62 (s, 8H), 2.56 (s, 3H), 2.35 (d, J = 15.0 Hz, 3H), 1.46 (d, J = 5.9 Hz, 3H).

Example 16. Synthesis of 2-(l-(2,4-Dimethyl-5-(3-(6-methylpyridin-2-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carbon l)benzyl)piperidin-4-yl)benzonitrile, 1-95

1-95

Synthetic scheme:

Procedures and characterization:

[00421] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: tert-Butyl 3-(6-methylpyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-ca rboxylate

[00422] A mixture of 2-bromo-6-methylpyridine (210 mg, 1.21 mmol), fert-butyl-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate (200 mg, 1.01 mmol), CS2CO3 (659 mg, 2.02 mmol), XantPhos (117 mg, 0.2 mmol), and Pd ₂ (dba)3 (92 mg, 0.1 mmol) in 1,4-dioxane (10 mL) was stirred at 110 °C for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE = 1/8) to afford tert-butyl 3-(6-methylpyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-ca rboxylate (137 mg, 0.47 mmol, 47%) as product. ESI-MS (EI ⁺ , m/z): 290.3 [M+H] ⁺ .

Step 2: 3-(6-Methylpyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane

[00423] To a solution of TFA (5 mL) and DCM (5 mL) was added ferf-butyl-3-(6- methylpyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxy late (80 mg, 0.28 mmol). After 3 h of stirring at 0 °C, the mixture was concentrated and purified by prep-HPLC to afford 3-(6- methylpyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane (32 mg, 0.17 mmol, 60%). ESI-MS (EI ⁺ , m/z): 190.2 [M+H] ⁺ .

Step 3: 5-((4-(2-Cyanophenyl)piperidin-l-yl)methyl)-2,4-dimethylbenz oic acid

[00424] To a solution of 5-formyl-2,4-dimethylbenzoic acid (1.82 g, 10.2 mmol) and 2- (piperidin-4-yl)benzonitrile (1.9 mg, 10.2 mmol) in AcOH (0.5 mL) and ethanol (100 mL) was added NaC BH ₃ (1.29 mg, 20.43 mmol) with ice-bath cooling. After 20 h of stirring at 20 °C, the mixture was purified by chromatography (silica, EtOAc/PE = 1/2) to afford 5-((4-(2- cyanophenyl)piperidin-l-yl)methyl)-2,4-dimethylbenzoic acid (1.06 g, 3.06 mmol, 30%). ESI- MS (EI ⁺ , m/z): 349.3 [M+H] ⁺ .

The synthesis of 2-(l-(2,4-Dimethyl-5-(3-(6-methylpyridin-2-yl)-3,6- diazabicyclo[3.1.1]heptane-6-carbonyl)benzyl)piperidin-4-yl) benzonitrile 1-95 was the same as Example 4 : ESI-MS (EI ⁺ , m/z): 520.2 [M+H] ⁺ . ¹ H MR (500 MHz, CDC1 ₃ ) δ 7.62 (d, J= 7.7 Hz, 1H), 7.54 (t, J= 7.7 Hz, 1H), 7.39-7.34 (m, 2H), 7.29 (t, J= 6.7 Hz, 1H), 7.24 (s, 1H), 6.99 (s, 1H), 6.46 (d, J = 7.2 Hz, 1H), 6.27 (d, J = 8.4 Hz, 1H), 4.72 (s, 1H), 4.30 (dd, J= 27.5, 16.8 Hz, 2H), 3.64-3.38 (m, 5H), 2.94 (m, 3H), 2.35 (s, 6H), 2.27-2.10 (m, 5H), 1.87-1.66 (m, 5H).

Example 17. Synthesis of 2-(l-(5-(3-(5-Fluoropyridin-2-yl)-3,6-diazabicyclo[3.1.1]hep tane- 6-carbonyl)-2,4-dimethylbenzyl)piperidin-4-yl)benzonitrile, 1-96

1-96

Synthetic scheme:

Procedures and characterization:

[00425] Analysis was performed following Method B. Separation was performed following Method D.

[00426] The procedure was the same as Examples 1 and 16.

2-(l-(5-(3-(5-Fluoropyridin-2-yl)-3,6-diazabicyclo[3.1.1]hep tane-6-carbonyl)-2,4- dimethylbenzyl)piperidin-4-yl)benzonitrile I-96: ESI-MS (EI ⁺ , m/z): 524.2 [M+H] ⁺ ¾ MR (500 MHz, CDCb) δ 8.00 (d, J = 2.9 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.59-7.47 (m, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.32-7.22 (m, 3H), 6.99 (s, 1H), 6.42 (dd, J= 9.2, 3.1 Hz, 1H), 4.71 (s, 1H), 4.39-4.14 (m, 2H), 3.48 (m, 5H), 3.17-2.77 (m, 4H), 2.34 (s, 3H), 2.25-2.08 (m, 5H), 1.89-1.62 (m, 5H).

Example 18. Synthesis of 2-(l-(5-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2,4- dimethylbenzyl)piperidin-4- l)benzonitrile, 1-200

1-200

Synthetic scheme:

Procedures and characterization:

[00427] The procedure was the same as Example 16.

The analysis method was following Method B and the separation method was following Method D.

2-(l-(5-(4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl)-2,4- dimethylbenzyl)piperidin-4- yl)benzonitrile 1-200: ESI-MS (EI ⁺ , m/z): 512.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 8.04 (d, J= 3.0 Hz, 1H), 7.60 (dt, 7= 21.7, 10.8 Hz, 1H), 7.57-7.50 (m, 1H), 7.38 (d, 7= 7.9 Hz, 1H), 7.28 (m, 2H), 7.15 (s, 1H), 7.04 (s, 1H), 6.64 (dd, 7 = 9.2, 3.3 Hz, 1H), 4.06-3.86 (m, 2H), 3.64-3.30 (m, 8H), 2.98 (t, 7 = 10.8 Hz, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 2.19 (dd, 7 = 23.0, 11.9 Hz, 2H), 1.89-1.75 (m, 4H).

Example 19. Synthesis of (S)-2-(4-(5-(4-(lH-indol-4-yl)-2-methylpiperazine-l-carbonyl )-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile, 1-201

1-201

Synthetic scheme:

Procedures and characterization:

[00428] Analysis was performed following Method A. Separation was performed following Method C.

[00429] The synthesis of (5)-2-(4-(5-(4-(lH-indol-4-yl)-2-methylpiperazine-l-carbonyl )-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile 1-201 was the same as Example 16: ESI-MS (EI ⁺ , m/z): 547.2 [M+H] ⁺ . ¾ NMR (500 MHz, DMSO-^) δ 10.80 (t, J = 43.4 Hz, 1H), 9.86 (s, 1H), 7.78 (s, 1H), 7.70-7.58 (m, 1H), 7.43 (d, J= 28.3 Hz, 1H), 7.34-7.18 (m, 5H), 6.91 (q, J= 7.2 Hz, 1H), 6.76-6.55 (m, 1H), 6.44 (s, 1H), 4.71 (d, J = 247.5 Hz, 4H), 3.62 (s, 4H), 3.42 (s, 3H), 3.16 (dd, J= 56.3, 38.4 Hz, 4H), 2.45 (d, J= 12.5 Hz, 4H), 2.34-2.21 (m, 3H), 1.51-1.24 (m, 4H).

Example 20. Synthesis of 2-(4-(5-((4-(2-Chlorophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)piperazin-l- l)benzonitrile, 1-307

1-307

Synthetic scheme:

Procedures and characterization:

[00430] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 5-((4-(2-Chlorophenyl)piperazin-l-yl)methyl)-2,4-dimethylben zoic acid:

[00431] To a solution of 5-formyl-2,4-dimethylbenzoic acid (500 mg, 2.8 mmol) and l-(2- chlorophenyl)piperazine (830 mg, 4.2 mmol) in AcOH (0.1 mL) and EtOH (20 mL) was added

NaC B b (360 mg, 5.6 mmol) with ice-bath cooling. After 20 h of stirring at 20 °C, the mixture was purified by prep-HPLC to afford 5-((4-(2-chlorophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoic acid (501 mg, 1.4 mmol, 50%) as a white solid. ESI-MS (EI ⁺ , m/z): 359.2

[M+H] ⁺ .

[00432] The synthesis of 2-(4-(5-((4-(2-Chlorophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile 1-307 was the same as Example 1: ESI-MS (EI ⁺ , m/z): 528.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 7.59 (dd, J= 7.7, 1.5 Hz, 1H), 7.54-7.48 (m, 1H), 7.34 (dd, J= 7.9, 1.5 Hz, 1H), 7.20 (td, J= 8.0, 1.5 Hz, 1H), 7.14 (s, 1H), 7.10-6.99 (m, 4H), 6.95 (td, J= 7.7, 1.5 Hz, 1H), 4.04 (s, 2H), 3.51 (d, J= 15.5 Hz, 4H), 3.26 (t, J= 4.7 Hz, 2H), 3.07 (m, 6H), 2.63 (s, 4H), 2.37 (s, 3H), 2.29 (s, 3H).

Example 21. Synthesis of (S)-2-(4-(5-((4-(2-chlorophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)benzonitrile, 1-308

1-308

Synthetic scheme:

Procedures and characterization:

[00433] The procedure for compound 2 was the same as Example 20.

[00434] Analysis was performed following Method B. Separation was performed following Method D.

(S)-2-(4-(5-((4-(2-chlorophenyl)piperazin-l-yl)methyl)-2,4-d imethylbenzoyl)-3- methylpiperazin-l-yl)benzonitrile 1-308: ESI-MS (EI+, m/z): 542.3 [M+H]+. ¾ MR (500 MHz, CDC13) δ 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.51 (s, 1H), 7.37-7.30 (m, 1H), 7.24-6.98 (m, 6H), 6.99-6.91 (m, 1H), 5.14 (s, 0.5H), 4.78 (m, 0.5H), 3.73-3.28 (m, 5H), 2.91 (m, 6H), 2.63 (s, 4H), 2.37 (s, 3H), 2.31 (s, 3H), 2.21 (d, J = 7.7 Hz, 0.5H), 2.07-1.98 (m, 0.5H), 1.26 (s, 3H).

Example 22. Synthesis of (5-((4-(2-Chlorophenyl)piperazin-l-yl)methyl)-2,4- dimethylphenyl)(4-phenylpiperaz -l-yl)methanone, 1-309

1-309

Synthetic scheme:

Procedures and characterization:

[00435] The procedure for compound II was the same as Example 20.

[00436] Analysis was performed following Method B. Separation was performed following

Method D.

(5-((4-(2-Chlorophenyl)piperazin-l-yl)methyl)-2,4-dimethylph enyl)(4-phenylpiperazin-l- yl)methanone 1-309: ESI-MS (EI ⁺ , m/z): 503.3 [M+H] ⁺ . ¹ H MR (500 MHz, CDCb) δ 7.34 (dd, J= 7.9, 1.3 Hz, 1H), 7.28 (t, J= 6.4 Hz, 2H), 7.23-7.17 (m, 1H), 7.14 (s, 1H), 7.07-7.00 (m, 2H), 6.99-6.88 (m, 4H), 3.97 (s, 2H), 3.60-3.33 (m, 4H), 3.27 (s, 2H), 3.04 (s, 6H), 2.63 (s, 4H), 2.37 (s, 3H), 2.29 (s, 3H).

Example 23. Synthesis of 2-(4-(5-(4-(2-Cyanophenyl)piperazin-l-yl)-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-341

1-341

Synthetic scheme:

Procedures and characterization:

[00437] The procedure for 2-(4-(5-bromo-2,4-dimethylbenzoyl)piperazin-l-yl)benzonitril e was the same as Example 1.

[00438] Analysis was performed following Method B. Separation was performed following Method D.

Step 2: 2-(4-(5-(4-(2-Cyanophenyl)piperazin-l-yl)-2,4-dimethylbenzoy l)piperazin-l- yl)benzonitrile, 1-341

[00439] To a solution of 2-(4-(5-bromo-2,4-dimethylbenzoyl)piperazin-l-yl)benzonitril e (200 mg, 0.5 mmol) and 2-(piperazin-l-yl)benzonitrile (112 mg, 0.6 mmol ) in toluene (20 mL) was added Pd ₂ (dba) ₃ (23 mg, 0.025 mmol), BINAP (31 mg, 0.05 mmol) and t-BuONa (96 mg, 1.0 mmol). The mixture was stirred at 80 °C for 4 h under nitrogen. The resulting mixture was concentrated in vacuo and the residue was purified by prep-HPLC to give 2-(4-(5-(4-(2- cyanophenyl)piperazin-l-yl)-2,4-dimethylbenzoyl)piperazin-l- yl)benzonitrile 1-341 (36.9 mg, 0.07 mmol, 15%) as a white solid. ESI-MS (EI ⁺ , m/z): 505.2 [M+H] ⁺ . ¾- MR (500 MHz, CDC1 ₃ )5: 7.58-7.59 (m, 2H), 7.49-7.53 (m, 2H), 7.01-7.08 (m, 5H), 7.06-7.09 (m, 3H), 6.91 (s, 1H), 4.17 (s, 1H), 3.91 (d, J= 7.0 Hz, 1H), 3.50 (s, 2H), 3.25-3.39 (m, 6H), 3.08-3.13 (m, 6H), 2.31 (s, 3H), 2.25 (s, 3H).

Example 24. Synthesis of 2-(4-(5-((3,4-Dihydropyrazino[l,2-a]indol-2(li?)-yl)methyl)- 2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-155

1-155

Synthetic scheme:

Procedures and characterization:

[00440] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: Ethyl l-(2-((tert-butoxycarbonyl)amino)ethyl)-lH-indole-2-carboxyl ate

[00441] To a rt solution of ethyl- lH-indole-2-carboxylate (2.0 g, 10.57 mmol) in anhydrous DMF (40 mL) was added fert-butyl (2-bromoethyl)carbamate (4.74 g, 21.14 mmol) and Cs ₂ C0 ₃ (10.31 g, 31.71 mmol). The reaction mixture was stirred at 100 °C for 16 h, then cooled to rt, diluted with H ₂ 0 (200 mL) and extracted with EtOAc (80 mL x 3). The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by chromatography (silica, EtOAc/PE = 1/10) to afford ethyl- l-(2-((tert-butoxycarbonyl)amino)ethyl)-lH-indole-2- carboxylate ( 2.2 g, 6.62 mmol, 63%) as a white solid. ESI-MS (EI ⁺ , m/z): 333.3 [M+H] ⁺ .

Step 2: Ethyl l-(2-aminoethyl)-lH-indole-2-carboxylate [00442] To a rt solution of ethyl- l-(2-((tert-butoxycarbonyl)amino)ethyl)-lH-indole-2- carboxylate ( 2.0 g, 6.02 mmol) in anhydrous DCM (20 mL) was added TFA (8 mL). The reaction mixture was stirred at rt for 16 h, then concentrated to afford ethyl- l-(2-aminoethyl)- lH-indole-2- carboxylate (2.3 g, 5.72 mmol, 95%). ESI-MS (EI ⁺ , m/z): 233.4 [M+H] ⁺ .

Step 3: 3,4-Dihydropyrazino[l,2-a]indol-l(2H)-one

[00443] To a rt solution of ethyl-l-(2-aminoethyl)-lH-indole-2-carboxylate (2.3 g, 5.72 mmol) in THF (40 mL) and H ₂ 0 (20 mL) was added NaHCOs (6.0 g, 71.4 mmol). The mixture was stirred at 60 °C for 16 h, then cooled to rt and extracted with EtOAc (80 mL x 3). The organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered, concentrated, and purified by chromatography (silica, EtOAc/PE = 1/5) to afford 3,4-dihydropyrazino[l,2-a]indol-l(2H)-one (1.1 g, 5.43 mmol, 98%) as an white solid. ESI-MS (EI ⁺ , m/z): 187.3 [M+H] ⁺ .

Step 4: l,2,3,4-Tetrahydropyrazino[l,2-a]indole

[00444] To a 0 °C solution of 3,4-dihydropyrazino[l,2-a]indol-l(2H)-one (1.05 g, 5.63 mmol) in THF (20 mL) was added LiAlH ₄ (428 mg, 11.27 mmol). The reaction mixture was stirred at 40 °C for 16 h, then quenched with H ₂ 0 (100 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , filtered, concentrated, and purified by chromatography (silica, EtOAc/PE = 1/1) to afford l,2,3,4-tetrahydropyrazino[l,2- a]indole (920 mg, 5.35 mmol, 95%) as a solid. ESI-MS (EI ⁺ , m/z): 173.2 [M+H] ⁺ .

Step 5: 2-(4-(5-((3,4-Dihydropyrazino[l,2-a]indol-2(lH)-yl)methyl)-2 ,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-155

[00445] To a 0 °C solution of l,2,3,4-tetrahydropyrazino[l,2-a]indole (100 mg, 0.58 mmol) in EtOH (20 mL) was added 2-(4-(5-formyl-2,4-dimethylbenzoyl)piperazin-l-yl)benzonitri le (202 mg, 0.58 mmol), NaBH ₃ CN (110 mg, 1.74 mmol) and two drops of acetic acid. The reaction mixture was stirred at rt for 16h, then purified by prep-HPLC to afford 2-(4-(5-((3,4- dihydropyrazino[l,2-a]indol-2(lH)-yl)methyl)-2,4-dimethylben zoyl)piperazin-l-yl)benzonitrile 1-155 (60 mg, 0.12 mmol, 20%) as a white solid. ESI-MS (EI ⁺ , m/z): 504.0 [M+H] ⁺ . ¾ MR (500 MHz, CDC1 ₃ ) δ 7.61-7.49 (m, 2H), 7.48-7.40 (m, 1H), 7.26 (d, J= 6.4 Hz, 1H), 7.15 (dd, J = 15.0, 7.9 Hz, 2H), 7.11-7.03 (m, 3H), 6.94 (d, J = 8.3 Hz, 1H), 6.16 (s, 1H), 4.03 (t, J = 19.5 Hz, 4H), 3.77 (dd, J = 49.3, 8.8 Hz, 3H), 3.-3.42 (m, 3H), 3.24 (s, 2H), 3.08 (s, 2H), 2.97 (d, J = 3.5 Hz, 2H), 2.36 (s, 3H), 2.31 (s, 3H). Example 25. Synthesis of 2-(4-(2,4-Dimethyl-5-(l,2,3,4-tetrahydropyrazino[l,2-a]indol e-2- carbonyl)benzyl)-l,4-diazepa -l-yl)benzonitrile, 1-88

1-88

Synthetic scheme:

Procedures and characterization:

[00446] Analysis was performed following Method A. Separation was performed following Method D.

[00447] ESI-MS (EI ⁺ , m/z): 518.0 [M+H] ⁺ . ¾ MR (500 MHz, DMSO-d ₆ ) δ 7.41 (ddd, J = 30.7, 28.7, 20.5 Hz, 4H), 7.18-6.99 (m, 4H), 6.95 (dd, J = 24.2, 8.5 Hz, 1H), 6.77 (d, J= 8.5 Hz, 1H), 6.27 (d, J= 111.7 Hz, 1H), 5.06 (d, J= 124.6 Hz, lH), 4.58 (s, 1H), 4.11 (d, J= 82.0 Hz, 3H), 3.60 (dd, J= 52.0, 27.2 Hz, 7H), 2.76 (s, 2H), 2.61 (s, 2H), 2.31 (s, 3H), 2.14 (d, J= 54.9 Hz, 3H), 1.90 (s, 2H).

Example 26. Synthesis of (S)-4-(4-(5-(4-(2-cyanophenyl)piperazine-l-carbonyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5-difluorobenzoni trile, 1-45

1-45

Synthetic scheme:

Procedures and characterization:

[00448] Analysis was performed following Method A. Separation was performed following Method D.

[00449] ESI-MS (EI ⁺ , m/z): 582.8 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.60 (d, J= 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.22 (dd, J = 11.8, 5.8 Hz, 1H), 7.18-7.12 (m, 1H), 7.12-6.91 (m, 3H), 6.62 (s, 1H), 4.79 (dd, J= 112.9, 90.2 Hz, 1H), 4.14 (s, 1H), 3.92 (s, 1H), 3.72-2.63 (m, 12H), 2.30 (d, J= 32.5 Hz, 6H), 1.49-1.24 (m, 3H).

Example 27. Synthesis of (S)-2-(4-(5-(4-(2-cyanophenyl)piperazine-l-carbonyl)-2,4- dimethylbenzoyl)-3-methylpi erazin-l-yl)benzenesulfonamide, 1-19

1-19 Synthetic scheme:

Procedures and characterization:

[00450] Analysis was performed following Method A. Separation was performed following Method D.

[00451] ESI-MS (EI ⁺ , m/z): 600.8 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 8.02 (d, J= 7.7 Hz, 1H), 7.73-7.52 (m, 2H), 7.52 (t, J = 7.7 Hz, 1H), 7.37 (dt, J = 15.1, 11.4 Hz, 2H), 7.23-6.84 (m, 4H), 5.34 (d, J= 229.0 Hz, 2H), 4.89-3.67 (m, 3H), 3.64-2.92 (m, 11H), 2.77 (d, J= 50.7 Hz, 1H), 2.33 (dd, J= 37.0, 20.4 Hz, 6H), 1.53 (d, J= 6.7 Hz, 3H).

Example 28. Synthesis of 2-[4-(5-{[4-(2-Chlorophenyl)piperazin-l-yl] methylbenzoyl)piperazin-l-yl]benzonitrile, 1-329

1-329

[00452] 5-{[4-(2-Chlorophenyl)piperazin-l-yl]methyl}-2-methylbenzoic acid (30 mg, 0.09 mmol) [Intermediate B] and HATU (40 mg, 0.10 mmol) were dissolved in DMF (1ml). DIPEA (50 μΐ, 0.28 mmol) was added and the reaction was stirred for 30 min at room temperature. 2- (Piperazin-l-yl)benzonitrile [Amine 72] (16 mg, 0.09 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a white solid (31.1 mg, 83 %).

[00453] 1H NMR (500 MHz, Chloroform-d) δ 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.51 (t, 1H), 7.34 (dd, J = 7.9, 1.4 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.25 - 7.15 (m, 3H), 7.11 - 7.00 (m, 3H), 6.97 (t, J = 7.3 Hz, 1H), 4.19 - 3.93 (m, 2H), 3.69 - 3.41 (m, 4H), 3.32 - 3.23 (m, 2H), 3.22 - 2.95 (m, 6H), 2.84 - 2.47 (m, 3H), 2.33 (s, 3H).

[00454] LCMS Method 7 - Tr = 2.54 min (ES+) (M+H)+ 514.2 / 516.2

Example 29. Synthesis of (S)-4-(4-(5-((l-(2-cyanophenyl)piperidin-4-ylamino)methyl)-2 ,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5-difluorobenzoni trile, 1-345

1-345

Synthetic scheme:

Procedures and characterization:

[00455] Analysis was performed following Method B. Separation was performed following Method D.

[00456] The procedure was the same as Example 28.

(S)-4-(4-(5-((l-(2-cyanophenyl)piperidin-4-ylamino)methyl)-2 ,4-dimethylbenzoyl)-3- methylpiperazin-l-yl)-2,5-difluorobenzonitrile, 1-345: ESI-MS (EI ⁺ , m/z): 583.3 [M+H] ⁺ ¾ MR (500 MHz, CDCb) δ 7.54 (dd, J= 7.6, 1.3 Hz, 1H), 7.51-7.41 (m, 1H), 7.25-6.90 (m, 5H), 6.73-6.58 (m, 1H), 4.92 (m, 1H), 4.02-3.22 (m, 8H), 3.20-2.66 (m, 5H), 2.44-2.17 (m, 6H), 2.07 (s, 2H), 1.38 (m, 5H). Example 30. Synthesis of (S)-4-(4-(5-((4-(2-cyanophenyl)-l,4-diazepan-l-yl)methyl)-2, 4- dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5-difluorobenzoni trile, 1-41

1-41

Synthetic scheme:

Procedures and characterization:

[00457] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 2-(l,4-Diazepan-l-yl)benzonitrile

[00458] A mixture of K ₂ C0 ₃ (10.4 g, 75 mmol), 2-fluorobenzonitrile (3 g, 25 mmol), and 1,4- diazepane (5 g, 50 mmol) in DMSO (50 mL) was stirred at 110 °C for 16 h. The mixture was filtered and the filtrate was washed with water, extracted with EtOAc, concentrated, and purified by chromatography (silica, EtOAc/PE = 3/1) to afford 2-(l,4-diazepan-l-yl)benzonitrile (3.52 g, 17.5 mmol, 70%) as product. ESI-MS (EI ⁺ , m/z): 202.3 [M+H] ⁺ .

Step 2: 5-((4-(2-Cyanophenyl)-l,4-diazepan-l-yl)methyl)-2,4-dimethyl benzoic acid

[00459] A mixture of 5-formyl-2,4-dimethylbenzoic acid (400 mg, 2.25 mmol) and 2-(l,4- diazepan-l-yl)benzonitrile (678 mg, 3.37 mmol) in AcOH (0.05 mL) and EtOH (10 mL) was heated to 40 °C for 1 h, then the mixture was cooled to rt. NaC BH ₃ (284 mg, 4.5 mmol) was added and after 20 h of stirring at 20 °C, the mixture was quenched with water and purified by prep-HPLC to afford 5-((4-(2-cyanophenyl)-l,4-diazepan-l-yl)methyl)-2,4-dimethyl benzoic acid (327 mg, 0.9 mmol, 40%). ESI-MS (EI ⁺ , m/z): 364.2 [M+H] ⁺ .

The procedure for (S)-4-(4-(5-((4-(2-cyanophenyl)-l,4-diazepan-l-yl)methyl)-2, 4- dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5-difluorobenzoni trile 1-41 was the same as Example 1 : ESI-MS (EI ⁺ , m/z): 583.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.47 (d, J = 7.4 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.21 (dd, J= 11.9, 5.9 Hz, 1H), 7.07 (m, 2H), 6.89-6.54 (m, 3H), 4.92 (m, 1H), 4.05-3.20 (m, 10H), 3.20-2.59 (m, 6H), 2.26 (m, 6H), 2.01 (s, 2H), 1.52-1.29 (m, 3H).

Example 31. Synthesis of (S)-2-(4-(5-((4-(2-cyanophenyl)-l,4-diazepan-l-yl)methyl)-2, 4- dimethylphenylsulfonyl)-3-m hylpiperazin-l-yl)benzonitrile, 1-346

1-346

Synthetic scheme:

Procedures and characterization:

[00460] Analysis was peformed following Method B. Separation was performed following Method D.

Step 1 : (S)-2-(4-(5-(hydroxymethyl)-2,4-dimethylphenylsulfonyl)-3-me thylpiperazin-l- yl)benzonitrile [00461] A mixture of (S)-5-(4-(2-cyanophenyl)-2-methylpiperazin-l-ylsulfonyl)-2,4 - dimethylbenzoic acid (2.8 g, 6.78 mmol) and BH ₃ THF (10.17 mL, 10.17 mmol) in THF was stirred at 0 °C to rt for 6 h. The mixture was washed with water, concentrated, and purified by prep-HPLC to yield (,S)-2-(4-(5-(hydroxymethyl)-2,4-dimethylphenylsulfonyl)-3- methylpiperazin-l-yl)benzonitrile (1.75 g, 4.41 mmol, 65%) as product. ESI-MS (EI, m/z): 398.0 [M-H] ⁺ .

Step 2: (S)-2-(4-(5-formyl-2,4-dimethylphenylsulfonyl)-3-methylpiper azin-l-yl)benzonitrile

[00462] A mixture of (S)-2-(4-(5-(hydroxymethyl)-2,4-dimethylphenylsulfonyl)-3- methylpiperazin-l-yl)benzonitrile (500 mg, 1.25 mmol) and IBX (702 mg, 2.51 mmol) in DMSO (10 mL) was stirred at 25°C for 16 h. The mixture was washed with water, concentrated, and purified by chromatography (silica, EtOAc/PE = 1/5) to yield (,S)-2-(4-(5-formyl-2,4- dimethylphenylsulfonyl)-3-methylpiperazin-l-yl)benzonitrile (347 g, 0.88 mmol, 70%) as product. ESI-MS (EI ⁺ , m/z): 398.2 [M+H] ⁺ .

Step 3: (S)-2-(4-(5-((4-(2-cyanophenyl)-l,4-diazepan-l-yl)methyl)-2, 4- dimethylphenylsulfonyl)-3-methylpiperazin-l-yl)benzonitrile, 1-346

[00463] A mixture of (,S)-2-(4-(5-formyl-2,4-dimethylphenylsulfonyl)-3-methylpipe razin-l- yl)benzonitrile (100 mg, 0.25 mmol) and 2-(l,4-diazepan-l-yl)benzonitrile (76 mg, 0.38 mmol) in AcOH (0.05 mL) and EtOH (5 mL) was heated to 40 °C for 1 h. Then the mixture was cooled to rt and NaC BH ₃ (32 mg, 0.50 mmol) was added. After 20 h of stirring at 20 °C, the mixture was quenched with water and purified by prep-HPLC to afford (,S)-2-(4-(5-((4-(2-cyanophenyl)-l,4- diazepan- 1 -yl)methyl)-2,4-dimethylphenylsulfonyl)-3 -methylpiperazin- 1 -yl)benzonitrile 1-346 (36 mg, 0.06 mmol, 25%). ESI-MS (EI ⁺ , m/z): 583.3 [M+H] ⁺ . ¾ MR (500 MHz, CDC1 ₃ ) δ 7.92 (s, 1H), 7.58 (d, J = 7.7 Hz, 1H), 7.54-7.44 (m, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.07 (dd, J = 16.9, 9.3 Hz, 2H), 7.00 (d, J= 8.3 Hz, 1H), 6.85 (d, J= 8.7 Hz, 1H), 6.76 (t, J= 7.5 Hz, 1H), 4.18 (s, 1H), 3.75-3.45 (m, 8H), 3.38 (dd, J= 19.0, 11.6 Hz, 2H), 3.11 (dd, J= 11.6, 3.2 Hz, 1H), 2.99- 2.76 (m, 3H), 2.74-2.65 (m, 2H), 2.57 (s, 3H), 2.36 (s, 3H), 2.02 (s, 2H), 1.43 (d, J= 6.8 Hz, 3H).

Example 32. Synthesis of (S)-2-(4-(5-((4-(2-cyanophenyl)-l,4-diazepan-l-yl)methyl)-2, 4- dimethylphenylsulfonyl)-3-methylpiperazin-l-yl)nicotinonitri le, 1-368

1-368

Synthetic scheme:

Procedures and characterization:

[00464] Anaylsis was performed following Method B. Separation was performed following Method D.

[00465] The procedure was the same as Example 31.

(S)-2-(4-(5-((4-(2-Cyanophenyl)-l,4-diazepan-l-yl)methyl)-2, 4-dimethylphenylsulfonyl)-3- methylpiperazin-l-yl)nicotinonitrile 1-368: ESI-MS (EI ⁺ , m/z): 584.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 8.34 (dd, J = 4.8, 1.9 Hz, 1H), 7.92 (s, 1H), 7.78 (dd, J = 7.6, 1.9 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.9 Hz, 1H), 7.09 (s, 1H), 6.89-6.71 (m, 3H), 4.31-4.10 (m, 3H), 3.71-3.52 (m, 7H), 3.51-3.39 (m, 1H), 3.31 (dd, J = 13.3, 3.8 Hz, 1H), 3.06 (td, J= 12.4, 3.4 Hz, 1H), 2.91-2.80 (m, 2H), 2.75-2.64 (m, 2H), 2.57 (s, 3H), 2.36 (s, 3H), 2.01 (s, 2H), 1.32 (d, J= 6.7 Hz, 3H).

Example 33. Synthesis of (S)-2-(4-(5-((4-(2-cyanophenyl)-l,4-diazepan-l-yl)methyl)-2, 4- dimethylbenzoyl)-3-methylpiperazin-l-yl)benzenesulfonamide, 1-26

1-26

Synthetic scheme:

Procedures and characterization:

[00466] Analysis was performed following Method B. Separation was performed following Method D.

[00467] The procedure was the same as Example 1. (S)-2-(4-(5-((4-(2-cyanophenyl)-l,4- diazepan- 1 -yl)methyl)-2,4-dimethylbenzoyl)-3 -methylpiperazin- 1 -yl)benzenesulfonamide 1-26: ESI-MS (EI ⁺ , m/z): 601.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 8.04 (d, J= 7.7 Hz, 1H), 7.60 (s, 1H), 7.55-7.29 (m, 4H), 7.22-6.96 (m, 2H), 6.79 (d, J= 37.0 Hz, 2H), 5.54 (s, 2H), 5.30 (s, 2H), 4.08-3.46 (m, 7H), 3.25 (m, 4H), 2.76 (m, 5H), 2.30 (m, 6H), 1.99 (s, 2H), 1.52 (d, J = 6.6 Hz, 2H).

Example 34. Synthesis of (S)-(5-((4-(2-(3-aminopropyl)phenyl)piperazin-l-yl)methyl)-2 ,4- dimethylphenyl)(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-l -yl)methanone 2,2,2- trifluoroacetate, 1-195

1-195

Synthetic scheme:

Procedures and characterization:

[00468] Analysis was performed following Method A. Separation was performed following Method C.

Step 1 : (S)-5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l-carbony l)-2,4- dimethylbenzaldehyde

[00469] A mixture of (<S)-l-(5-fluoropyridin-2-yl)-3-methylpiperazine (250 mg, 1.28 mmol), 5- formyl-2,4-dimethylbenzoic acid (190 mg, 1.07 mmol), HATU (609 mg, 1.60 mmol), and DIPEA (413 mg, 3.20 mmol) in DMF (5.00 mL) was stirred at 20 °C for 16 h. The mixture was purified by prep-HPLC to afford (,S)-5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l-carbon yl)-2,4- dimethylbenzaldehyde (83 mg, 0.23 mmol, 22%) as product. ESI-MS (EI ⁺ , m/z): 356.2 [M+H] ⁺ . Step 2: (S)-ieri-butyl-3-(2-(4-(5-(4-(5-fluoropyridin-2-yl)-2-methyl piperazine-l-carbonyl)- 2,4-dimethylbenzyl)piperazin-l-yl)phenyl)propyl(methoxymethy l)carbamate

[00470] To a solution of (,S)-5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l-carbon yl)-2,4- dimethylbenzaldehyde (244 mg, 0.69 mmol) and tert-butyl-methoxymethyl(3-(2-(piperazin-l- yl)phenyl)propyl)carbamate (250 mg, 0.69 mmol) in AcOH (0.025 mL) and ethanol (6 mL) was added NaCNBH ₃ (87 mg, 1.38 mmol) with ice-bath cooling. After 20 h of stirring at 20 °C, the mixture was purified by prep-HPLC to afford (,S)-tert-butyl-3-(2-(4-(5-(4-(5-fluoropyridin-2-yl)- 2-methylpiperazine- 1 -carbonyl)-2,4-dimethylbenzyl)piperazin- 1 - yl)phenyl)propyl(methoxymethyl)carbamate (254 mg, 0.38 mmol, 55%). ESI-MS (EI ⁺ , m/z): 671.4 [M+H] ⁺ .

Step 3: (S)-(5-((4-(2-(3-aminopropyl)phenyl)piperazin-l-yl)methyl)-2 ,4-dimethylphenyl)(4- (5-fluoropyridin-2-yl)-2-methylpiperazin-l-yl)methanone 2,2,2-trifluoroacetate, 1-195

[00471] A solution of (5)-tert-butyl-3-(2-(4-(5-(4-(5-fluoropyridin-2-yl)-2-methyl piperazine-l- carbonyl)-2,4-dimethylbenzyl)piperazin-l-yl)phenyl)propyl(me thoxymethyl)carbamate (280 mg, 0.4 mmol) in TFA (5 mL) and DCM (5 mL) was stirred at 20°C for 2 h. The mixture was purified by prep-HPLC to afford (,S)-(5-((4-(2-(3-aminopropyl)phenyl)piperazin-l-yl)methyl)- 2,4- dimethylphenyl)(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-l -yl)methanone 2,2,2- trifluoroacetate 1-195 (200 mg, 0.36 mmol, 90%). ESI-MS (EI ⁺ , m/z): 559.3 [M+H] ⁺ . ¾ MR (500 MHz, DMSO^) δ 9.78 (s, 1H), 8.09 (d, J = 2.9 Hz, 1H), 7.84 (s, 3H), 7.55 (t, J = 7.2 Hz, 1H), 7.48-7.15 (m, 4H), 6.89 (d, J= 9.3 Hz, 1H), 4.98-4.05 (m, 5H), 3.64-3.28 (m, 4H), 3.22-2.90 (m, 6H), 2.45 (s, 3H), 2.21 (m, 3H), 1.98-1.72 (m, 2H), 1.19 (m, 3H).

Example 35. Synthesis of 6-(4-(5-((4-(2-Cyano-3,4,5-trifluorophenyl)piperazin-l-yl)me thyl)- 2,4-dimethylbenzoyl)piperazin-l-yl)-2,3,4-trifluorobenzonitr ile, 1-347

1-347

Procedures and characterization:

[00472] Analysis was performed following Method B. Separation was performed following Method D.

[00473] 6-(4-(5-((4-(2-Cyano-3,4,5-trifluorophenyl)piperazin-l-yl)me thyl)-2,4- dimethylbenzoyl)piperazin-l-yl)-2,3,4-trifluorobenzonitrile 1-347: ESI-MS (EI ⁺ , m/z): 627.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.07 (d, J = 15.0 Hz, 2H), 6.56 (m, 2H), 4.02 (m, 2H), 3.46 (m, 5H), 3.17 (m, 8H), 2.63 (m, 3H), 2.35 (s, 3H), 2.28 (s, 3H).

Example 36. Synthesis of 6-(4-(5-(4-(2-Cyanophenyl)piperazine-l-carbonyl)-2,4- dimethylbenzyl)piperazin-l-yl)-2,3,4-trifluorobenzonitrile, 1-82

1-82

Procedures and characterization:

[00474] Analysis was performed following Method A. Separation was performed following Method D.

Step 1 : 6-(4-(5-(4-(2-Cyanophenyl)piperazine-l-carbonyl)-2,4-dimethy lbenzyl)piperazin-l- yl)-2,3,4-trifluorobenzonitrile, 1-82

[00475] A solution of 2-(4-(5-formyl-2,4-dimethylbenzoyl)piperazin-l-yl)benzonitri le (100 mg, 0.28 mmol), and crude 2,3,4-trifluoro-6-(piperazin-l-yl)benzonitrile hydrochloride salt (100 mg, 0.43 mmol) in EtOH (5 mL) was stirred at rt for 1 h. Then catalytic HOAc and NaBH ₃ CN (44 mg, 0.56 mmol) were added and stirred at rt for 17 h. The solution was purified by prep-HPLC (Boston CI 8 21 *250mm ΙΟμπι, mobile phase: A: 0.1 % trifluoroacetic acid; B: acetonitrile) to afford 6-(4-(5-(4-(2-cyanophenyl)piperazine-l-carbonyl)-2,4-dimethy lbenzyl)piperazin-l-yl)- 2,3,4-trifluorobenzonitrile 1-82 (20.6 mg, 0.036 mmol, 12%) as a white solid. ESI-MS (EI ⁺ , m/z): 573.0 [M+H] ⁺ . ¾ MR (500 MHz, CDC1 ₃ ) δ 7.59 (dd, J = 7.5, 1.5 Hz, 1H), 7.56-7.48 (m, 1H), 7.26 (s, 5H), 7.13-6.99 (m, 4H), 6.54 (m, 1H), 4.04 (s, 2H), 3.51 (m, 4H), 3.26 (m, 2H), 3.18 (m, 4H), 3.12 (m, 2H), 2.63 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H).

Example 37. Synthesis of 2-((S)-4-(5-((S)-4-(2-Cyanophenyl)-2-methylpiperazin-l- ylsulfonyl)-2,4-dimethylbenzoyl)-3-methylpiperazin-l-yl)benz onitrile, 1-90

1-90 Synthetic scheme:

Procedures and characterization:

[00476] Analysis was performed following Method A. Separation was performed following Method D.

Step: 2-((S)-4-(5-((S)-4-(2-cyanophenyl)-2-methylpiperazin-l-ylsul fonyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)benzonitrile, 1-90

[00477] To a solution of (S)-2-(3-methylpiperazin-l-yl)benzonitrile (3.02 g, 15 mmol), TEA (1.52 g, 15 mmol) in DCM (50 mL) was added dropwise a solution of 5-(chlorosulfonyl)-2,4- dimethylbenzoic acid (1.86 g, 7.5 mmol) in THF (50 mL) at -10 °C with stirring. The mixture was stirred at -10 °C for 2 h, then concentrated and purified by prep-HPLC to afford 2-((,S)-4-(5-(( ₎ S)- 4-(2-cyanophenyl)-2-methyl-piperazin-l-ylsulfonyl)-2,4-dimet hylbenzoyl)-3-methylpiperazin-l- yl)benzonitrile 1-90 (550 mg,0.92 mmol, 12%) as a white solid.

[00478] ESI-MS (EI ⁺ , m/z): 597.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.94-7.75 (m, 1H), 7.60 (t, J = 7.5 Hz, 2H), 7.56-7.46 (m, 2H), 7.21 (s, 1H), 7.13-6.94 (m, 4H), 5.18-4.60 (m, 1H), 4.15 (s, 1H), 3.93-3.23 (m, 8H), 3.19-2.68 (m, 4H), 2.60 (s, 3H), 2.39 (d, 3H), 1.60-1.42 (m, 6H).

Example 38. Synthesis of 2-((S)-4-(5-(((S)-4-(2-cyanophenyl)-2-methylpiperazin-l- yl)methyl)-2,4-dimethylphenylsulfonyl)-3-methylpiperazin-l-y l)benzonitrile, 1-89

1-89

Synthetic scheme:

Procedures and characterization:

[00479] Analysis was performed following Method A. Separation was performed following Method D.

Step: 2-((S)-4-(5-(((S)-4-(2-cyanophenyl)-2-methylpiperazin-l-yl)m ethyl)-2,4- dimethylphenylsulfonyl)-3-methylpiperazin-l-yl)benzonitrile, 1-89

[00480] To a solution of 2-((5)-4-(5-((5)-4-(2-cyanophenyl)-2-methyl piperazin-l-ylsulfonyl)- 2,4-dimethylbenzoyl)-3-methylpiperazin-l-yl)benzonitrile (500 mg, 0.84 mmol) in THF (20 mL) was added dropwise B¾ THF (1M, 2.5 mL) at 0 °C with stirring. The mixture was stirred at rt for 16 h, then purified by prep-HPLC to afford 2-((S)-4-(5-(((S)-4-(2-cyanophenyl)-2- methylpiperazin-l-yl)methyl)-2,4-dimethylphenylsulfonyl)-3-m ethylpiperazin-l-yl)benzonitrile 1-89 (63 mg, 0.108 mmol, 13%) as white solid. ESI-MS (EI ⁺ , m/z): 583.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.97 (s, 1H), 7.57 (q, J= 7.5 Hz, 2H), 7.52-7.43 (m, 2H), 7.11 (s, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.99 (t, J= 8.2 Hz, 3H), 4.185 (q, J= 6.5 Hz, 1H), 4.03 (d, J= 13.5 Hz, 1H), 3.66 (d, J = 13.0 Hz, 1H), 3.54 (t, J = 11.2 Hz, 1H), 3.45-3.32 (m, 3H), 3.29-3.20 (m, 2H), 3.16-3.08 (m, 1H), 3.05-2.85 (m, 3H), 2.83-2.72 (m, 2H), 2.57 (s, 3H), 2.41 (s, 4H), 1.44 (d, J = 6.5 Hz, 3H), 1.25 (d, J= 6.0 Hz, 3H).

Example 39. Synthesis of 2-(8-(5-((3-(2-Cyanophenyl)-3,8-diazabicyclo[3.2.1]octan-8- yl)methyl)-2,4-dimethylbenzo l)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile, 1-348

1-348

Synthetic scheme:

1-348

Procedures and characterization:

[00481] The analysis method was following Method B and the separation method was following Method D.

Step 1: ieri-Butyl-3-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-8 -carboxylate

[00482] A mixture of 2-iodobenzonitrile (115 mg, 0.5 mmol), (\R,5S)-tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (53 mg, 0.25 mmol), CS2CO3 (163 mg, 0.5 mmol), XantPhos (12 mg, 0.02 mmol) and Pd ₂ (dba)3 (9 mg, 0.01 mmol) in 1,4-dioxane (10 mL) was stirred at 110 °C for 8 h. The mixture was purified by chromatography (silica, EtOAc/PE = 1/8) to afford ter/-butyl-3-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-8 -carboxylate (35 mg, 0.11 mmol, 45%) as product. ESI-MS (EI ⁺ , m/z): 314.3 [M+H] ⁺ .

Step 2: 2-(3,8-Diazabicyclo[3.2.1]octan-3-yl)benzonitrile

[00483] To a solution of HC1 (4 N, dioxane) (15 mL) was added ter/-butyl-3-(2-cyanophenyl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.96 mmol) with ice bath cooling. After 16 h of stirring at 20 °C, the mixture was concentrated to afford 2-(3,8-diazabicyclo[3.2.1]octan-3- yl)benzonitrile (184 mg, 0.86 mmol, 90%). ESI-MS (EI ⁺ , m/z): 214 [M+H] ⁺ .

Step 3: 2-(8-(5-Formyl-2,4-dimethylbenzoyl)-3,8-diazabicyclo[3.2.1]o ctan-3-yl)benzonitrile

[00484] A mixture of 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile (120 mg, 0.56 mmol), 5-formyl-2,4-dimethylbenzoic acid (84 mg, 0.47 mmol), HATU (270 mg, 0.71 mmol) and DIPEA (182 mg, 1.41 mmol) in DMF (4 mL) was stirred at rt for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE = 1/8) to afford 2-(8-(5-formyl-2,4-dimethylbenzoyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)benzonitrile (114 mg, 0.31 mmol, 65%). ESI-MS (EI ⁺ , m/z): 374.3 [M+H] ⁺ .

Step 4: 2-(8-(5-((3-(2-Cyanophenyl)-3,8-diazabicyclo[3.2.1]octan-8-y l)methyl)-2,4- dimethylbenzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitr ile, 1-348

[00485] To a solution of 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitrile (62 mg, 0.29 mmol) and 2-(8-(5-fomyl-2,4-dimethylbenzoyl)-3,8-diazabicyclo[3.2.1]oc tan-3-yl)benzonitrile (90 mg, 0.24 mmol) in AcOH (0.025 mL) and ethanol (5 mL) was added NaCNBH ₃ (31 mg, 0.48 mmol) with ice bath cooling. After 20 h of stirring at 20 °C, the mixture was purified by prep-HPLC to afford 2-(8-(5-((3-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octan-8-y l)methyl)-2,4- dimethylbenzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)benzonitr ile 1-348 (34 mg, 0.06 mmol, 25%). ESI-MS (EI ⁺ , m/z): 571.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDC1 ₃ ) δ 7.57 (d, J= 7.2 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.48-7.35 (m, 2H), 7.25 (d, J = 6.1 Hz, 1H), 7.04 (dd, J = 9.0, 5.9 Hz, 2H), 7.01-6.93 (m, 2H), 6.89 (d, J= 8.3 Hz, 1H), 5.00 (d, J= 6.3 Hz, 1H), 3.88 (s, 1H), 3.53-3.16 (m, 9H), 3.03 (t, J= 8.8 Hz, 2H), 2.93 (d, J= 10.3 Hz, 1H), 2.38 (s, 3H), 2.33 (s, 3H), 2.28 (d, J= 5.6 Hz, 2H), 2.14-1.97 (m, 6H).

Example 40. Synthesis of 2-(4-(5-((3-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octan-8- yl)methyl)-2,4-dimethylbenzo l)piperazin-l-yl)-4,5-difluorobenzonitrile, 1-349

1-349

Procedures and characterization:

[00486] The analysis method was following Method B and the separation method was following Method D.

The procedure was the same as Example 39.

2-(4-(5-((3-(2-Cyanophenyl)-3,8-diazabicyclo[3.2.1]octan-8-y l)methyl)-2,4- dimethylbenzoyl)piperazin-l-yl)-4,5-difluorobenzonitrile 1-349: ESI-MS (EI ⁺ , m/z): 581.3 [M+H] ⁺ . ¾ MR (500 MHz, CDC1 ₃ ) δ 7.53 (d, J = 7.5 Hz, 1H), 7.44 (t, J= 7.9 Hz, 1H), 7.25- 7.17 (m, 2H), 7.05 (s, 1H), 6.99-6.88 (m, 2H), 6.64 (dd, J = 10.5, 7.0 Hz, 1H), 4.00 (s, 2H), 3.45 (s, 4H), 3.41-3.27 (m, 4H), 3.24 (s, 2H), 3.09 (m, 4H), 2.38 (s, 3H), 2.29 (s, 3H), 2.16-1.97 (m, 4H). Example 41. Synthesis of 2-((S)-4-(5-(((S)-4-(2-cyanophenyl)-2-methylpiperazin-l- yl)methyl)-2,4-dimethylbenzoyl)-3-methylpiperazin-l-yl)benze nesulfonamide, 1-25

1-25

Procedures and characterization:

[00487] The procedure was same as Example 3.

Analysis was preformed following Method B. Separation was preformed following Method D.

[00488] 2-((5)-4-(5-(((5)-4-(2-cyanophenyl)-2-methylpiperazin-l-yl)m ethyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)benzenesulfonamide 1-25: ESI-MS (EI ⁺ , m/z): 601.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 8.02 (d, J= 7.7 Hz, 1H), 7.60 (t, J= 7.5 Hz, 1H), 7.54 (d, J= 7.4 Hz, 1H), 7.45 (m, 2H), 7.34 (t, J= 7.6 Hz, 1H), 7.20-6.89 (m, 4H), 5.61 (s, 2H), 5.31-4.66 (m, 1H), 4.18-3.46 (m, 2H), 3.22 (m, 6H), 3.04-2.56 (m, 6H), 2.46-2.17 (m, 7H), 1.60-1.16 (m, 6H).

Example 42. Synthesis of l-(2-Cyanophenyl)-4-(5-(4-(2-cyanophenyl)piperazine-l- carbonyl)-2,4-dimethylbenzyl)piperidine-4-carboxylic acid trifluoroacetate salt, 1-350.

1-350

Synthetic scheme:

Procedures and characterization:

[00489] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: 5-Bromo-2,4-dimethylbenzoic acid

[00490] To a solution of 2,4-dimethylbenzoic acid (2 g, 13.33 mmol) in TFA (30mL) was added BS (2.61 g, 14.66 mmol). The mixture was stirred at 80 °C for 16 h. The resulting mixture was poured into water (300 mL) and stirred for 20 min at rt. The precipitate was collected by filtration and purified by recrystallized from EtOAc to give 5-bromo-2,4-dimethylbenzoic acid (2.1 g, 9.17 mmol, 70%) as a white solid. ESI-MS (EI ⁺ , m/z): 227.1 [M-H] ⁺ .

Step 2: (5-Bromo-2,4-dimethylphenyl)methanol

[00491] To a solution of 5-bromo-2,4-dimethylbenzoic acid (1 g, 4.37 mmol) in THF (40 mL) at 0 °C was added BH ₃ (1 Min THF, 8.74 mL), then the mixture was warmed to rt and stirred for 4 h. The mixture was quenched with MeOH (10 mL) and concentrated. The residue was diluted with EtOAc (100 mL), washed with saturated aqueous NaHC0 ₃ (50 mL), water (50 mL), and brine (50 mL). The organic phase was dried and concentrated to give (5-bromo-2,4- dimethylphenyl)methanol (960 mg, 4.46 mmol, 98%) as a white solid. ESI-MS (EI ⁺ , m/z): 215.1 [M+H] ⁺ .

Step 3: l-Bromo-5-(bromomethyl)-2,4-dimethylbenzene

[00492] To a solution of (5-bromo-2,4-dimethylphenyl)methanol (910 mg, 4.23 mmol) in DCM (50 mL) at 0 °C was added PBr ₃ (0.8 mL, 8.46 mmol), then the mixture was warmed to rt and stirred for 2 h. The mixture was poured into ice water and extracted with EtOAc (100 mL). The organic phase was dried and concentrated, then residue was purified by column chromatography on silica gel to give l-bromo-5-(bromomethyl)-2,4-dimethylbenzene (930 mg, 3.34 mmol, 74%) as a white solid.

Step 4: Ethyl-l-(2-cyanophenyl)piperidine-4-carboxylate

[00493] To a solution of ethyl-piperidine-4-carboxylate (2.6 g, 16.5 mmol) and 2- fluorobenzonitrile(l g, 16.5 mmol) in DMF (20 mL) was added K ₂ C0 ₃ (4.5 g, 33.0 mmol). The mixture was stirred at 80 °C for 3h, then diluted with EtOAc (200 mL), washed with water (100 mL) and brine (50 mL). The organic phase was dried and concentrated, then the residue was purified by column chromatography on silica gel to give ethyl- l-(2-cyan ophenyl)piperidine-4- carboxylate (1.6 g, 6.2 mmol, 75%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 259.3 [M+H] ⁺ .

Step 5: Ethyl-4-(5-bromo-2,4-dimethylbenzyl)-l-(2-cyanophenyl)piperi dine-4-carboxylate

[00494] To a solution of ethyl -piperidine-4-carboxylate (891 mg, 3.45 mmol) in THF (50 mL) at -78 °C was added LDA (2 M in THF, 2.36 mL) over 30 min. After the mixture was stirred 1 h, a solution of l-bromo-5-(bromomethyl)-2,4-dimethylbenzene (10 mL, 810 mg, 3.14 mmol) in THF was added. The resulting mixture was stirred at -78 °C for 3 h. The mixture was quenched with saturated aqueous NH ₄ C1 (10 mL), diluted with EtOAc (200 mL), and washed with water (50 mL) and brine (50 mL). The organic phase was dried and concentrated, then residue was purified by column chromatography on silica gel to give ethyl-4-(5-bromo-2,4-dimethylbenzyl)-l-(2- cyanophenyl)piperidine-4-carboxylate (380 mg, 0.83 mmol, 25%) as a yellow liquid. ESI-MS (EI ⁺ , m/z): 455.1 [M+H] ⁺ .

Step 6: 5-((l-(2-Cyanophenyl)-4-(ethoxycarbonyl)piperidin-4-yl)methy l)-2,4- dimethylbenzoic acid

[00495] To a solution of ethyl-l-(2-cyanophenyl)-4-(5-formyl-2,4-dimethylbenzyl)piper idine- 4-carboxylate (130 mg, 0.32 mmol) in CH ₃ CN (15 mL) and water (2 mL) was added NaC10 ₂ (57.6 mg, 0.64 mmol), NaH ₂ P0 ₄ (77 mg, 0.64 mmol) and H ₂ 0 ₂ (30%, 0.16 mL). The mixture was stirred at rt for 2 h, then quenched with Na ₂ S0 ₃ , diluted with EtOAc (200 mL), and washed with water (50 mL) and brine (50 mL). The organic phase was dried and concentrated, then the residue was purified by column chromatography on silica gel to give 5-((l-(2-cyanophenyl)-4- (ethoxycarbonyl)piperidin-4-yl)methyl)-2,4-dimethylbenzoic acid (150 mg, 0.35 mmol, 96%) as a yellow liquid. ESI-MS (EI ⁺ , m/z): 419.2 [M-H]\ Step 7: l-(2-cyanophenyl)-4-(5-(4-(2-cyanophenyl)piperazine-l-carbon yl)-2,4- dimethylbenzyl)piperidine-4-carboxylic acid trifluoroacetate salt, 1-350

[00496] To a solution of ethyl-l-(2-cyanophenyl)-4-(5-(4-(2-cyanophenyl)piperazine-l- carbonyl)-2,4-dimethylbenzyl)piperidine-4-carboxylate(160 mg, 0.27 mmol) in DCM (2 mL) at - 78 °C was added BBr ₃ (17% in DCM, 3 mL). Then the mixture was slowly warmed to rt and stirred overnight. Then the mixture was quenched with water (20 mL) and extracted with EtOAc (100 mL x 2). The combined organic phases were washed with water (50 mL), dried over Na ₂ S04, concentrated, and the residue was purified by prep-HPLC to give (l-(2-cyanophenyl)-4-(5-(4-(2- cyanophenyl)piperazine- 1 -carbonyl)-2,4-dimethylbenzyl)piperidine-4-carboxylic acid trifluoroacetate salt 1-350 (46.2 mg, 0.068 mmol, 27%) as a white solid. ESI-MS (EI ⁺ , m/z): 561.8 [M+H] ⁺ . ¾ MR (500 MHz, MeOD)5: 7.51-7.53 (dd, Ji = 1.5 Hz, J ₂ = 9.0 Hz, 1H), 7.38-7.48 (m, 3H), 7.08 (d, J= 10.5 Hz, 1H), 6.90-7.03 (m, 5H), 3.80-3.93 (m, 2H), 3.33-3.42 (m, 4H), 2.82- 3.18 (m, 6H), 2.69-2.75 (t, J= 14.5 Hz, 2H), 2.25 (s, 3H), 2.10-2.22 (m, 5H), 1.67-1.74 (m, 2H).

Example 43. Synthesis of 2-(4-(5-((4-Amino-l-(2-cyanophenyl)piperidin-4-yl)methyl)-2, 4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-2

1-2

Synthetic scheme:

Procedures and characterization:

[00497] Analysis was performer following Method A. Separation was performed following Method D.

[00498] The procedure for 4-(5-bromo-2,4-dimethylbenzyl)-l-(2-cyanophenyl)piperidine-4 - carboxylic acid was th same as Example 109. ESI-MS (EI ⁺ , m/z): 425.0 [M-H]-.

Step 7: 2-(4-(5-bromo-2,4-dimethylbenzyl)-4-isocyanatopiperidin-l-yl )benzonitrile

[00499] To a solution of 4-(5-bromo-2,4-dimethylbenzyl)-l-(2-cyanophenyl)piperidine-4 - carboxylic acid (320 mg, 0.75 mmol) in toluene (20 mL) was added DPPA (227 mg, 0.82 mmol) and TEA (0.11 mL, 0.82 mmol). Then the mixture was stirred at 110 °C for 2 h. The reaction mixture was cooled to 0 °C, diluted with EtOAc (200 mL), washed with saturated aqueous Na ₂ C03

(50 mL), water (50 mL), and brine (50 mL). The organic phase was dried over Na ₂ S0 ₄ and concentrated to give 2-(4-(5-bromo-2,4-dimethylbenzyl)-4-isocyanatopiperidin-l-yl )benzonitrile

(310 mg, crude) as a yellow liquid. ESI-MS (EI ⁺ , m/z): 424.2 [M+H] ⁺ .

Step 8: 2-(4-Amino-4-(5-bromo-2,4-dimethylbenzyl)piperidin-l-yl)benz onitrile

[00500] To a solution of 2-(4-(5-bromo-2,4-dimethylbenzyl)-4-isocyanatopiperidin-l- yl)benzonitrile (310 mg, crude) in DMA (10 mL) was added /-BuONa (77 mg, 0.80 mmol), then the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (200 mL),and washed with water (50 mL x 2) and brine (50 mL). The organic phase was dried over Na ₂ S0 ₄ and concentrated to give 2-(4-amino-4-(5-bromo-2,4-dimethylbenzyl)piperidin-l-yl)benz onitrile (260 mg, crude) as a yellow liquid. ESI-MS (EI ⁺ , m/z): 398.1 [M+H] ⁺ .

Step 9: ieri-Butyl-4-(5-bromo-2,4-dimethylbenzyl)-l-(2-cyanophenyl)p iperidin-4- ylcarbamate

[00501] To a solution of 2-(4-amino-4-(5-bromo-2,4-dimethylbenzyl)piperidin-l- yl)benzonitrile (200 mg, crude) and Boc ₂ 0 (218 mg, 1.0 mmol) in THF (40 mL) was added saturated aqueous NaHC0 ₃ (8 mL), then the mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (200 mL), and washed with water (50 mL x 2) and brine (50 mL). The organic phase was dried over Na ₂ S0 ₄ and concentrated. The residue was purified by column chromatography on silica gel to give tert-butyl-4-(5-bromo-2,4-dimethylbenzyl)-l-(2- cyanophenyl)piperidin-4-ylcarbamate (270 mg, 0.54 mmol, 83% for three steps) as a white solid. ESI-MS (EI ⁺ , m/z): 498.1 [M+H] ⁺ .

Step 10: 2-(4-(5-((4-Amino-l-(2-cyanophenyl)piperidin-4-yl)methyl)-2, 4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-2

[00502] To a solution of ter/-butyl-l-(2-cyanophenyl)-4-(5-(4-(2-cyanophenyl)piperazi ne-l- carbonyl)-2,4-dimethylbenzyl)piperidin-4-ylcarbamate (120 mg, 0.24 mmol) in CH3OH (2 mL) was added HCl (4 M in dioxane, 6 mL). The mixture was stirred at rt for 2h. The resulting mixture was concentrated and the residue was dissolved in water (20 mL). Saturated aqueous NaHC0 ₃ was added the pH of the mixture was 8. The resulting mixture was extracted with EtOAc (100 mL x 2). The combined organic phases were concentrated and the residue was purified by prep-HPLC to give 2-(4-(5-((4-amino- 1 -(2-cyanophenyl)piperidin-4-yl)methyl)-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile 1-2 (61.3 mg, 0.11 mmol, 52%) as a white solid. ESI-MS (EI ⁺ , m/z): 533.0 [M+H] ⁺ . ¾- MR (500 MHz, CDC1 ₃ )5: 7.43-7.59 (m, 4H), 6.95-7.08 (m, 6H), 4.08 (s, 1H), 3.99 (s, 1H), 3.09-3.50 (m, 10H), 2.71-2.80 (m, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 1.97-2.00 (m, 2H), 1.49-1.62 (m, 2H).

Example 44: 2-(4-(6-((4-(4-Cyanophenyl)piperazin-l-yl)methyl)-3,5- dimethylpicolinoyl)piperazin-l-yl)-2,5-difluorobenzonitrile, 1-150

1-150

Synthetic scheme:

Procedures and characterization:

The analysis method was following Method B and the separation method was following Method D.

Step 1: 6-Bromo-3,5-dimethylpicolinaldehyde:

[00503] To a solution of 2,6-dibromo-3,5-dimethylpyridine (1.0 g, 3.77 mmol) in toluene (30 mL) was added «-BuLi (1.5 mL, 3.77 mmol) dropwise at -78 °C. After 1 h, DMF (358 mg, 4.9 mmol) was added to the mixture for additional lh. The mixture was adjusted to pH = 3-4 using HC1 and extracted with EtOAc (50 mL x 3) and the organic layers were concentrated and purified by chromatography (silica, ethyl acetate/petroleum ether =1/10) to afford 6-bromo-3,5- dimethylpicolinaldehyde (242 mg, 1.13 mmol, 30%) as a white solid. ESI-MS (EI ⁺ , m/z): 214.1 [M+H] ⁺ .

Step 2: 2-(4-((6-Bromo-3,5-dimethylpyridin-2-yl)methyl)piperazin-l-y l)benzonitrile:

[00504] A mixture of 6-bromo-3,5-dimethylpicolinaldehyde (500 mg, 2.35 mmol) and 2- (piperazin-l-yl)benzonitrile (439 mg, 2.35 mmol) in AcOH (0.1 mL) and ethanol (10 mL) was heated to 40 °C for 2 h. Then the mixture was cooled to rt. NaCNBH ₃ (296 mg, 4.69 mmol) was added. After 10 h of stirring at 20 °C, the mixture was quenched with water and purified by prep- HPLC to afford 2-(4-((6-bromo-3,5-dimethylpyridin-2-yl)methyl)piperazin-l-y l)benzonitrile (190 mg, 0.49 mmol, 21%). ESI-MS (EI ⁺ , m/z): 385.1 [M+H] ⁺ .

Step 3: Methyl 6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5-dimethylpico linate:

[00505] A mixture of 2-(4-((6-bromo-3,5-dimethylpyridin-2-yl)methyl)piperazin-l- yl)benzonitrile (100 mg, 0.26 mmol), CH ₃ COONa (64 mg, 0.78 mmol) and Pd(dppf)Cl ₂ (10 mg, 0.01 mmol) in MeOH (15 mL) was stirred at 90 °C under CO (1 MPa) for 16 h. The mixture was washed with water and extracted with EtOAc (40 mL x 3) to afford methyl 6-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-3,5-dimethylpicolinate (57 mg, 0.16 mmol, 60%). ESI-MS (EI ⁺ , m/z): 365.2 [M+H] ⁺ .

Step 4: 6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5-dimethylpico linic acid:

[00506] A mixture of methyl 6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5- dimethylpicolinate (600 mg, 1.65 mmol) and NaOH (2 N, 5 mL) in THF (5 mL) and MeOH (5 mL) was stirred at rt for 4 hrs. The mixture was adjusted to pH = 3-4 and extracted with EtOAc (50 mL x 3). The organice layer was concentrated to give 6-((4-(2-cyanophenyl)piperazin-l- yl)methyl)-3,5-dimethylpicolinic acid (520 mg, 1.49 mmol, 90%) as a brown solid. ESI-MS (EI, m/z): 349 [M-H]\

[00507] Step 5: 2-(4-(6-((4-(4-Cyanophenyl)piperazin-l-yl)methyl)-3,5- dimethylpicolinoyl)piperazin-l-yl)-2,5-difluorobenzonitrile, 1-150: A mixture of 6-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-3,5-dimethylpicolinic acid (100 mg, 0.285 mmol), 2,5- difluoro-4-(piperazin-l-yl)benzonitrile (74 mg, 0.33 mmol), HATU (163 mg, 0.43 mmol) and DIPEA (111 mg, 0.86 mmol) in DMF (4.00 mL) was stirred at 20 °C for 16h. The mixture was purified by prep-HPLC to afford 4-(4-(6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5- dimethylpicolinoyl)piperazin-l-yl)-2,5-difluorobenzonitrile 1-150 (53 mg, 34%) as a white solid ESI-MS (EI ⁺ , m/z): 555.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.55 (dd, J = 7.7, 1.4 Hz, 1H), 7.49 _ 7.43 ( _m> 1H), 7.37 (s, 1H), 7.21 (dd, J = 12.0, 5.9 Hz, 1H), 6.98 (dd, J = 17.8, 8.0 Hz, 2H), 6.68 (dd, J = 10.6, 6.9 Hz, 1H), 4.06 - 3.92 (m, 2H), 3.72 (s, 2H), 3.48 - 3.41 (m, 2H), 3.38 - 3.31 (m, 2H), 3.22 (dd, J = 13.4, 8.7 Hz, 6H), 2.70 (s, 4H), 2.43 (s, 3H), 2.33 (s, 3H).

Example 45. Synthesis of 4-((S)-4-(5-(((2R,6S)-4-(2-cyanophenyl)-2,6-dimethylpiperazi n-l- yl)methyl)-2,4-dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5- difluorobenzonitrile, 1-351

1-351

Synthetic scheme:

Procedures and characterization:

[00508] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: Methyl-5-(hydroxymethyl)-2,4-dimethylbenzoate

[00509] To a solution of methyl-5-(hydroxymethyl)-2,4-dimethylbenzoate (19.2 g, 100.0 mmol) in MeOH (40 mL) was added NaBH ₄ (7.6 g, 200.0 mmol) in portions at 0 °C for 0.5 h. Then the solution was quenched with water (200 mL) and extracted with DCM (3 x 150 mL). The organic phases were combined and concentrated in vacuo, yielding the crude product as a white solid (13.0 g, 67 mmol) which was used without further purification.

Step 2: Methyl 5-(chloromethyl)-2,4-dimethylbenzoate

[00510] To a solution of methyl-5-(hydroxymethyl)-2,4-dimethylbenzoate (13.0 g, 67 mmol) and DIPEA (17.3 g, 134 mmol) in DCM (100 mL) was added MsCl (11.4 g, 100 mmol) dropwise at rt. Then the solution was stirred at rt for 12 h. After the completion of the reaction, as monitored by TLC, the reaction was quenched with H ₂ 0 (150 mL) and extracted with DCM (3 x 150 mL). The organic phases were combined and concentrated to yield the crude mixture which was then purified by column chromatography (EtOAc/PE = 1 :20 to 1 :5). The desired product was obtained as a white solid (9.0 g, 42 mmol).

Step 3: 2-(cis-3,5-Dimethylpiperazin-l-yl)benzonitrile

[00511] A solution of 2-fluorobenzonitrile (2.42 g, 20 mmol) and potassium carbonate (6.90 g, 50 mmol) in DMF (15 mL) was added c/s-2,6-dimethylpiperazine (2.51 g, 22 mmol) at rt. The reaction was heated to 110 °C for 12 h. Then the reaction mixture was cooled to rt, diluted with H ₂ 0 (100 mL) and extracted with EtOAc (3 x 80 mL). The organic phases were combined, washed with brine twice, and concentrated. The crude mixture was then purified by reverse phase flash chromatography (H ₂ 0/MeCN = 95:5 to 20:80) to afford the yellow solid (2.37 g, 11 mmol). ESI- MS (EI ⁺ , m/z): 216.2 [M+H] ⁺ .

Step 4: Methyl-5-((4-(2-cyanophenyl)-ci ^' s-2,6-dimethylpiperazin-l-yl)methyl)-2,4- dimethylbenzoate

[00512] To a solution of 2-(cis-3,5-dimethylpiperazin-l-yl)benzonitrile (2.37 g, 11 mmol) and potassium carbonate (3.04 g, 22 mmol) in DMF (20 mL) was added methyl-5-(chloromethyl)-2,4- dimethylbenzoate (3.20 g, 15 mmol) at rt. The reaction was heated to 50 °C for 12 h. The reaction mixture was cooled to rt, diluted with H ₂ 0 (100 mL) and extracted with EtOAc (3 x 80 mL). The organic phases were combined, washed twice with brine, and concentrated. The crude mixture was then purified by column chromatography (EtOAc/PE = 1 : 10 to 1 :2) to afford a yellow solid (1.80 g, 4.6 mmol). ESI-MS (EI ⁺ , m/z): 392.3 [M+H] ⁺ .

Step 5: 5-((4-(2-Cyanophenyl)-ci ^' s-2,6-dimethylpiperazin-l-yl)methyl)-2,4-dimethylbenzo ic acid [00513] To a solution of methyl 5-((4-(2-cyanophenyl)-cz ^' s-2,6-dimethylpiperazin-l- yl)methyl)-2,4-dimethylbenzoate (1.17 g, 3 mmol) in DCM (20 mL) was added borontribromide (7.5 g, 30 mmol) dropwise at 0 °C. The reaction mixture was warmed to rt and stirred for 12 h. Then the reaction was quenched with H ₂ 0 (40 mL) and the pH was adjusted to 7. The mixture was extracted with DCM (3 x 40 mL) and the organic phases were combined and concentrated. A crude mixture was obtained as brown oil (415 mg, 1.1 mmol) which was used without further purification. ESI-MS (EI ⁺ , m/z): 378.3 [M+H] ⁺ .

Step 6: 4-((S)-4-(5-(((2R,6S)-4-(2-cyanophenyl)-2,6-dimethylpiperazi n-l-yl)methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5-difluorobenzoni trile, 1-351

[00514] To a solution of 5-((4-(2-cyanophenyl)-cis-2,6-dimethylpiperazin-l-yl)methyl) -2,4- dimethylbenzoic acid (377 mg, 1.0 mmol), HATU (494 mg, 1.3 mmol), and DIPEA (645 mg, 5.0 mmol) in DMF (4 mL) was added (,S)-4,5-difluoro-2-(3-methylpiperazin-l-yl)benzonitrile hydrochloride (411 mg, 1.5 mmol) at rt. The reaction was stirred at rt overnight. Then the solution was purified by prep-HPLC (Boston CI 8 21 *250mm ΙΟμπι, Mobile phase: A: 0.1 % ammonium hydrogen carbonate; B: acetonitrile) to afford 4-((S)-4-(5-(((2R,6S)-4-(2-cyanophenyl)-2,6- dimethylpiperazin-l-yl)methyl)-2,4-dimethylbenzoyl)-3-methyl piperazin-l-yl)-2,5- difluorobenzonitrile 1-351 (13.4 mg, 0.022 mmol, 2%) as a white solid. MS (EI ⁺ , m/z): 597.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDC13) δ 7.64 (s, 1H), 7.57 (d, J= 7.5 Hz, 1H), 7.50-7.47 (m, 1H), 7.21 (dd, J= 12.0, 6.0 Hz, 1H), 7.00 (t, J = 7.5 Hz, 3H), 6.62 (s, 1H), 3.66 (s, 2H), 3.57-3.41 (m, 5H), 2.94 (s, 3H), 2.74 (s, 2H), 2.29-2.22 (m, 6H), 1.56 (s, 6H), 0.95 (s, 6H).

Example 46. Synthesis of (S)-4-(4-(5-((4-(2-cyanophenyl)-2,2-dimethylpiperazin-l- yl)methyl)-2,4-dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5- difluorobenzonitrile, 1-352

1-352

Synthetic scheme:

Procedures and characterization:

[00515] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: (2-(3,3-Dimethylpiperazin-l-yl)benzonitrile

[00516] A solution of 2-fluorobenzonitrile (2.42 g, 20 mmol) and potassium carbonate (6.90 g, 50 mmol) in DMF (15 mL) was added 2,2-dimethylpiperazine (2.51 g, 22 mmol) at rt. The reaction was heated to 110 °C for 12 h. Then the solvent was cooled down to rt, diluted with H ₂ 0 (100 mL), and extracted with EtOAc (3 x 80 mL). The organic phases were combined, washed with brine twice, and concentrated. The crude mixture was then purified by reverse flash chromatography (H ₂ 0/MeCN = 95:5 to 20:80) to afford a yellow solid (2.92 g, 13.6 mmol). ESI- MS (EI ⁺ , m/z): 216.2 [M+H] ⁺ .

Step 2: Methyl 5-((4-(2-cyanophenyl)-2,2-dimethylpiperazin-l-yl)methyl)-2,4 - dimethylbenzoate

[00517] To a solution of 2-(3,3-dimethylpiperazin-l-yl)benzonitrile (2.92 g, 13.6 mmol) and potassium carbonate (3.75 g, 27.2 mmol) in DMF (20 mL) was added methyl-5-(chloromethyl)- 2,4-dimethylbenzoate (4.24 g, 20 mmol) at rt. The reaction was heated to 50 °C for 12 h, then the reaction mixture was cooled to rt, diluted with H ₂ 0 (100 mL), and extracted with EtOAc (3 x 80 mL). The organic phase was combined, washed with brine twice, and concentrated. The crude mixture was then purified by column chromatography (EtOAc/PE = 1 : 10 to 1 :2) to afford a yellow solid (2.42 g, 6.2 mmol). ESI-MS (EI ⁺ , m/z): 392.3 [M+H] ⁺ .

Step 3: 5-((4-(2-cyanophenyl)-2,2-dimethylpiperazin-l-yl)methyl)-2,4 -dimethylbenzoic acid

[00518] A solution of methyl-5-((4-(2-cyanophenyl)-2,2-dimethylpiperazin-l-yl)meth yl)-2,4- dimethylbenzoate (1.17 g, 3 mmol) in DCM (20 mL) was added borontribromide (7.5 g, 30 mmol) dropwise at 0 °C. The reaction mixture was warmed to rt and stirred for 12 h, then the reaction was quenched with H ₂ 0 (40 mL) and the pH was adjusted to 7. The mixture was extracted with DCM (3 x 40 mL) and the organic phases were combined and concentrated. The crude mixture was obtained as brown oil (528 mg, 1.4 mmol) which was used without further purification. ESI- MS (EI+, m/z): 378.3 [M+H]+.

Step 4: (S)-4-(4-(5-((4-(2-cyanophenyl)-2,2-dimethylpiperazin-l-yl)m ethyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5-difluorobenzoni trile, 1-352

[00519] To a solution of 5-((4-(2-cyanophenyl)-2,2-dimethylpiperazin-l-yl)methyl)-2,4 - dimethylbenzoic acid (377 mg, 1.0 mmol), HATU (494 mg, 1.3 mmol), and DIPEA (645 mg, 5.0 mmol) in DMF (4 mL) was added (,S)-4,5-difluoro-2-(3-methylpiperazin-l-yl)benzonitrile hydrochloride (411 mg, 1.5 mmol) at rt. The reaction was stirred at rt overnight, then the solution was purified by prep-HPLC (Boston C18 21 *250mm ΙΟμπι, mobile phase: A: 0.1 % ammonium hydrogen carbonate; B: acetonitrile) to afford (S)-4-(4-(5-((4-(2-cyanophenyl)-2,2- dimethylpiperazin-l-yl)methyl)-2,4-dimethylbenzoyl)-3-methyl piperazin-l-yl)-2,5- difluorobenzonitrile 1-352 (32.5 mg, 0.055 mmol, 5.5%) as a white solid. MS (EI ⁺ , m/z): 597.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 7.56 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.23- 7.19 (m, 2H), 7.06-6.92 (m, 3H), 6.64 (s, 1H), 3.52-3.38 (m, 6H), 3.01-2.83 (m, 6H), 2.61 (s, 2H), 2.35-2.22 (m, 6H), 2.22 (s, 1H), 1.56 (s, 9H).

Example 47. Synthesis of (S)-2-(4-(5-(l-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4- dimethylbenzoyl)piperazin-l- l)benzonitrile, 1-86

1-86

Synthetic scheme:

Procedures and characterization:

[00520] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: 5-bromo-2,4-dimethylbenzoic acid

[00521] To a solution of 2,4-dimethylbenzoic acid (10.0 g, 66.6 mmol) in TFA (100 mL) was added NBS (11.8 g, 66.6 mmol) and the solution was stirred for 17 h at 50 °C. The solution was concentrated to give the crude, which was recrystallized from EtOAc (20 mL) to afford 5-bromo- 2,4-dimethylbenzoic acid (7.8 g, 34.6 mmol, 51%) as a white solid. MS (EI ⁺ , m/z): 229.1 [M+2] ⁺ . ¾ NMR (500 MHz, CD ₃ OD) δ 8.22 (s, 1H), 7.14 (s, 1H), 2.57 (s, 3H), 2.41 (s, 3H).

Step 2: 5-bromo-N-methoxy-N,2,4-trimethylbenzamide

[00522] To a solution of 5-bromo-2,4-dimethylbenzoic acid (3.0 g,13.1 mmol) in DMF (20 mL) was added HATU (6.4 g, 17.0 mmol), DIPEA (6.9 g, 53.7 mmol), and Ν,Ο- dimethylhydroxylamine (1.4 g,14.4 mmol). The mixture was stirred for 17 h at rt. The mixture was diluted with water (50 mL), and extracted with DCM (50 mL x 3). The organic layer was washed with brine (50 mL x 3), dried (Na ₂ S04), filtered, and concentrated in vacuum. The crude product was purified by chromatography (silica, EtOAc/PE = 1/10) to afford 5-bromo-N-methoxy- N,2,4-trimethylbenzamide (4.7 g) as a yellow oil. ESI-MS (EI+, m/z): 273 [M+2] ⁺ .

Step 3: l-(5-bromo-2,4-dimethylphenyl)ethanone

[00523] To a solution of 5-bromo-N-methoxy-N,2,4-trimethylbenzamide (4.3 g, 15.86 mmol) in THF (60 mL) was added MeMgBr (11.6 mL, 34.89 mmol) dropwise at -78 °C, then the mixture was stirred at rt for 17 h. The solution was diluted with water (20 mL) and extracted with EtOAc (50 x 3 mL). The organic phase was dried (Na ₂ S04), filtered, and concentrated in vacuo. The crude product was purified by chromatography (silica, EtOAc/PE = 1/10) to afford l-(5-bromo- 2,4-dimethylphenyl)ethanone (2.4 g, 66.6%) as a brown oil. ESI-MS (EI+, m/z): 227 [M+l] ⁺ . Step 4: 2-(4-(l-(5-bromo-2,4-dimethylphenyl)ethyl)piperazin-l-yl)ben zonitrile

[00524] To a solution of l-(5-bromo-2,4-dimethylphenyl)ethanone (500 mg, 2.21 mmol) in THF (20 mL) was added 2-(piperazin-l-yl)benzonitrile (496.5 mg, 2.65 mmol), Ti(OiPr) ₄ (0.93 mL, 4.42 mmol). The mixture was stirred for 17 h at 78 °C. To the mixture was added NaB¾CN (416.8 mg, 6.63 mmol) and MeOH (2 mL) at 0 °C. The mixture was stirred at rt for 3h, then diluted with water (20 mL), and extracted with EtOAc (50 x 3 mL). The organic phase was dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuo. The crude product was purified by chromatography (silica, EtOAc/PE = 1/10) to afford 2-(4-(l-(5-bromo-2,4-dimethylphenyl)ethyl)piperazin-l- yl)benzonitrile (490 mg, 55%). ESI-MS (EI+, m/z): 398 [M+H] ⁺ . ¾ NMR (500 MHz, DMSO) δ 7.61 (s, 1H), 7.54-7.56 (m, 1H), 7.45-7.47(m, 1H), 3.57(s, 1H), 3.17-.23 (m, 4H), 2.72 (s, 2H), 2.60 (s, 2H), 2.33 (s, 3H), 2.28 (s, 3H), 1.24-1.30 (m, 3H).

Step 5: methyl 5-(l-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4-dimethylben zoate

[00525] To a solution of 2-(4-(l-(5-bromo-2,4-dimethylphenyl)ethyl)piperazin-l- yl)benzonitrile (1.0 g, 2.51 mmol) in MeOH (20 mL) was added Pd(dppf)Cl ₂ (180 mg, 0.26 mmol) and NaOAc (619.7 mg, 7.53 mmol). The mixture was stirred for 17 h under CO at 110 °C. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum, the crude product was purified by chromatography (silica, EtOAc/PE = 1/5) to afford methyl-5-(l-(4-(2-cyanophenyl)piperazin-l- yl)ethyl)-2,4-dimethylbenzoate (300 mg, 20%) as yellow oil. ESI-MS (EI+, m/z): 378 [M+H] ⁺ . Step 6: 5-(l-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4-dimethylben zoic acid

[00526] To a solution of methyl-5-(l-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4- dimethylbenzoate (380 mg, 1.0 mmol) in MeOH (10 mL) was added LiOHH ₂ 0 (168 mg, 4.03 mmol), and H ₂ 0 (1 mL). The mixture was stirred for 17 h at rt. The solution was diluted with 1 M HC1 (20 mL) and extracted with DCM (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuum to afford 5-(l-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4- dimethylbenzoic acid (290 mg, 79%) as pay solid. ESI-MS (EI+, m/z): 364[M+H] ⁺ .

Step7: (S)-2-(4-(5-(l-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-86 [00527] To a solution of 5-(l-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4-dimethylben zoic acid (290 mg, 0.79 mmol) in DMF (10 mL) was added HATU (333.65 mg, 0.88 mmol), DIPEA (309.3mg, 2.39 mmol), and 2-(piperazin-l-yl)benzonitrile (149.3 mg, 0.79 mmol). The mixture was stirred for 17 h at rt, then diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phases were dried (Na ₂ S04), filtered, and concentrated in vacuo. The crude product was purified by TLC to give the crude and further purified by CHIRAL-HPLC to give (S)-2-(4- (5-(l-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4-dimethylbe nzoyl)piperazin-l- yl)benzonitrile(30 mg, 14% ) 1-86 as white solid. The stereochemistry was arbitrarily assigned.

[00528] ESI-MS (EI+, m/z): 533[M+H]+. ¾ MR (500 MHz, CDC13) δ 7.50-7.57 (m, 5H), 7.11-7.16 (m, 5H), 4.46-4.54 (m, 1H), 4.26-4.31 (m, 1H), 4.10 (s, 1H), 1.43 (s, 3H), 3.78-3.80 (m, 1H), 3.58-3.60 (m, 6H), 3.26-3.29 (m, 7H), 2.40-2.42 (m, 3H), 2.30-2.32 (m, 3H), 1.78-1.79 (m, 3H).

Example 48. Synthesis of 2-[(3S)-4-(5-{[(2S)-4-(2-cyanophenyl)-2-methylpiperazin-l- yl]methyl}-2,4-dimethylbenzenesulfonyl)-3-methylpiperazin-l- yl]pyridine-3-carbonitrile, I-

47

1-47

Synthetic scheme:

Procedures and characterization:

[00529] Analysis was performed following Method B. Separation was performed following Method D.

Stepl : (S)-2-(3-methylpiperazin-l-yl)nicotinonitrile

[00530] To a solution of 2-chloronicotinonitrile (3.0 g, 21.7 mmol) and (S)-2-methylpiperazine (2.17 g, 21.7 mmol) in DMF (10 mL) was added K ₂ C0 ₃ (9.0 g, 65.1 mmol). The mixture was stirred at 120 °C for 17 h. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phases were dried (Na ₂ S04), filtered, and concentrated in vacuo to afford (S)-2-(3-methylpiperazin-l-yl)nicotinonitrile (3.03 g, 80%) as yellow oil. ESI-MS (EI+, m/z: 203 [M+H] ⁺ .

Step2: (S)-5-(4-(3-cyanopyridin-2-yl)-2-methylpiperazin-l-ylsulfony l)-2,4-dimethylbenzoic acid

[00531] To a solution of 5-(chlorosulfonyl)-2,4-dimethylbenzoic acid (1.82 g, 7.4 mmol) in DCM (100 mL) was added Et ₃ N (0.7 g, 7.4 mmol) and a solution of (S)-2-(3-methylpiperazin-l- yl)nicotinonitrile (3.0 g, 14.8 mmol) in THF (100 mL) dropwise at -78 °C. The mixture was stirred at -78 °C for 3 h. The solution was diluted with water (100 mL) and extracted with DCM (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuo to give the crude product which was further purified by chromatography (silica, EtOAc/PE = 1/1) to afford (S)-5- (4-(3-cyanopyridin-2-yl)-2-methylpiperazin-l-ylsulfonyl)-2,4 -dimethylbenzoic acid (0.92 g, 80%) as yellow oil (purity about 70%). ESI-MS (EI+, m/z: 415 [M+H] ⁺ .

Step3: (S)-2-(4-(5-(hydroxymethyl)-2,4-dimethylphenylsulfonyl)-3-me thylpiperazin-l- yl)nicotinonitrile

[00532] To a solution of (S)-5-(4-(3-cyanopyridin-2-yl)-2-methylpiperazin-l-ylsulfony l)-2,4- dimethylbenzoic acid (l .Og, 1.44 mmol) in THF (20 mL) was added borane (4.35 mL, 4.35 mmol) at 0 °C. The mixture was stirred at rt for 17 h, then diluted with water (100 mL) and extracted with DCM (50 mL x 3). The organic phases were dried (Na ₂ S04), filtered and concentrated in vacuo to afford (S)-2-(4-(5-(hydroxymethyl)-2,4-dimethylphenylsulfonyl)-3-me thylpiperazin-l- yl)nicotinonitrile (0.4 g, 69%) as yellow oil. ESI-MS (EI+, m/z: 401 [M+H] ⁺ .

Step4: (S)-2-(4-(5-formyl-2,4-dimethylphenylsulfonyl)-3-methylpiper azin-l- yl)nicotinonitrile

[00533] To a solution of (S)-2-(4-(5-(hydroxymethyl)-2,4-dimethylphenylsulfonyl)-3- methylpiperazin-l-yl)nicotinonitrile (0.4 g, 0.99 mmol) in DMSO (10 mL) was added IBX (554.8 mg, 1.98 mmol) The mixture was stirred at rt for 17 h, then diluted with water (100 mL) and extracted with DCM (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuo to afford (S)-2-(4-(5-formyl-2,4-dimethylphenylsulfonyl)-3- methylpiperazin-l-yl)nicotinonitrile (0.35 g, 87%) as a white solid. ESI-MS (EI+, m/z: 399 [M+H] ⁺ .

Step 5: (S)-2-(3-methylpiperazin-l-yl)benzonitrile

[00534] To a solution of 2-fluorobenzonitrile (2.6 g, 14.3 mmol), (S)-2-methylpiperazine (1.43 g, 14.3 mmol) in DMF (10 mL) was added K ₂ C0 ₃ (5.9 g, 43.1 mmol). The mixture was stirred at 120 °C for 17 h, then diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phase was washed with brine (50 mL x 3), dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuo to afford (S)-2-(3-methylpiperazin-l-yl)benzonitrile (3.03 g, 80%) as a yellow oil. ESI-MS (EI+, m/z: 202 [M+H] ⁺ ).

Step 6: 2-((S)-4-(5-(((S)-4-(2-cyanophenyl)-2-methylpiperazin-l-yl)m ethyl)-2,4- dimethylphenylsulfonyl)-3-methylpiperazin-l-yl)nicotinonitri le, 1-47

[00535] To a solution of (S)-2-(4-(5-formyl-2,4-dimethylphenylsulfonyl)-3-methylpiper azin-l- yl)nicotinonitrile (120 mg, 0.3 mmol) and (S)-2-(3-methylpiperazin-l-yl)benzonitrile (60.1 mg, 0.3 mmol) in EtOH (10 mL) was added NaBH ₃ CN (56.5 mg, 0.9 mmol) and AcOH (0.1 mL). The mixture was stirred at rt for 17 h, then diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phase was washed with brine (50 mL x 3), dried (Na ₂ S04), filtered, and concentrated in vacuo to afford 2-((S)-4-(5-(((S)-4-(2-cyanophenyl)-2-methylpiperazin-l- yl)methyl)-2,4-dimethylphenylsulfonyl)-3-methylpiperazin-l-y l)nicotinonitrile 1-47 (30 mg, 20%) as a white solid. ESI-MS (EI+, m/z: 584 [M+H] ⁺ ). ¾ MR (500 MHz, CDC13) δ 8.32- 8.33 (m, 1H), 7.97 (s, 1H), 7.77-7.78 (m, 1H), 7.54-7.55 (m, 1H), 7.44-7.48 (m, 1H), 7.09 (s, 1H), 6.97-9.99 (m, 2H), 6.77-6.81 (m, 1H), 4.02-4.20 (m, 3H), 4.00-4.02 (m, 1H), 3.32-3.59 (m, 6H), 2.77-3.09 (m, 5H), 2.56 (s, 3H), 2.39 (s, 4H), 1.23-1.34 (m, 6H).

Example 49. Synthesis of 2-(4-(5-((4-(2-cyanophenyl)-3-oxopiperazin-l-yl)methyl)-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-108

1-108

Synthetic scheme:

Procedures and characterization:

[00536] Analysis was performed following Method A. Separation was performed following Method D.

Stepl: 5-formyl-2,4-dimethylbenzoic acid

[00537] To a solution of 5-bromo-2,4-dimethylbenzoic acid (4.8 g, 21.06 mmol), in THF (200 mL) was added «-Buli (21 mL, 52.65 mmol) at -78 °C dropwise. The mixture was stirred at -78 °C for 4h and DMF (5.85 g, 80.03mmol) was added to the mixture and then the mixture was stirred at -78 °C for 3h. The solution was diluted with 1M HC1 (100 mL) and extracted with EtOAc (100 mL x 3). The organic phase was washed brine (50 mL x 3), dried (Na ₂ S04), filtered and concentrated in vacuum to give the crude product. The crude product was purified by recrystallization from EtOAc (20 mL) to afford 5-formyl-2,4-dimethylbenzoic acid (1.82 g, 10.22 mmol, 48%) as a white solid. MS (EI-, m/z): 179 [M+l] ⁺ . ¾ MR (500 MHz, CD30D) δ 10.20 (s, 1H), 8.57 (s, 1H), 7.20 (s, 1H), 2.70 (s, 3H), 2.69 (s, 3H).

Step2: 2-(4-(5-formyl-2,4-dimethylbenzoyl)piperazin-l-yl)benzonitri le

[00538] To a solution of 5-formyl-2,4-dimethylbenzoic acid (1.82 g, 10.21 mmol) in DMF (20 mL) was added HATU (4.6 g, 12.26 mmol), DIPEA (3.96 g, 30.65 mmol), and 2-(piperazin-l- yl)benzonitrile (1.91 g, 10.21 mmol). The mixture was stirred for 17 h at rt. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuum. The crude product was purified by prep-HPLC to give 2-(4-(5-formyl-2,4-dimethylbenzoyl)piperazin-l-yl)benzonitri le (4.3 g) as a yellow solid. ESI-MS (EI+, m/z): 348 [M+H] ⁺ .

Step3: 2-(2-oxopiperazin-l-yl) benzonitrile

[00539] To a solution of ter/-butyl-4-(2-cyanophenyl)-3-oxopiperazine-l-carboxylate (300 mg, 0.99 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at 0 °C for 1 h. The solution was concentrated in vacuum and the crude product was washed with diethyl ether (10 mL) to give 2-(2-oxopiperazin-l-yl)benzonitrile crude product (400 mg) as a yellow solid. ESI- MS (EI+, m/z): 202 [M+H] ⁺ .

Step 4: 2-(4-(5-((4-(2-cyanophenyl)-3-oxopiperazin-l-yl)methyl)-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-108

[00540] To a solution of 2-(2-oxopiperazin-l-yl)benzonitrile (100 mg, 0.63 mmol) and 2-(4-(5- formyl-2,4-dimethylbenzoyl)piperazin-l-yl)benzonitrile (218.7 mg, 0.63 mmol) in EtOH (10 mL) was added NaBFLCN (1 17.8 mg, 1.89 mmol) and AcOH(0.1 mL). The mixture was stirred at rt for 17 h. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phase was washed brine (50 mL x 3), dried (Na ₂ S04), filtered, concentrated in vacuum and was purified by prep-HPLC to give 2-(4-(5-((4-(2-cyanophenyl)-3-oxopiperazin-l- yl)methyl)-2,4-dimethylbenzoyl)piperazin-l-yl)benzonitrile 1-108 (20 mg, 0.037mmol, 5%). ESI- MS (EI ⁺ , m/z): 533 [M+H] ⁺ . ¾ MR (500 MHz, CD30D) δ 7.48-7.77 (m, 6H), 7.15 (s, 1H), 7.02-7.07 (m, 3H), 3.98-4.11 (m, 2H), 3.63-3.56 (m, 4H), 3.49-3.58 (m, 4H), 3.27 (s, 1H), 3.11 (s, 1H), 2.87 (s, 2H), 2.38 (s, 3H), 2.30 (s, 2H).

Example 50. Synthesis of 2-[(3S)-4-{5-[(2S)-4-(3-cyanopyridin-2-yl)-2-methylpiperazin e-l- carbonyl]-2,4-dimethylbenzenesulfonyl}-3-methylpiperazin-l-y l]pyridine-3-carbonitrile, I- 85

1-85

Synthetic scheme:

Procedures and characterization:

[00541] Analysis was performed following Method A. Separation was performed following Method D.

Stepl: (S)-2-(3-methylpiperazin-l-yl)nicotinonitrile [00542] To a solution of 2-chloronicotinonitrile (3.0 g, 21.7 mmol) in DMF (15 mL) was added (S)-2-methylpiperazine (2.17 g, 21.7 mmol),and K2CO3 (9.0 g, 65.1 mmol). The mixture was stirred at 120 °C for 17 h. The solution was diluted with water (30 mL) and extracted with DCM (50 mL x 3). The organic phases were washed with brine (50 mL x 3), dried (Na ₂ S04), filtered, and concentrated in vacuo to afford (S)-2-(3-methylpiperazin-l-yl)nicotinonitrile (3.03 g, 15.0 mmol, 69%) as a pale oil. ESI-MS (EI+, m/z): 202 [M+H] ⁺ .

Step2: 2-((S)-4-(5-((S)-4-(3-cyanopyridin-2-yl)-2-methylpiperazin-l -ylsulfonyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)nicotinonitrile, 1-85

[00543] To a solution of (S)-2-(3-methylpiperazin-l-yl)nicotinonitrile (1.82 g, 7.4 mmol) in DCM (100 mL) was added TEA (704 mg, 7.4 mmol), and a solution of 5-(chlorosulfonyl)-2,4- dimethylbenzoic acid (3.0 g, 14.8 mmol) in THF dropwise at -78 °C. The mixture was stirred at -78 °C for 3 h, then diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic phases were washed with brine (50 mL x 3), dried (Na ₂ S04), filtered, and concentrated in vacuo. The crude product was purified by chromatography (silica, EtOAc/PE = 1/1) to afford

2- ((S)-4-(5-((S)-4-(3-cyanopyridin-2-yl)-2-methylpiperazin-l-y lsulfonyl)-2,4-dimethylbenzoyl)-

3- methylpiperazin-l-yl)nicotinonitrile 1-85 (760 mg, 1.27 mmol, 17%) as a white solid. ESI-MS (EI ⁺ , m/z): 599 [M+H] ⁺ . ¾ MR (500 MHz, DMSO) δ 8.41-8.42 (m, 2H), 8.09-8.11 (m, 2H), 7.60-7.74 (m, 1H), 7.38-7.40 (m, 1H), 6.95-6.99 (m, 2H), 4.85 (s, 0.5H), 4.47 (s, 0.5H), 3.91- 4.23 (m, 7H), 3.18-3.45 (m, 5H), 2.90-2.92 (m, 1H), 2.55 (s, 3H), 2.28 (s, 3H), 1.31-1.32 (m, 6H).

Example 51. Synthesis of 2-[(3S)-4-(5-{[l-(2-cyanophenyl)piperidin-4-ylidene]methyl}- 2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl]benzene-l-sulfonamid e, 1-20

1-20

Synthetic scheme:

Procedures and characterization:

[00544] Analysis was performed following Method B. Separation was performed following Method D.

Step 1 : ieri-butyl-4-(5-(methoxycarbonyl)-2,4-dimethylbenzylidene)pi peridine-l- carboxylate

[00545] To a solution of methyl-5-bromo-2,4-dimethylbenzoate (9.8 g, 40.09 mmol) in CH ₃ CN (50 mL) was added added tert-butyl 4-methylenepiperidine-l-carboxylate (11.85 g, 60.14 mmol), Et ₃ N (14.3 g, 142.1 mmol), tri(o-tolyl)phosphine (106.28 mg, 0.34 mmol), Pd(OAc) ₂ (19.59 mg, 0.082 mmol). The mixture was stirred for 17 h at 80 °C, then diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic phases were washed with brine (50 mL x 3), dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuo. The crude product was purified by chromatography (silica, EtOAc/PE = 1/20) to afford fer/-butyl-4-(5-(methoxycarbonyl)-2,4- dimethylbenzylidene)piperidine-l-carboxylate (1.22 g, 3.4 mmol, 8%) as a white solid. ESI-MS (EI+, m/z): 360 [M+H] ⁺ . ¾ MR (500 MHz, CDC13) δ 7.64 (s, 1H), 7.05 (s, 1H), 6.25 (s, 1H), 3.86 (s, 3H), 3.50-3.52 (m, 2H), 3.36-3.38 (m, 2H), 2.53-2.55 (m, 3H), 2.32-2.34 (m, 2H), 2.23- 2.26 (m, 4H), 1.48 (s, 10H).

Step 2: methyl 2,4-dimethyl-5-(piperidin-4-ylidenemethyl)benzoate

[00546] To a solution of tert-butyl 4-(5-(methoxycarbonyl)-2,4- dimethylbenzylidene)piperidine-l-carboxylate (900 mg, 2.5 mmol) in MeOH (10 mL) was added 4 M HCl/dioxane (10 mL) which was then stirred at rt for 3 h. The mixture was concentrated and the residue was diluted with NaHC0 ₃ (50 mL) and extracted with DCM (100 mL x 3). The organic phases were washed with brine (50 mL x 3), dried (Na ₂ S04), filtered, and concentrated in vacuo to afford methyl-2,4-dimethyl-5-(piperidin-4-ylidenemethyl)benzoate (600 mg, 2.31 mmol, 92%) as a yellow solid. ESI-MS (EI+, m/z): 260 [M+H] ⁺ .

Step 3: Methyl-5-((l-(2-cyanophenyl)piperidin-4-ylidene)methyl)-2,4- dimethylbenzoate

[00547] To a solution of methyl-2,4-dimethyl-5-(piperidin-4-ylidenemethyl)benzoate (800 mg, 3.08 mmol) in DMF (20 mL) was added K ₂ C0 ₃ (1.2 g, 9.25 mmol) and 2-fluorobenzonitrile (747.1 mg, 6.17 mmol). The mixture was stirred for 17 h at 120 °C, then diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic phases were washed with brine (50 mL x 3), dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuo, the crude product was purified by chromatography (silica, EtOAc/PE = 1/20) to afford methyl-5-((l-(2-cyanophenyl)piperidin-4- ylidene)methyl)-2,4-dimethylbenzoate (400 mg, 1.11 mmol, 36%) as a yellow oil. ESI-MS (EI+, m/z): 361 [M+H] ⁺ .

Step 4: 5-((l-(2-cyanophenyl)piperidin-4-ylidene)methyl)-2,4-dimethy lbenzoic acid

[00548] To a solution of methyl-5-((l-(2-cyanophenyl)piperidin-4-ylidene)methyl)-2,4- dimethylbenzoate (400 mg, 1.11 mmol) in MeOH (10 mL) was added LiOHH ₂ 0 (186 mg, 4.44 mmol) and H ₂ 0 (2 mL). The mixture was stirred for 17 h at rt, then concentrated in vacuo to afford the crude product. The crude product was diluted with 1M HCl (20 mL) and extracted with DCM (100 mL x 3). The organic phases were dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuo to afford 5-((l-(2-cyanophenyl)piperidin-4-ylidene)methyl)-2,4-dimethy lbenzoic acid (220 mg, 0.63 mmol, 57%) as a yellow solid. ESI-MS (EI+, m/z): 347[M+H] ⁺ .

Step 5: (S)-2-(4-(5-((l-(2-cyanophenyl)piperidin-4-ylidene)methyl)-2 ,4-dimethylbenzoyl)-3- methylpiperazin-l-yl)benzenesulfonamide, 1-20

[00549] To a solution of 5-((l-(2-cyanophenyl)piperidin-4-ylidene)methyl)-2,4- dimethylbenzoic acid (220 mg, 0.63 mmol) in DMF (10 mL) was added HATU (6.4 g, 17.0 mmol), DIPEA (6.9 g, 53.7 mmol), and (S)-2-(3-methylpiperazin-l-yl)benzenesulfonamide (162.1 mg, 03-.63 mmol). The mixture was stirred for 17 h at rt, then diluted with water (50 mL), and the solution was extracted with DCM (50 mL x 3). The organic layers were washed with brine (50 mL x 3) , dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuum. The crude product was purified by prep-HPLC to afford (S)-2-(4-(5-((l-(2-cyanophenyl)piperidin-4-ylidene)methyl)-2 ,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)benzenesulfonamide 1-20 (40 mg, 0.068 mmol, 10.8%) as a white solid. [00550] ESI-MS (EI+ m/z): 584 [M+l] ⁺ . ¾ MR (500 MHz, CDC13) δ 7.99-8.00 (m, 1H), 7.54-7.59 (m, 4H), 7.32 (s, 1H), 6.95-7.0 (m, 4H), 6.27 (s, 1H), 5.61 (s, 2H), 4.72-5.13 (m, 1H), 3.50-3.58 (m, 1H), 3.23-3.39 (m, 4H), 3.11-3.12 (m, 3H), 2.85-2.93 (m, 1H), 2.50-2.60 (m, 4H), 2.23-2.49 (m, 6H), 1.50-1.51 (m, 2H).

Example 52. Synthesis of 2-{4-[(lR)-l-{5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4 - dimethylphenyl}ethyl]piperazin-l-yl}benzonitrile, 1-87

1-87

Synthetic scheme:

Procedures and characterization:

[00551] Analysis was performed following Method A. Separation was performed following Method D.

[00552] The procedure for 2-amino-3-(l-m ethyl cyclobutyl)propanoic acid was the same as Example 47. Step 7: (S)-2-(4-(5-(l-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-87

[00553] To a solution of 5-(l-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4-dimethylben zoic acid (290 mg, 0.79 mmol) in DMF (10 mL) was added HATU (333.65 mg, 0.88 mmol) , DIPEA (309.3mg, 2.39 mmol), and 2-(piperazin-l-yl)benzonitrile (149.3 mg, 0.79 mmol). The mixture was stirred for 17 h at rt. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phases were dried (Na ₂ S04), filtered, and concentrated in vacuo. The crude product was purified by TLC then by CHIRAL-HPLC to give 2-{4-[(lR)-l-{5-[4-(2- cyanophenyl)piperazine-l-carbonyl]-2,4-dimethylphenyl}ethyl] piperazin-l-yl}benzonitrile (30 mg, 14% ) 1-87 as white solid. The stereochemistry was arbitrarily assigned. ESI-MS (EI+, m/z): 533[M+H]+. ¾ MR (500 MHz, CDCb) δ 7.51-7.58 (m, 5H), 7.04-7.17 (m, 5H), 4.45-4.54 (m, 1H), 4.25-4.35 (m, 1H), 4.06 (s, 1H), 3.73 (s, 1H), 3.50-3.63 (m, 6H), 2.86-3.61 (m, 7H), 2.40- 2.42 (m, 3H), 2.29-2.34 (m, 3H), 1.78-1.79 (m, 3H).

Example 53. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(6-methylpyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperidin- 1-yl] benzonitrile, 1-191

1-191

Synthetic scheme:

Procedures and characterization:

[00554] Analysis was performed following Method A. Separation was performed following Method D.

Stepl: ieri-butyl-4-(5-(methoxycarbonyl)-2,4-dimethylbenzylidene)pi peridine-l-carboxylate

[00555] To a solution of methyl-5-bromo-2,4-dimethylbenzoate (9.8 g, 40.09 mmol) in CH ₃ CN (50 mL) was added added tert-butyl 4-methylenepiperidine-l-carboxylate (11.85 g, 60.14 mmol), Et ₃ N (14.3 g, 142.1 mmol), tri(o-tolyl)phosphine (106.28 mg, 0.34 mmol), and Pd(OAc) ₂ (19.59 mg, 0.082 mmol). The mixture was stirred for 17 h at 80 °C. The solution was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic phase was washed brine (50 mL x 3), dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuo. The crude product was purified by chromatography (silica, EtOAc/PE = 1/20) to afford ter/-butyl-4-(5-(methoxycarbonyl)-2,4- dimethylbenzylidene)piperidine-l-carboxylate (1.22 g, 3.4 mmol, 8%) as a white solid. ESI-MS (EI+, m/z): 360 [M+H] ⁺ . ¾ MR (500 MHz, CDC13) δ 7.64 (s, 1H), 7.05 (s, 1H), 6.25 (s, 1H), 3.86 (s, 3H), 3.50-3.52 (m, 2H), 3.36-3.38 (m, 2H), 2.53-2.55 (m, 3H), 2.32-2.34 (m, 2H), 2.23- 2.26 (m, 4H), 1.48 (s, 10H).

Step 2: ieri-butyl-4-(5-(methoxycarbonyl)-2,4-dimethylbenzyl)piperid ine-l-carboxylate: [00556] To a mixture of tert-butyl-4-(5-(methoxycarbonyl)-2,4- dimethylbenzylidene)piperidine-l-carboxylate (640 mg, 1.78 mmol) in MeOH (30mL) was added Pd/C (300 mg). The mixture was stirred at rt for 17 h under H ₂ . The solution was filtered and concentrated in vacuo to afford tert-butyl-4-(5-(methoxycarbonyl)-2,4- dimethylbenzyl)piperidine-l-carboxylate (610 mg, 1.69 mmol, 95%) as a white solid. MS (EI+, m/z): 362 [M+H] ⁺ .

Step 3: Methyl-2,4-dimethyl-5-(piperidin-4-ylmethyl)benzoate

[00557] To a solution of tert-butyl-4-(5-(methoxycarbonyl)-2,4-dimethylbenzyl)piperid ine-l- carboxylate (1.8 g, 4.98 mmol) in DCM (10 mL) was added 4 M HCl/dioxane (10 mL) followed by stirring at rt for 3 h. The solution was concentrated in vacuo, then diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic phases were dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuo to afford methyl-2,4-dimethyl-5-(piperidin-4-ylmethyl)benzoate (1.2 g, 4.59 mmol, 97%) as a yellow oil. MS (EI+, m/z): 262 [M+H] ⁺ .

Step 4: Methyl-5-((l-(2-cyanophenyl)piperidin-4-yl)methyl)-2,4-dimet hylbenzoate

[00558] To a solution of methyl-2,4-dimethyl-5-(piperidin-4-ylmethyl)benzoate (1.2 g, 4.59 mmol) in DMF (20 mL) was added K ₂ C0 ₃ (1.9 g, 13.78 mmol) and 2-fluorobenzonitrile (834.2 mg, 6.88 mmol). The mixture was stirred for 17 h at 120 °C. The solution was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic phase was washed brine (50 mL x 3), dried (Na ₂ S0 ₄ ), filtered, and concentrated in vacuo. The crude product was purified by chromatography (silica, EtOAc/PE = 1/20) to afford methyl-5-((l-(2-cyanophenyl)piperidin-4- yl)methyl)-2,4-dimethylbenzoate (1.1 g, 3.03 mmol, 66%) as yellow oil. ESI-MS (EI+, m/z): 363 [M+H] ⁺ .

Step 5: 5-((l-(2-cyanophenyl)piperidin-4-yl)methyl)-2,4-dimethylbenz oic acid

[00559] To a solution of methyl-5-((l-(2-cyanophenyl)piperidin-4-yl)methyl)-2,4- dimethylbenzoate (800 mg, 3.04 mmol) in MeOH (10 mL) was added LiOHH ₂ 0 (382.1 mg, 9.12 mmol) and H ₂ 0 (1 mL). The mixture was stirred for 17 h at rt, concentrated in vacuo to give the crude, then diluted with 1M HC1 (20 mL) and extracted with DCM (100 mL x 3). The organic phases were dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuo to afford 5-((l-(2- cyanophenyl)piperidin-4-yl)methyl)-2,4-dimethylbenzoic acid (630 mg, 1.81 mmol, 90%) as a yellow solid. ESI-MS (EI+, m/z): 349 [M+H] ⁺ . Step 6: 2-(4-(2,4-dimethyl-5-(4-(6-methylpyridin-2-yl)piperazine-l- carbonyl)benzyl)piperidin-l-yl)benzonitrile, 1-191

[00560] To a solution of 5-((l-(2-cyanophenyl)piperidin-4-yl)methyl)-2,4-dimethylbenz oic acid (140 mg, 0.4 mmol) in DMF (10 mL) was added HATU (198.7 mg, 0.52 mmol), DIPEA (155mg, 1.2 mmol), and l-(6-methylpyridin-2-yl)piperazine (71.27 mg, 0.4 mmol). The mixture was stirred for 17 h at rt, then diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phases were dried (Na ₂ S04), filtered, and concentrated in vacuo. The crude product was purified first by TLC then by CHIRAL-HPLC to give 2-(4-(2,4-dimethyl-5-(4-(6- methylpyridin-2-yl)piperazine-l-carbonyl)benzyl)piperidin-l- yl)benzonitrile 1-191 (85.0 mg, 0.16 mmol, 45%) as white solid. ESI-MS (EI+, m/z): 508[M+H]+. ¹ H MR (500 MHz, DMSO) δ 7.65-7.67 (m, 1H), 7.53-7.56 (m, 1H), 7.41-7.44 (m, 1H), 7.11-7.13 (m, 1H), 7.04-7.06 (m, 2H), 6.96 (s, 1H), 6.52-6.61(m, 2H), 3.49-3.74 (m, 4H), 3.38-3.40 (m, 4H), 3.23 (s, 2H), 2.70-2.72 (m, 2H), 2.57-2.58 (m, 2H), 2.28 (s, 6H), 2.16 (s, 3H).

Example 54. Synthesis of 2-[4-({5-[4-(2-cyanophenyl)-3-oxopiperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)-2-oxopiperazin-l-yl]benzonitrile, 1-353

1-353

Synthetic scheme:

Procedures and characterization:

[00561] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 2-(2-oxopiperazin-l-yl)benzonitrile

[00562] To a solution of tert-butyl 4-(2-cyanophenyl)-3-oxopiperazine-l-carboxylate (300 mg, 0.99 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction mixture was stirred for 3 h at rt. The solution was concentrated in vacuo to give the crude product (400 mg) as a yellow oil which was used without futher purification. MS (EI+, m/z): 202 [M+H] ⁺ .

Step 2: 2-(4-(5-formyl-2,4-dimethylbenzoyl)-2-oxopiperazin-l-yl)benz onitrile

[00563] To a solution of 5-formyl-2,4-dimethylbenzoic acid (113 mg, 0.63 mmol) in DMF (10 mL) was added HATU (239.5 mg, 0.63 mmol), DIPEA (325.3mg, 2.52 mmol), and 2-(2- oxopiperazin-l-yl)benzonitrile (110 mg, 0.63 mmol). The mixture was stirred for 17 h at rt, then diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phases were dried (Na ₂ S04), filtered, and concentrated in vacuo. The crude product was purified by TLC to give the 2-(4-(5-formyl-2,4-dimethylbenzoyl)-2-oxopiperazin-l-yl)benz onitrile as a white solid (100 mg, 0.27 mmol, 43 %). ESI-MS (EI+, m/z): 362 [M+H] ⁺ .

Step 3: 2-(4-(5-((4-(2-cyanophenyl)-3-oxopiperazin-l-yl)methyl)-2,4- dimethylbenzoyl)-2- oxopiperazin-l-yl)benzonitrile, 1-353

[00564] To a solution 2-(4-(5-formyl-2,4-dimethylbenzoyl)piperazin-l-yl)benzonitri le (51.7 mg, 0.149 mmol) in EtOH (10 mL) was added NaBH ₃ CN (28.1 mg, 0.447 mmol), 2-(2- oxopiperazin-l-yl)benzonitrile(30.0 mg, 0.149 mmol), and AcOH(0.1 mL). The mixture was stirred at rt for 17 h, then diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phases were washed with brine (50 mL x 3), dried (Na ₂ S0 ₄ ), filtered, concentrated in vacuo, then purified by prep-HPLC to give 2-(4-(5-((4-(2-cyanophenyl)-3-oxopiperazin-l- yl)methyl)-2,4-dimethylbenzoyl)-2-oxopiperazin-l-yl)benzonit rile 1-353 (15 mg, 0.027mmol, 18%). ESI-MS (EI+, m/z): 547 [M+H] ⁺ . ¾ MR (500 MHz, CD30D) δ 7.73-7.75 (m, 4H), 7.40- 7.50 (m, 1H), 7.23 (s, 1H), 7.09 (s, 1H), 4.70 (s, 1H), 4.16-4.25 (m, 2H), 3.86 (s, 1H), 3.61-3.74 (m, 5H), 3.38-3.47 (m, 2H), 2.84-2.91 (m, 2H), 2.39 (s, 3H), 2.32 (s, 3H).

Example 55. Synthesis of 2-[4-({2,4-Dimethyl-5-[(2S)-2-methyl-4-(l-methyl-lH-pyrazol- 5- yl)piperazine-l-carbonyl]phenyl}methyl)piperazin-l-yl]benzon itrile, 1-152

1-152

Synthetic scheme:

Procedures and characterization:

[00565] The general procedure for Intermediate 83 was used obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

[00566] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: (S)-ieri-butyl-2-methyl-4-(l-methyl-4-nitro-lH-pyrazol-5-yl) piperazine-l- carboxylate

[00567] A mixture of 5-chloro-l -methyl-4-nitro-lH-pyrazole (1.00 g, 6.21 mmol), (S)-tert- butyl-2-methylpiperazine-l-carboxylate (1.86 g, 9.32 mmol), DIPEA (2.40 g, 18.6 mmol) in EtOH (20 mL) was microwave irradiated for 3 h at 130 °C. The reaction mixture was then cooled down, concentrated, and purified by chromatography (silica, PE/EtOAc = 10/1 to 5/1) to afford (,S)-tert- butyl-2-methyl-4-(l-methyl-4-nitro-lH-pyrazol-5-yl)piperazin e-l-carboxylate (1.92 g, 5.90 mmol, 95%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 326.0 [M+H] ⁺ .

Step 2: (S)-ieri-butyl-4-(4-amino-l-methyl-lH-pyrazol-5-yl)-2-methyl piperazine-l- carboxylate

[00568] A solution of (,S)-tert-butyl-2-methyl-4-(l-methyl-4-nitro-lH-pyrazol-5-yl )piperazine- 1-carboxylate (1.92 g, 5.90 mmol), HCOO H4 (1.49 g, 23.6 mmol) and Pd/C (400 mg) in MeOH (50 mL) was stirred at 80 °C for 2.5 h. The reaction mixture was then cooled down, filtered, and concentrated to give (,S)-tert-butyl-4-(4-amino-l-methyl-lH-pyrazol-5-yl)-2-methy lpiperazine-l- carboxylate (1.69 g, 5.72 mmol, 97%) as a white solid. ESI-MS (EI ⁺ , m/z): 296.0 [M+H] ⁺ .

Step 3: (S)-5-(4-(ieri-butoxycarbonyl)-3-methylpiperazin-l-yl)-l-met hyl-lH-pyrazole-4- diazonium

[00569] To a solution of (,S)-tert-butyl-4-(4-amino-l-methyl-lH-pyrazol-5-yl)-2- methylpiperazine-1 -carboxylate (1.20 g, 4.07 mmol) in EtOH (40 mL) was added HO Ac (20 mL), NaN0 ₂ (1M, 4.8 mL), and HC1 (1 M, 8 mL), successively, at 0 °C. The reaction was stirred at rt for 15 min, then concentrated, filtered, and concentrated further to afford the crude product (S)-5- (4-(tert-butoxycarbonyl)-3-methylpiperazin-l-yl)-l -methyl- lH-pyrazole-4-diazonium (1.23 g, 4.07 mmol, 100%) as a brown oil which was used without further purification. ESI-MS (EI ⁺ , m/z): 307.4 [M] ⁺ .

Step 4: (S)-ieri-butyl-2-methyl-4-(l-methyl-lH-pyrazol-5-yl)piperazi ne-l-carboxylate

[00570] A solution of (,S)-5-(4-(tert-butoxycarbonyl)-3-methylpiperazin-l-yl)-l-me thyl-lH- pyrazole-4-diazonium (1.23 g, 4.07 mmol) and Cu powder (0.60 g) in HO Ac (24 mL) was stirred at 100 °C for 0.5 h. The reaction mixture was filtered and concentrated to give (S)-fert-butyl-2- methyl-4-(l-methyl-lH-pyrazol-5-yl)piperazine-l-carboxylate (1.00 g, 3.57 mmol, 88%) as a brown oil. ESI-MS (EI ⁺ , m/z): 281.3 [M+H] ⁺ .

Step 5: (S)-3-methyl-l-(l-methyl-lH-pyrazol-5-yl)piperazine

[00571] A solution of (,S)-tert-butyl-2-methyl-4-(l-methyl-lH-pyrazol-5-yl)piperaz ine-l- carboxylate (500 mg, 1.78 mmol) in HCl/Dioxane (4 , 10 mL) and DCM (10 mL) was stirred at rt for 1 h. The reaction mixture was concentrated to afford (S)-3 -methyl- 1-(1 -methyl- lH-pyrazol- 5-yl)piperazine (300 mg, 1.67 mmol, 94%) as a brown oil. ESI-MS (EI ⁺ , m/z): 181.0 [M+H] ⁺ . Step 6: 2-[4-({2,4-Dimethyl-5-[(2S)-2-methyl-4-(l-methyl-li -pyrazol-5-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, I- 152

[00572] A mixture of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (180 mg, 0.51 mmol), (,S)-3-methyl-l-(l-methyl-lH-pyrazol-5-yl)piperazine (90 mg, 0.51 mmol), HATU (228 mg, 0.60 mmol), DIPEA (99 mg, 0.78 mmol) in DMF (4 mL) was stirred at rt for 1 h. The reaction mixture was then filtered and purified by prep-HPLC to afford 2-[4-({2,4-dimethyl- 5-[(2,S)-2-methyl-4-(l-methyl-lH-pyrazol-5-yl)piperazine-l-c arbonyl]phenyl}methyl)piperazin- l-yl]benzonitrile 1-152 (49.3 mg, 0.096 mmol, 19%) as a white solid. ESI-MS (EI ⁺ , m/z): 512 A [M+H] ⁺ . ¹ H MR (500 MHz, MeOD) δ 7.62 (d, J= 7.5 Hz, 1H), 7.57 (t, J= 7.5 Hz, 1H), 7.35 (s, 1H), 7.20-7.14 (m, 3H), 7.09 (t, J= 7.0 Hz, 1H), 5.96 (s, 1H), 3.76 (d, J= 1.5 Hz, 3H), 3.63-3.58 (m, 3H), 3.26-2.96 (m, 8H), 2.83-2.69 (m, 6H), 2.42 (s, 3H), 2.33-2.25 (m, 3H), 1.58-1.47 (m, 3H).

Example 56. Synthesis of 2-[4-({5-[(2S)-4-[2-(3-aminopropyl)phenyl]-2-methylpiperazin e-l- carbonyl]-2,4-dimethylphen l}methyl)piperazin-l-yl]benzonitrile, 1-192

1-192

Synthetic scheme:

Procedures and characterization:

[00573] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: terf-Butyl-3-(2-bromophenyl)propylcarbamate

[00574] To a solution of 3-(2-bromophenyl)propan-l-amine (3.0 g, 14.1 mmol) in THF (30 mL) was added saturated aqueous NaHCCb solution (30 mL), and Boc ₂ 0 (3.38 g, 15.5 mmol). The mixture was stirred at rt for 2 h, then H ₂ 0 (30 mL) and EtOAc (30 mL) were added and the organic phase was separated. The aqueous layer was further extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na ₂ S0 ₄ , filtered, and concentrated. The crude product was then purified by chromatography (silica, PE/EtOAc = 10/1) to afford ter/-butyl-3-(2-bromophenyl)propylcarbamate (3.80 g, 12.1 mmol, 86%) as a slight oil. ESI-MS (EI ⁺ , m/z): 336.0 [M+Na] ⁺ .

Step 2: ieri-Butyl-3-(2-bromophenyl)propyl(methoxymethyl)carbamate

[00575] To a solution of tert-butyl 3-(2-bromophenyl)propylcarbamate (2.8 g, 8.90 mmol) in DMF (50 mL) was added NaH (1.1 g, 26.8 mmol) at 0 °C. After being stirred at rt for 30 min, MOMBr (3.4 g, 26.8 mmol) was added and heated at 70 °C for 1 h. The reaction mixture was cooled down to rt and sat. aq. NH4CI (50 mL) and EtOAc (50 mL) were added. The organic phase was separated and the aqueous layer was further extracted with EtOAc (2 x 40 mL). The organic layers were combined, washed with brine (40 mL), dried over anhydrous Na ₂ S04, filtered, concentrated, and purified by chromatography (silica, PE/EtOAc = 10/1) to afford ter/-butyl-3-(2- bromophenyl)propyl(methoxymethyl)carbamate (1.70 g, 4.76 mmol, 54%) as a yellow oil. ESI- MS (EI ⁺ , m/z): 380.0 [M+Na] ⁺ .

Step 3: (S)-ieri-butyl-methoxymethyl(3-(2-(3-methylpiperazin-l- yl)phenyl)propyl)carbamate

[00576] A solution of ter/-butyl-3-(2-bromophenyl)propyl(methoxymethyl)carbamate (250 mg, 0.70 mmol), (,S)-2-methylpiperazine (140 mg, 1.40 mmol), Pd ₂ (dba) ₃ (64 mg, 0.07 mmol), BINAP (87 mg, 0.14 mmol), /-BuONa (202 mg, 2.10 mmol) in PhMe (10 mL) was stirred at 80 °C for 16 h under N ₂ atmosphere, then concentrated, and purified by chromatography (silica, PE/EtOAc = 10/1 to 5/1) to afford (5)-tert-butyl-methoxymethyl(3-(2-(3-methylpiperazin-l- yl)phenyl)propyl)carbamate (150 mg, 0.40 mmol, 57 %) as a yellow oil. ESI-MS (EI ⁺ , m/z): 378.0 [M+H] ⁺ .

Step 4: (S)-teri-butyl-3-(2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl) methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)phenyl)propyl(methox ymethyl)carbamate

[00577] A mixture of (,S)-tert-butyl-methoxymethyl(3-(2-(3-methylpiperazin-l- yl)phenyl)propyl)carbamate (150 mg, 0.40 mmol), 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)- 2,4-dimethylbenzoic acid (154 mg, 0.44 mmol), HATU (182 mg, 0.48 mmol), and DIPEA (103 mg, 0.80 mmol) in DMF (5 mL) was stirred at rt for 16 h. The mixture was then filtered to afford the crude product (,S)-tert-butyl-3-(2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl )methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)phenyl)propyl(methox ymethyl)carbamate (200 mg, 0.28 mmol, 70 %) as a brown liquid. ESI-MS (EI ⁺ , m/z): 709.0 [M+H] ⁺ .

Step 5: 2-[4-({5-[(2S)-4-[2-(3-aminopropyl)phenyl]-2-methylpiperazin e-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-192

[00578] A mixture of (_S)-ferf-butyl 3-(2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)phenyl)propyl(methox ymethyl)carbamate (200 mg, 0.28 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at rt for 2 h. The mixture was then concentrated and purified by prep-HPLC to afford 2-[4-({5-[(2S)-4-[2-(3-aminopropyl)phenyl]-2- methylpiperazine-l-carbonyl]-2,4-dimethylphenyl}methyl)piper azin-l-yl]benzonitrile 1-192 (92 mg, 0.16 mmol, 58%) as a white solid. ESI-MS (EI ⁺ , m/z): 565.0 [M+H] ⁺ . ¾ MR (500 MHz, MeOD) δ 7.71 (d, J= 7.5 Hz, 1H), 7.66 (t, J= 8.0 Hz, 1H), 7.47-7.34 (m, 2H), 7.27-7.20 (m, 5H), 7.13 (t, J = 7.0 Hz, 1H), 5.00 (br, 1H), 4.59-4.51(m, 2H), 3.72-3.36 (m, 9H), 3.03-2.79 (m, 8H), 2.53 (s, 3H), 2.41-2.32 (m, 3H), 2.06-2.00 (m, 2H), 1.62-1.31 (m, 4H).

Example 57. Synthesis of 2-[4-({5-[(2R)-4-[2-(3-aminopropyl)phenyl]-2-methylpiperazin e-l- carbonyl]-2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitr ile, 1-193

Procedures and characterization:

[00579] Analysis was performed following Method A. Separation was performed following Method C.

[00580] The procedure for tert-butyl-3-(2-bromophenyl)propyl(methoxymethyl)carbamate was the same as Example 56.

Step 1: (R)-terf-butyl methoxymethyl(3-(2-(3-methylpiperazin-l- yl)phenyl)propyl)carbamate

[00581] A solution of tert-butyl-3-(2-bromophenyl)propyl(methoxymethyl)carbamate (250 mg, 0.70 mmol), (R)-2-methylpiperazine (140 mg, 1.40 mmol), Pd ₂ (dba)3 (64 mg, 0.07 mmol), BINAP (87 mg, 0.14 mmol), t-BuONa (202 mg, 2.10 mmol) in PhMe (10 mL) was stirred at 80 °C for 16 h under N ₂ atmosphere. The solution was then concentrated and purified by chromatography (silica, PE/EtOAc = 10/1 to 5/1) to afford (R)-tert-butyl-methoxymethyl(3-(2-(3- methylpiperazin-l-yl)phenyl)propyl)carbamate (130 mg, 0.34 mmol, 49%) as a yellow oil. ESI- MS (EI ⁺ , m/z): 378.0 [M+H] ⁺ .

Step 2: (R)-teri-butyl-3-(2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl) methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)phenyl)propyl(methox ymethyl)carbamate

[00582] A mixture of (R)-tert-butyl-methoxymethyl(3-(2-(3-methylpiperazin-l- yl)phenyl)propyl)carbamate (130 mg, 0.34 mmol), 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)- 2,4-dimethylbenzoic acid (120 mg, 0.34 mmol), HATU (155 mg, 0.41 mmol), and DIPEA (88 mg, 0.68 mmol) in DMF (5 mL) was stirred at rt for 16 h. The mixture was then filtered to afford the crude product (R)-tert-butyl-3-(2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl) methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)phenyl)propyl(methox ymethyl)carbamate (200 mg, 0.28 mmol, 83 %) as a brown liquid. ESI-MS (EI ⁺ , m/z): 709.0 [M+H] ⁺ .

Step 3: 2-[4-({5-[(2R)-4-[2-(3-aminopropyl)phenyl]-2-methylpiperazin e-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-193

[00583] A mixture of (R)-fert-butyl 3-(2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)phenyl)propyl(methox ymethyl)carbamate (200 mg, 0.28 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at rt for 2 h. The mixture was then concentrated and purified by prep-HPLC to afford 2-[4-({5-[(2R)-4-[2-(3-aminopropyl)phenyl]- 2-methylpiperazine-l-carbonyl]-2,4-dimethylphenyl }methyl)piperazin-l-yl]benzonitrile 1-193 (32.3 mg, 0.057 mmol, 20% ) as a white solid. ESI-MS (EI ⁺ , m/z): 565.0 [M+H] ⁺ . ¾ MR (500 MHz, MeOD) δ 7.71 (d, J = 7.5 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.45-7.33 (m, 2H), 7.27-7.21 (m, 5H), 7.13 (t, J = 7.0 Hz, 1H), 5.00 (br, 1H), 4.64-4.50(m, 2H), 3.67-3.39 (m, 9H), 3.03-2.82 (m, 8H), 2.53 (s, 3H), 2.44-2.30 (m, 3H), 2.06-1.98 (m, 2H), 1.61-1.32 (m, 4H).

Example 58. Synthesis of 2-[6-({5-[4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl]-2,4 - dimethylphenyl} methyl)-3,6-diazabic clo [3.1.1] heptan-3-yl] benzonitrile, 1-144

1-144

Synthetic scheme:

1-144

Procedures and characterization:

[00584] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: ieri-Butyl-3-(2-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptane- 6-carboxylate

[00585] A mixture of tert-butyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (210 mg, 1.06 mmol), 2-iodobenzonitrile (364 mg, 1.59 mmol) and cesium carbonate (690 mg, 2.12 mmol), XantPhos (123 mg, 0.21 mmol), and Pd ₂ (dba)3 (101 mg, 0.11 mmol) in dioxane (20 mL) was stirred at 110 °C for 16 h. The mixture was then cooled, concentrated, and purified by chromatography (silica, PE/EtOAc = 10/1 to 5/1) to afford tert-butyl-3-(2-cyanophenyl)-3,6- diazabicyclo[3.1.1]heptane-6-carboxylate(100 mg, 0.33 mmol, 32%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 322.0 [M+Na] ⁺ .

Step 2: 2-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)benzonitrile

[00586] A mixture of tert-butyl-3-(2-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptane- 6- carboxylate (90 mg, 0.30 mmol) in TFA (2 mL) and DCM (2mL) was stirred at rt for 3 h. The mixture was then concentrated to afford the crude product 2-(3,6-diazabicyclo[3.1.1]heptan-3- yl)benzonitrile (60 mg, 0.30 mmol, 100 %) as a yellow oil. ESI-MS (EI ⁺ , m/z): 200.0 [M+H] ⁺ . Step 3: 2-[6-({5-[4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl]-2,4 - dimethylphenyl} methyl)-3,6-diazabicyclo [3.1.1] heptan-3-yl] benzonitrile, 1-144

[00587] A mixture of 2-(3,6-diazabicyclo[3.1.1]heptan-3-yl)benzonitrile (60 mg, 0.30 mmol), 5-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2,4-dimeth ylbenzaldehyde (123 mg, 0.36 mmol), and NaBH ₃ CN (38 mg, 0.60 mmol) in EtOH (5 mL) was stirred at 40 °C for 24 h. The mixture was then filtered and purified by prep-HPLC to afford 2-[6-({5-[4-(5-fluoropyridin-2- yl)piperazine-l-carbonyl]-2,4-dimethylphenyl}methyl)-3,6-dia zabicyclo[3.1.1]heptan-3- yl]benzonitrile 1-144 (7.4 mg, 0.014 mmol, 5%) as a white solid. ESI-MS (EI+, m/z): 525 [M+H] ⁺ . ¾ NMR (500 MHz, MeOD) δ 8.03 (d, J = 3.0 Hz, 1H), 7.54-7.41(m, 3H), 7.23 (s, 1H), 7.13 (s, 1H), 7.06 (d, J= 9.0 Hz, 1H), 6.89 (dd, J= 9.5 Hz, 3.5 Hz, 1H), 6.82 (t, J= 7.5 Hz, 1H), 3.99-3.76 (m, 8H), 3.68-3.61 (m, 4H), 3.46-3.36 (m, 4H), 2.71-2.67 (m, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 1.72 (d, J= 8.0 Hz, 1H).

Example 59. Synthesis of 4-(2-Aminoethyl)-2-[4-(5-{[4-(2-cyanophenyl)piperazin-l- yl]methyl}-2,4-dimethylbenzoyl)piperazin-l-yl]benzonitrile, 1-64

1-64

Synthetic scheme:

Procedures and characterization:

[00588] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: terf-Butyl-4-cyano-3-fluorophenethylcarbamate

[00589] A mixture of 4-bromo-2-fluorobenzonitrile (1.0 g, 5.0 mmol), potassium (2- tert- butoxycarbonylamino)ethyl)trifluoroborate (1.88 g, 7.5 mmol), cesium carbonate (3.26 g, 10 mmol), butyl-di-l-adamantylphosphine (358 mg, 1.0 mmol), and Pd(OAc) ₂ (112 mg, 0.5 mmol) in dioxane (20 mL) and H ₂ 0 (2 mL) was stirred at 110 °C for 16 h. The mixture was then cooled down, concentrated, and purified by chromatography (silica, PE/EtOAc = 10/1 to 3/1) to afford- tert-butyl-4-cyano-3-fluorophenethylcarbamate (530 mg, 2.0 mmol, 40%) as a yellow oil. ESI- MS (EI+, m/z): 265.0 [M+H] ⁺ .

Step 2: terf-Butyl-4-cyano-3-(piperazin-l-yl)phenethylcarbamate

[00590] A mixture of tert-butyl-4-cyano-3-fluorophenethylcarbamate (530 mg, 2.0 mmol), piperazine (258 mg, 3.0 mmol), and DIPEA (516 mg, 4.0 mmol) in DMSO (10 mL) was stirred at 140 °C in sealed tube for 16 h. H ₂ 0 (20 mL) and EtOAc (20 mL) were then added and the organic phase was separated. The aqueous was extracted further with EtOAc (2 x 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na ₂ S0 ₄ , filtered, concentrated, and purified by chromatography (silica, PE/EtOAc = 10/1 to 3/1) to afford tert-butyl- 4-cyano-3-(piperazin-l-yl)phenethylcarbamate (610 mg, 1.85 mmol, 92%) as a brown oil. ESI- MS (EI ⁺ , m/z): 331.0 [M+H] ⁺ .

Step 3: ieri-Butyl-4-cyano-3-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl )methyl)-2,4- dimethylbenzoyl)piperazin-l-yl)phenethylcarbamate

[00591] A mixture of tert-butyl 4-cyano-3-(piperazin-l-yl)phenethylcarbamate (100 mg, 0.30 mmol), 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (120 mg, 0.34 mmol), HATU (155 mg, 0.41 mmol), and DIPEA (88 mg, 0.68 mmol) in DMF (5 mL) was stirred at rt for 16 h. The reaction mixture was then filtered and purified by prep-HPLC to afford tert- butyl-4-cyano-3-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)meth yl)-2,4- dimethylbenzoyl)piperazin-l-yl)phenethylcarbamate (85 mg, 0.13 mmol, 43 %) as a white solid. ESI-MS (EI ⁺ , m/z): 662.0 [M+H] ⁺ .

Step 4: 4-(2-Aminoethyl)-2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)m ethyl)-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-64

[00592] A mixture of tert-butyl-4-cyano-3-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl )methyl)- 2,4-dimethylbenzoyl)piperazin-l-yl)phenethylcarbamate (85 mg, 0.13 mmol) in TFA (3 mL) and DCM (3 mL) was stirred at rt for 1 h. The mixture was concentrated and purified by prep-HPLC to afford 4-(2-aminoethyl)-2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)m ethyl)-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile 1-64 (44 mg, 0.078 mmol, 60 %) as a white solid.

[00593] ESI-MS (EI ⁺ , m/z): 562.0 [M+H] ⁺ . ¾ MR (500 MHz, MeOD) δ 7.71 (d, J= 7.0 Hz, 1H), 7.68-7.65 (m, 2H), 7.43 (s, 1H), 7.36 (s, 1H), 7.24 (dd, J= 16.5 Hz, 8.5 Hz, 2H), 7.12 (s, 1H), 7.08 (d, J= 8.0 Hz, 1H), 4.56-4.51 (m, 2H), 4.08-3.96 (m, 2H), 3.60-3.33 (m, 10H), 3.28-3.17 (m, 6H), 3.02 (t, J= 8.0 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H).

Example 60. Synthesis of 3-(2-Aminoethyl)-2-[4-(5-{[4-(2-cyanophenyl)piperazin-l- yl]methyl}-2,4-dimethylbenzoyl)piperazin-l-yl]benzonitrile, 1-27

1-27

Synthetic scheme:

Procedures and characterization:

[00594] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: Benzyl 4-(2-bromo-6-cyanophenyl)piperazine-l-carboxylate

[00595] A mixture of 3-bromo-2-fluorobenzonitrile (2.0 g, 10.1 mmol), benzyl piperazine-1- carboxylate (3.3 g, 15.1 mmol), and DIPEA (2.6 g, 20.2 mmol) in DMSO (15 mL) was stirred at 140 °C in sealed tube for 16 h. H ₂ 0 (20 mL) and EtOAc (20 mL) was then added and the organic layer was separated. The aqueous layer was further extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na ₂ S0 ₄ , filtered, concentrated, and purified by chromatography (silica, PE/EtOAc = 10/1 to 3/1) to afford benzyl- 4-(2-bromo-6-cyanophenyl)piperazine-l-carboxylate (2.1 g, 5.26 mmol, 52%) as a yellow oil. ESI-MS (EI+, m/z): 400.1 [M+H] ⁺ .

Step 2: Benzyl-4-(2-(2-(tert-butoxycarbonylamino)ethyl)-6-cyanopheny l)piperazine-l- carboxylate

[00596] A mixture of benzyl-4-(2-bromo-6-cyanophenyl)piperazine-l-carboxylate (1.5 g, 3.76 mmol), potassium (2-(tert-butoxycarbonylamino)ethyl)trifluoroborate (944 mg, 3.76 mmol), cesium carbonate (2.45 g, 7.52 mmol), butyl-di-l -adamantylphosphine (272 mg, 0.76 mmol), and Pd(OAc) ₂ (85 mg, 0.38 mmol) in dioxane (30 mL) and H ₂ 0 (2 mL) was stirred at 80 °C for 16 h. The reaction was cooled down, concentrated, and purified by chromatography (silica, PE/EtOAc = 10/1 to 5/1) to afford benzyl-4-(2-(2-(tert-butoxycarbonylamino)ethyl)-6- cyanophenyl)piperazine-l-carboxylate (120 mg, 0.26 mmol, 7%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 465.0 [M+H] ⁺ .

Step 3: ieri-Butyl-3-cyano-2-(piperazin-l-yl)phenethylcarbamate

[00597] A mixture of benzyl-4-(2-(2-(tert-butoxycarbonylamino)ethyl)-6- cyanophenyl)piperazine-l-carboxylate (120 mg, 0.26 mmol), Pd/C (60 mg), and HCOO H ₄ (82 mg, 1.3 mmol) in MeOH (10 mL) was stirred at 30 °C for 16 h. The mixture was then filtered and concentrated to afford the crude tert-butyl-3-cyano-2-(piperazin-l-yl)phenethylcarbamate (86 mg, 0.26 mmol, 100 % ) as a yellow oil.

Step 4: ieri-Butyl-3-cyano-2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl )methyl)-2,4- dimethylbenzoyl)piperazin-l-yl)phenethylcarbamate

[00598] A mixture of tert-butyl-3-cyano-2-(piperazin-l-yl)phenethylcarbamate (86 mg, 0.26 mmol), 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (91 mg, 0.26 mmol), HATU (1 19 mg, 0.31 mmol), and DIPEA (69 mg, 0.52 mmol) in DMF (4 mL) was stirred at rt for 2 h. The reaction mixture was then filtered and purified by prep-HPLC to afford tert-butyl-3-cyano-2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl )methyl)-2,4- dimethylbenzoyl)piperazin-l-yl)phenethylcarbamate (60 mg, 0.091 mmol, 35 %) as a white solid. ESI-MS (EI ⁺ , m/z): 662.0 [M+H] ⁺ . Step 5: 3-(2-Aminoethyl)-2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]m ethyl}-2,4- dimethylbenzoyl)piperazin-l-yl]benzonitrile, 1-27

[00599] A mixture of tert-butyl-3-cyano-2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl )methyl)- 2,4-dimethylbenzoyl)piperazin-l-yl)phenethylcarbamate (60 mg, 0.091 mmol) in HCl/MeOH (3 , 5 mL) was stirred at rt for 6 h. The mixture was then concentrated and purified by prep-HPLC to afford 3-(2-aminoethyl)-2-[4-(5-{ [4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]benzonitrile 1-27 (24 mg, 0.043 mmol, 47 %) as a white solid.

[00600] ESI-MS (EI ⁺ , m/z): 562.3 [M+H] ⁺ . ¾ MR (500 MHz, MeOD) δ 7.71-7.63(m, 5H), 7.39-7.35 (m, 2H), 7.28-7.20 (m, 2H), 4.57 (br, 3H), 3.73-3.38 (m, 12H), 3.19 (br, 5H), 2.54 (s, 3H), 2.40 (s, 3H), 1.31 (br, 2H).

Example 61. Synthesis of 2-[(3S)-4-(5-{[(2S)-4-(2-cyanophenyl)-2-methylpiperazin-l- yl]methyl}-2,4-dimethylbenzoyl)-3-methylpiperazin-l-yl]-4,5- difluorobenzonitrile, 1-354

1-354

Synthetic scheme:

Procedures and characterization:

[00601] The procedure for 5-formyl-2,4-dimethylbenzoic acid was the same as Example 49.

[00602] Anaylsis was performed following Method A. Separation was performed following Method D.

Step 1: (S)-5-((4-(2-cyanophenyl)-2-methylpiperazin-l-yl)methyl)-2,4 -dimethylbenzoic acid [00603] A mixture of (<S)-2-(3-methylpiperazin-l-yl)benzonitrile (503 mg, 2.5 mmol), 5- formyl-2,4-dimethylbenzoic acid (445 mg, 2.5 mmol), and NaB¾CN (315 mg, 5.0 mmol) in EtOH (20 mL) was stirred at 40 °C for 16 h. The mixture was then filtered to afford (S)-5-((4-(2- cyanophenyl)-2-methylpiperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (480 mg, 1.32 mmol, 53%) as a white solid. ESI-MS (EI ⁺ , m/z): 364.0 [M+H] ⁺ .

Step 2: 2-[(3S)-4-(5-{[(2S)-4-(2-cyanophenyl)-2-methylpiperazin-l-yl ]methyl}-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl]-4,5-difluorobenzoni trile, 1-354

[00604] A mixture of (,S)-5-((4-(2-cyanophenyl)-2-methylpiperazin-l-yl)methyl)-2, 4- dimethylbenzoic acid (100 mg, 0.28 mmol), (,S)-4,5-difluoro-2-(3-methylpiperazin-l- yl)benzonitrile (65 mg, 0.28 mmol), HATU (128 mg, 0.34 mmol), and DIPEA (72 mg, 0.56 mmol) in DMF (4 mL) was stirred at rt for 2 h. The mixture was then filtered and purified by prep-HPLC to afford 2-[(35)-4-(5-{[(25)-4-(2-cyanophenyl)-2-methylpiperazin-l-yl ]methyl}-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl]-4,5-difluorobenzoni trile 1-354 (48.8 mg, 0.084 mmol, 30%) as a white solid. ESI-MS (EI ⁺ , m/z): 583.3 [M+H] ⁺ . ¾ MR (500 MHz, MeOD) δ 7.61 (d, J = 7.5 Hz, 1H), 7.57 (t, J= 7.5 Hz, 1H), 7.48 (dd, J = 12.5 Hz, 6.0 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.08 (t, J = 7.0 Hz, 1H), 7.02-6.94 (m, 1H), 5.01 (br, 0.5 H), 4.65 (br, 0.5 H), 4.18-4.11(m, 1H), 3.74-3.50 (m, 3H), 3.41 (d, J = 11.5 Hz, 2H), 3.25-3.12 (m, 3H), 3.05-2.73 (m, 6H),2.43 (s, 3H), 2.31-2.24 (m, 3H), 1.49-1.29 (m, 6H).

Example 62. Synthesis of 2-(4-(5-(4-(5-fluoropyridin-2-yl)-l,4-diazepane-l-carbonyl)- 2,4- dimethylbenzyl)piperazin- l-yl)benzonitrile, 1-190

1-190

Synthetic scheme:

Procedures and characterization:

[00605] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

[00606] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: terf-Butyl-4-(6-fluoropyridin-2-yl)-l,4-diazepane-l-carboxyl ate

[00607] A mixture of 2-bromo-6-fluoropyridine (352mg, 2mmol), ter/-butyl-l,4-diazepane-l- carboxylate (400mg, 2mmol), Pd ₂ (dba) ₃ (91.5mg, O. lmmol), BINAP (124.4mg, 0.2mmol), and t-

BuONa (384mg, 4mmol) in toluene (20 ml) was stirred at 80 °C for 3h under N ₂ atmosphere. The mixture was then purified by chromatography (silica, PE/EtOAc = 5: 1) to afford ter/-butyl-4-(6- methylpyridin-2-yl)-l,4-diazepane-l-carboxylate (400mg, 1.35mmol, 68%) as yellow oil. ESI-

MS (EI+, m/z): 296.1 [M+H] ⁺ .

Step 2: l-(6-fluoropyridin-2-yl)-l,4-diazepane

[00608] TFA (2ml) was added to a solution of tert-butyl-4-(6-methylpyridin-2-yl)-l,4- diazepane-l-carboxylate (400mg, 1.35mmol) in CH ₂ C1 ₂ (10ml). The mixture was stirred at 25 °C for 2h, then concentrated to afford l-(6-fluoropyridin-2-yl)-l,4-diazepane(264mg, 1.35mmol, 100%) as yellow oil. ESI-MS (EI+ m/z): 196.1 [M+H] ⁺ .

Step 3: 2-(4-(5-(4-(6-fluoropyridin-2-yl)-l,4-diazepane-l-carbonyl)- 2,4- dimethylbenzyl)piperazin- l-yl)benzonitrile, 1-190

[00609] HATU (114mg, 0.3mmol) and DIPEA (64.5mg, 0.5mmol) were added to a solution of l-(6-fluoropyridin-2-yl)-l,4-diazepane(48.75mg, 0.25mmol) and 5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenzoic acid (105mg, 0.3mmol) in DMF (4ml). The mixture was stirred at 25 °C for 2h, then the mixture was purified by prep-HPLC to afford 2- (4-(5-(4-(6-fluoropyridin-2-yl)- 1 ,4-diazepane- 1 -carbonyl)-2,4-dimethylbenzyl)piperazin- 1 - yl)benzonitrile 1-190 as a white solid. ESI-MS (EI+, m/z): 527.1 [M+H] ⁺ . ¾ MR (500 MHz, DMSO) δ 7.93-8.03 (d, 1H), 7.56-7.58(d, lH),7.23-7.28(m, 1H), 6.89-7.04(m, 4H), 6.46-6.52(m, 1H), 3.50-3.87(m, 9H), 3.21-3.26(m, 5H), 2.65(s, 4H), 2.36-2.37 (m, 3H), 2.20 (s, 3H), 2.07(s, 2H), 1.69-1.71(m, 1H).

Example 63. Synthesis of 2-(4-(2,4-dimethyl-5-(4-(6-methylpyridin-2-yl)-l,4-diazepane -l- carbonyl)benzyl)piperazin- l-yl)

1-189

Synthetic scheme:

1-189

Procedures and characterization:

[00610] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid. [00611] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: tert-butyl 4-(6-methylpyridin-2-yl)-l,4-diazepane-l-carboxylate

[00612] A mixture of 2-bromo-6-methylpyridine (344mg, 2mmol), tert-butyl- 1,4-diazepane-l - carboxylate (400mg, 2mmol), Pd ₂ (dba) ₃ (91.5mg, O. lmmol), BINAP(124.4mg, 0.2mmol), and t-

BuONa (384mg, 4mmol) in toluene (20 ml) was stirred at 80 °C for 3h under N ₂ atmosphere. The mixture was then purified by chromatography (silica, PE/EA = 5: 1) to afford tert-butyl-4-(6- methylpyridin-2-yl)-l,4-diazepane-l-carboxylate(300mg, 1.03mmol, 52%) as a yellow oil. ESI-

MS (EI+, m/z): 292.1 [M+H] ⁺ .

Step 2: l-(6-methylpyridin-2-yl)-l,4-diazepane

[00613] TFA (2ml) was added to a solution of tert-butyl -4-(6-methylpyridin-2-yl)- 1,4- diazepane-l -carboxylate (300mg, 1.03mmol) in CH ₂ C1 ₂ (10ml). The mixture was stirred at 25 °C for 2h, then the mixture was concentrated to afford l-(6-methylpyridin-2-yl)-l,4- diazepane(192mg, l .Ommol, 100%) as a yellow oil. ESI-MS (EI+, m/z): 192.1 [M+H] ⁺ .

Step 3: 2-(4-(2,4-dimethyl-5-(4-(6-methylpyridin-2-yl)-l,4-diazepane -l- carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-189

[00614] HATU (114 mg, 0.3 mmol) and DIPEA (64.5 mg, 0.5 mmol) were added to a solution of l-(6-methylpyridin-2-yl)-l,4-diazepane (47.8 mg, 0.25 mmol) and 5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenzoic acid (105 mg, 0.3 mmol) in DMF (4 ml). The mixture was stirred at 25 °C for 2 h. Then the mixture was purified by prep-HPLC to afford 2-(4-(2,4-dimethyl-5-(4-(6-methylpyridin-2-yl)-l,4-diazepane -l- carbonyl)benzyl)piperazin-l-yl)benzonitrile 1-189 as a white solid. ESI-MS (EI+, m/z): 523.1 [M+H] ⁺ . ¾ MR (500 MHz, DMSO) δ 7.56-7.58 (d, 1H), 7.47-7.51 (m, 1Η),7.33-7.37 (m, 1H), 6.91-7.05 (m, 4H), 6.43-6.44 (d, 1H), 6.31-6.36 (m, 4H), 3.41-3.92(m, 8H), 3.20-3.25 (m, 5H), 2.65(s, 4H), 2.37-2.39 (d, 4H), 2.22-2.26 (d, 3H), 2.07-2.13 (m, 3H), 1.70-1.72 (m, 1H).

Example 64. Synthesis of 2-(4-(5-(l-(5-fluoropyridin-2-yl)piperidine-4-carbonyl)-2,4- dimethylbenzyl)piperazin- l-yl)benzonitrile, 1-169

1-169

Synthetic scheme:

Procedures and characterization:

[00615] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: tert-butyl 4-(5-bromo-2,4-dimethylbenzoyl)piperidine-l-carboxylate

[00616] «-BuLi (4 mL, 10 mmol, 2.5M in hexanes) was added slowly to THF (10 mL). The mixture was was cooled to -78 °C. A solution of l,5-dibromo-2,4-dimethylbenzene (2.65g, 10 mmol) in THF (50 mL) was added. The resulting mixture was stirred at -78 °C for 1 h, then a solution of tert-butyl-4-(methoxy(methyl)carbamoyl)piperidine-l-carboxyl ate (3.26 g, 12 mmol) was added to the solution slowly and the mixture was stirred at -78 °C for lh. The mixture was quenched with H4CI solution. The mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated to obtain the crude product which was purified by chromatography (silica, EtOAc/PE = 1/2) to afford tert-butyl 4-(5-bromo-2,4- dimethylbenzoyl)piperidine-l-carboxylate(2.5g, 6.3 mmol, 63%) as yellow solid. ESI-MS (EI+, m/z):342.1 [M-55] ⁺ .

Step 2: (5-bromo-2,4-dimethylphenyl)(piperidin-4-yl)methanone

[00617] TFA (5 mL) was added to a solution of fer/-butyl-4-(5-bromo-2,4- dimethylbenzoyl)piperidine-l-carboxylate (1.5 g, 3.8 mmol) in DCM (30 mL). The mixture was stirred at 25 °C for 2 h, then the mixture was concentrated. The residue was dissolved in DCM (100 ml), washed with sat. aq. NaHC0 ₃ solution and brine, dried, and concentrated to afford (5- bromo-2,4-dimethylphenyl)(piperidin-4-yl)methanone (1.12 g, 3.8 mmol, 100%) as a yellow oil. ESI-MS (EI+, m/z): 296.3 [M+H] ⁺ .

Step 3: (5-bromo-2,4-dimethylphenyl)(l-(5-fluoropyridin-2-yl)piperid in-4-yl)methanone

[00618] A mixture of (5-bromo-2,4-dimethylphenyl)(piperidin-4-yl)methanone (1 g, 3.4 mmol), 2-bromo-5-fluoropyridine, Pd ₂ (dba) ₃ (156 mg, 0.17 mmol), BINAP (211 mg, 0.34 mmol) and /-BuONa (653 mg, 6.8 mmol) in toluene (30 ml) was stirred at 90 °C for 2 h under N ₂ atmosphere. The mixture was then poured into water (30 ml) and extracted with EtOAc (50ml x 2). The combined organic layers were dried, concentrated, and purified by chromatography (silica, EtOAc/PE = 1/1) to afford (5-bromo-2,4-dimethylphenyl)(l-(5-fluoropyridin-2-yl)piperid in-4- yl)methanone (500 mg, 1.28 mmol, 34%) as a yellow solid. ESI-MS (EI+, m/z): 391.1[M+H] ⁺ . Step 4: (2,4-dimethyl-5-vinylphenyl)(l-(5-fluoropyridin-2-yl)piperid in-4-yl)methanone

[00619] A mixture of (5-bromo-2,4-dimethylphenyl)(l-(5-fluoropyridin-2-yl)piperid in-4- yl)methanone (400 mg, 1.02 mmol), 4,4,5, 5-tetramethyl-2-vinyl-l, 3, 2-dioxaborolane (231 mg, 1.5 mmol), Pd(dppf)Cl ₂ (82 mg, 0.1 mmol) and KOAc (196 mg, 2.0 mmol) in 1,4-dioxane (25 ml) and H ₂ 0 (3 ml) was stirred at 90 °C for 1 h under N ₂ atmosphere. The mixture was then poured into water (50 ml) and extracted with EtOAc (50 ml x 2). The combined organic layers were dried and concentrated to obtain the crude product. The crude product was purified by chromatography (silica, EtOAc/PE = 1/1) to afford (2,4-dimethyl-5-vinylphenyl)(l-(5-fluoropyridin-2- yl)piperidin-4-yl)methanone (290mg, 0.86 mmol, 86%) as a yellow solid. ESI-MS (EI+, m/z):339.1 [M+H] ⁺ .

Step 5: 5-(l-(5-fluoropyridin-2-yl)piperidine-4-carbonyl)-2,4-dimeth ylbenzaldehyde

[00620] A mixture of (2,4-dimethyl-5-vinylphenyl)(l-(5-fluoropyridin-2-yl)piperid in-4- yl)methanone (290 mg, 0.86 mmol), K ₂ 0s0 ₄ 2H ₂ 0 (16 mg, 0.04 mmol) and MO (201 mg, 1.72 mmol) in acetone (15 mL) and H ₂ 0 (15 mL) was stirred at 25 °C for 8 h. Then NaI0 ₄ (552 mg, 0.86 mmol) was added to the mixture. The resulting mixture was stirred at 25 °C for 2 h, then quenched with Na ₂ S0 ₃ (30 mL), stirred for 0.5 h and again filtered. The filtrate was extracted with EtOAc (50 mL), washed with brine, dried, and concentrated to obtain a brown solid. The brown solid was purified by chromatography (silica, EtOAc/PE = 1/2) to afford 5-(l-(5-fluoropyridin-2- yl)piperidine-4-carbonyl)-2,4-dimethylbenzaldehyde(130 mg, 0.38 mmol, 44%) as ayellow solid. ESI-MS (EI+, m/z): 341.3[M+H] ⁺ .

Step 6: 2-(4-(5-(l-(5-fluoropyridin-2-yl)piperidine-4-carbonyl)-2,4- dimethylbenzyl)piperazin- l-yl)benzonitrile, 1-169

[00621] NaBH ₃ CN (37mg, 0.58mmol) and CH ₃ COOH (3 drops) were added to a solution of 5-(l-(5-fluoropyridin-2-yl)piperidine-4-carbonyl)-2,4-dimeth ylbenzaldehyde(100 mg, 0.29 mmol) and 2-(piperazin-l-yl)benzonitrile (54 mg, 0.29 mmol) in EtOH (20 mL). The mixture was stirred at 25 °C for 2 h, then poured into water (30ml) and extracted with EtOAc (50 mL). The organic layer was dried and concentrated to obtain a residue. The residue was purified by prep-HPLC to afford 2-(4-(5-(l-(5-fluoropyridin-2-yl)piperidine-4-carbonyl)-2,4- dimethylbenzyl)piperazin-l-yl)benzonitrile 1-169 (43.4 mg,0.08 mmol, 29%) as a white solid. ESI-MS (EI+, m/z): 512.3[M+H] ⁺ . ¾ NMR (500 MHz, DMSO) δ 8.05-8.06 (d, 1H), 7.58-7.59 (d, 1H), 7.55(s, 1H), 7.48-7.52 (t, 1H), 7.25-7.27 (m, 1H),7.10 (s, 1H), 7.01-7.04 (t, 2H), 6.66- 6.68 (m, 1H), 4.21-4.24 (m, 2H), 3.58 (s, 2H), 3.32-3.36 (m, 1H), 3.23-3.25 (t, 4H), 3.0-3.05 (t, 2H), 2.69-2.71 (t, 4H), 2.41-2.43 (d, 6H).

Example 65. Synthesis of 2-(4-(5-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2,4- dimethylphenylsulfonyl)pi erazin-l-yl)benzonitrile, 1-168

1-168

Synthetic scheme:

Procedures and characterization:

[00622] Analysis was following following Method A. Separation was performed following Method D.

Step 1: 5-(chlorosulfonyl)-2,4-dimethylbenzoic acid

[00623] A mixture of 2,4-dimethylbenzoic acid (7.5 g, 50 mmol) in sulfurochloridic acid (30 ml) was stirred at 140 °C for 3h, then cooled, and slowly added to ice-water (500 mL). The mixture was filtered and the solid was washed with water (200 mL) and dried to afford 5-(chlorosulfonyl)- 2,4-dimethylbenzoic acid (5 g, 20 mmol, 40%) as a white solid. ESI-MS (EI+, m/z): 249.3 [M+H] ⁺ . Step 2: 5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-dimethylbenz oic acid

[00624] Et ₃ N (202 mg, 2.0 mmol) was added to a solution of 5-(chlorosulfonyl)-2,4- dimethylbenzoic acid (250 mg, 1.0 mmol) and 2-(piperazin-l-yl)benzonitrile (187 mg, 1.0 mmol) in DCM (15 ml). The mixture was stirred at 25 °C for 2 h, then the mixture was washed with water (15 mL) and concentrated to obtain the crude product. The crude product was purified by chromatography (silica, DCM/MeOH = 15/1) to afford 5-(4-(2-cyanophenyl)piperazin-l- ylsulfonyl)-2,4-dimethylbenzoic acid (220 mg, 0.55 mmol, 88%) as a yellow solid. ESI-MS (EI+, m/z): 400.2[M+H] ⁺ .

Step 3: 2-(4-(5-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2,4- dimethylphenylsulfonyl)piperazin-l-yl)benzonitrile, 1-168

[00625] HATU (148 mg, 0.39 mmol) and DIPEA (84 mg, 0.65 mmol) were added to a solution of 5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-dimethylbenz oic acid (130 mg , 0.33 mmol) and l-(5-fluoropyridin-2-yl)piperazine (59 mg, 0.33 mmol) in DMF (6 mL). The mixture was stirred at 25 °C for 2 h, then the mixture was purified by prep-HPLC to afford 2-(4-(5-(4-(5- fluoropyridin-2-yl)piperazine-l-carbonyl)-2,4-dimethylphenyl sulfonyl)piperazin-l- yl)benzonitrile 1-168 (36 mg, 0.064 mmol, 20%) as a white solid. ESI-MS (EI+, m/z): 563.4[M+H] ⁺ . ¾ MR (500 MHz, DMSO) δ 8.08-8.09 (d, IH), 7.79 (s, IH), 7.59-7.61 (d, IH), 7.52-7.55 (t, IH), 7.26-7.33 (m, 2H), 7.08-7.11 (t, IH), 7.02-7.04 (d, lH), 6.66-6.68 (m, IH), 3.96 (s, 2H), 3.61 (s, 2H), 3.42 (s, 8H), 3.27 (s, 4H), 2.67 (s, 3H), 2.40 (s, 3H).

Example 66. Synthesis of 2-(4-(5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4- dimethylbenzoyl)piperazin-l- l)benzenesulfonamide, 1-337

1-337

Synthetic scheme:

Procedures and characterization:

[00626] The synthesis of 5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-dimethylbenz oic acid was the same as Example 65.

[00627] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: 2-(4-(5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-dimeth ylbenzoyl)piperazin-l- yl)benzenesulfonamide, 1-337

[00628] EDCI (45.8 mg, 0.24 mmol), HOBt (32.4 mg, 0.24 mmol), and DIPEA (51.6 mg, 0.4 mmol) were added to a solution of 5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4- dimethylbenzoic acid (80 mg , 0.2 mmol) and 2-(piperazin-l-yl)benzenesulfonamide (48.2 mg, 0.2 mol) in DMF (5 ml). The mixture was stirred at 25 °C for 2 h, then purified by prep-HPLC to afford 2-(4-(5 -(4-(2-cyanophenyl)piperazin- 1 -ylsulfonyl)-2,4-dimethylbenzoyl)piperazin- 1 - yl)benzenesulfonamide 1-337 (25 mg, 0.04 mmol, 20%) as a white solid. ESI-MS (EI+, m/z): 623.3[M+H] ⁺ . ¾ NMR (500 MHz, DMSO) δ 8.05-8.07 (d, 1H),7.80 (s, IH), 7.62-7.65 (t, IH), 7.57-7.59 (d, IH), 7.51-7.55 (t, IH), 7.41-7.43 (d, IH), 7.37-7.40 (t, IH), 7.27-7.29(m,3H), 7.08- 7.11 (t, IH), 7.02-7.03 (d, 1H),5.52 (s, 2H), 2.98-3.50 (m, 14H), 2.66 (s, 3H), 2.42 (s, 3H).

Example 67. Synthesis of (S)-2-(4-(5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4- dimethylbenzoyl)-3-meth lpiperazin-l-yl)-4,5-difluorobenzonitrile, 1-342

1-342

Synthetic scheme:

Procedures and characterization:

[00629] The synthesis of 5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-dimethylbenz oic acid was the same as Example 65.

[00630] Anaylsis was performed following Method B. Separation was performed following Method D.

Step 1 : (S)-2-(4-(5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-di methylbenzoyl)-3- methylpiperazin-l-yl)-4,5-difluorobenzonitrile, 1-342

[00631] The procedure was the same as Example 66. ESI-MS (EI+, m/z): 619.2[M+H] ⁺ . ¾ NMR (500 MHz, DMSO) δ 7.74-7.81 (m, IH), 7.59-7.61 (d, IH), 7.52-7.56 (t, IH), 7.23-7.29 (m, 2H), 7.09-7.12 (t, IH), 7.02-7.04 (d, IH), 6.63-6.72 (m,lH), 4.68-5.12 (m, IH), 2.99-3.65 (m, 14H), 2.67 (s, 3H), 2.35-2.43 (d, 3H), 1.28-1.51 (m, 3H).

Example 68. Synthesis of (S)-2-(4-(5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4- dimethylbenzoyl)-3-meth lpiperazin-l-yl)benzenesulfonamide, 1-335

1-335

Synthetic scheme:

Procedures and characterization:

[00632] The synthesis of 5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-dimethylbenz oic acid was the same as Example 65.

[00633] Analysis was performed following Method B. Separation was performed following Method D.

Step 1 : (S)-2-(4-(5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-di methylbenzoyl)-3- methylpiperazin-l-yl)benzenesulfonamide, 1-335

[00634] The procedure was the same as Example 67. ESI-MS (EI+, m/z): 637.2[M+H] ⁺ . ¾ MR (500 MHz, DMSO) δ 8.03-8.05 (d, IH), 7.83 (s, IH), 7.57-7.64 (m, 2H), 7.51-7.54 (t, IH), 7.40-7.48 (m, IH), 7.35-7.38 (t, IH), 7.24-7.29 (m, IH), 7.07-7.10 (t, IH), 7.01-7.03 (d, IH), 5.57 (s, 2H), 4.74-5.14 (m, IH), 2.73-3.60 (m, 14H), 2.66 (s, 3H), 2.35-2.45 (m, 3H), 1.41-1.56 (m, 3H).

Example 69. Synthesis of 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylphenylsulfonyl)piperazin-l-yl)benzonitrile, 1-104

1-104

Syn hetic scheme:

Procedures and characterization:

[00635] The synthesis of 5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-dimethylbenz oic acid was the same as Example 65.

[00636] Analysis was performed following Method B. Separation was performed following Method D.

Step 1 : 2-(4-(5-(hydroxymethyl)-2,4-dimethylphenylsulfonyl)piperazin -l-yl)benzonitrile

[00637] L1AIH4 (38 mg, 1.0 mmol) was added to a solution of 5-(4-(2-cyanophenyl)piperazin- l-ylsulfonyl)-2,4-dimethylbenzoic acid (399 mg, 1.0 mmol) in THF (10 mL). The mixture was stirred at 0 °C for 1 h, then the mixture was quenched with Na ₂ S04 IOH2O. The mixture was filtered and concentrated to afford 2-(4-(5-(hydroxymethyl)-2,4- dimethylphenylsulfonyl)piperazin-l-yl)benzonitrile (300 mg, 0.78 mmol, 78%) as a yellow oil. ESI-MS (EI+, m/z):386.1 [M+H] ⁺ .

Step 2: 2-(4-(5-formyl-2,4-dimethylphenylsulfonyl)piperazin-l-yl)ben zonitrile

[00638] IBX (437 mg, 1.56 mmol) was added to a solution of 2-(4-(5-(hydroxymethyl)-2,4- dimethylphenylsulfonyl)piperazin-l-yl)benzonitrile (500 mg, 1.3 mmol) in DMSO (10 ml). The mixture was stirred at 25 °C for 2h, then the mixture was poured into water (50 ml) and extracted with EtOAc (50 ml). The organic layer was dried, concentrated, and purified by chromatography (silica, EtOAc/PE = 1/5) to afford 2-(4-(5-formyl-2,4-dimethylphenylsulfonyl)piperazin-l- yl)benzonitrile (300 mg, 0.78 mmol, 60%) as a yellow oil. ESI-MS (EI+, m/z): 384.1 [M+H] ⁺ . Step 3: 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylphenylsulfonyl)piperazin-l-yl)benzonitrile, 1-104

[00639] NaBH ₃ CN (66 mg, 1.04 mmol) and AcOH (3 drops) were added to a solution of 2-(4- (5-formyl-2,4-dimethylphenylsulfonyl)piperazin-l-yl)benzonit rile (200 mg, 0.52 mmol) and 2- (piperazin-l-yl)benzonitrile (97 mg, 0.52 mmol) in EtOH (20 mL). The mixture was stirred at 25 °C for 18 h, then the mixture was purified by prep-HPLC to afford 2-(4-(5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylphenylsulfonyl)piperazin- 1 -yl)benzonitrile I- 104 (50 mg, 0.09 mmol, 17%) as white solid. ESI-MS (EI+, m/z): 555.3[M+H] ⁺ . ¹ H MR (500 MHz, DMSO) δ 7.86 (s, 1H), 7.58-7.60 (t, 2H), 7.51-7.55 (t, 1H), 7.47-7.50 (t, 1H), 7.16 (s, 1H), 7.07-7.10 (t, 1H), 7.00-7.05 (m, 3H), 3.58 (s, 2H), 3.39-3.41 (s, 4H), 3.25-3.29 (m, 8H), 2.69-2.71 (t, 4H), 2.63 (s, 3H), 2.43 (s, 3H).

Example 70. Synthesis of 2-(4-(5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4- dimethylbenzyl)piperazin-l-yl)nicotinonitrile, 1-83

1-83

Synthetic scheme:

Procedures and characterization:

[00640] The synthesis of 2-(4-(5-formyl-2,4-dimethylphenylsulfonyl)piperazin-l- yl)benzonitrile was the same as Example 69.

[00641] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 2-(4-(5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-dimeth ylbenzyl)piperazin-l- yl)nicotinonitrile, 1-83

[00642] The procedure was the same as Example 69. ESI-MS (EI+, m/z): 556.3 [M+H] ⁺ . ¾ MR (500 MHz, DMSO) δ 8.36-8.37 (d, 1H), 7.88 (s, 1H), 7.79-7.80 (d, 1H), 7.57-7.59 (d, 1H), 7.48-7.51 (t, 1H), 7.15 (s, 1H), 7.00-7.03 (m, 2H), 6.83-6.85 (m, 1H), 3.75-3.77 (t, 4H), 3.57 (s, 2H), 3.32-3.34 (t, 4H), 3.24 (s, 4H), 2.69 (s, 4H), 2.63 (s, 3H), 2.43 (s, 3H).

Example 71. Synthesis of 2-(4-(5-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2,4- dimethylphenylsulfonyl)piperazin-l-yl)benzonitrile, 1-155

1-155

Synthetic scheme:

Procedures and characterization:

[00643] The procedure for 5-(chlorosulfonyl)-2,4-dimethylbenzoic acid was the same as Example 65.

[00644] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: 5-(4-(5-fluoropyridin-2-yl)piperazin-l-ylsulfonyl)-2,4-dimet hylbenzoic acid

[00645] Et ₃ N (513 mg, 5.08 mmol) was added to a mixture of 5-(chlorosulfonyl)-2,4- dimethylbenzoic acid (630 mg, 2.54 mmol) and l-(5-fluoropyridin-2-yl)piperazine (475 mg, 2.54 mmol) in DCM (50 ml). The mixture was stirred at 25 °C for 2 h, then the mixture was washed with brine, dried, and concentrated to afford 5-(4-(5-fluoropyridin-2-yl)piperazin-l-ylsulfonyl)- 2,4-dimethylbenzoic acid (900 mg, 2.29 mmol, 90%) as a yellow solid. ESI-MS (EI+, m/z): 394.0[M+H] ⁺ .

Step 2: (5-(4-(5-fluoropyridin-2-yl)piperazin-l-ylsulfonyl)-2,4-dime thylphenyl)methanol

[00646] L1AIH4 (145 mg, 3.81 mmol) was added to a solution of 5-(4-(5-fluoropyridin-2- yl)piperazin-l-ylsulfonyl)-2,4-dimethylbenzoic acid (500 mg, 1.27 mmol) in THF (50 mL). The mixture was stirred at 25 °C for 2 h, then the mixture was quenched with Na ₂ S04- 10H ₂ O. The mixture was filtered and concentrated to afford (5-(4-(5-fluoropyridin-2-yl)piperazin-l- ylsulfonyl)-2,4-dimethylphenyl)methanol (200 mg, 0.53 mmol, 41%) as a yellow oil. ESI-MS (EI+, m/z): 380.0[M+H] ⁺ .

Step 3: 5-(4-(5-fluoropyridin-2-yl)piperazin-l-ylsulfonyl)-2,4-dimet hylbenzaldehyde

[00647] mX (177 mg, 0.63 mmol) was added to a solution of (5-(4-(5-fluoropyridin-2- yl)piperazin-l-ylsulfonyl)-2,4-dimethylphenyl)methanol (200 mg, 0.53 mmol) in DMSO (10 mL). The mixture was stirred at 25 °C for 2 h, then the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL). The organic layer was dried and concentrated to obtain a residue which was purified by chromatography (silica, EtOAc/PE = 1/1) to afford 5-(4-(5-fluoropyridin- 2-yl)piperazin-l-ylsulfonyl)-2,4-dimethylbenzaldehyde (180 mg, 0.48 mmol, 90%) as a yellow oil. ESI-MS (EI+ m/z): 378.0[M+H] ⁺ .

Step 4: 2-(4-(5-(4-(5-fluoropyridin-2-yl)piperazin-l-ylsulfonyl)-2,4 - dimethylbenzyl)piperazin- l-yl)benzonitrile, 1-155

[00648] NaBH ₃ CN (34 mg, 0.53 mmol) and AcOH (3 drops) were added to a solution of 5-(4- (5-fluoropyridin-2-yl)piperazin-l-ylsulfonyl)-2,4-dimethylbe nzaldehyde (100 mg, 0.265 mmol) and 2-(piperazin-l-yl)benzonitrile (49.6 mg, 0.265 mmol) in EtOH (15 mL). The mixture was stirred at 25 °C for 2 h, then the mixture was purified by prep-HPLC to afford 2-(4-(5-(4-(5- fluoropyridin-2-yl)piperazin-l-ylsulfonyl)-2,4-dimethylbenzy l)piperazin-l-yl)benzonitrile 1-155 (33.1 mg, 0.06 mmol, 23%) as a white solid. ESI-MS (EI+, m/z): 549.2[M+H] ⁺ . ¾ MR (500 MHz, DMSO) δ 8.04-8.05 (d, 1H), 7.87 (s, 1H), 7.57-7.59 (d, 1H), 7.48-7.52 (t, 1H), 7.25-7.30 (m, 1H), 7.14 (s, 1H), 7.00-7.04 (m, 1H), 6.61-6.64 (m, 1H), 3.55-3.57 (d, 6H), 3.28-3.30 (t, 4H), 3.22-3.24 (t, 4H), 2.67-2.69 (t, 4H), 2.62 (s, 3H), 2.42 (s, 3H).

Example 72. Synthesis of 2-(4-(5-(2-(2-cyanophenyl)-5,6,7,8-tetrahydro-[l,2,4]triazol o[l,5- a]pyrazine-7-carbonyl)-2,4-dimethylbenzyl)piperazin-l-yl)ben zonitrile, 1-42

1-42

Synthetic scheme: NH ₂

Procedures and characterization:

[00649] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- Cyanophenyl)piperazin-l -yl)methyl)-2,4-dimethylbenzoic acid.

[00650] Analysis was performed following Method B. Separatoion was performed following Method D.

Step 1: 2-cyano-N-(pyrazin-2-yl)benzimidamide

[00651] Under a stream of nitrogen, t-BuOK (4.48 g, 40 mmol) was added to a well-stirred solution of pyrazin-2-amine (1.9 g, 20 mmol) in DMSO (10 mL). After the mixture was stirred at 25 °C for 15 min, phthalonitrile (5.12 g, 40 mmol) was added dropwise. The reaction mixture was stirred at 25 °C for 30 min and then heated at 50 °C for 2 h. The mixture was then was poured into water (30 mL) and extracted with DCM (30mL x 2). The combined organic layers were dried and concentrated to obtain a residue which was purified by chromatography (silica, DCM/MeOH = 15/1) to afford 2-cyano-N-(pyrazin-2-yl)benzimidamide (900 mg, 4.0 mmol, 20%) as a yellow solid. ESI-MS (EI+, m/z):224.0[M+H] ⁺ .

Step 2: 2-([l,2,4]triazolo[l,5-a]pyrazin-2-yl)benzonitrile

[00652] A mixture of KI (234 mg, 1.5 mmol) and I ₂ (304.8 mg, 1.2 mmol) in DMSO (5 mL) was stirred at 25 °C for 10 min and then treated with 2-cyano-N-(pyrazin-2-yl)benzimidamide (223 mg, 1.0 mmol), followed by the addition of K ₂ C0 ₃ (414 mg, 3.0 mmol). The reaction mixture was heated at 100 °C for 2 h. After cooling to rt, the reaction mixture was quenched with 5% aq. Na ₂ S ₂ 0 ₃ (0.5 mL) solution, followed by the addition of brine (15 ml), and then the mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried and concentrated to obtain a residue which was purified by chromatography (silica, DCM/MeOH = 15/1) to afford 2- ([l,2,4]triazolo[l,5-a]pyrazin-2-yl)benzonitrile (80 mg, 0.36 mmol, 36%) as a yellow solid. ESI- MS (EI+, m/z): 222.0[M+H] ⁺ .

Step 3: 2-(5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyrazin-2-yl)ben zonitrile

[00653] Pd/C (15 mg) was added to a solution of 2-([l,2,4]triazolo[l,5-a]pyrazin-2- yl)benzonitrile (150 mg, 0.68 mmol) in MeOH (30 mL). The mixture was stirred at 30 °C for 18 h, then the mixture was filtered and concentrated to afford 2-(5,6,7,8-tetrahydro- [l,2,4]triazolo[l,5-a]pyrazin-2-yl)benzonitrile (60 mg, 0.27 mmol, 40%) as a yellow solid. ESI- MS (EI+, m/z): 226.0[M+H] ⁺ .

Step 4: 2-(4-(5-(2-(2-cyanophenyl)-5,6,7,8-tetrahydro-[l,2,4]triazol o[l,5-a]pyrazine-7- carbonyl)-2,4-dimethylbenzyl)piperazin-l-yl)benzonitrile, 1-42

[00654] EDCI (23 mg, 0.12 mmol), HOBt (16.2 mg, 0.12 mmol), and DIPEA(26 mg, 0.2 mmol) were added to a solution of 2-(5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyrazin-2-yl)ben zonitrile (22.5 mg , 0.1 mmol) and 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (34.9 mg, 0.1 mol) in DMF (5 mL). The mixture was stirred at 25 °C for 2 h, then purified by prep-HPLC to afford 2-(4-(5-(2-(2-cyanophenyl)-5,6,7,8-tetrahydro-[l,2,4]triazol o[l,5- a]pyrazine-7-carbonyl)-2,4-dimethylbenzyl)piperazin-l-yl)ben zonitrile 1-42 (37.2 mg,0.067 mmol, 67%) as white solid. ESI-MS (EI+, m/z): 557.3 [M+H] ⁺ . ¾ MR (500 MHz, DMSO) δ 8.10-8.20 (m, 1H), 7.78-7.81 (m, 1H), 7.64-7.71 (m, 1H), 7.55-7.57 (d, 1H), 7.47-7.53 (m, 2H), 7.18-7.23 (d, 1H), 7.08-7.12 (d, 1H), 6.97-7.02 (m, 2H), 5.01-5.37 (m, 1H), 4.71 (s, 1H), 4.29-4.47 (d, 3H), 3.87 (s, 1H), 3.53 (s, 2H), 3.21 (s, 4H), 2.68 (s, 4H), 2.40 (s, 3H), 2.22-2.33 (d, 3H).

Example 73. Synthesis of 2-(4-(2,4-dimethyl-5-(2-phenyl-5,6,7,8-tetrahydro-

[l,2,4]triazolo[l,5-a]pyrazin -7-carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-43

1-43 Synthetic scheme:

Procedures and characterization:

[00655] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

[00656] Analysis was performed following Method B. Separation was perfomed following Method D.

[00657] The procedure was the same as Example 72. ESI-MS (EI+, m/z): 532.3 [M+H] ⁺ . ¾ MR (500 MHz, DMSO) δ 8.02-8.09 (t, 2H), 7.55-7.57 (d, 1H), 7.42-7.46 (m, 4H), 7.18-7.23 (d, 1H), 7.07-7.11 (d, 1H), 6.93-7.01 (m, 2H), 4.99-5.37 (m, 1H), 4.66 (s, 1H), 4.22-4.41 (d, 3H), 3.85 (s, 1H), 3.52 (s, 2H), 3.19 (s, 4H), 2.68 (s, 4H), 2.39 (s, 3H), 2.23-2.33 (d, 3H).

Example 74. Synthesis of 2-(4-(5-((4-(2-cyanophenyl)-4-hydroxypiperidin-l-yl)methyl)- 2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-105

1-105 Synthetic scheme:

Procedures and characterization:

[00658] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: tert-Butyl 4-(2-bromophenyl)-4-hydroxypiperidine-l-carboxylate

[00659] /-PrMgCl (1.76 ml, 1.76 mmol, 1 M in THF) was added dropwise to a solution of 1- bromo-2-iodobenzene (0.5 g, 1.76 mmol) in THF (15 mL) at -15 °C. The mixture was stirred at - 15 °C for 0.5 h, then tert-butyl 4-oxopiperidine-l-carboxylate (350 mg, 1.76 mmol) in THF (10 mL) was added to the mixture and stirred at 25 °C for 18 h. The mixture was quenched with aq. H4CI solution and poured into water (30 mL), then extracted with EtOAc (2 x 30 mL). The organic layers were dried and concentrated to obtain a residue which was dissolved in MeOH (20 mL) and NaBH ₄ (67 mg, 1.76 mmol) was added. The mixture was stirred at 25 °C for 2 h, then poured into water (30 mL) and extracted with EtOAc (50 mL). The organic layer was concentrated to obtain a residue which was purified by chromatography (silica, EtOAc/PE = 1/1) to afford tert- butyl-4-(2-bromophenyl)-4-hydroxypiperidine-l-carboxylate (500 mg, 1.4 mmol, 80%) as a yellow solid. ESI-MS (EI+, m/z): 378.0[M+23] ⁺ .

Step 2: tert-butyl 4-(2-cyanophenyl)-4-hydroxypiperidine-l-carboxylate

[00660] Pd(/-Bu ₃ P) ₂ (102 mg, 0.2 mmol) and Zn(CN) ₂ (346 mg, 2.96 mmol) were added to a solution of ter/-butyl-4-(2-bromophenyl)-4-hydroxypiperidine-l-carboxyla te (700mg, 1.97 mmol) in DMF (6 mL). The mixture was stirred at 140 °C for 2 h under microwave irradiation. After cooling, the mixture was poured into water (50 mL) and extracted with EtOAc (50 x 2 mL). The combined organic layers were dried and concentrated to obtain a residue which was purified by prep-HPLC to afford tert-butyl-4-(2-cyanophenyl)-4-hydroxypiperidine-l-carboxyla te (210 mg, 0.69 mmol, 35%) as a yellow oil. ESI-MS (EI+ m/z): 303.0[M+H] ⁺ .

Step 3: 2-(4-hydroxypiperidin-4-yl)benzonitrile

[00661] TFA (1 mL) was added slowly to a solution of tert-butyl-4-(2-cyanophenyl)-4- hydroxypiperidine-l-carboxylate (120 mg, 0.4 mmol) in DCM (5 mL). The mixture was stirred at 25 °C for 1 h, then the mixture was concentrated to afford 2-(4-hydroxypiperidin-4- yl)benzonitrile (80 mg, 0.4 mmol, 100%) as a yellow oil. ESI-MS (EI+, m/z): 203.0[M+H] ⁺ . Step 4: 2-(4-(5-((4-(2-cyanophenyl)-4-hydroxypiperidin-l-yl)methyl)- 2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-105

[00662] NaBH ₃ CN (18 mg, 0.29 mmol) and AcOH (2 drops) were added to a solution of 2-(4- hydroxypiperidin-4-yl)benzonitrile (29 mg, 0.144 mmol) and 2-(4-(5-formyl-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile (50 mg, 0.144 mmol) in EtOH (15 mL). The mixture was stirred at 25 °C for 18 h, then the mixture was purified by prep-HPLC to afford 2-(4-(5-((4- (2-cyanophenyl)-4-hydroxypiperidin-l-yl)methyl)-2,4-dimethyl benzoyl)piperazin-l- yl)benzonitrile 1-105 (7.4 mg, 0.014 mmol, 9.7%) as a white solid. ESI-MS (EI+, m/z): 534.3 [M+H] ⁺ . ¾ MR (500 MHz, DMSO) δ 7.82-7.83 (d, 1H), 7.60-7.62 (d, 1H), 7.52-7.58 (m, 2H), 7.46-7.49 (t, 1H), 7.33-7.35 (d, 1H), 7.20 (s, 1H), 7.08-7.11 (t, 2H), 7.03-7.05 (d, 1H), 4.07 (s, 2H), 3.52-3.58 (m, 4H), 3.28 (s, 2H), 3.12 (s,2H), 2.89 (s, 2H), 2.53-2.57 (t, 2H), 2.41 (s, 3H), 2.32 (s, 2H), 1.65-1.73 (m, 3H).

Example 75. Synthesis of 2-(4-(5-(4-(2-cyanophenyl)-4-hydroxypiperidine-l-carbonyl)-2 ,4- dimethylbenzyl)piperazin-l-yl)benzonitrile, 1-84

1-84

Synthetic scheme:

1-84

Procedures and characterization:

[00663] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

[00664] Analysis was performed following Method B. Separation was performed following Method D.

Step 1 : 2-(4-(5-(4-(2-cyanophenyl)-4-hydroxypiperidine-l-carbonyl)-2 ,4- dimethylbenzyl)piperazin-l-yl)benzonitrile, 1-84

[00665] HATU (160 mg, 0.42 mmol) and DIPEA (54 mg, 0.42 mmol) were added to a solution of 2-(4-hydroxypiperidin-4-yl)benzonitrile (70 mg, 0.35 mmol) and 5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenzoic acid (122 mg, 0.35 mol) in DMF (5 mL). The mixture was stirred at 25 °C for 2h, then the mixture was purified by prep-HPLC to afford 2-(4-(5-(4-(2-cyanophenyl)-4-hydroxypiperidine-l-carbonyl)-2 ,4-dimethylbenzyl) piperazin-l-yl)benzonitrile 1-84 (16.3 mg, 0.03 mmol, 8.8%) as a white solid. ESI-MS (EI+, m/z): 534.3[M+H] ⁺ . ¾NMR (500 MHz, DMSO) δ 7.86 (s, 1H), 7.57-7.61 (m, 2H), 7.47-7.53 (m, 2H), 7.38 (s, 1H), 7.17-7.22 (d, 1H), 7.08 (s, 1H), 6.97-7.03 (m, 2H), 4.92 (s, 1H), 3.53-3.60 (m, 4H), 3.32 (m ,1H), 3.22 (s, 4H), 2.69 (s, 4H), 2.31-2.41 (m, 6H), 1.88-1.91 (m, 2H), 1.66 (s, 3H).

Example 76. Synthesis of (R)-(5-((4-(2-(3-aminopropyl)phenyl)piperazin-l-yl)methyl)-2 ,4- dimethylphenyl)(4-(5-fluoropyridin-2-yl)-2-methylpiperazin-l -yl)methanone

ditrifluoroacetate salt, 1-355

Procedures and characterization:

[00666] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: (R)-l-(5-fluoropyridin-2-yl)-3-methylpiperazine

[00667] A solution of (R)-2-methylpiperazine (2 g, 20 mmol), 2-bromo-5-fluoro pyridine (3.72 g, 20 mmol), t-BuONa (3.844 g, 40 mmol), BINAP (1.245 g, 2 mmol), and Pd ₂ (dba) ₃ (916 mg, 1 mmol) in dry toluene (20 mL) was stirred under N ₂ at 80 °C for 16 h. The reaction mixture was concentrated and purified by chromatography (silica, EtOAc/PE = 1/5) to afford (R)-l-(5- fluoropyridin-2-yl)-3-methylpiperazine (2.7 g, 13.8 mmol, 69%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 196.1 [M+H] ⁺ .

Step 2: (R)-5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l-carbony l)-2,4- dimethylbenzaldehyde

[00668] A mixture of 5-formyl-2,4-dimethylbenzoic acid (110 mg, 0.6 mmol), (R)-l-(5- fluoropyridin-2-yl)-3-methylpiperazine (234 mg, 1.2 mmol), HATU (296 mg, 0.78 mmol), and DIPEA (387 g, 3 mmol) in DMF (5 mL) was stirred at rt for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/3) to afford (R)-5-(4-(5-fluoropyridin-2-yl)-2- methylpiperazine-l-carbonyl)-2,4-dimethylbenzaldehyde (210 mg, 0.59 mmol, 98%) as yellow oil. ESI-MS (EI ⁺ , m/z): 356.3 [M+H] ⁺ .

Step 3: (R)-tert-butyl 3-(2-(4-(5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l-ca rbonyl)- 2,4-dimethylbenzyl)piperazin-l-yl)phenyl)propyl(methoxymethy l) carbamate

[00669] To a solution of (R)-5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l-carbony l)-2,4- dimethylbenzaldehyde (108 mg, 0.3 mmol), ter/-butyl-methoxymethyl(3-(2-(piperazin-l- yl)phenyl)propyl)carbamate (110 mg, 0.3 mmol) in EtOH (3 mL) and HOAc (1 drop) was stirred at rt for 2 h. Then NaB¾CN (38 mg, 0.6 mmol) was added and stirred at rt for 14 h. The mixture was poured into water, extracted with EtOAc (50 mL x 2), and concentrated to yield crude product (R)-tert-buty\ 3-(2-(4-(5-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l-ca rbonyl)-2,4- dimethylbenzyl) piperazin-l-yl)phenyl)propyl(methoxymethyl)carbamate (200 mg, 0.285mmol, 95%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 703.5 [M+H] ⁺ .

Step 4: (R)-(5-((4-(2-(3-aminopropyl)phenyl)piperazin-l-yl)methyl)-2 ,4-dimethyl phenyl)(4- (5-fluoropyridin-2-yl)-2-methylpiperazin-l-yl)methanone ditrifluoroacetate salt, 1-355

[00670] A mixture of (R)-tert-butyl-3-(2-(4-(5-(4-(5-fluoropyridin-2-yl)-2-methyl piperazine- 1 -carbonyl)-2,4-dimethylbenzyl)piperazin- 1 -yl)phenyl)propyl(methoxym ethyl) carbamate (100 mg, 0.14 mmol) in TFA (3 mL) was stirred at rt for 2 h. The reaction mixture was concentrated to give crude then purified by prep-HPLC to afford (R)-(5-((4-(2-(3-aminopropyl) phenyl)piperazin- l-yl)methyl)-2,4-dimethylphenyl)(4-(5-fluoropyridin-2-yl)-2- methyl piperazin-l-yl)methanone ditrifluoroacetate salt 1-355 (18.9 mg, 0.024 mmol, 17%) as a white solid. ESI-MS (EI+, m/z): 559.5 [M+H] ⁺ . ¹ H- MR (500 MHz, OMSO-d ₆ ) δ 9.72 (s, 1H), 8.09 (d, J = 2.9 Hz, 1H), 7.81 (s, 3H), 7.54 (t, J= 7.2 Hz, 1H), 7.40 (s, 1H), 7.33-7.18 (m, 3H), 7.16-7.10 (m, 2H), 6.89 (d, J= 9.3 Hz, 1H), 4.82 (s, 1H), 4.45 (s, 2H), 4.36-3.90 (m, 3H), 3.60-3.26 (s, 4H), 3.25-3.0 (s, 5H), 2.81 (s, 3H), 2.68 (t, J= 7.4 Hz, 2H), 2.45 (s, 3H), 2.21 (d, 3H), 1.92-1.75 (m, 2H), 1.27-1.22 (m, 3H).

Example 77. Synthesis of 2-(4-(5-(4-(4-Fluoro-l-methyl-lH-indol-7-yl)piperazine-l- carbonyl)-2,4-dimethylbenzyl)piperazin-l-yl)benzonitrile, 1-106

1-106

Synthetic scheme

Procedures and characterization:

[00671] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

[00672] Analysis was performed following Method B. Separation was performed following method D.

Step 1: 7-Bromo-4-fluoro-l-methyl-lH-indole

[00673] To a mixture of 7-bromo-4-fluoro-lH-indole (214 mg, 1 mmol) in DMF (5 mL) was added NaH (36 mg, 1.5 mmol) at 0 °C under stirring. After 1 h, iodomethane (284 mg, 2 mmol) was added and the mixture was stirred at rt for 16 h. The mixture was added to water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na ₂ S04, concentrated, and purified by chromatography (silica, PE/EtOAc = 20/1) to afford 7-bromo-4- fluoro-1 -methyl- lH-indole (182 mg, 0.8 mmol, 80%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 228.1 [M+H] ⁺ .

Step 2: 4-Fluoro-l-methyl-7-(piperazin-l-yl)-lH-indole

[00674] A solution of 7-bromo-4-fluoro-l -methyl- lH-indole (73 mg, 0.32 mmol), piperazine (55 mg, 0.64 mmol), /-BuONa (62 mg, 0.64 mmol), BrettPhos (34 mg, 0.064 mmol), and Pd ₂ (dba) ₃ (29 mg, 0.032 mmol) in dry toluene (3 mL) was stirred under N ₂ at 85 °C for 16 h. The reaction mixture was concentrated and purified by prep-HPLC to afford 4-fluoro-l-methyl-7-(piperazin-l- yl)-lH-indole (50 mg, 0.214 mmol, 67%) as a white solid. ESI-MS (EI ⁺ , m/z): 234.3 [M+H] ⁺ . Step 3: 2-(4-(5-(4-(4-Fluoro-l-methyl-lH-indol-7-yl)piperazine-l-car bonyl)-2,4- dimethylbenzyl)piperazin- l-yl)benzonitrile, 1-106

[00675] A mixture of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethyl benzoic acid (75 mg, 0.21 mmol), 4-fluoro-l-methyl-7-(piperazin-l-yl)-lH-indole (50 mg, 0.21 mmol), HATU (104 mg, 0.27 mmol), DIPEA (136 mg, 1.05 mmol) in DMF (3 mL) was stirred at rt for 16 h. The mixture was purified by prep-HPLC twice to afford 2-(4-(5-(4-(4-fluoro-l -methyl- lH-indol-7- yl)piperazine-l-carbonyl)-2,4-dimethyl benzyl) piperazin-l-yl)benzonitrile 1-106 (8.6 mg, 0.015 mmol, 7%) as a white solid. ESI-MS (EI ⁺ , m/z): 565.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.55 (d, J = 8.0 Hz, 1H), 7.47 (t, J= 7.9 Hz, 1H), 7.24-7.02 (m, 2H), 7.02-6.95 (m, 2H), 6.93 (d, J = 1.5 Hz, 1H), 6.90-6.78 (m, 1H), 6.66 (t, J = 9.0 Hz, 1H), 6.53 (d, J = 3.0 Hz, 1H), 4.87 (t, J = 1.5 Hz, 1H), 4.15 (s, 3H), 3.53 (d, J = 19.0 Hz, 3H), 3.44-3.29 (m, 1H), 3.29-3.10 (m, 6H), 3.07- 2.74 (m, 3H), 2.66 (s, 4H), 2.32 (d, 6H).

Example 78. Synthesis of 2-(4-(2,4-Dimethyl-5-(4-(2-oxoindolin-7-yl)piperazine-l- carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-65

1-65

Synthetic scheme:

Procedures and characterization:

[00676] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid. [00677] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: tert-Butyl 4-(lH-indol-7-yl)piperazine-l-carboxylate

[00678] Vinylmagnesium bromide (1 M in THF, 13 mL) and Et ₂ 0 (32.5 mL, 2.5 ml mmol ^"1 ) were mixed in an oven dried flask and cooled to -40 °C under N ₂ with stirring. tert-Butyl 4-(2- nitrophenyl)piperazine-l-carboxylate (1 g, 3.25 mmol) was dissolved in THF (8 mL, 2.5 ml mmol ^-1 ) and added dropwise to the Grignard mixture. The solution was stirred at -40 °C for 4 h, and then quenched with sat. aq. NH4CI. The aqueous layer was separated and extracted using EtOAc. The organic layer was dried over MgS0 ₄ , concentrated in vacuo, and purified by chromatography (silica, PE/EtOAc =2/1) to yield the title compound tert-butyl-4-(lH-indol-7- yl)piperazine-l-carboxylate (500 mg, 1.66 mmol, 51%) as yellow solid. ESI-MS (EI ⁺ , m/z): 302.3 [M+H] ⁺ .

Step 2: terf-Butyl 4-(2-oxoindolin-7-yl)piperazine-l-carboxylate

[00679] To a 50 mL vial was added tert-butyl 4-(lH-indol-7-yl)piperazine-l-carboxylate (410 mg, 1.36 mmol) in t-butanol (12 mL) and water (5.5 mL). The solution was stirred at rt and then BS (242 mg, 1.36 mmol) was added. The reaction was allowed to stir at rt for 3 h, then the mixture was diluted with EtOAc and washed with water. The organic layer was separated, washed with brine and dried over Na ₂ S0 ₄ . The solvent was evaporated in vacuo and the resulting crude oil was purified by prep-HPLC to afford the desired product tert-butyl-4-(2-oxoindolin-7- yl)piperazine-l-carboxylate (19.4 mg, 0.061 mmol, 4.5%) as white solid. ESI-MS (EI ⁺ , m/z): 318.2 [M+H] ⁺ .

Step 3: 7-(Piperazin-l-yl)indolin-2-one

[00680] The mixture of tert-butyl 4-(2-oxoindolin-7-yl)piperazine-l-carboxylate (21 mg, 0.066 mmol) in TFA (0.5 mL) and DCM (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated to give crude product 7-(piperazin-l-yl)indolin-2-one as a yellow solid that was used without further purification. ESI-MS (EI ⁺ , m/z): 218.3 [M+H] ⁺ .

Step 4: 2-(4-(2,4-Dimethyl-5-(4-(2-oxoindolin-7-yl)piperazine-l-carb onyl)benzyl) piperazin- l-yl)benzonitrile, 1-65

[00681] A mixture of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethyl benzoic acid (23 mg, 0.066 mmol), 7-(piperazin-l-yl)indolin-2-one (15 mg, 0.066 mmol), HATU (33 mg, 0.086 mmol), and DIPEA (43 mg, 0.33 mmol) in DMF (2 mL) was stirred at rt for 16 h. The mixture was purified by prep-HPLC to afford 2-(4-(2,4-dimethyl-5-(4-(2-oxoindolin-7-yl)piperazine-l- carbonyl)benzyl) piperazin-l-yl)benzonitrile 1-65 (14 mg, 0.0255 mmol, 39%) as a white solid. ESI-MS (EI ⁺ , m/z): 549.3 [M+H] ⁺ . ¾- ΜΡν (500 MHz, CDCb) δ 7.84 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.47 (t, J= 7.5 Hz, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 7.03-6.90 (m, 5H), 3.98 (d, 2H), 3.57 (s, 2H), 3.53 (d, J= 4.5 Hz, 2H), 3.43 (d, J= 4.0 Hz, 2H), 3.20 (s, 4H), 3.02 (s, 2H), 2.83 (d, 2H), 2.66 (s, 4H), 2.37 (s, 3H), 2.31 (s, 3H).

Example 79. Synthesis of 2-(6-(5-((3-(2-Cyanophenyl)-3,6-diazabicyclo[3.1.1]heptan-6- yl)methyl)-2,4-dimethylbenzoyl)-3,6-diazabicyclo [3.1.1] heptan-3-yl)benzonitrile, 1-48

Procedures and characterization:

[00682] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: tert-Butyl 3-(2-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxyla te

[00683] A solution of tert-butyl-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (198 mg, 1 mmol), 2-iodobenzonitrile (458 mg, 2 mmol), CS2CO3 (652 mg, 2 mmol), XantPhos (116 mg, 0.2 mmol), and Pd ₂ (dba)3 (92 mg, 0.1 mmol) in dioxane (10 mL) was stirred under N ₂ at 110 °C for 16 h. The reaction mixture was concentrated and the mixture was purified by chromatography (silica, PE/EtOAc = 2/1) to afford ter/-butyl-3-(2-cyanophenyl)-3,6-diazabicyclo[3.1.1] heptane- 6-carboxylate (210 mg, 0.70 mmol, 70%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 300.3 [M+H] ⁺ . Step 2: 2-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)benzonitrile [00684] A mixture of tert-butyl-3-(2-cyanophenyl)-3,6-diazabicyclo[3.1.1]heptane- 6- carboxylate (210 mg, 0.7 mmol) in TFA (1 mL) and DCM (4 mL) was stirred at rt for 3 h. The reaction mixture was concentrated to give crude product 2-(3,6-diazabicyclo[3.1.1]heptan-3-yl) benzonitrile as a yellow solid that was used without further purification. ESI-MS (EI ⁺ , m/z): 200.2 [M+H] ⁺ .

Step 3: 2-(6-(5-formyl-2,4-dimethylbenzoyl)-3,6-diazabicyclo[3.1.1]h eptan-3-yl)

benzonitrile

[00685] A mixture of 5-formyl-2,4-dimethylbenzoic acid (80 mg, 0.45 mmol), 2-(3,6- diazabicyclo[3.1.1]heptan-3-yl)benzonitrile (89 mg, 0.45 mmol), HATU (222 mg, 0.585 mmol), DIPEA (291 mg, 2.25 mmol) in DMF (5 mL) was stirred at rt for 16 h. The mixture was then purified by chromatography (silica, PE/EtOAc = 1/1) to afford 2-(6-(5-formyl-2,4- dimethylbenzoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl) benzonitrile (100 mg, 0.278 mmol, 62%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 360.2 [M+H] ⁺ .

Step 4 : 2-(6-(5-((3-(2-Cyanophenyl)-3,6-diazabicyclo [3.1.1] heptan-6-yl)methyl)-2,4- dimethylbenzoyl)-3,6-diazabicyclo [3.1.1] heptan-3-yl)benzonitrile, 1-48

[00686] A solution of 2-(6-(5-formyl-2,4-dimethylbenzoyl)-3,6-diazabicyclo[3.1.1] heptan-3- yl)benzonitrile (100 mg, 0.278 mmol), 2-(3,6-diazabicyclo[3.1.1]heptan-3-yl) benzonitrile (111 mg, 0.556 mmol) in EtOH (4 mL) and HOAc (1 drop) was stirred at 45 °C for 2 h. The reaction mixture was then cooled to rt, NaB¾CN (35 mg, 0.556 mmol) was added and the mixture was stirred at rt for 2 h. The mixture was purified by prep-HPLC to afford 2-(6-(5-((3-(2-cyanophenyl)- 3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-2,4-dimethylbenzo yl)-3,6-diazabicyclo[3.1.1] heptan-3-yl)benzonitrile 1-48 (60 mg, 0.11 mmol, 40%) as white solid. ESI-MS (EI ⁺ , m/z): 543.2 [M+H] ⁺ . ¹ H- MR (500 MHz, CDCb) δ 7.54 (d, J = 8.0 Hz, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.44- 7.37 (m, 2H), 7.28 (s, 1H), 6.99 (s, 1H), 6.86 (d, J= 9.0 Hz, 1H), 6.84-6.73 (m, 3H), 4.70 (s, 1H), 4.44 (d, J = 10.5 Hz, 1H), 4.25 (s, 1H), 3.81-3.97 (m, 3H), 3.79-3.66 (m, 5H), 3.60 (d, J = 10.5 Hz, 1H), 3.56-3.47 (m, J= 8.9 Hz, 2H), 2.85 (q, J= 7.0 Hz, 1H), 2.62 (q, J= 7.0 Hz, 1H), 2.25 (s, 3H), 2.18 (s, 3H), 1.75 (d, J= 8.5 Hz, 1H), 1.62 (d, J= 8.5 Hz, 1H).

Example 80. Synthesis of 2-(4-(5-((4-(2-Cyanophenyl)-2,5-dioxopiperazin-l-yl)methyl)- 2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-356

1-356

Synthetic scheme:

Procedures and characterization:

[00687] Analysis was following Method B and the separation method was following Method D.

Step 1: terf-Butyl-2-(2-cyanophenylamino)acetate

[00688] The mixture of 2-fluorobenzonitrile (1 g, 8.26 mmol), tert-butyl-2-aminoacetate (2.166 g, 16.51 mmol) and K ₂ C0 ₃ (2.282 g, 16.51 mmol) in DMF (20 mL) was stirred at 120 °C for 16 h. The mixture was purified by chromatography (silica, PE/EtOAC = 3/1) to afford tert-butyl-2- (2-cyanophenylamino)acetate (288 mg, 1.24 mmol, 15%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 233.2 [M+H] ⁺ .

Step 2: 2-(2-Cyanophenylamino)acetic acid

[00689] The mixture of ter/-butyl-2-(2-cyanophenylamino)acetate (290 mg, 1.25 mmol) in TFA (1 mL) and DCM (4 mL) was stirred at rt for 16 h. The reaction mixture was concentrated to give crude product 2-(2-cyanophenylamino)acetic acid as white solid that was used without further purification. ESI-MS (EI ⁺ , m/z): 177.2 [M+H] ⁺ .

Step 3: Methyl-2-(5-(4-(2-cyanophenyl)piperazine-l-carbonyl)-2,4-dim ethylbenzyl amino)acetate [00690] The mixture of methyl-2-aminoacetate hydrochloride (282 mg, 2.25 mmol), KOAc (220 mg, 2.25 mmol) in EtOH (30 mL) was stirred at 45 °C for 0.5 h, then 2-(4-(5-formyl-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile (520 mg, 1.5 mmol) and HO Ac (3 drops) were added and the mixture was stirred at 45 °C for another 0.5 h. The reaction mixture was then cooled to rt, NaB¾CN (188 mg, 3 mmol) was added and the mixture was stirred at rt for 16 h. The mixture was purified by chromatography (silica, PE/EtOAc = 2/1) to afford methyl-2-(5-(4-(2- cyanophenyl)piperazine-l-carbonyl)-2,4-dimethylbenzylamino)a cetate (498 mg, 1.185 mmol, 79%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 421.0 [M+H] ⁺ .

Step 4: Methyl-2-(N-(5-(4-(2-cyanophenyl)piperazine-l-carbonyl)-2,4- dimethyl benzyl)-2- (2-cyanophenylamino)acetamido)acetate

[00691] A mixture of methyl-2-(5-(4-(2-cyanophenyl)piperazine-l-carbonyl)-2,4- dimethylbenzylamino)acetate (630 mg, 1.5 mmol), 2-(2-cyanophenylamino)acetic acid (270 mg, 1.5 mmol), HATU (741 mg, 1.95 mmol), and DIPEA (968 mg, 7.5 mmol) in DMF (5 mL) was stirred at rt for 16 h. The mixture was purified by prep-HPLC to afford methyl-2-(N-(5-(4-(2- cyanophenyl)piperazine- 1 -carbonyl)-2,4-dimethyl benzyl)-2-(2- cyanophenylamino)acetamido)acetate (391 mg, 0.675 mmol, 45%) as white solid. ESI-MS (EI ⁺ , m/z): 579.2 [M+H] ⁺ .

Step 5: 2-(4-(5-((4-(2-Cyanophenyl)-2,5-dioxopiperazin-l-yl)methyl)- 2,4-dimethyl benzoyl)piperazin-l-yl)benzonitrile, 1-356

[00692] To a mixture of methyl-2-(N-(5-(4-(2-cyanophenyl)piperazine-l-carbonyl)-2,4- dimethyl benzyl)-2-(2-cyanophenylamino)acetamido)acetate (200 mg, 0.346 mmol) in THF (4 mL) was added NaH (60%, 15 mg, 0.38 mmol) at 0 °C with stirring, then stirred at 0 °C for 1 h. The mixture was purified by prep-HPLC to afford 2-(4-(5-((4-(2-cyanophenyl)-2,5- dioxopiperazin-l-yl)methyl)-2,4-dimethyl benzoyl)piperazin-l-yl)benzonitrile 1-356 (39.7 mg, 0.073 mmol, 21%) as white solid. ESI-MS (EI ⁺ , m/z): 547.3 [M+H] ⁺ . ¾- MR (500 MHz, CDCb) δ 7.76 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.39 (d, J= 8.0 Hz, 1H), 7.11 (d, J= 4.5 Hz, 2H), 7.07 (t, J= 7.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 4.81 (d, J= 14.5 Hz, 1H), 4.62 (d, J= 14.5 Hz, 1H), 4.44 (d, J= 8.0 Hz, 2H), 4.19- 3.86 (m, 4H), 3.48 (d, J = 4.5 Hz, 2H), 3.27 (t, J = 4.5 Hz, 2H), 3.10 (t, J = 4.5 Hz, 2H), 2.35 (s, 3H), 2.31 (s, 3H). Example 81. Synthesis of 2-(8-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4,5-difl uorobenzonitrile

trifluoroacetate salt, 1-357

1-357

Synthetic scheme:

Procedures and characterization:

[00693] Followed the general procedure for Intermediate 83 to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

[00694] Analysis was performed following Method B. Separation was performed following Method C.

Step 1: ieri-Butyl-3-(2-Cyano-4,5-difluorophenyl)-3,8-diazabicyclo[3 .2.1]octane-8- carboxylate

[00695] The mixture of 2,4,5-trifluorobenzonitrile (300 mg, 1.91 mmol), fert-butyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (486 mg, 2.92 mmol) and K2CO3 (396 mg, 2.86 mmol) in DMSO (20 mL) was stirred at 100 °C for 16 h. The mixture was purified by chromatography (silica, PE/EtOAc = 3/1) to afford ter/-butyl-3-(2-cyano-4,5-difluorophenyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.343 mmol, 18 %) as yellow solid. ESI-MS (EI ⁺ , m/z): 350.2 [M+H] ⁺ .

Step 2: 2-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-4,5-difluorobenzonitri le

[00696] The mixture of ter/-butyl-3-(2-cyano-4,5-difluorophenyl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (60 mg, 0.172 mmol) in TFA (0.5 mL) and DCM (2 mL) was stirred at rt for 2 h. The reaction mixture was concentrated to give crude product 2-(3,8- diazabicyclo[3.2.1]octan-3-yl)-4,5-difluorobenzonitrile as a yellow solid that was used without further purification. ESI-MS (EI ⁺ , m/z): 250.1 [M+H] ⁺ .

Step 3: 2-(8-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4-dimeth ylbenzoyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-4,5-difluorobenzonitrile trifluoroacetate salt, 1-357

[00697] A mixture of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethyl benzoic acid (62.8 mg, 0.172 mmol), 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-4,5-difluoro benzonitrile (45 mg, 0.172 mmol), HATU (85 mg, 0.0.224 mmol), and DIPEA (111 mg, 0.86 mmol) in DMF (4 mL) was stirred at rt for 16 h. The mixture was purified by prep-HPLC to afford 2-(8-(5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenzoyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)- 4,5-difluorobenzonitrile trifluoroacetate salt 1-357 (79 mg, 0.117 mmol, 68%) as a white solid. ESI-MS (EI ⁺ , m/z): 581.3 [M+H] ⁺ . ¾ MR (500 MHz, OMSO-d ₆ ) δ 10.01 (s, 1H), 7.83-7.74 (m, 2H), 7.66 (t, J= 7.5 Hz, 1H), 7.46 (s, 1H), 7.30 - 7.23 (m, 2H), 7.20 (t, J= 7.5 Hz, 1H), 7.08 (dd, J = 12.0, 7.5 Hz, 1H), 4.79 (s, 1H), 4.49 (s, 2H), 3.78 (s, 1H), 3.72-3.32 (m, 8H), 3.26-3.10 (m, 3H), 3.00 (d, J= 9.5 Hz, 1H), 2.44 (s, 3H), 2.27 (s, 3H), 1.99-1.76 (m, 4H).

Example 82. Synthesis of 4-(4-(5-((8-(2-Cyanophenyl)-3,8-diazabicyclo[3.2.1]octan-3 yl)methyl)-2,4-dimethylbenzoyl)piperazin-l-yl)-2,5-difluorob enzonitrile, 1-358

1-358

Synthetic scheme:

Procedures and characterization: [00698] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: ieri-Butyl-8-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-3 -carboxylate

[00699] A solution of tert-butyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (212 mg, 1 mmol), 2-iodobenzonitrile (458 mg, 2 mmol), CS2CO3 (652 mg, 2 mmol), XantPhos (116 mg, 0.2 mmol), and Pd ₂ (dba)3 (92 mg, 0.1 mmol) in dioxane (10 mL) was stirred under N ₂ at 110 °C for 16 h. The reaction mixture was concentrated and purified by chromatography (silica, PE/EtOAc = 5/1) to afford ter/-butyl-8-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-3 -carboxylate (150 mg, 0.48 mmol, 48%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 258.1 [M-55] ⁺ .

Step 2: 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)benzonitrile

[00700] A mixture of ter/-butyl-8-(2-cyanophenyl)-3,8-diazabicyclo[3.2.1]octane-3 - carboxylate (150 mg, 0.479 mmol) in TFA (1 mL) and DCM (4 mL) was stirred at rt for 2 h. To the mixture was added H ₂ 0 (20 mL) and the mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na ₂ S0 ₄ , and concentrated in vacuo to give crude product 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)benzonitrile as a yellow solid that was used without further purification. ESI-MS (EI+, m/z): 214.2 [M+H] ⁺ .

Step 3: 4-(4-(5-((8-(2-Cyanophenyl)-3,8-diazabicyclo[3.2.1]octan-3-y l)methyl)-2,4- dimethylbenzoyl)piperazin-l-yl)-2,5-difluorobenzonitrile, 1-358

[00701] A solution of 2,5-difluoro-4-(4-(5-formyl-2,4-dimethylbenzoyl)piperazin-l- yl)benzonitrile (38 mg, 0.1 mmol), 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)benzonitrile (21 mg, 0.1 mmol) in EtOH (2 mL) and HO Ac (1 drop) was stirred at 45 °C for 4 h. Then the reaction mixture was cooled to rt, NaBLbCN (13 mg, 0.2 mmol) was added and the reaction mixture was stirred at rt for 2 h. The mixture was purified by prep-HPLC to afford 4-(4-(5-((8-(2-cyanophenyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)methyl)-2,4-dimethylbenzoyl)pi perazin-l-yl)-2,5-difluoro benzonitrile 1-358 (15 mg, 0.026 mmol, 26%) as white solid. ESI-MS (EI ⁺ , m/z): 581.4 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 7.51 (d, J= 7.5 Hz, 1H), 7.37 (t, J= 8.0 Hz, 1H), 7.22 (q, 6.0 Hz, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 6.89-6.78 (m, 2H), 6.68 (dd, J = 10.5, 7.0 Hz, 1H), 4.25 (d, 2H), 3.98 (d, 2H), 3.45 (s, 4H), 3.31 (s, 2H), 3.13 (s, 2H), 2.69-2.61 (m, 2H), 2.54 (s, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 1.85 (s, 4H). Example 83. Synthesis of 4-(3-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2,5-difl uorobenzonitrile, 1-359

Procedures and characterization:

[00702] Followed the general procedure for Intermediate 83 to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

[00703] The analysis method was performed following Method B and the separation method was performed following Method D.

Step 1: ieri-Butyl-8-(2-cyano-4,5-difluorophenyl)-3,8-diazabicyclo[3 .2.1]octane-3- carboxylate

[00704] A mixture of 2,4,5-trifluorobenzonitrile (314 mg, 2 mmol), fert-butyl-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (212 mg, 1 mmol) and K2CO3 (276 mg, 2 mmol) in DMSO (5 mL) was stirred at 100 °C for 16 h. The mixture was purified by chromatography (silica, PE/EtOAc = 3/1) to afford fer/-butyl-8-(2-cyano-4,5-difluorophenyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (91 mg, 0.26 mmol, 26%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 350.2 [M+H] ⁺ .

Step 2: 2-(3,8-Diazabicyclo[3.2.1]octan-8-yl)-4,5-difluorobenzonitri le

[00705] A mixture of ter/-butyl-8-(2-cyano-4,5-difluorophenyl)-3,8-diazabicyclo [3.2. l]octane-3-carboxylate (100 mg, 0.286 mmol) in TFA (1 mL) and DCM (4 mL) was stirred at rt for 2 h. The reaction mixture was concentrated to give crude product 2-(3,8- diazabicyclo[3.2.1]octan-8-yl)-4,5-difluorobenzonitrile as a yellow solid that was used without further purification. ESI-MS (EI ⁺ , m/z): 250.1 [M+H] ⁺ .

Step 3: 4-(3-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4-dimeth ylbenzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl)-2,5-difluorobenzonitrile, 1-359

[00706] A mixture of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethyl benzoic acid (60 mg, 0.172 mmol), 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-4,5-difluorobenzonitri le (47 mg, 0.189 mmol), HATU (85 mg, 0.224 mmol), and DIPEA (111 mg, 0.86 mmol) in DMF (3 mL) was stirred at rt for 16 h. The mixture was purified by prep-HPLC to afford 4-(3-(5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenzoyl)-3,8- diazabicyclo[3.2.1]octan-8-yl)- 2,5-difluorobenzonitrile 1-359 (54 mg, 0.093 mmol, 54%) as white solid. ESI-MS (EI ⁺ , m/z): 581.3 [M+H] ⁺ . ¹ H- MR (500 MHz, CDCb) δ 7.56 (d, J = 7.5 Hz, 1H), 7.52-7.45 (m, 1H), 7.24-7.06 (m, 2H), 7.05-6.92 (m, 3H), 6.57 (s, 1H), 4.59 (t, J= 12.5 Hz, 1H), 4.45 (d, J= 5.5 Hz, 1H), 4.25 (s, 1H), 3.72-3.00 (m, 9H), 2.67 (s, 4H), 2.258 (d, 6H), 2.12-1.78 (m, 4H).

Example 84. Synthesis of 2-(4-(2,4-Dimethyl-5-(3-phenyl-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazi -7-carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-103

1-103

Synthetic scheme:

Procedures and characterization:

[00707] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: terf -Butyl 2-bromo-5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazine-7(8H)-car boxylate

[00708] A mixture of 2-bromo-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyrazine hydrochloride (1.3 g, 6.4 mmol), Et ₃ N (0.78 g, 7.68 mmol) and (Boc) ₂ 0 (1.53 g, 7.04 mmol) in DCM (50 mL) was stirred at 20 °C for 3 h. The mixture was concentrated and purified by chromatography (silica, EtOAc/PE = 1/10) to afford ter/-butyl-2-bromo-5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazin e-7(8H)- carboxylate as a white solid (1.4 g, 4.61 mmol, 72%). ESI-MS (EI ⁺ , m/z): 303.1 [M+H] ⁺ .

Step 2: tert-Butyl 2-phenyl-5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazine-7(8H)-ca rboxylate

[00709] To a solution of ter/-butyl-2-bromo-5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazin e-7(8H)- carboxylate (300 mg, 0.99 mmol) and phenylboronic acid (362 mg, 2.97 mmol) in 1,4-dioxane (20 mL) and H ₂ 0 (8 mL) were added Pd(PPh ₃ ) ₄ (123 mg, 0.1 mmol) and Cs ₂ C0 ₃ (968 mg, 2.97 mmol) at 80 °C. After 16 h of stirring, the reaction mixture was filtered and extracted with EtOAc (100 mL x 3). The organic layers were concentrated and purified by chromatography (silica, EtOAc/PE = 1/10) to afford ter/-butyl-2-phenyl-5,6-dihydro-[l,2,4]triazolo[l,5-a]pyrazi ne-7(8H)- carboxylate (163 mg, 0.54 mmol, 55%) as product. ESI-MS (EI ⁺ , m/z): 301.2 [M+H] ⁺ .

Step 3: 2-Phenyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[l,5-a]pyrazine

[00710] To a solution of HC1 (4 N, dioxane, 15 mL) was added tert-butyl-2-phenyl-5,6-dihydro- [l,2,4]triazolo[l,5-a]pyrazine-7(8H)-carboxylate (163 mg, 0.54 mmol) with ice-bath cooling. After 16 h of stirring at 20 °C, the mixture was concentrated to afford 2-phenyl-5,6,7,8-tetrahydro- [l,2,4]triazolo[l,5-a]pyrazine (97 mg, 0.49 mmol, 90%).ESI-MS (EI ⁺ , m/z): 201.2 [M+H] ⁺ . Step 4: 2-(4-(2,4-Dimethyl-5-(3-phenyl-5,6,7,8-tetrahydro-[l,2,4]tri azolo[4,3-a]pyrazine-7- carbonyl)benzyl)piperazin- l-yl)benzonitrile, I- 103

[00711] ESI-MS (EI ⁺ , m/z): 532.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.71 (s, 2H), 7.52 (m, 5H), 7.17 (s, 1H), 7.08 (s, 1H), 6.97 (d, J= 8.3 Hz, 2H), 5.06 (m, 2H), 4.51-3.37 (m, 6H), 3.19 (s, 4H), 2.66 (s, 4H), 2.45-2.20 (m, 6H).

Example 85. Synthesis of 2-(4-(5-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2,4- dimethylbenzyl)piperazin-l- l)benzonitrile, 1-263

1-263

Procedures and characterization:

[00712] Analysis was performed following Method A. Separation was performed following Method D.

[00713] The procedure was the same as Example 1 and general procedure for Intermediate 83. 2-(4-(5-(4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl)-2,4- dimethylbenzyl)piperazin-l- yl)benzonitrile 1-263: ESI-MS (EI ⁺ , m/z): 513.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 8.05 (d, J= 3.0 Hz, 1H), 7.55 (dd, J= 7.6, 1.5 Hz, 1H), 7.50-7.43 (m, 1H), 7.32-7.27 (m, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 7.03-6.94 (m, 2H), 6.64 (dd, J= 9.2, 3.3 Hz, 1H), 3.94 (t, J= 4.9 Hz, 2H), 3.54 (d, J = 20.4 Hz, 4H), 3.39 (s, 4H), 3.20 (s, 4H), 2.66 (s, 4H), 2.37 (s, 3H), 2.28 (s, 3H).

Example 86. Synthesis of 2-(l-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)piperidin-4-yl)benzonitrile, 1-87

Procedures and characterization:

[00714] Analysis was performed following Method A. Separation was performed following Method D.

[00715] The procedure was same as Example 1 and general procedure for Intermediate 83. Step 1: terf -Butyl 4-(2-cyanophenyl)-5,6-dihydropyridine-l(2H)-carboxylate

[00716] To a solution of 2-iodobenzonitrile (300 mg, 1.31 mmol) and tert-butyl 4-(4,4,5,5- tetram ethyl- 1, 3, 2-dioxaborolan-2-yl)-5,6-dihydropyri dine- l(2H)-carboxylate (486 mg, 1.57 mmol) in 1,4-dioxane (15 mL) and H ₂ 0 (5 mL) were added Pd(dppf)Cl ₂ (15 mg, 0.02 mmol) and Na ₂ CC"3 (347 mg, 3.28 mmol) at 80 °C. After 16 h of stirring, the reaction mixture was filtered ands extracted with EtOAc (100 mL x 3). The organic layers were concentrated and purified by chromatography (silica, EtOAc/PE = 1/10) to afford tert-butyl 4-(2-cyanophenyl)-5,6- dihydropyridine-l(2H)-carboxylate (242 mg, 0.85 mmol, 65%) as product. ESI-MS (EI ⁺ , m/z): 229.1 [M-55] ⁺ .

Step 2: tert-Butyl 4-(2-cyanophenyl)piperidine-l-carboxylate

[00717] A mixture of tert-butyl 4-(2-cyanophenyl)-5,6-dihydropyridine-l(2H)-carboxylate (450 mg, 1.58 mmol) and Pd(OH) ₂ /C (90 mg, 0.64 mmol) in MeOH (25 mL) was stirred at rt for 16 h under H ₂ atmosphere. The mixture was filtered and concentrated to afford tert-butyl 4-(2- cyanophenyl)piperidine-l-carboxylate (407 mg, 1.42 mmol, 90%) as product. ESI-MS (EI ⁺ , m/z):

231.2 [M-55] ⁺ .

Step 3: 2-(Piperidin-4-yl)benzonitrile

[00718] To a solution of HC1 (4 N in dioxane, 15 mL) was added fert-butyl 4-(2- cyanophenyl)piperidine-l-carboxylate (407 mg, 1.42 mmol) with ice-bath cooling. After 16 h of stirring at 20 °C, the mixture was concentrated to afford 2-(piperidin-4-yl)benzonitrile (238 mg, 1.28 mmol, 90%). ESI-MS (EI ⁺ , m/z): 187.2 [M+H] ⁺ .

2-(l-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4-dimeth ylbenzoyl)piperidin-4- yl)benzonitrile, 1-87: ESI-MS (EI ⁺ , m/z): 518.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.64 (d, J= 7.7 Hz, 1H), 7.57 (dd, J= 16.7, 8.2 Hz, 2H), 7.46 (s, 1H), 7.35 (dt, J= 14.7, 7.5 Hz, 2H), 7.14 (d, J = 22.4 Hz, 1H), 7.07-6.87 (m, 3H), 5.02 (s, 1H), 3.78-3.42 (m, 3H), 3.21 (m, 6H), 2.92 (t, J = 11.9 Hz, 1H), 2.66 (s, 4H), 2.44-2.23 (m, 6H), 2.25-1.68 (m, 3H).

Example 87. Synthesis of 2-(4-(5-(4-(2-cyanophenyl)-l,4-diazepane-l-carbonyl)-2,4- dimethylbenzyl)piperazin- l-yl)benzonitrile, 1-185

1-185

Synthetic scheme:

Procedures and characterization:

[00719] Analysis was performed following Method B. Separation was performed following Method D.

[00720] The procedure was same as Example 1 and general procedure for Intermediate 83. Step 1: 2-(Azepan-4-yl)benzonitrile

[00721] A mixture of K ₂ C0 ₃ (10.4 g, 75 mmol), 2-fluorobenzonitrile (3 g, 25 mmol) and 1,4- diazepane (5 g, 50 mmol) in DMF (50 mL) was stirred at 110 °C for 16 h. The mixture was filtered, concentrated, and purified by chromatography (silica, EtOAc/PE = 3/1) to afford 2-(azepan-4- yl)benzonitrile (2.41 g, 12 mmol, 48%) as product. ESI-MS (EI ⁺ , m/z): 202.3 [M+H] ⁺ .

2-(4-(5-(4-(2-Cyanophenyl)-l,4-diazepane-l-carbonyl)-2,4- dimethylbenzyl)piperazin-l- yl)benzonitrile, 1-185: ESI-MS (EI ⁺ , m/z): 533.3 [M+H] ⁺ . ¾ MR (500 MHz, CDC1 ₃ ) δ 7.47 (m, 4H), 7.15-6.83 (m, 6H), 4.11-3.70 (m, 2H), 3.71-3.31 (m, 8H), 3.18 (d, J = 3.9 Hz, 4H), 2.63 (d, J= 3.2 Hz, 4H), 2.35 (d, J= 2.2 Hz, 3H), 2.29-2.14 (m, 4H), 1.96 (m, 1H).

Example 88. Synthesis of (S)-2-(4-(5-(2-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4- dimethylbenzoyl)-3-methylpiperazi -l-yl)-4,5-difluorobenzonitrile, 1-24

1-24

Synthetic scheme:

Procedures and characterization:

[00722] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: (S)-terf-butyl 4-(4-cyano-2,5-difluorophenyl)-2-methylpiperazine-l-carboxyl ate

[00723] The mixture of 2,4,5-trifluorobenzonitrile (1.0 g, 6.4 mmol), (S)-fert-butyl 2- methylpiperazine-l-carboxylate (1.53 g, 7.6 mmol) and K2CO3 (2.64 g, 19.1 mmol) in MeCN (20 mL) were stirred at 80 °C for 16 h. The mixture was then filtered, washed with MeCN (5 mL x 2), concentrated, and purified by chromatography (PE:EtOAc = 2:3) to afford (S)-tert-butyl 4-(2- cyano-4,5-difluorophenyl)-2-methylpiperazine-l-carboxylate (1.8 g, 84%) as a white solid. MS (EI+, m/z): 338.2 [M+H] ⁺ .

Step 2: (S)-2,5-difluoro-4-(3-methylpiperazin-l-yl)benzonitrile

[00724] To a solution of (S)-tert-butyl 4-(2-cyano-4,5-difluorophenyl)-2-methylpiperazine-l- carboxylate (1.7 g, 5.0 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction mixture was stirred for 1 h at rt then the solvent was removed by coevaporated with DCE (8 mL x 2). The residue was extracted with sat. NaHCOs (20 mL) and DCM:MeOH (20 mL x 4, v/v =10: 1), dried, and concentrated to afford (S)-4,5-difluoro-2-(3-methylpiperazin-l-yl)benzonitrile (1.2 g, crude) as a colorless oil which used for the next step directly. ESI-MS (EI+, m/z): 238.1 [M+H] ⁺ . Step 3: (S)-2,5-difluoro-4-(4-(5-formyl-2,4-dimethylbenzoyl)-3-methy lpiperazin-l- yl)benzonitrile

[00725] A mixture of (S)-4,5-difluoro-2-(3-methylpiperazin-l-yl)benzonitrile (1.2 g, 5.1 mmol), 5-formyl-2,4-dimethylbenzoic acid (751 mg, 4.2 mmol), HATU (2.41 g, 6.3 mmol), and DIPEA (1.9 mL, 12.6 mmol) in DMF (10 mL) were stirred at rt for lh, then poured into ice-water (30 mL), filtered, washed with water (5 mL x 2), and dried to afford (S)-2,5-difluoro-4-(4-(5- formyl-2,4-dimethylbenzoyl)-3-methylpiperazin-l-yl)benzonitr ile (1.6 g, 96%) as a pale white solid. ESI-MS (EI+, m/z): 398.2 [M+H] ⁺ .

Step 4 : (R,E)-2,5-difluoro-4-(4-(5-(2-methoxy vinyl)-2,4-dimethylbenzoyl)-3- methylpiperazin-l-yl)benzonitrile

[00726] To a solution of diphenyl(methoxymethyl)-phosphineoxide (356 mg, 1.45 mmol) in THF (8 mL) at -78 °C, was added LDA (0.72 mL, 1.45 mmol, 2 M in THF) and after 3 min, (S)- 2,5-difluoro-4-(4-(5-formyl-2,4-dimethylbenzoyl)-3-methylpip erazin-l-yl)benzonitrile (500 mg, 1.26 mmol) was added and the solution was warmed to rt. NaH (50 mg, 1.26 mmol, 60% dispersion in paraffin liquid) and DMF (8 mL) were added and the mixture was heated to 60 °C for 3 h. The reaction mixture was cooled and poured into sat. NaLhPC^ solution, extracted with MTBE (5 mL x 2), washed with water (2 mL) and brine (2 mL), then concentrated to afford (R,E)- 2,5-difluoro-4-(4-(5-(2-methoxyvinyl)-2,4-dimethylbenzoyl)-3 -methylpiperazin-l- yl)benzonitrile (600 mg, crude) as a colorless oil which used directly for the next step. ESI-MS (EI+, m/z): 426.1 [M+H] ⁺ .

Step 5: (R)-4-(4-(2,4-dimethyl-5-(2-oxoethyl)benzoyl)-3-methylpipera zin-l-yl)-2,5- difluorobenzonitrile

[00727] To a solution of (R,E)-2,5-difluoro-4-(4-(5-(2-methoxyvinyl)-2,4-dimethylbenz oyl)-3- methylpiperazin-l-yl)benzonitrile (600 mg crude, 1.41 mmol) in dioxane (6 mL) was added 1 M HC1 (6 mL). The mixture was stirred at 60 °C for 3 h, then cooled to rt and sat. NaHCCb was added. The pH was adjusted to 9, extracted with EtOAc (15 mL x 3), dried, and concentrated to give a residue which was purified by a flash column (PE:EtOAc = 3 :7) to afford (R)-4-(4-(2,4- dimethyl-5-(2-oxoethyl)benzoyl)-3-methylpiperazin-l-yl)-2,5- difluorobenzonitrile (40 mg, 6%) as a white solid. ESI-MS (EI+, m/z): 412.2 [M+H] ⁺ .

Step 6: (S)-4-(4-(5-(2-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4-d imethylbenzoyl)-3- methylpiperazin-l-yl)-2,5-difluorobenzonitrile, 1-24 [00728] To a mixture of (R)-4-(4-(2,4-dimethyl-5-(2-oxoethyl)benzoyl)-3-methylpipera zin-l- yl)-2,5-difluorobenzonitrile (35 mg, 0.09 mmol) and 2-(piperazin-l-yl)benzonitrile (32 mg, 0.17 mmol) in EtOH (1 mL) was added AcOH (2 drops) at rt. The reaction mixture was stirred at 25 °C for 30 min. NaB¾CN (16 mg, 0.26 mmol) was then added and the mixture was stirred at 25 °C for 1.5 h. The mixture was then filtered and purified by prep-HPLC ( H4HCO3 buffer) to afford (S)-4-(4-(5-(2-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4-d imethylbenzoyl)-3- methylpiperazin-l-yl)-2,5-difluorobenzonitrile 1-24 (23 mg, 46%) as a white solid. ESI-MS (EI+, m/z): 583.2 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.67-7.41 (m, 2H), 7.22 (dd, J= 11.8, 5.8 Hz, 1H), 7.04 (s, 4H), 6.63 (s, 1H), 5.10 (s, 1H), 4.75 (s, 1H), 3.62-3.16 (m, 8H), 2.82 (s, 9H), 2.25 (d, J = 36.1 Hz, 3H), 1.46 (d, J= 6.3 Hz, 2H), 1.33 (s, 1H).

Example 89. Synthesis of 2-(4-(5-(2-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-46

1-46

Synthetic scheme:

Procedures and characterization:

[00729] Analysis was performed following Method B. Separation was performed following Method D.

Step 1 : (E)-2-(4-(5-(2-methoxyvinyl)-2,4-dimethylbenzoyl)piperazin-l -yl)benzonitrile [00730] To a solution of diphenyl(methoxymethyl)-phosphineoxid (245 mg, 0.86 mmol) in THF (5 mL) at -78 °C, was added LDA (0.5 mL, 0.99 mmol, 2 M in THF) and, after 3 min, 2-(4- (5-formyl-2,4-dimethylbenzoyl)piperazin-l-yl)benzonitrile (300 mg, 0.86 mmol) was added and the solution was warmed to rt. NaH (35 mg, 0.86 mmol, 60% dispersion in Paraffin Liquid) and DMF (5 mL) were added and the mixture was heated to 60 °C for 3h. The reaction mixture was cooled and poured into sat. NaLhPC^ solution, extracted with MTBE (10 mL x 2), washed with water (5 mL) and brine (5 mL), and concentrated to afford (R,E)-4,5-difluoro-2-(4-(5-(2- methoxyvinyl)-2,4-dimethylbenzoyl)-3-methylpiperazin-l-yl)be nzonitrile (400 mg, crude) as a colorless oil which was used without further purification. ESI-MS (EI+, m/z): 376.2 [M+H] ⁺ . Step 2: 2-(4-(2,4-dimethyl-5-(2-oxoethyl)benzoyl)piperazin-l-yl)benz onitrile

[00731] To a solution of (E)-2-(4-(5-(2-methoxyvinyl)-2,4-dimethylbenzoyl)piperazin-l - yl)benzonitrile (400 mg crude, 0.86 mmol) in dioxane (4 mL) was added 1 M HC1 (4 mL). The mixture was stirred at 60 °C for 3h, then cooled to rt and sat. NaHC0 ₃ was added. The pH was adjusted to 9, extracted with EtOAc (20 mL x 3), dried, concentrated, and purified by chromatography (PE:EtOAc = 3 :7) to afford 2-(4-(2,4-dimethyl-5-(2-oxoethyl)benzoyl)piperazin- l-yl)benzonitrile (120 mg, 25%) as a yellow oil. ESI-MS (EI+, m/z): 362.2 [M+H] ⁺ .

Step 3: 2-(4-(5-(2-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)-2,4-dimet hylbenzoyl)piperazin-l- yl)benzonitrile, 1-46

[00732] To a mixture of 2-(4-(2,4-dimethyl-5-(2-oxoethyl)benzoyl)piperazin-l-yl)benz onitrile (100 mg, 0.28 mmol) and 2-(piperazin-l-yl)benzonitrile (62 mg, 0.33 mmol) in DCE (3 mL) was added HOAc (2 drops) at rt. After stirring at 25 °C for 30 min, NaBH(OAc) ₃ (176 mg, 0.83 mmol) was added and the reaction mixture was stirred at 25 °C for 3 h. The mixture was then filtered and purified by prep-HPLC ( H ₄ HC0 ₃ ) to afford 2-(4-(5-(2-(4-(2-cyanophenyl)piperazin-l-yl)ethyl)- 2,4-dimethylbenzoyl)piperazin-l-yl)benzonitrile 1-46 (3.3 mg, 2%) as a white solid. ESI-MS (EI+, m/z): 533.2 [M+H] ⁺ ; ¹ H MR (500 MHz, MeOD) δ 7.80-7.44 (m, 4H), 7.16 (ddd, J= 28.1, 19.2, 8.2 Hz, 6H), 4.02 (d, J= 16.5 Hz, 2H), 3.51 (s, 2H), 3.15 (d, J= 13.9 Hz, 2H), 2.99-2.88 (m, 2H), 2.82 (s, 4H), 2.72-2.56 (m, 2H), 2.39 (s, 3H), 2.28 (s, 3H).

Example 90. Synthesis of (S)-4-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5-difluorobenzoni trile, 1-40

1-40

Synthetic scheme:

Procedures and characterization:

[00733] The general procedure for Intermediate 83 was followed to obtain 5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,4-dimethylbenzoic acid.

[00734] Analysis was performed following Method B. Separation was performed following Method D.

Step 1 : (S)-4-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-di methylbenzoyl)-3- methylpiperazin-l-yl)-2,5-difluorobenzonitrile, 1-40

[00735] A mixture of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenz oic acid (100 mg, 0.29 mmol), (R)-2,5-difluoro-4-(3-methylpiperazin-l-yl)benzonitrile (81 mg, 0.34 mmol), HATU (163 mg, 0.43 mmol), and DIPEA(113 mg, 0.86 mmol) in DMF (2 mL) were stirred at rt for 0.5 h, then filtered and purified by prep-HPLC ( H4HCO3) to afford (S)-4-(4-(5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,4-dimethylbenzoyl)-3-me thylpiperazin-l-yl)-2,5- difluorobenzonitrile 1-40 (62 mg, 40%) as a white solid. MS (EI+, m/z): 569.2 [M+H] ⁺ ; ¾ MR (500 MHz, CDC1 ₃ ) 5 7.60-7.52 (m, 1H), 7.51-7.41 (m, 1H), 7.19 (dd, J= 18.5, 12.7 Hz, 1H), 7.14- 6.89 (m, 4H), 6.64 (s, 1H), 5.10 (s, 1H), 4.76 (s, 1H), 3.68-3.27 (m, 6H), 3.19 (s, 4H), 2.65 (s, 4H), 2.35 (d, J = 22.4 Hz, 3H), 2.30 (s, 2H), 2.19 (d, J= 42.5 Hz, 1H), 2.01 (s, 2H), 1.46 (d, J= 6.1 Hz, 2H), 1.33 (s, 2H). Example 91. Synthesis of (S)-4-(4-(5-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,4-dimethylbenzoyl)-3-m ethylpiperazin-l-yl)-2,5- difluorobenzonitrile, 1-23

1-23

Synthetic scheme:

Procedures and characterization:

[00736] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: Methyl 5-formyl-2,4-dimethylbenzoate

[00737] To a solution of 5-formyl-2,4-dimethylbenzoic acid (2.0 g, 11.2 mmol) and MeOH (30 mL) was carefully added con. H2SO4 (2 mL) at rt. The mixture was stirred at 80 °C for 2 h then cooled to rt. The solvent was removed and the residue was adjusted to pH = 9 with sat. NaHCCb. The mixture was extracted with EtOAc (50 mL x 3), washed with brine (50 mL x 2), dried, and concentrated to afford methyl 5-formyl-2,4-dimethylbenzoate (2.0 g, 93%) as a pale white solid. MS (EI+, m/z): 193.2 [M+H] ⁺ .

Step 2: (E)-Methyl 2,4-dimethyl-5-((2-(pyrazin-2-yl)hydrazono)methyl)benzoate

[00738] The mixture of methyl 5-formyl-2,4-dimethylbenzoate (800 mg, 41.7 mmol) and 2- hydrazinylpyrazine (458 mg, 41.7 mmol) in EtOH (10 mL) was stirred at 90 °C for 3 h, then cooled to rt. The solvent was removed to afford (E)-methyl 2,4-dimethyl-5-((2-(pyrazin-2- yl)hydrazono)methyl)benzoate (1.2 g crude) as a yellow solid which was used without further purification. ESI-MS (EI+, m/z): 285.1 [M+H] ⁺ .

Step 3: Methyl 5-([l,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,4-dimethylbenzoate

[00739] Under N ₂ , to a solution of (E)-methyl 2,4-dimethyl-5-((2-(pyrazin-2- yl)hydrazono)methyl)benzoate (700 mg, 2.5 mmol) in MeTHF (15 mL) was added chloramine-T (1.4 g, 6.2 mmol) at rt. The mixure was stirred at 60 °C for 1 h, then water (25 mL) was added and the organic layer was separated, filtered, and washed with DCM/MeOH (50 mL x 2, v/v = 10: 1). The organic layers were combined, concentrated, and purified by chromatography (PE:EtOAc = 3 :7) to afford methyl 5-([l,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,4-dimethylbenzoate (430 mg, 37%) as a pale white solid. ESI-MS (EI+, m/z): 283.2 [M+H] ⁺ .

Step 4: Methyl 2,4-dimethyl-5-(5,6,7,8-tetrahydro- [1,2,4] triazolo[4,3-a] pyrazin-3- yl)benzoate

[00740] A mixture of methyl 5-([l,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,4-dimethylbenzoate (400 mg, 1.4 mmol) and Pd/C (200 mg, 10%, 50% of water) in MeOH (6 mL) was charged with PL- three times, then stirred at 25 °C for 2 h. The mixture was then filtered, washed with MeOH (5 mL x 3), and concentrated to afford methyl 2,4-dimethyl-5-(5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyrazin-3-yl)benzoate (450 mg crude) as a corlorless oil which was used without further purification. ESI-MS (EI+, m/z): 287.1 [M+H] ⁺ .

Step 5: Methyl 5-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-[l,2,4]triazo lo[4,3-a]pyrazin- 3-yl)-2,4-dimethylbenzoate

[00741] A mixture of methyl 2,4-dimethyl-5-(5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyr azin- 3-yl)benzoate (200 mg, 0.7 mmol), 2-bromo-3-chloropyridine (162 mg, 0.84 mmol), Pd ₂ (dba) ₃ (64 mg, 0.07 mmol), BINAP (43 mg, 0.07 mmol), and t-BuONa (101 mg, 1.0 mmol) in toluene (4 mL) was charged with N ₂ three times, then stirred at 100 °C for 6 h. The solvent was removed to afford methyl 5-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-[l,2,4]triazo lo[4,3-a]pyrazin-3-yl)-2,4- dimethylbenzoate (300 mg crude) as a yellow solid which was used without further purification. ESI-MS (EI+, m/z): 398.2 [M+H] ⁺ .

Step 6 : 5-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrah dro- [1 ,2,4] triazolo [4,3-a] pyrazin-3-yl)-2,4- dimethylbenzoic acid

[00742] To a solution of methyl 5-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,4-dimethylbenzoate (300 mg crude, 0.8 mmol) in MeOH (5 mL) was added a solution of LiOH H ₂ 0 (127 mg, 3.0 mmol) in water (3 mL). The mixture was stirred at 25 °C for 16 h, then filtered and purified by prep-HPLC ( H4HCO3) to afford 5-(7-(3- chloropyridin-2-yl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a ]pyrazin-3-yl)-2,4-dimethylbenzoic acid (40 mg, three steps yield 14%) as a white solid. ESI-MS (EI+, m/z): 384.2 [M+H] ⁺ .

Step 7: (S)-4-(4-(5-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-[l, 2,4]triazolo[4,3-a]pyrazin- 3-yl)-2,4-dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5-diflu orobenzonitrile, 1-23

[00743] A mixture of 5-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-[l,2,4]triazo lo[4,3- a]pyrazin-3-yl)-2,4-dimethylbenzoic acid (40 mg, 0.1 mmol), (S)-2,5-difluoro-4-(3- methylpiperazin-l-yl)benzonitrile (32 mg, 0.14 mmol), HATU (60 mg, 0.16 mmol), and DIPEA (40 mg, 0.31 mmol) in DMF (1 mL) was stirred at 25 °C for 1 h. The mixture was then filtered and purified by prep-HPLC ( H4HCO3) to afford (S)-4-(4-(5-(7-(3-chloropyridin-2-yl)-5,6,7,8- tetrahydro-[l,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,4-dimethylb enzoyl)-3-methylpiperazin-l-yl)-2,5- difluorobenzonitrile 1-23 (20 mg, 32%) as a white solid. ESI-MS (EI+, m/z): 603.2 [M+H] ⁺ ; ¾ MR (500 MHz, CDCb) δ 8.22 (d, J= 3.4 Hz, 1H), 7.68 (d, J= 6.4 Hz, 1H), 7.15 (d, J= 24.3 Hz, 1H), 6.97 (dd, J= 7.8, 4.7 Hz, 1H), 6.62 (s, 1H), 5.07 (s, 1H), 4.86 (d, J= 8.6 Hz, 2H), 4.74-4.58 (m, 1H), 3.87 (dd, J = 107.0, 59.6 Hz, 5H), 3.65-3.16 (m, 4H), 2.96 (dd, J= 89.8, 41.1 Hz, 2H), 2.36 (d, J= 36.2 Hz, 6H), 1.48 (d, J= 6.8 Hz, 2H), 1.33 (s, 2H).

Example 92. Synthesis of (S)-4-(4-(5-(7-(2-cyanophenyl)-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,4-dimethylbenzoyl)-3-m ethylpiperazin-l-yl)-2,5- difluorobenzonitrile, 1-22

1-22

Synthetic scheme:

Procedures and characterization:

[00744] The procedure for methyl 2,4-dimethyl-5-(5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyrazin-3-yl)benzoate was the same as Example 91.

[00745] Analysis was performed following Method B. Separation was performed following Method D.

Step 5: methyl 5-(7-(2-cyanophenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyrazin-3-yl)- 2,4-dimethylbenzoate

[00746] A mixture of methyl 2,4-dimethyl-5-(5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyr azin- 3-yl)benzoate (200 mg, 0.7 mmol), 2-bromobenzonitrile (152 mg, 0.8 mmol), Pd ₂ (dba)3 (64 mg, 0.07 mmol), BINAP (43 mg, 0.07 mmol), and t-BuONa (101 mg, 1.0 mmol) in toluene (4 mL) was charged with N ₂ three times then stirred at 100 °C for 6 h. The mixture was cooled to rt and the solvent was removed to afford methyl 5-(7-(2-cyanophenyl)-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,4-dimethylbenzoate (300 mg crude) as a pale white solid which used without further purification. MS (EI+, m/z): 388.1 [M+H] ⁺ .

Step 6 : 5-(7-(2-cyanophenyl)-5,6,7,8-tetrah dro- [1 ,2,4] triazolo [4,3-a] pyrazin-3-yl)-2,4- dimethylbenzoic acid

[00747] To a solution of methyl 5-(7-(2-cyanophenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyrazin-3-yl)-2,4-dimethylbenzoate (300 mg crude, 0.8 mmol) in MeOH (5 mL) was added a solution of LiOH H ₂ 0 (127 mg, 3.0 mmol) in water (3 mL). The mixture was stirred at 25 °C for 16 h, then filtered and purified by prep-HPLC ( H4HCO3 buffer) to afford 5-(7-(2-cyanophenyl)- 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,4-d imethylbenzoic acid (15 mg, two steps yield 4%) as a white solid. ESI-MS (EI+, m/z): 374.1 [M+H] ⁺ .

Step 7 : (S)-4-(4-(5-(7-(2-cyanophenyl)-5,6,7,8-tetrahydro- [1 ,2,4] triazolo [4,3-a] pyrazin-3-yl)- 2,4-dimethylbenzoyl)-3-methylpiperazin-l-yl)-2,5-difluoroben zonitrile, 1-22

[00748] A mixture of 5-(7-(2-cyanophenyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyrazin-3- yl)-2,4-dimethylbenzoic acid (15 mg, 0.04 mmol), (S)-2,5-difluoro-4-(3-methylpiperazin-l- yl)benzonitrile (12 mg, 0.05 mmol), HATU (23 mg, 0.06 mmol) and DIPEA (16 mg, 0.12 mmol) in DMF (0.5 mL) was stirred at 25 °C for 1 h. The mixture was then filtered and purified by prep- HPLC ( H4HCO3 buffer) to afford (S)-4-(4-(5-(7-(2-cyanophenyl)-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazin-3-yl)-2,4-dimethylbenzoyl)-3-m ethylpiperazin-l-yl)-2,5- difluorobenzonitrile 1-22 (7.7 mg, 9%) as a white solid. ESI-MS (EI+, m/z): 593.2 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.84-7.50 (m, 2H), 7.16 (dd, J= 15.9, 7.7 Hz, 4H), 6.63 (s, 1H), 4.65 (s, 2H), 4.00 (s, 2H), 3.70 (s, 2H), 3.61-3.22 (m, 4H), 3.16-2.72 (m, 2H), 2.39 (s, 2H), 2.33 (s, 4H), 1.40 (d, J= 71.1 Hz, 5H).

Example 93. Synthesis of 2-(4-(5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4- dimethylphenylsulfonyl)piperazin-l-yl)benzenesulfonamide, 1-334

1-334

Synthetic scheme:

Procedures and characterization:

[00749] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 4,6-dimethylbenzene-l,3-disulfonyl dichloride

[00750] A mixture of 2,4-dimethylbenzenesulfonic acid (1.0 g, 5.4 mmol) in CISO3H (5 mL) was stirred at 150 °C for 2 h. The reaction mixture was cooled to rt and poured into 50 mL of ice- water at -20 °C, filtered, washed with water (5 mL), and dried to afford 4,6-dimethylbenzene-l,3- disulfonyl dichloride (1.1 g, 68%) as a white solid. MS (EI+, m/z): 303.2 [M+H] ⁺ .

Step 2: 5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4-dimethylbenz ene-l-sulfonyl chloride

[00751] To a mixture of 4,6-dimethylbenzene-l,3-disulfonyl dichloride (100 mg, 0.33 mmol) and Et ₃ N (0.2 mL, 1.32 mmol) in DCM (2 mL) at 0 °C was added a solution of 2-(piperazin-l- yl)benzonitrile (62 mg, 0.33 mmol) in DCM (1 mL). The reaction mixture was stirred at rt for 30 min. The reaction mixture was used directlyin the next step. ESI-MS (EI+, m/z): 454.2 [M+H] ⁺ . Step 3: 2-(4-(5-(4-(2-cyanophenyl)piperazin-l-ylsulfonyl)-2,4- dimethylphenylsulfonyl)piperazin-l-yl)benzenesulfonamide, 1-334

[00752] To the solution from the above step was added a solution of 2-(piperazin-l- yl)benzenesulfonamide (96 mg, 0.4 mmol) in DCM (3 mL). The reaction mixure was stirred at 0 °C to rt for 1 h. The solvent was removed in vacuo and the crude product was dissolved in DMF (2 mL), filtered, and purified by prep-HPLC ( H ₄ HC0 ₃ ) to afford 2-(4-(5-(4-(2- cyanophenyl)piperazin- 1 -ylsulfonyl)-2,4-dimethylphenylsulfonyl)piperazin- 1 - yl)benzenesulfonamide 1-344 (27 mg, two steps yield 12%) as a white solid. ESI-MS (EI+, m/z): 659.2 [M+H] ⁺ ; ¾ NMR (500 MHz, CDCb) δ 8.38 (s, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.46 - 7.31 (m, 3H), 7.27 (s, 1H), 7.14 - 6.92 (m, 2H), 5.44 (s, 2H), 3.40 (d, J= 4.3 Hz, 5H), 3.32 - 3.24 (m, 5H), 3.18 (s, 4H), 2.01 (s, 1H), 1.61 (s, 2H).

Example 94. Synthesis of 2-(4-(4-Methyl-3-(4-(6-methylpyridin-2-yl)piperidine-l- carbonyl)benzyl)piperazin-l- l)benzonitrile, 1-270

1-270

Synthetic scheme:

Procedures and characterization:

[00753] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: tert-Butyl 4-(6-methylpyridin-2-yl)-5,6-dihydropyridine-l(2H)-carboxyla te

[00754] To a solution of 2-bromo-6-methylpyridine (300 mg, 1.74 mmol) and tert-butyl 4-

(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro pyridine-l(2H)-carboxylate (647 mg, 2.09 mmol) in 1,4-dioxane (15 mL) and H ₂ 0 (5 mL) were added Pd(dppf)Cl ₂ (15 mg, 0.02 mmol) and Na ₂ CC"3 (461 mg, 4.35 mmol) at 80 °C. After 17 h of stirring, filtered, the filtrate was extracted with EtOAc (100 mL x 3), and the organic layers were concentrated and purified by chromatography (silica, EtOAc/PE =1/10) to afford tert-butyl 4-(6-methylpyridin-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (324 mg, 1.18 mmol, 68%) as product. ESI-MS (EI ⁺ , m/z): 275.2 [M+H] ⁺ .

Step 2: tert-Butyl 4-(6-methylpyridin-2-yl) piperidine-l-carboxylate

[00755] A mixture of tert-butyl 4-(6-methylpyridin-2-yl)-5,6-dihydropyridine-l(2H)- carboxylate (650 mg, 2.37 mmol) and Pd(OH) ₂ /C (130 mg, 0.93 mmol) in MeOH (25 mL) was stirred at rt for 17 h under a H ₂ atmosphere. The mixture was filtered and the filtrate was concentrated and purified by chromatography (silica, EtOAc/PE =1/12) to afford tert-butyl 4-(6- methylpyridin-2-yl) piperidine-l-carboxylate (621 mg, 2.25 mmol, 95%) as product. ESI-MS (EI ⁺ , m/z): 277.3 [M+H] ⁺ .

Step 3: 2-Methyl-6-(piperidin-4-yl) pyridine

[00756] To a solution of HCl (4 N in dioxane, 15 mL) was added tert-butyl 4-(6-methylpyridin- 2-yl) piperidine-l-carboxylate (490 mg, 1.78 mmol) with ice-bath cooling. After 16 h of stirring at 20 °C, the mixture was concentrated to afford 2-methyl-6-(piperidin-4-yl) pyridine (282 mg, 1.60 mmol, 90%).ESI-MS (EI ⁺ , m/z): 177.3 [M+H] ⁺ .

[00757] The synthesis of 2-(4-(4-Methyl-3-(4-(6-methylpyridin-2-yl)piperidine-l- carbonyl)benzyl)piperazin-l-yl)benzonitrile 1-270 was the same as Example 35: ESI-MS (EI ⁺ , m/z): 494.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.50 (m, 3H), 7.27 - 7.14 (m, 3H), 7.04 - 6.88 (m, 4H), 4.96 (s, 1H), 3.67 - 3.49 (m, 3H), 3.21 (s, 3H), 3.11 (dd, J = 23.0, 11.1 Hz, 1H), 2.99 - 2.84 (m, 2H), 2.73 - 2.60 (m, 4H), 2.52 (s, 3H), 2.33 (m, 3H), 2.26 - 1.70 (m, 4H).

Example 95. Synthesis of 2-(l-(4-methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l- carbonyl)benzyl)piperidin-4- l)benzonitrile, 1-281

1-281 Synthetic scheme:

2 1-281

Procedures and characterization:

[00758] Analysis was performed following Method B. Separation was performed following Method D.

[00759] The procedure was same as example 89.

Step 1 : 2-(l-(4-Methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l-carbo nyl)benzyl)piperidin- 4-yl)benzonitrile, 1-281

[00760] To a solution of 2-(piperidin-4-yl)benzonitrile (80 mg, 0.43 mmol) and 4-methyl-3-(4- (6-methylpyridin-2-yl)piperazine-l-carbonyl)benzaldehyde (153 mg, 0.47 mmol) in AcOH (0.025 mL) and ethanol (5 mL) was added NaC BH ₃ (54 mg, 0.86 mmol) with ice-bath cooling. After 20 h of stirring at 20 °C, the mixture was purified by prep-HPLC to afford 2-(l-(4-methyl- 3-(4-(6-methylpyridin-2-yl)piperazine-l-carbonyl)benzyl)pipe ridin-4-yl)benzonitrile 1-281 (40 mg, 0.08 mmol, 19%). ESI-MS (EI ⁺ , m/z): 494.3 [M+H] ⁺ . ¾ MR (500 MHz, CDC1 ₃ ) δ 7.61 (dd, J = 7.7, 1.1 Hz, 1H), 7.59 - 7.48 (m, 1H), 7.46 - 7.35 (m, 2H), 7.31 - 7.27 (m, 1H), 7.23 - 7.16 (m, 2H), 6.54 (d, J = 7.3 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 3.94 (t, J = 5.1 Hz, 2H), 3.63 (d, J = 5.0 Hz, 2H), 3.51 (m, 4H), 3.37 (s, 2H), 3.07 - 2.92 (m, 3H), 2.38 (s, 3H), 2.32 (s, 3H), 2.16 (td, J = 11.6, 2.6 Hz, 2H), 1.90 - 1.73 (m, 4H).

Example 96. Synthesis of 2-(4-(4-Methyl-3-(4-(6-methylpyridin-2-yl)-l,4-diazepane-l- carbonyl)benzyl)piperazin-l- l)benzonitrile, 1-283

1-283 Synthetic scheme:

Procedures and characterization:

[00761] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: tert-Butyl 4-(6-methylpyridin-2-yl)-l,4-diazepane-l-carboxylate

[00762] A mixture of 2-bromo-6-methylpyridine (1 g, 5.81 mmol), tert-butyl 1,4-diazepane-l- carboxylate (1.16 g, 5.81 mmol), t-BuONa (837 mg, 8.71 mmol), BINAP (40 mg, 0.06 mmol) and

Pd ₂ (dba)3 (20 mg, 0.02 mmol) in toluene (20 mL) was stirred at 80 °C for 3 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/8) to afford tert-butyl 4-(6-methylpyridin-2- yl)-l,4-diazepane-l-carboxylate (947 mg, 3.25 mmol, 56%) as product. ESI-MS (EI ⁺ , m/z): 292.2

[M+H] ⁺ .

Step 2: l-(6-Methylpyridin-2-yl)-l,4-diazepane

[00763] To a solution of HCl (4 N in dioxane, 15 mL) was added tert-butyl 4-(6-methylpyridin- 2-yl)-l,4-diazepane-l-carboxylate (900 mg, 3.09 mmol) with ice-bath cooling. After 16 h of stirring at 20 °C, the mixture was concentrated to afford l-(6-methylpyridin-2-yl)-l,4-diazepane (543 mg, 2.84 mmol, 92%). ESI-MS (EI ⁺ , m/z): 192.3 [M+H] ⁺ .

[00764] The synthesis of 2-(4-(4-Methyl-3-(4-(6-methylpyridin-2-yl)-l,4-diazepane-l- carbonyl)benzyl)piperazin-l-yl)benzonitrile 1-283 was the same as Example 35: ESI-MS (EI ⁺ , m/z): 509.3 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCb) δ 7.55 (dt, J= 7.9, 1.8 Hz, 1H), 7.50 - 7.44 (m, 1H), 7.37 - 7.29 (m, 1H), 7.25 - 7.21 (m, 1H), 7.18 - 7.06 (m, 1H), 7.03 - 6.95 (m, 2H), 6.92 (d, J = 1.4 Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 6.32 (dd, J = 15.8, 8.4 Hz, 1H), 4.01 - 3.34 (m, 9H), 3.21 (m, 5H), 2.71 - 2.55 (m, 4H), 2.37 (s, 1H), 2.26 - 2.05 (m, 6H). Example 97. Synthesis of 2-(l-(4-methyl-3-(4-methylpiperazine-l- carbonyl)benzyl)piperidin-4- l)benzonitrile, 1-360

1-360

Synthetic scheme:

Procedures and characterization:

[00765] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 5-((4-(2-Cyanophenyl)piperidin-l-yl)methyl)-2-methylbenzoic acid

[00766] To a solution of 2-(piperidin-4-yl)benzonitrile (200 mg, 1.1 mmol) and 5-formyl-2- methylbenzoic acid (190 mg, 1.2 mmol) in AcOH (0.05 mL) and ethanol (10 mL) was added NaC BH ₃ (140 mg, 2.2 mmol) with ice-bath cooling. After 20 h of stirring at 20 °C, the mixture was purified by prep-HPLC to afford 5-((4-(2-cyanophenyl)piperidin-l-yl)methyl)-2- methylbenzoic acid (129 mg, 0.39 mmol, 35%). ESI-MS (EI ⁺ , m/z): 335.2 [M+H] ⁺ .

Step 2: 2-(l-(4-Methyl-3-(4-methylpiperazine-l-carbonyl)benzyl)piper idin-4- yl)benzonitrile, 1-360

[00767] A mixture of 5-((4-(2-cyanophenyl)piperidin-l-yl)methyl)-2-methylbenzoic acid (35 mg, 0.105 mmol), 1-methylpiperazine (13 mg, 0.126 mmol), HATU (60 mg, 0.158 mmol) and DIPEA (41 mg, 0.315 mmol) in DMF (4 mL) was stirred at rt for 16 h. The mixture was purified by prep-HPLC to afford 2-(l-(4-methyl-3-(4-methylpiperazine-l-carbonyl)benzyl)piper idin-4- yl)benzonitrile 1-360 (10 mg, 0.023 mmol, 22%). ESI-MS (EI ⁺ , m/z): 417.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 7.61 (dd, 7= 7.7, 1.1 Hz, 1H), 7.59 - 7.51 (m, 1H), 7.40 (d, J= 7.9 Hz, 1H), 7.29 (dt, J = 5.2, 2.6 Hz, 1H), 7.26 - 7.23 (m, 1H), 7.17 (m, 2H), 3.84 (d, J = 16.7 Hz, 2H), 3.53 (d, J= 2.9 Hz, 2H), 3.27 (t, J= 4.5 Hz, 2H), 3.08 - 2.94 (m, 3H), 2.48 (dd, J= 22.4, 16.5 Hz, 2H), 2.31 (m, 8H), 2.21 - 2.10 (m, 2H), 1.91 - 1.76 (m, 4H).

Example 98. Synthesis of 2-(l-(3-(4-Acetylpiperazine-l-carbonyl)-4- methylbenzyl)piperidin-4- l)benzonitrile, 1-361

1-361

S nthetic scheme:

Procedures and characterization:

[00768] Analysis was performed following Method B. Separation was performed following Method D.

[00769] The procedure was the same as example 97.

2-(l-(3-(4-Acetylpiperazine-l-carbonyl)-4-methylbenzyl)piper idin-4-yl)benzonitrile 1-361: ESI- MS (EI ⁺ , m/z): 445.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 7.61 (dd, J= 7.7, 1.0 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.40 (d, J= 7.9 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.23 - 7.14 (m, 2H), 3.98 - 3.68 (m, 3H), 3.66 - 3.46 (m, 4H), 3.47 - 2.93 (m, 7H), 2.30 (s, 3H), 2.14 (m, 5H), 1.82 (m, 3H).

Example 99. Synthesis of 2-(l-(4-Methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l- carbonyl)benzyl)pyrrolidin-3-yl)benzonitrile, 1-265

1-265

Synthetic scheme:

Procedures and characterization:

[00770] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: terf -Butyl 3-(2-cyanophenyl)-2H-pyrrole-l(5H)-carboxylate

[00771] At room temperature, to a solution of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2H-pyrrole-l(5H)-carboxylate (1.5 g, 5.08 mmol) in 1,4-dioxane (50 mL) was added 2-iodobenzonitrile (1.4 g, 6.10 mmol), Pd(dppf) ₂ Cl ₂ (414 mg, 0.508 mmol), Na ₂ C0 ₃ (1.62 g, 15.25 mmol) and H ₂ 0 (12 mL) under nitrogen. The reaction mixture was stirred at 80 °C for 16 h, then cooled to room temperature and filtered, concentrated and purified by chromatography (silica, EtOAc/PE =1/20) to afford tert-butyl 3-(2-cyanophenyl)-2H-pyrrole-l(5H)-carboxylate (960 mg, 3.55 mmol, 70%) as an oil. ESI-MS (EI ⁺ , m/z): 271.2 [M+H] ⁺ .

Step 2: tert-Butyl 3-(2-cyanophenyl)pyrrolidine-l-carboxylate

[00772] To a solution of tert-butyl 3-(2-cyanophenyl)-2H-pyrrole-l(5H)-carboxylate (900 mg, 3.33 mmol) in MeOH (10 mL) was added Pd/C (300 mg). The mixture was hydrogenated for 16 h at room temperature. Then the mixture was filtered and concentrated to afford tert-butyl 3-(2- cyanophenyl)pyrrolidine-l-carboxylate (600 mg, 2.20 mmol, 71%) as a solid. ESI-MS (EI ⁺ , m/z): 273.3 [M+H] ⁺ . Step 3: 2-(Pyrrolidin-3-yl)benzonitrile hydrochloride

[00773] To a solution of tert-butyl 3-(2-cyanophenyl)pyrrolidine-l-carboxylate (320 mg, 1.18 mmol) in 1, 4-dioxane (2 mL) was added 4 HCl/dioxane (10 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to afford 2-(pyrrolidin-3-yl)benzonitrile hydrochloride (215 mg, 1.03 mmol) as a solid. ESI-MS (EI ⁺ , m/z): 173.3 [M+H] ⁺ .

Step 4: 2-(l-(4-Methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l-carbo nyl)benzyl)pyrrolidin- 3-yl)benzonitrile, 1-265

[00774] At 0 °C , to a solution of 2-(pyrrolidin-3-yl)benzonitrile hydrochloride (165 mg, 0.96 mmol) in EtOH (15.0 mL) was added 4-methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l- carbonyl)benzaldehyde (310 mg, 0.96 mmol), NaB¾CN (181 mg, 2.88 mmol) and two drops of acetic acid. The reaction mixture was stirred at room temperature for 16 h, then purified by prep- HPLC to afford 2-(l-(4-methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l- carbonyl)benzyl)pyrrolidin-3-yl)benzonitrile 1-265 (15 mg, 0.03 mmol) as a white solid. ESI-MS (EI ⁺ , m/z): 480.2 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 7.60 (s, 1H), 7.57 - 7.47 (m, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.23 (dd, J = 42.1, 6.3 Hz, 4H), 6.54 (d, J= 7.2 Hz, 1H), 6.44 (d, J= 8.4 Hz, 1H), 3.93 (s, 2H), 3.79 (s, 1H), 3.66 (dd, J= 30.8, 23.5 Hz, 4H), 3.39 (d, J= 76.1 Hz, 4H), 2.99 - 2.78 (m, 2H), 2.69 (s, 2H), 2.53 - 2.43 (m, 1H), 2.39 (s, 3H), 2.31 (s, 3H), 1.85 (dd, J= 13.6, 6.7 Hz, 1H).

Example 100. Synthesis of 2-(4-(4-Methyl-3-(3-(6-methylpyridin-2-yl)pyrrolidine-l- carbonyl)benzyl)piperazin-l-yl)

1-266

Synthetic scheme:

Procedures and characterization:

[00775] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: terf -Butyl 3-(6-methylpyridin-2-yl)-2H-pyrrole-l(5H)-carboxylate

[00776] At rt, to a solution of tert-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2H- pyrrole-l(5H)-carboxylate (1.4 g, 4.74 mmol) in DMF (20 mL) was added 2-bromo-6- methylpyridine (815 mg, 4.74 mmol), Pd(dppf) ₂ Cl ₂ (387 mg, 0.474 mmol) and K ₂ C0 ₃ (1.96 g, 14.23 mmol) under nitrogen. The reaction mixture was stirred at 100 °C for 4 h, then cooled to rt and diluted with H ₂ 0 (100 mL), extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by chromatography (silica, EtOAc/PE =1/5) to afford tert-butyl 3-(6-methylpyridin-2-yl)-2H-pyrrole-l(5H)- carboxylate (590 mg, 2.27 mmol, 48%) as a white solid. ESI-MS (EI ⁺ , m/z): 261.3 [M+H] ⁺ . Step 2: tert-Butyl 3-(6-methylpyridin-2-yl)pyrrolidine-l-carboxylate

[00777] To a solution of tert-butyl 3-(6-methylpyridin-2-yl)-2H-pyrrole-l(5H)-carboxylate (530 mg, 2.04 mmol) in MeOH (5 mL) was added Pd/C (250 mg). The mixture was hydrogenated for 16 h at rt. The mixture was filtered and concentrated to afford tert-butyl 3-(6-methylpyridin-2- yl)pyrrolidine-l-carboxylate (420 mg, 1.60 mmol, 79%) as a solid. ESI-MS (EI ⁺ , m/z): 263.4 [M+H] ⁺ .

Step 3: 2-Methyl-6-(pyrrolidin-3-yl)pyridine hydrochloride

[00778] To a solution of tert-butyl 3-(6-methylpyridin-2-yl)pyrrolidine-l-carboxylate (220 mg, 0.84 mmol) in 1,4-dioxane (2 mL) was added 4 M HCl/dioxane (10 mL). The mixture was stirred at rt for 2 h, then the mixture was concentrated to afford 2-methyl-6-(pyrrolidin-3-yl)pyridine hydrochloride (150 mg, 0.75 mmol, 90%) as a solid. ESI-MS (EI ⁺ , m/z): 163.5 [M+H] ⁺ .

Step 4: 2-(4-(4-Methyl-3-(3-(6-methylpyridin-2-yl)pyrrolidine-l-carb onyl)benzyl)piperazin- l-yl)benzonitrile, 1-266

[00779] At 0 °C, to a solution of 2-methyl-6-(pyrrolidin-3-yl)pyridine hydrochloride (120 mg, 0.60 mmol) in DMF (6.0 mL) was added 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2- methylbenzoic acid (373 mg, 1.11 mmol), HATU (422 mg, 1.11 mmol) and DIPEA (310 mg, 2.4 mmol). The reaction mixture was stirred at rt for 16 h, then purified by Prep-HPLC to afford 2-(4- (4-methyl-3-(3-(6-methylpyridin-2-yl)pyrrolidine-l-carbonyl) benzyl)piperazin-l-yl)benzonitrile 1-266 (250 mg, 0.52 mmol, 86%) as a white solid. ESI-MS (EI+, m/z): 480.3 [M+Na] ⁺ . ¾ MR (500 MHz, CDCb) δ 9.76 (s, 2H), 8.23 (d, J= 31.2 Hz, 1H), 7.70 - 7.48 (m, 4H), 7.44 (d, J= 21.0 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.15 (dt, J= 11.9, 6.0 Hz, 1H), 7.06 (t, J= 9.4 Hz, 1H), 4.39 - 4.10 (m, 3H), 4.07 - 3.74 (m, 3H), 3.64 (s, 2H), 3.60 - 3.45 (m, 3H), 3.39 (d, J= 28.8 Hz, 3H), 3.14 (s, 2H), 2.80 (d, J = 40.1 Hz, 3H), 2.55 (s, 1H), 2.36 (d, J= 6.4 Hz, 3H).

Example 101. Synthesis of 2-(4-(4-Methyl-3-(2-phenyl-5,6,7,8-tetrahydroimidazo[l,2- a]pyrazine-7-carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-233

1-233

Synthetic scheme:

Procedures and characterization:

[00780] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: 8-Chloro-2-phenylimidazo[l,2-a]pyrazine

[00781] At rt, to a solution of 3-chloropyrazin-2-amine (5.0 g, 38.68 mmol) in anhydrous DMF (60 mL) was added 2-boryl-l -phenyl ethanone (9.23 g, 46.43 mmol). The reaction mixture was stirred at 50 °C for 16 h, then cooled down to rt and diluted with H ₂ 0 (200 mL) and extracted with EtOAc (100 mL x 2). The organic layer was washed with brine (100 mL), dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo, the crude product was purified by chromatography (silica, EtOAc/PE =1/5) to afford 8-chloro-2-phenylimidazo[l,2-a]pyrazine (2.4 g, 10.45 mmol, 27%) as a solid. ESI-MS (EI ⁺ , m/z): 230.2 [M+H] ⁺ .

Step 2: 2-Phenyl-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine

[00782] To a solution of 8-chloro-2-phenylimidazo[l,2-a]pyrazine (600 mg, 2.60 mmol) in MeOH (20 mL) was added Pd/C (300 mg). The mixture was hydrogenated for 16 h at rt. The mixture was filtered and concentrated to afford 2-phenyl-5,6,7,8-tetrahydroimidazo[l,2- a]pyrazine (450 mg, 2.26 mmol, 87%) as a solid. ESI-MS (EI ⁺ , m/z): 200.4 [M+H] ⁺ .

Step 3 : 2-(4-(4-Methyl-3-(2-phenyl-5,6,7,8-tetrahydroimidazo [1 ,2-a] pyrazine-7- carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-233

[00783] At 0 °C , to a solution of 2-phenyl-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine (250 mg, 1.25 mmol) in DMF (10 mL) was added 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2- methylbenzoic acid (421 mg, 1.25 mmol), HATU (716 mg, 1.89 mmol) and DIPEA (487 mg, 3.77 mmol). The reaction mixture was stirred at rt for 16 h, then purified by prep-HPLC to afford 2- (4-(4-methyl-3-(2-phenyl-5,6,7,8-tetrahydroimidazo[l,2-a]pyr azine-7- carbonyl)benzyl)piperazin-l-yl)benzonitrile 1-233 (250 mg, 0.48 mmol, 39%) as a white solid. ESI-MS (EI ⁺ , m/z): 517.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 7.71 (dd, J= 39.6, 7.5 Hz, 2H), 7.54 (d, J = 7.1 Hz, 1H), 7.44 (dd, J= 18.4, 10.2 Hz, 1H), 7.34 (ddd, J= 29.4, 14.4, 7.3 Hz, 3H), 7.25 - 7.11 (m, 4H), 7.04 - 6.89 (m, 2H), 5.43 - 4.49 (m, 2H), 4.42 - 3.65 (m, 4H), 3.56 (d, J = 24.8 Hz, 2H), 3.20 (s, 4H), 2.65 (s, 4H), 2.33 - 2.21 (m, 3H).

Example 102. Synthesis of (3-((4-(2-chlorophenyl)piperazin-l-yl)methyl)-2-methyl phenyl)(4-phenylpiperazin-l-yl)methanone, 1-306

1-306

Synthetic scheme:

Procedures and characterization:

[00784] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: (3-Bromo-2-methylphenyl)(4-phenylpiperazin-l-yl)methanone

[00785] A mixture of 3-bromo-2-methylbenzoic acid (5.16 g, 24 mmol), 1-phenyl piperazine (4.67 g, 28.8 mmol), HATU (11.86 g, 31.2 mmol), DIPEA (6.20 g, 48 mmol) in DMF (50 mL) was stirred at rt for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/4) to afford (3-bromo-2-methylphenyl)(4-phenyl piperazin-l-yl)methanone (8.5 g, 23.66 mmol, 99%) as yellow solid. ESI-MS (EI ⁺ , m/z): 359.1 [M+H] ⁺ .

Step 2: (2-Methyl-3-vinylphenyl)(4-phenylpiperazin-l-yl)methanone

[00786] A mixture of (3-bromo-2-methylphenyl)(4-phenylpiperazin-l-yl)methanone (3.59 g, 10 mmol), potassium trifluoro(vinyl)borate (2.01 g, 15 mmol), Pd(dppf)Cl2 (817 mg, 1 mmol), K2CO3 (2.76 g, 20 mmol) in CH3CN (80 mL) and H ₂ 0 (80 mL) was stirred under N ₂ at 80 °C for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/10) to afford (2-methyl- 3-vinylphenyl)(4-phenylpiperazin-l-yl)methanone (2.445 g, 7.98 mmol, 80%) as yellow solid, ESI-MS (EI+, m/z): 307.1 [M+H] ⁺ .

Step 3: 2-Methyl-3-(4-phenylpiperazine-l-carbonyl)benzaldehyde

[00787] A mixture of (2-methyl-3-vinylphenyl)(4-phenylpiperazin-l-yl)methanone (500 mg, 1.63 mmol) in DCM (20 mL) was stirred under 0 ₃ at -78 °C for 2 h. Then PPh ₃ (514 mg, 1.96 mmol) was added and the reaction mixture was stirred for 1 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/2) to afford 2-methyl-3-(4-phenylpiperazine-l-carbonyl) benzaldehyde (57 mg, 0.185 mmol, 11%) ESI-MS (EI ⁺ , m/z): 309.1 [M+H] ⁺ .

Step 4: (3-((4-(2-Chlorophenyl)piperazin-l-yl)methyl)-2-methylphenyl )(4-phenylpiperazin- l-yl)methanone, 1-306

[00788] A solution of 2-methyl-3-(4-phenylpiperazine-l-carbonyl)benzaldehyde (90 mg, 0.29 mmol), l-(2-chlorophenyl)piperazine (69 mg, 0.58 mmol) in EtOH (5 mL) and HOAc (1 drop) was stirred at rt for 2 h. Then NaBH ₃ CN (36 mg, 0.58 mmol) was added and the reaction mixture was stirred at rt for 14 h. The mixture was purified by prep-HPLC to afford (3-((4-(2- chlorophenyl)piperazin-l-yl)methyl)-2-methylphenyl)(4-phenyl piperazin-l-yl)methanone 1-306 (29.4 mg, 0.06 mmol, 21%) as yellow solid. ESI-MS (EI ⁺ , m/z): 489.2 [M+H] ⁺ . ¾ NMR (500 MHz, CDC1 ₃ ) δ 7.56 (d, J= 7.5 Hz, 1H), 7.41 - 7.29 (m, 5H), 7.28-7.24 (m, 1H), 7.16 - 6.91 (m, 5H), 4.55 (d, J= 13.3 Hz, 1H), 4.19 (d, J= 13.3 Hz, 1H), 4.17-4.00 (m, 2H), 3.82 (s, 1H), 3.61 (s, 1H), 3.63-3.03 (m, 12H), 2.42 (s, 3H).

Example 103. Synthesis of 2-(4-(4-Methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l- carbonyl)benzyl)-l,4-diazepan-l-yl)benzonitrile, 1-282

1-282

Synthetic scheme:

Procedures and characterization:

[00789] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 5-Formyl-2-methylbenzoic acid

[00790] To a solution of 5-bromo-2-methylbenzoic acid (10 g, 46.5 mmol) in THF (50 mL) was added «-BuLi (hexanes, 2.5 M, 47 mL) dropwise at -78 °C. After 2 h, DMF (13.6 g, 187 mmol) was added to the mixture and the reaction mixture was stirred for an additional 3 h. H ₂ 0 (10 mL) was added to quench the reaction. The pH was adjusted to 3-4 with HCl (aq. 6 M). The mixture was extracted with EtOAc (100 mL x 3), and the organic layers were concentrated and the crude product was purified by chromatography (silica, EtOAc/PE =1/10) to afford 5-formyl-2- methylbenzoic acid (5.65 g, 34.4 mmol, 74%) as yellow oil. ESI-MS (EI ⁺ , m/z): [M+H] ⁺ .

Step 2: 4-Methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l-carbonyl)be nzaldehyde

[00791] A mixture of 5-formyl-2-methylbenzoic acid (2.24 g, 13.6 mmol), l-(6-methylpyridin- 2-yl)piperazine (3.62 g, 20.4 mmol), HATU (6.72 g, 17.7 mmol), and DIPEA (8.77 g, 68 mmol) in DMF (20 mL) was stirred at rt for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/3) to afford 4-methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l- carbonyl)benzaldehyde (2.79 g, 8.64 mmol, 64%) as yellow oil. ESI-MS (EI ⁺ , m/z): 324.2 [M+H] ⁺ .

Step 3: 2-(4-(4-Methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l-carbo nyl)benzyl)-l,4- diazepan-l-yl)benzonitrile, 1-282

[00792] A solution of 4-methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l- carbonyl)benzaldehyde (194 mg, 0.6 mmol), 2-(l,4-diazepan-l-yl)benzonitrile (145 mg, 0.72 mmol) in EtOH (5 mL) and HO Ac (1 drop) was stirred at rt for 2 h. NaBH ₃ CN (75 mg, 1.2 mmol) was added and the reaction mixture was stirred at rt for 14 h. The mixture was purified by prep- HPLC to afford 2-(4-(4-methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l-carbo nyl)benzyl)-l,4- diazepan-l-yl)benzonitrile 1-282 (16 mg, 0.03 mmol, 5%) as a white solid. ESI-MS (EI ⁺ , m/z): 509.2 [M+H] ⁺ . ¾- MR (500 MHz, CDCb) δ 7.46 (dd, J = 7.8, 1.6 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.36-7.33 (m, 1H), 7.26 (d, J = 5.6 Hz, 1H), 7.18 (d, J = 9.1 Hz, 2H), 6.83 (d, J = 8.6 Hz, 1H), 6.74 (t, J= 7.5 Hz, 1H), 6.54 (d, J= 13 Hz, 1H), 6.45 (d, J= 8.4 Hz, 1H), 3.93 (s, 2H), 3.71 - 3.57 (m, 8H), 3.41 (d, 4H), 2.84 (t, J = 5.0 Hz, 2H), 2.69 (t, J = 5.0 Hz, 2H), 2.39 (s, 3H), 2.31 (s, 3H), 2.01 (s, 2H).

Example 104. Synthesis of 2-(4-(4-methyl-3-(l,2,3,4-tetrahydrobenzo[4,5]imidazo[l,2- a]pyrazine-2-carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-280

1-280

Synthetic scheme:

Procedures and characterization:

[00793] Analysis was performed following Method B. Separation was performed foil Method D.

Step 1: 5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2-methylbenzoic acid [00794] A solution of 5-formyl-2-methylbenzoic acid (6.56 g, 40 mmol), 2-(piperazin-l- yl)benzonitrile (8.98 g, 48 mmol) in EtOH (50 mL) and HO Ac (3 drops) was stirred at rt for 2 h. NaB¾CN (5 g, 80 mmol) was added and the reaction mixture was stirred at rt for 14 h. The mixture was concentrated and purified by prep-HPLC to afford 5-((4-(2-cyanophenyl) piperazin- l-yl)methyl)-2-methylbenzoic acid (2.9 g, 8.65 mmol, 21.6%) as yellow solid. ESI-MS (EI ⁺ , m/z): 336.2 [M+H] ⁺ .

Step 2: l,2,3,4-Tetrahydro-benz[4,5]imidazo[l,2-a]pyrazine

[00795] A mixture of tert-Butyl 3,4-dihydropyrazino[l,2-a]benzimidazole-2(lH)-carboxylate (350 mg, 1.28 mmol) in HCl/dioxane (4 M, 5 mL) was stirred at rt for 16 h. The reaction mixture was concentrated to give crude product l,2,3,4-Tetrahydro-benz[4,5]imidazo[l,2-a]pyrazin (200 mg) as yellow solid. ESI-MS (EI ⁺ , m/z): 174.2 [M+H] ⁺ .

Step 3: 2-{4-[(4-Methyl-3-{l,8,ll-triazatricyclo[7.4.0.0 ² , ⁷ ]trideca-2,4,6,8-tetraene-ll- carbonyl}phenyl)methyl]piperazin-l-yl}benzonitrile, 1-280

[00796] A mixture of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2-methylbenzoic acid (100 mg, 0.3 mmol), l,2,3,4-Tetrahydro-benz[4,5]imidazo[l,2-a]pyrazin (84 mg, 0.45 mmol), HATU (148 mg, 0.39 mmol), and DIPEA (195 mg, 1.5 mmol) in DMF (5 mL) was stirred at rt for 16 h. The mixture was purified by prep-HPLC to afford 2-{4-[(4-methyl-3-{ 1,8,11- triazatricyclo[7.4.0.0 ² , ⁷ ]trideca-2,4,6,8-tetraene-l l-carbonyl}phenyl)methyl]piperazin-l- yl}benzonitrile 1-280 (53.9 mg, 0.11 mmol, 37%) as a white solid. ESI-MS (EI ⁺ , m/z): 491.2 [M+H] ⁺ . 1H MR (500 MHz, CDC13) δ 7.72 (m, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.40 - 7.29 (m, 4H), 7.25-7.19 (m, 2H), 7.0 - 6.95 (m, 2H), 5.45 - 4.74 (m, 2H), 4.52 - 3.54 (m, 6H), 3.20 (s, 4H), 2.65 (d, J= 3.3 Hz, 4H), 2.35-2.25 (d, 3H).

Example 105. Synthesis of 2-(4-(4-Methyl-3-(l,2,3,4-tetrahydropyrazino[l,2-a]indole-2- carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-269

1-269

Synthetic scheme:

Procedures and characterization:

[00797] The procedure was the same as example 104.

[00798] Analysis was performed following Method B. Separation was performed following Method D.

2-(4-(4-methyl-3-(l,2,3,4-tetrahydropyrazino[l,2-a]indole-2- carbonyl)benzyl)piperazin-l- yl)benzonitrile, 1-269

[00799] ESI-MS (EI ⁺ , m/z): 490.2 [M+H] ⁺ . ¾- MR (500 MHz, CDCh) δ 7.61 - 7.51 (m, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.34-7.10 (m, 6H), 7.01 - 6.93 (m, 2H), 6.39-6.13 (d, 1H), 5.34 - 4.63 (m, 2H), 4.40 - 3.56 (m, 6H), 3.20 (d, J = 13.5 Hz, 4H), 2.65 (d, J = 3.9 Hz, 4H), 2.33-2.22 (d, 3H).

Example 106. Synthesis of S 2-[4-({4-methyl-3-[4-(6-methylpyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperidin- 1-yl] benzonitrile, 1-232

1-232

Synthetic scheme:

Procedures and characterization:

[00800] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: tert-butyl 4-(3-(methoxycarbonyl)-4-methylbenzylidene)piperidine-l-carb oxylate

[00801] To a solution of tert-butyl 4-methylenepiperidine-l-carboxylate (2.0 g, 8.73 mmol) in CH ₃ CN (50 mL) was added added tert-butyl methyl 5-bromo-2-methylbenzoate (2.58 g, 13.09 mmol), Et ₃ N (3.12 g, 30.34 mmol), tri(o-tolyl)phosphine (106.28 mg, 0.34 mmol), Pd(OAc) ₂ (19.59 mg, 0.082 mmol). The mixture was stirred for 17 h at 80 °C. The solution was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic phase was washed with brine (50 mL x 3), dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum, the crude product was purified by chromatography (silica, EtOAc/PE =1/20) to afford tert-butyl 4-(3-(methoxycarbonyl)-4- methylbenzylidene)piperidine-l-carboxylate tert-butyl 4-(3-(methoxycarbonyl)-4-methylbenzyl)- 3,6-dihydropyridine-l(2H)-carboxylate (290 mg, 0.84 mmol, 9%) as a white solid. ESI-MS (EI+, m/z): 346 [M+H] ⁺ . 1H MR (500 MHz, DMSO) δ 7.64 (s, 1H), 7.29-7.32 (m, 2H), 6.37 (s, 1H), 3.81 (s, 3H), 3.41 (s, 2H), 2.47-2.50(m, 4H), 2.36 (s, 2H), 2.28 (s, 2H), 1.40 (s, 10H), 1.38 (s, 1H). Step 2: tert-butyl 4-(3-(methoxycarbonyl)-4-methylbenzyl)piperidine-l-carboxyla te

[00802] To a mixture of tert-butyl 4-(3-(methoxycarbonyl)-4-methylbenzylidene)piperidine-l- carboxylate and tert-butyl 4-(3-(methoxycarbonyl)-4-methylbenzyl)-3,6-dihydropyridine-l (2H)- carboxylate (600 mg, 1.7 mmol) in MeOH (30mL) was added Pd/C (300 mg). The mixture was stirred at rt for 17 h under H ₂ . The solution was filtered and concentrated in vacuum to afford tert- butyl 4-(3-(methoxycarbonyl)-4-methylbenzyl)piperidine-l -carboxylate (506 mg, 1.46 mmol, 86%) as a white solid. MS (EI+, m/z): 348 [M+H] ⁺ .

Step 3: methyl 2-methyl-5-(piperidin-4-ylmethyl)benzoate

[00803] To a solution of tert-butyl 4-(3-(methoxycarbonyl)-4-methylbenzyl)piperidine-l- carboxylate (1.3 g, 3.75 mmol) in DCM (10 mL) was added 4 M HCl/dioxane (10 mL). The reaction mixture was stirred for 3 h at rt. The solution was concentrated in vacuum to give the crude product. The crude product was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum to afford methyl 2-methyl-5-(piperidin-4-ylmethyl)benzoate (0.9 g, 4.59 mmol, 97%) as a yellow oil. MS (EI+, m/z): 248 [M+H]+.

Step 4: methyl 5-((l-(2-cyanophenyl)piperidin-4-yl)methyl)-2-methylbenzoate

[00804] To a solution of methyl 2-methyl-5-(piperidin-4-ylmethyl)benzoate (0.85 g, 3.44 mmol) in DMF (20 mL) was added K ₂ C0 ₃ (1.43 g, 10.32 mmol) and 2-fluorobenzonitrile (624.86 mg, 5.16 mmol). The mixture was stirred for 17 h at 120 °C. The solution was diluted with water (100 mL) and extracted with DCM (100 mL x 3). The organic phase was washed with brine (50 mL x 3), dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum. The crude product was purified by chromatography (silica, EtOAc/PE =1/20) to afford methyl 5-((l-(2-cyanophenyl)piperidin-4- yl)methyl)-2-methylbenzoate (480 mg, 1.37 mmol, 43%) as yellow oil. ESI-MS (EI+, m/z): 349[M+H]+.

Step 5: 5-((l-(2-cyanophenyl)piperidin-4-yl)methyl)-2-methylbenzoic acid

[00805] To a solution of methyl 5-((l-(2-cyanophenyl)piperidin-4-yl)methyl)-2- methylbenzoate (480 mg, 1.38 mmol) in MeOH (10 mL) was added LiOHH ₂ 0 (287.1 mg, 6.9 mmol) and H ₂ 0 (1 mL). The mixture was stirred for 17 h at rt. The solution was concentrated in vacuum to give the crude product which was diluted with 1M HC1 (20 mL) and extracted with DCM (100 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum to afford 5-((l-(2-cyanophenyl)piperidin-4-yl)methyl)-2,4-dimethylbenz oic acid (400 mg, 1.19 mmol, 97%) as yellow solid. ESI-MS (EI+ +, m/z): 335 [M+H] ⁺ .

Step 6: 2-(4-(4-methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l-carbo nyl)benzyl)piperidin- l-yl)benzonitrile, 1-232 [00806] To a solution of 5-((l-(2-cyanophenyl)piperidin-4-yl)methyl)-2,4-dimethylbenz oic acid (200 mg, 0.58 mmol) in DMF (10 mL) was added HATU (286.6 mg, 0.75 mmol) , DIPEA (224.8mg, 1.74 mmol), and l-(6-methylpyridin-2-yl)piperazine (103 mg, 0.58 mmol). The mixture was stirred for 17 h at rt. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phase was dried (Na ₂ S04), filtered and concentrated in vacuum, the crude product was purified by TLC to give the crude product which was further purified by CHTRAL- HPLC to give 2-(4-(4-methyl-3-(4-(6-methylpyridin-2-yl)piperazine-l- carbonyl)benzyl)piperidin-l-yl)benzonitrile 1-232 (50 mg, 0.10 mmol, 20%) as white solid. ESI- MS (EI+, m/z): 494[M+H]+. 1H MR (500 MHz, DMSO) δ 7.65-7.67 (m, 1H), 7.54-7.57 (m, 1H), 7.20-7.22 (m, 1H), 7.03-7.18 (m, 4H), 6.65-6.81 (m, 1H), 3.73-3.75 (m, 5H), 3.47-3.49(m, 4H), 3.26 (s, 2H), 2.70-2.74 (m, 2H), 2.58 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 1.70 (s, 3H), 1.27-1.35 (m, 2H).

Example 107. Synthesis of 2-(4-(3-(4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl)-2- methylbenzyl)piperazin- -yl)benzonitrile, 1-231

1-231

Synthetic scheme:

Procedures and characterization:

[00807] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 3-Formyl-2-methylbenzoic acid [00808] To a solution of 3-bromo-2-methylbenzoic acid (2.15 g, 10 mmol) in THF (50 mL) was added «-BuLi (hexanes, 2.5 M, 10 mL) dropwise at -78 °C. After 2 h, DMF (2.92 g, 40 mmol) was added and the mixture was stirred for 1 h. H ₂ 0 (2 mL) was added to quench the reaction. The pH was adjusted to 3-4 with HC1 (aq. 6 M). The mixture was extracted with EtOAc (100 mL x 3), and the organic layers were concentrated and purified by chromatography (silica, EtOAc/PE =1/10) to afford 3-formyl-2-methylbenzoic acid (1 g, 6.1 mmol, 61%) as white solid. ESI-MS (EI ⁺ , m/z): 164.0 [M+H] ⁺ .

Step 2: 3-(4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl)-2-methylbe nzaldehyde

[00809] A mixture of 3-formyl-2-methylbenzoic acid (500 mg, 3 mmol), l-(5-fluoropyridin-2- yl)piperazine (815 mg, 4.5 mmol), HATU (1.482 g, 3.9 mmol), and DIPEA (1.939 g, 15 mmol) in DMF (10 mL) was stirred at rt for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/5) to afford 3-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2- methylbenzaldehyde (300 mg, 0.92 mmol, 31%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 328.1 [M+H] ⁺ .

Step 3: 2-(4-(3-(4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl)-2-me thylbenzyl) piperazin- l-yl)benzonitrile, 1-231

[00810] A solution of 3-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2- methylbenzaldehyde (100 mg, 0.3 mmol), 2-(piperazin-l-yl)benzonitrile (67 mg, 0.36 mmol) in EtOH (4 mL) and HO Ac (1 drop) was stirred at rt for 2 h. NaBH ₃ CN (38 mg, 0.6 mmol) was added and the reaction mixture was stirred at rt for 14 h. The mixture was purified by prep-HPLC to afford 2-(4-(4-methyl-3 -(4-(6-methylpyridin-2-yl)piperazine- 1 -carbonyl) benzyl)- 1 ,4-diazepan- 1 - yl)benzonitrile 1-231 (40 mg, 0.08 mmol, 27%) as white solid. ESI-MS (EI ⁺ , m/z): 499.3 [M+H] ⁺ . ¾- MR (500 MHz, CDC1 ₃ ) δ 8.06 (d, J= 2.9 Hz, 1H), 7.56 (dd, J= 7.8, 1.3 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 7.01 - 6.98 (m, 2H), 6.64 (dd, J = 9.2, 3.2 Hz, 1H), 4.02 - 3.91 (m, 2H), 3.64- 3.49 (m, 4H), 3.45 - 3.33 (m, 4H), 3.21 (s, 4H), 2.67 (s, 4H), 2.35 (s, 3H).

Example 108. Synthesis of 2-(4-(2,6-dimethyl-3-(4-(pyridazin-3-yl)piperazine-l- carbonyl)benzyl)piperazin- l-yl)benzonitrile, 1-107

1-107

Synthetic scheme:

Procedures and characterization:

[00811] The procedure for compound 2 was same as example 109.

[00812] Analysis was performed following Method B. Separation was performed following Method D.

Step: 2-(4-(2,6-Dimethyl-3-(4-(pyridazin-3-yl)piperazine-l-carbony l)benzyl) piperazin-1- yl)benzonitrile, 1-107

[00813] ESI-MS (EI+ m/z): 496.2 [M+H] ⁺ . ¾- MR(500 MHz, CDCb) δ 8.63 (d, J= 4.0 Hz, 1H), 7.55 (d, J= 7.5 Hz, 1H), 7.47(dt, J = 9.0, 1.5 Hz, 1H), 7.25 (t, J = 4.5 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 7.06 - 6.96 (m, 3H), 6.94 (d, J = 9.5 Hz, 1H), 4.08 - 3.99 (m, 1H), 3.97 - 3.89 (m, 1H), 3.80 - 3.62 (m, 4H), 3.61 (s, 2H), 3.44 - 3.32 (m, 2H), 3.16 (s, 4H), 2.68 (s, 4H), 2.44 (s, 3H), 2.38 (s, 3H).

Example 109. Synthesis of 2-(4-(2,6-Dimethyl-3-(3-phenyl-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazine-7-carbon l)benzyl)piperazin-l-yl)benzonitrile, 1-102

1-102

Synthetic scheme:

Procedures and characterization:

[00814] Analysis was performed following Method B. Separation was performed following Method D.

[00815] 2-(4-(2,6-Dimethyl-3-(3-phenyl-5,6,7,8-tetrahydro-[l,2,4]tri azolo[4,3-a]pyrazine- 7-carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-102: ESI-MS (EI ⁺ , m/z): 532.3 [M+H] ⁺ ¾ MR (500 MHz, CDCb) δ 7.70 (dd, J = 1 1.8, 8.2 Hz, 2H), 7.54 (dd, J = 10.2, 5.5 Hz, 3H), 7.52 - 7.43 (m, 2H), 7.15 - 6.94 (m, 4H), 5.63 - 4.59 (m, 2H), 4.36 - 4.22 (m, 2H), 4.21 - 3.53 (m, 4H), 3.16 (s, 4H), 2.69 (s, 4H), 2.50 - 2.30 (m, 6H).

Example 110. Synthesis of 2-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,3- dimethylbenzoyl)piperazin-l- l)benzonitrile, 1-174

1-174

Synthetic scheme:

Procedures and characterization:

[00816] Analysis was performed following Method B. Separation was performed following Method D.

[00817] 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,3- dimethylbenzoyl)piperazin-l-yl)benzonitrile, 1-174: ESI-MS (EI ⁺ , m/z): 519 3 [M+H] ⁺ ¾ MR (500 MHz, CDCb) δ 7.59 (dd, J= 7.7, 1.4 Hz, 1H), 7.57 - 7.44 (m, 3H), 7.16 (s, 1H), 7.06 (dd, J = 14.5, 6.9 Hz, 1H), 7.05 - 6.96 (m, 3H), 4.14 - 3.95 (m, 2H), 3.64 - 3.35 (m, 4H), 3.34 - 3.04 (m, 8H), 2.73 - 2.60 (m, 4H), 2.30 (s, 3H), 2.22 (s, 3H).

Example 111. Synthesis of 2-(4-(3-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4- difluorobenzoyl)piperazin-l- l)benzonitrile, 1-149

1-149

Synthetic scheme:

Procedures and characterization:

[00818] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 2,4-Difluoro-3-formylbenzoic acid

[00819] To a solution of 5-bromo-2,4-difluorobenzoic acid (4 g, 16.88 mmol) in THF (100 mL) was added «-BuLi (hexanes, 2.5 M) (16.9 mL, 42.2 mmol) dropwise at -78 °C. After 1 h, DMF (4.56 g, 62.5 mmol) was added to the mixture followed by an additional 3 h of stirring. H ₂ 0 (5 mL) was added to quench the reaction. The pH was adjusted to 3-4 using HCl (aq. 6 M). The mixture was extracted with EtOAc (200 mL x 3), and the organic layers were concentrated and purified by chromatography (silica, EtOAc/PE =1/5) to afford 2,4-difluoro-3-formylbenzoic acid (1.26 g, 6.75 mmol, 40%) as a white solid. ESI-MS (EI ⁺ , m/z): 187 [M+H] ⁺ .

Step 2: 3-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4-difluorobenz oic acid

[00820] To a solution of 2,4-difluoro-3-formylbenzoic acid (1 g, 5.38 mmol) and 2-(piperazin- l-yl)benzonitrile (1 g, 5.38 mmol) in AcOH (0.1 mL) and ethanol (20 mL) was added NaCNBH ₃ (677 mg, 10.75 mmol) with ice-bath cooling. After 20 h of stirring at 20 °C, the reaction mixture was filtered, the filter cake was washed with EtOAc (50 mL) and dried to afford 3-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,4-difluorobenzoic acid (1.05 g, 2.96 mmol, 55%) as a white solid.ESI-MS (EI ⁺ , m/z): 358.2 [M+H] ⁺ .

[00821] 2-(4-(3-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4- difluorobenzoyl)piperazin-l-yl)benzonitrile, 1-149: ESI-MS (EI ⁺ , m/z): 527 3 [M+H] ⁺ ¾ NMR (500 MHz, CDCb) δ 7.60 (dd, J= 7.7, 1.4 Hz, 1H), 7.57 - 7.44 (m, 3H), 7.39 (dd, J= 14.4, 7.7 Hz, 1H), 7.15 - 6.85 (m, 5H), 4.03 (s, 2H), 3.82 (s, 2H), 3.58 (s, 2H), 3.38 - 3.14 (m, 3H), 2.73 (s, 4H).

Example 112. Synthesis of 2-(4-(2,6-Difluoro-3-(4-(5-fluoropyridin-2-yl)piperazine-l- carbonyl)benzyl)piperazin- l-yl)benzonitrile, 1-148

1-148

Synthetic scheme:

Procedures and characterization:

[00822] Analysis was performed following Method B. Separation was performed following Method D.

[00823] The procedure was the same as example 111.

2-(4-(2,6-Difluoro-3-(4-(5-fluoropyridin-2-yl)piperazine-l-c arbonyl)benzyl)piperazin-l- yl)benzonitrile 1-148: ESI-MS (EI ⁺ , m/z): 521.3 [M+H] ⁺ . ¾ NMR (400 MHz, CDCb) δ 8.06 (d, J = 3.0 Hz, 1H), 7.56 (dd, J = 7.6, 1.4 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.40 (dd, J = 14.3, 7.7 Hz, 1H), 7.30 (ddd, J= 9.4, 7.9, 3.2 Hz, 1H), 7.10 - 6.95 (m, 3H), 6.68 (dd, J= 9.2, 3.3 Hz, 1H), 3.89 (m, 4H), 3.55 (m, 6H), 3.22 (s, 4H), 2.73 (s, 4H).

Example 113. Synthesis of 4-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- difluorobenzoyl)piperazin-l-yl)-2,5-difluorobenzonitrile, 1-362

1-362

Synthetic scheme:

Procedures and characterization:

[00824] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 5-Bromo-2,4-difluorobenzoic acid

[00825] At room temperature, to a solution of 2,4-difluorobenzoic acid (6.0 g, 37.97 mmol) in TFA (60 mL) and H2SO4 (20 mL) was added BS (6.76 g, 37.97 mmol). The reaction mixture was stirred at 50 °C for 16 h, then the mixture was cooled down to room temperature, poured into ice water (200 mL) filtered, and dried in vacuo to afford 5-bromo-2,4-difluorobenzoic acid (8.1 g, 34.17 mmol, 90%) as a white solid. ESI-MS (EI ⁺ , m/z): 272.2 [M+H] ⁺ .

Step 2: 2,4-Difluoro-5-vinylbenzoic acid

[00826] At room temperature, to a solution of 5-bromo-2,4-difluorobenzoic acid (4.0 g, 16.88 mmol) in CH3CN (21 mL) and H ₂ 0 (7.0 mL) was added potassium vinyltrifluoroborate (2.72 g, 20.26 mmol), Pd(dppf) ₂ Cl ₂ (1.37 g, 1.69 mmol) and K ₂ C0 ₃ (6.99 g, 50.64 mmol) under nitrogen. The reaction mixture was stirred at 85 °C for 16 h, then cooled down to room temperature, diluted with H ₂ 0 (200 mL), and extracted with EtOAc (80 mL x 3). The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by chromatography (silica, EtOAc/PE =1/5) to afford 2,4-difluoro-5-vinylbenzoic acid ( 2.86 g, 15.53 mmol, 92%) as a solid. ESI-MS (EI ⁺ , m/z): 185.4 [M+H] ⁺ .

Step 3: 2,4-Difluoro-5-formylbenzoic acid

[00827] At room temperature , to a solution of 2,4-difluoro-5-vinylbenzoic acid ( 2.0 g, 10.87 mmol) in acetone (40 mL) and H ₂ 0 (40 mL) was added MO (2.54 g, 21.74 mmol), K ₂ 0s0 ₄ H ₂ 0 (50 mg) and NaI0 ₄ (4.63 g, 21.74 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with H ₂ 0 (200 mL), extracted with EtOAc (100 mL x 2). The organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by chromatography (silica, EtOAc/PE =1/5) to afford 2,4-difluoro-5-formylbenzoic acid (1.4 g, 7.52 mmol, 69%) as a solid. ESI-MS (EI ⁺ , m/z): 187.3 [M+H] ⁺ .

Step 4: 5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4-difluorobenz oic acid

[00828] At 0 °C , to a solution of 2,4-difluoro-5-formylbenzoic acid (600 mg, 3.23 mmol) in EtOH (30.0 mL) was added 2-(piperazin-l-yl)benzonitrile (603 mg, 3.23 mmol), NaBH ₃ CN (610 mg, 9.68 mmol) and two drops of acetic acid. The reaction mixture was stirred at room temperature for 16 h, then diluted with H ₂ 0 (200 mL) and extracted with EtOAc (80 mL x 3). The organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by chromatography (silica, EtOAc/PE =1/3) to afford 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)- 2,4-difluorobenzoic acid (210 mg, 0.59 mmol, 18%) as a solid. ESI-MS (EI ⁺ , m/z): 358.4 [M+H] ⁺ . Step 5: 4-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-difluo robenzoyl)piperazin-l- yl)-2,5-difluorobenzonitrile, 1-362

[00829] At 0 °C, to a solution of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4- difluorobenzoic acid (200 mg, 0.56 mmol) in DMF (20 mL) was added 4,5-difluoro-2-(piperazin- l-yl)benzonitrile (125 mg, 0.56 mmol), HATU (320 mg, 0.84 mmol) and DIPEA (290 mg, 2.24 mmol). The reaction mixture was stirred at room temperature for 16 h, then purified by Prep- HPLC to afford 4-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,4-difluo robenzoyl) piperazin-l-yl)-2,5-difluorobenzonitrile 1-362 (80 mg, 0.14 mmol, 25%) as a white solid. ESI-MS (EI ⁺ , m/z): 563.3 [M+H] ⁺ . ¾ MR (400 MHz, CDC1 ₃ ) δ 7.64 - 7.41 (m, 3H), 7.26 - 7.18 (m, 1H), 7.06 - 6.94 (m, 2H), 6.88 (t, J = 9.4 Hz, 1H), 6.68 (dd, J = 10.6, 6.9 Hz, 1H), 3.97 (s, 2H), 3.66 (s, 2H), 3.54 (s, 2H), 3.37 - 3.11 (m, 8H), 2.83 - 2.55 (m, 4H).

Example 114. Synthesis of 2-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4- difluorobenzoyl)piperazin-l-yl)benzonitrile, 1-98

1-98

Synthetic scheme:

Procedures and characterization:

[00830] Analysis was performed following Method A. Separation was performed following Method D.

Step 1 : 2-(4-(2,4-Difluoro-5-formylbenzoyl)piperazin-l-yl)benzonitri le

[00831] At room temperature, to a solution of 2,4-difluoro-5-formylbenzoic acid (250 mg, 1.34 mmol) in DMF (20 mL) was added 2-(piperazin-l-yl)benzonitrile (252 mg, 1.34 mmol), HATU (1.02 g, 2.02 mmol) and DIPEA (260 mg, 2.02 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with H ₂ 0 (100 mL) and extracted with EtOAc (60 mL x 3). The organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by chromatography (silica, EtOAc/PE =1/3) to afford 2-(4-(2,4-difluoro-5-formylbenzoyl)piperazin- l-yl)benzonitrile (270 mg, 0.76 mmol, 57%) as a solid. ESI-MS (EI ⁺ , m/z): 356.3. [M+H] ⁺ . Step 2: 2-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4-difluo robenzoyl)piperazin-l- yl)benzonitrile, 1-98

[00832] At 0 °C, to a solution of 2-(4-(2,4-difluoro-5-formylbenzoyl)piperazin-l- yl)benzonitrile (270 mg, 0.76 mmol) in EtOH (10 mL) was added 2-(piperazin-l-yl)benzonitrile (109 mg, 0.76 mmol), NaB¾CN (144 mg, 2.28 mmol) and two drops of acetic acid. The reaction mixture was stirred at room temperature for 16 h, then diluted with H ₂ 0 (200 mL) and extracted with EtOAc (80 mL x 3). The organic layer was washed with brine , dried over Na ₂ S0 ₄ , filtered, concentrated and purified by prep-HPLC to afford 2-(4-(5-((4-(2-cyanophenyl)piperazin-l- yl)methyl)-2,4-difluorobenzoyl)piperazin-l-yl)benzonitrile 1-98 (120 mg, 0.23 mmol, 30%) as a solid. ESI-MS (EI ⁺ , m/z): 527.2 [M+H] ⁺ .¾ MR (400 MHz, CDCb) δ 7.64 - 7.58 (m, 1H), 7.58 - 7.44 (m, 4H), 7.08 (t, J= 7.5 Hz, 1H), 7.02 (dd, J= 14.4, 8.0 Hz, 3H), 6.87 (t, J = 9.4 Hz, 1H), 4.02 (s, 2H), 3.62 (d, J= 23.3 Hz, 4H), 3.23 (ddd, J= 15.8, 10.2, 4.8 Hz, 8H), 2.79 - 2.59 (m, 4H).

Example 115. Synthesis of 2-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4- difluorobenzoyl)piperazin-l-yl)nicotinonitrile, 1-97

Procedures and characterization:

[00833] Analysis was performed following Method A. Separation was performed following Method D.

Step 1 : 2-(4-(2,4-Difluoro-5-formylbenzoyl)piperazin-l-yl)nicotinoni trile

[00834] At room temperature, to a solution of 2,4-difluoro-5-formylbenzoic acid (300 mg, 1.61 mmol) in DMF (20.0 mL) was added 2-(piperazin-l-yl)nicotinonitrile (304 mg, 1.61 mmol), HATU (919 mg, 2.42 mmol) and DIPEA (313 mg, 2.42 mmol). The reaction mixture was stirred at room temperature for 16 h, then diluted with H ₂ 0 (100 mL) and extracted with EtOAc (80 mL x 3). The organic layer was washed with brine, dried over Na ₂ S0 ₄ , filtered, concentrated and purified by chromatography (silica, EtOAc/PE =1/3) to afford 2-(4-(2,4-difluoro-5- formylbenzoyl)piperazin-l-yl)nicotinonitrile (400 mg, 1.12 mmol, 70%) as a solid. ESI-MS (EI ⁺ , m/z): 357.3 [M+H] ⁺ .

Step 2: 2-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2,4-difluo robenzoyl)piperazin-l- yl)nicotinonitrile, 1-97

[00835] At room temperature, to a solution of 2-(4-(2,4-difluoro-5-formylbenzoyl)piperazin-l- yl)nicotinonitrile (400 mg, 1.12 mmol) in EtOH (20.0 mL) was added 2-(piperazin-l- yl)benzonitrile (210 mg, 1.12 mmol), NaB¾CN (212 mg, 3.37 mmol) and two drops of acetic acid. The reaction mixture was stirred at room temperature for 16 h, then diluted with H ₂ 0 (200 mL), extracted with EtOAc (80 mL x 3). The organic layer was washed with brine , dried over Na ₂ S0 ₄ , filtered, concentrated and purified by prep-HPLC to afford 2-(4-(5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,4-difluorobenzoyl)piper azin-l-yl)nicotinonitrile 1-97 (150 mg, 0.28 mmol, 25%) as a solid. ESI-MS (EI ⁺ , m/z): 528.2 [M+H] ⁺ . ¾ MR (400 MHz, CDCb) δ 8.38 (dd, J= 4.8, 1.8 Hz, 1H), 7.82 (dd, J = 7.6, 1.9 Hz, 1H), 7.62 - 7.44 (m, 3H), 7.01 (dd, J = 7.6, 6.4 Hz, 2H), 6.86 (dt, J = 7.6, 7.1 Hz, 2H), 3.97 (s, 2H), 3.80 (s, 2H), 3.73 - 3.67 (m, 2H), 3.64 (s, 2H), 3.53 (s, 2H), 3.30 - 3.14 (m, 4H), 2.78 - 2.62 (m, 4H).

Example 116. Synthesis of (S)-2-(4-(4-fluoro-3-(4-(5-fluoropyridin-2-yl)-2-methyl piperazine-l-carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-268

1-268

S nthetic scheme:

Procedures and characterization:

[00836] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: (S)-tert-butyl 4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l-carboxylate

[00837] A solution of 2-bromo-5-fluoropyridine (3.52 g, 20 mmol), (S)-tert-buty\ 2- methylpiperazine-l-carboxylate (2 g, 11.36 mmol), t-BuONa (1.922 g, 20 mmol), BINAP (623 mg, 1 mmol), and Pd ₂ (dba)3 (458 mg, 0.5 mmol) in dry toluene (20 mL) was stirred under N ₂ at 80 °C for 16 h. The reaction mixture was concentrated and the mixture was purified by chromatography (silica, EtOAc/PE =1/10) to afford (S)-tert-butyl 4-(5-fluoropyridin-2-yl)-2- methylpiperazine-l-carboxylate (2.9 g, 9.82 mmol, 86%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 296.2 [M+H] ⁺ .

Step 2: (S)-l-(5-Fluoropyridin-2-yl)-3-methylpiperazine

[00838] A mixture of (S)-tert-bu y\ 4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l -carboxylate (2.9 g, 9.8 mmol) in HCl/dioxane (4 , 20 mL) was stirred at rt for 2 h. The reaction mixture was concentrated to give crude product (,S)-l-(5-fluoropyridin-2-yl)-3-methylpiperazine (1.9 g) as yellow solid. ESI-MS (EI ⁺ , m/z): 196.0 [M+H] ⁺ .

Step 3: (S)-4-fluoro-3-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine- l- carbonyl)benzaldehyde

[00839] A mixture of 2-fluoro-5-formylbenzoic acid (200 mg, 1.2 mmol), (S)-l-(5- fluoropyridin-2-yl)-3-methylpiperazine (352 mg, 1.8 mmol), HATU (593 mg, 1.56 mmol), and DIPEA (775 mg, 6 mmol) in DMF (10 mL) was stirred at rt for 16 h. The mixture was poured into water, then extracted with EtOAc (lOOmL x 2), dried and concentrated. The crude was purified by chromatography (silica, EtOAc/PE =1/2) to afford (S)-4-fluoro-3-(4-(5-fluoropyridin- 2-yl)-2-methylpiperazine-l-carbonyl)benzaldehyde (400 mg, 1.158 mmol, 97%) as yellow oil. ESI-MS (EI+, m/z): 345.2 [M+H] ⁺ .

Step 4: (S)-2-(4-(4-fluoro-3-(4-(5-fluoropyridin-2-yl)-2-methylpiper azine-l- carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-268

[00840] A solution of (S)-4-fluoro-3-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine- l- carbonyl)benzaldehyde (140 mg, 0.4 mmol), 2-(piperazin-l-yl)benzonitrile (90 mg, 0.48 mmol) in EtOH (3 mL) and HO Ac (1 drop) was stirred at rt for 2 h. Then NaBFLCN (50 mg, 0.8 mmol) was added and the reaction mixture was stirred at rt for 14 h. The mixture was purified by prep-HPLC to afford (S)-2-(4-(4-fluoro-3-(4-(5-fluoropyridin-2-yl)-2-methylpiper azine-l-carbonyl)benzyl) piperazin-l-yl)benzonitrile 1-268 (77 mg, 0.149 mmol, 37%) as white solid. ESI-MS (EI ⁺ , m/z): 517.2 [M+H] ⁺ . ¾- ΜΡν(500 MHz, CDCb) δ 8.04 (d, J= 3.0 Hz, 1H), 7.56 (dd, J= 7.9, 1.6 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.41- 7.38 (m, 2H), 7.29 - 7.25 (m, 1H), 7.11 - 7.05 (m, 1H), 7.03 - 6.99 (m, 2H), 6.62 - 6.61 (m, 1H), 5.05 - 4.66 (m, 1H), 4.13 (m, 1H), 3.88 - 2.81 (m, 10 H), 2.67 - 2.54 (d, 4H), 1.39 - 1.27 (m, 3H).

Example 117. Synthesis of (S)-2-(4-(4-chloro-3-(4-(5-fluoropyridin-2-yl)-2-methyl piperazine-l-carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-202

1-202

Synthetic scheme:

Procedures and characterization:

[00841] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 2-Chloro-5-formylbenzoic acid

[00842] To a solution of (2.35 g, 10 mmol) in THF (50 mL) was added «-BuLi (hexanes, 2.5 , 10 mL) dropwise at -78 °C. After 2 h, DMF (13.6 g, 187 mmol) was added to the mixture followed by an additional 1 h of stirring. H ₂ 0 (2 mL) was added to quench the reaction. The pH was adjusted to 3-4 with HCl (aq. 6M). The mixture was extracted with EtOAc (100 mL x 2), and the organic layers were concentrated to purified by chromatography (silica, EtOAc/PE =1/10) to afford 2-chloro-5-formylbenzoic acid (400 mg, 2.17 mmol, 22%) as yellow solid. ESI-MS (EI ⁺ , m/z): 185.1 [M+H] ⁺ .

Step 2: (S)-4-Chloro-3-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine- l- carbonyl)benzaldehyde [00843] A mixture of 2-chloro-5-formylbenzoic acid (130 mg, 0.7 mmol), (S)-l-(5- fluoropyridin-2-yl)-3-methylpiperazine (205 mg, 1.05 mmol), HATU (346 mg, 0.91 mmol) and DIPEA (452 mg, 3.5 mmol) in DMF (5 mL) was stirred at rt for 16 h. The mixture was poured into water, then extracted with EtOAc (lOOmL x 2), dried and concentrated. The crude was purified by chromatography (silica, EtOAc/PE =1/3) to afford (S)-4-chloro-3-(4-(5-fluoropyridin-2-yl)-2- methylpiperazine-l-carbonyl)benzaldehyde (200 mg, 0.55 mmol, 79%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 361.9 [M+H] ⁺ .

Step 3: (S)-2-(4-(4-chloro-3-(4-(5-fluoropyridin-2-yl)-2-methylpiper azine-l- carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-202

[00844] A solution of (,S)-4-chloro-3-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine -l- carbonyl)benzaldehyde (110 mg, 0.3 mmol), 2-(piperazin-l-yl)benzonitrile (67 mg, 0.36 mmol) in EtOH (3 mL) and HOAc (1 drop) was stirred at rt for 2 h. NaBH ₃ CN (38 mg, 0.6 mmol) was added and the reaction mixture was stirred at rt for 14 h. The mixture was purified by prep-HPLC to afford (,S)-2-(4-(4-chloro-3-(4-(5-fluoropyridin-2-yl)-2-methylpipe razine-l-carbonyl)benzyl) piperazin-l-yl)benzonitrile 1-202 (30 mg, 0.056 mmol, 19%) as white solid. ESI-MS (EI ⁺ , m/z): 533.3 [M+H] ⁺ . ¾- MR(500 MHz, CDC1 ₃ ) δ 8.03 (t, J = 2.4 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.48 (t, J= 7.9 Hz, 1H), 7.43 - 7.22 (m, 4H), 7.11 - 6.88 (m, 2H), 6.72 - 6.51 (m, 1H), 5.16 - 4.60 (m, 1H), 4.25 - 3.88 (m, 2H), 3.86 - 3.35 (m, 3H), 3.35 - 3.12 (m, 6H), 3.09 - 2.77 (m, 1H), 2.66 (d, J= 3.3 Hz, 4H), 1.46 - 1.18 (m, 3H).

Example 118. Synthesis of 2-(4-(2,4-dichloro-5-((4-(2-cyanophenyl)piperazin-l- yl)methyl)benzoyl)piperazin-l-yl)benzonitrile, 1-363

1-363

Synthetic scheme:

Procedures and characterization:

[00845] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: 5-Bromo-2,4-dichlorobenzoic acid

[00846] A mixture of 2,4-dichlorobenzoic acid (10 g, 52 mmol), Br ₂ (4.18 g, 26 mmol) and S (83 mg, 2.6 mmol) in CISO3H (40 mL) was stirred at 70 °C for 16 h. The reaction mixture was cooled to rt, slowly poured into ice-water, filtered, washed with water (50mL x 2) to afford 5- bromo-2,4-dichlorobenzoic acid (14 g, 51.87 mmol, 99.7%) as white solid. ESI-MS (EI ⁺ , m/z): 269.0 [M+H] ⁺ .

Step 2: 2,4-Dichloro-5-formylbenzoic acid and 2,4-dichloro-3-formylbenzoic acid

[00847] To a solution of 5-bromo-2,4-dichlorobenzoic acid (6 g, 22.2 mmol) in THF (50 mL) was added «-BuLi (hexanes, 2.5 , 22.2 mL) dropwise at -78 °C. After 2 h, DMF (6.48 g, 88.8 mmol) was added to the mixture followed by an additional 3 h of stirring. H ₂ 0 (10 mL) was added to quench the reaction. The pH was adjusted to 3-4 with HCl (aq. 6 M). The mixture was extracted with EtOAc (100 mL x 3), and the organic layers were concentrated and purified by chromatography (silica, EtOAc/PE =1/5) to afford 2,4-dichloro-5-formylbenzoic acid (2.14 g, 9.77 mmol, 44%) as yellow solid. ESI-MS (EI ⁺ , m/z): 219.1 [M+H] ⁺ . ¾- MR(500 MHz, DMSO-^e) δ 8.34 (bs, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 6.63 (bs, 1H).

A later eluting fraction (EtOAc/PE =1/0) gave 2,4-dichloro-3-formylbenzoic acid (86 mg, 0.39 mmol, 1.77 %) as yellow solid. ESI-MS (EI ⁺ , m/z): 219.1 [M+H] ⁺ . ¾- MR(500 MHz, DMSO- d ₆ ) δ 13.91 (bs, 1H), 10.36 (s, 1H), 7.90 (d, J= 8.5 Hz, 1H), 7.67 (d, J= 8.5 Hz, 1H).

Step 3: 2,4-Dichloro-5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)benz oic acid [00848] A solution of 2,4-dichloro-5-formylbenzoic acid (504 mg, 2.3 mmol), 2-(piperazin-l- yl)benzonitrile (517 mg, 2.76 mmol) in EtOH (5 mL) and HO Ac (1 drop) was stirred at rt for 2 h. Then NaBH ₃ CN (290 mg, 4.6 mmol) was added and the reaction mixture was stirred at rt for 14 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/4) to afford 2,4-dichloro-5- ((4-(2-cyanophenyl)piperazin-l-yl)m ethyl )benzoic acid (500 mg, 1.28 mmol, 56%) as a white solid. ESI-MS (EI ⁺ , m/z): 390.0 [M+H] ⁺ .

Step 4: 2-(4-(2,4-Dichloro-5-((4-(2-cyanophenyl)piperazin-l-yl)methy l)benzoyl) piperazin-1- yl)benzonitrile, 1-363

[00849] A mixture of 2,4-dichloro-5-((4-(2-cyanophenyl)piperazin-l-yl)methyl) benzoic acid (150 mg, 0.385 mmol), 2-(piperazin-l-yl)benzonitrile (86 mg, 0.461 mmol), HATU (190 mg, 0.5mmol), and DIPEA (249 mg, 1.925 mmol) in DMF (3 mL) was stirred at rt for 16 h. The mixture was purified by prep-HPLC to afford 2-(4-(2,4-dichloro-5-((4-(2-cyanophenyl)piperazin-l- yl)methyl)benzoyl) piperazin-1 -yl)benzonitrile 1-363 (119 mg, 0.213 mmol, 55%) as a white solid. ESI-MS (EI ⁺ , m/z): 559.1 [M+H] ⁺ . ¾- MR (500 MHz, OMSO-d ₆ ) δ 7.92 - 7.71 (m, 4H), 7.67 - 7.59 (m, 2H), 7.18 (m, 4H), 4.06 - 3.90 (m, 1H), 3.82 (s, 1H), 3.64 - 2.70 (m, 14H), 2.08 (s, 1H).

Example 119. Synthesis of 2-(4-(2,4-Dichloro-5-(4-(5-fluoropyridin-2-yl)piperazine-l- carbonyl)benzyl)piperazin-l-yl)benzonitrile, 1-364

1-364

Synthetic scheme:

Procedures and characterization:

[00850] The procedure for compound 1 was same as example 118.

[00851] Analysis was performed following Method A. Separation was performed following Method C. Step 1 : 2-(4-(2,4-Dichloro-5-(4-(5-fluoropyridin-2-yl)piperazine-l-c arbonyl)benzyl) piperazin-l-yl)benzonitrile, 1-364:

[00852] ESI-MS (EI ⁺ , m/z): 553.2 [M+H] ⁺ . ¾- MR(500 MHz, OMSO-d ₆ ) δ 8.12 (d, J= 3.0 Hz, 1H), 7.85 (b, 2H), 7.75 (d, J= 6.7 Hz, 1H), 7.64 (t, J= 7.4 Hz, 1H), 7.55 (td, J= 9.0, 3.1 Hz, 1H), 7.29 - 7.07 (m, 2H), 6.93 (dd, J= 9.3, 3.3 Hz, 1H), 4.65 - 3.62 (m, 4H), 3.57 - 2.75 (m, 14H).

Example 120. Synthesis of 2-(4-(2,4-dichloro-3-((4-(2-cyanophenyl)piperazin-l-yl) methyl)benzoyl)piperazin-l-yl)benzonitrile, 1-146

1-146

Synthetic scheme:

Procedures and characterization:

[00853] The procedure was same as example 118.

[00854] Analysis was performed following Method B. Separation was performed following Method C.

2-(4-(2,4-Dichloro-3-((4-(2-cyanophenyl)piperazin-l-yl)methy l)benzoyl) piperazin-1- yl)benzonitrile, 1-146:

[00855] ESI-MS (EI ⁺ , m/z): 559.2 [M+H] ⁺ . ¾- ΜΚ (500 MHz, OMSO-d ₆ ) δ 7.88-7.69 (m, 3H), 7.69-7.50 (m, 3H), 7.30-7.09 (m, 4H), 4.61 (s, 1H), 3.85 (s, 2H), 3.78 - 3.17 (m, 11H), 3.12 (d, J= 5.1 Hz, 4H). Example 121. Synthesis of 2-(4-(2,6-dichloro-3-(4-(5-fluoropyridin-2-yl)piperazine-l- carbonyl)benzyl)piperazin- l-yl)benzonitrile, 1-145

1-145

Synthetic scheme:

Procedures and characterization:

[00856] The procedure was same as example 118.

[00857] Analysis was performed following Method B. Separation was performed following Method D.

2-(4-(2,6-Dichloro-3-(4-(5-fluoropyridin-2-yl)piperazine-l-c arbonyl)benzyl) piperazin-1- yl)benzonitrile, 1-145:

[00858] ESI-MS (EI ⁺ , m/z): 553.1 [M+H] ⁺ . ¾- MR(500 MHz, CDCb) δ 8.06 (d, J= 2.9 Hz, 1H), 7.56 (dd, J= 8.0, 1.5 Hz, 1H), 7.47 (dt, J= 8.0, 1.5 Hz, 1H), 7.41 (d, J= 8.0 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.19 (d, J= 8.5 Hz, 1H), 7.07 - 6.91 (m, 2H), 6.65 (dd, J= 9.0, 3.0 Hz, 1H), 4.03 - 3.80 (m, 4H), 3.65 - 3.49 (m, 3H), 3.46 - 3.36 (m, 2H), 3.36 - 3.28 (m, 1H), 3.18 (t, J = 4.0 Hz, 4H), 2.89 - 2.71 (m, 4H).

Example 122. Synthesis of (S)-2-(4-(4-(3-aminopropyl)-5-(4-(5-fluoropyridin-2-yl)-2- methylpiperazine-l-carbonyl)-2-methylbenzyl)piperazin-l-yl)b enzonitrile trifluoroacetate salt, 1-116

1-116

Synthetic scheme:

Procedures and characterization:

[00859] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: (S)-tert-butyl 3-(4-bromo-2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l- carbonyl)-5-methylphenyl)propylcarbamate

[00860] To a solution of 5-bromo-2-(3-(tert-butoxycarbonylamino)propyl)-4-methylbenzo ic acid (200 mg, 0.54 mmol) and (S)-l-(5-fluoropyridin-2-yl)-3-methylpiperazine (116 mg, 0.59 mmol) in DMF (10 mL) was added HATU (226 mg, 0.59 mmol) and DIPEA (0.45 mL, 2.7 mmol). The mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc (100 mL), washed with 1 hydrochloric acid solution (50 mL), water (50 mL) and brine (50 mL). The organic phase was dried over Na ₂ S04, filtered and concentrated to give (S)- tert-butyl 3-(4-bromo-2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l- carbonyl)-5- methylphenyl)propyl carbamate (300 mg, 0.54 mmol, 92%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 549.2 [M+H] ⁺ .

Step 2: (S)-tert-butyl 3-(2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l-carbonyl )-5- methyl-4-vinylphenyl)propylcarbamate

[00861] To a solution of (S)-tert-buty\ 3-(4-bromo-2-(4-(5-fluoropyridin-2-yl)-2- methylpiperazine-l-carbonyl)-5-methylphenyl)propylcarbamate (270 mg, 0.49 mmol) and vinyltrifluoroboric acid potassium(131 mg, 0.98 mmol) in CH ₃ CN(36 mL) and H ₂ 0 (9 mL) was added Pd(dppf)Cl ₂ (40 mg, 0.05 mmol) and K ₂ C0 ₃ (135 mg, 0.98 mmol). The mixture was stirred at 80 °C for 6 h. The resulting mixture was diluted with EtOAc (200mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica to give (S)-tert-buty\ 3-(2-(4-(5- fluoropyridin-2-yl)-2-methylpiperazine-l-carbonyl)-5-methyl- 4-vinylphenyl)propylcarbamate (250 mg, 0.50 mmol, 92%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 497.3 [M+H] ⁺ .

Step 3: (S)-tert-butyl 3-(2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l-carbonyl )-4- formyl-5-methylphenyl)propylcarbamate

[00862] To a solution of give (^-tert-butyl 3-(2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-

1- carbonyl)-5-methyl-4-vinylphenyl)propyl carbamate (200 mg, 0.40 mmol) in acetone (40 mL) and H ₂ 0 (40 mL) was added potassium osmate(VI) dihydrate (7.4 mg, 0.02 mmol), MO (2.34 mg, 0.02 mmol) and NaI0 ₄ (257 mg, 1.2 mmol). The mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with EtOAc (200mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica to give (S)-tert-buty\ 3-(2-(4-(5- fluoropyridin-2-yl)-2-methylpiperazine-l-carbonyl)-4-formyl- 5-methylphenyl)propyl carbamate (135 mg, 0.27 mmol, 54%) as a white solid. ESI-MS (EI+, m/z): 499.2 [M+H] ⁺ .

Step 4: (S)-tert-butyl 3-(4-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2-(4-(5-fluor opyridin-

2- yl)-2-methylpiperazine-l-carbonyl)-5-methylphenyl)propylcarb amate

[00863] To a solution of (S)-tert-butyl 3-(2-(4-(5-fluoropyridin-2-yl)-2-methylpiperazine-l- carbonyl)-4-formyl-5-methylphenyl)propylcarbamate (115 mg, 0.23 mmol) and 2-(piperazin-l- yl)benzonitrile (52 mg, 0.27 mmol) in ethanol (10 mL) was added NaBH ₃ CN (43 mg, 0.69 mmol) and a catalytic amount of AcOH. The mixture was stirred at room temperature overnight. The resulting mixture was concentrated and the residue was purified by prep-HPLC to give (S)-tert- butyl 3-(4-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2-(4-(5-fluor opyridin-2-yl)-2- methylpiperazine-l-carbonyl)-5-methylphenyl)propylcarbamate( 73 mg, 0.11 mmol, 45.8%) as a white solid. ESI-MS (EI ⁺ , m/z): 670.4 [M+H] ⁺ .

Step 5: (S)-2-(4-(4-(3-aminopropyl)-5-(4-(5-fluoropyridin-2-yl)-2-me thylpiperazine-l- carbonyl)-2-methylbenzyl)piperazin-l-yl)benzonitrile trifluoroacetate salt, 1-116

[00864] To a solution of (»S)-tert-butyl 3-(4-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2-(4-(5- fluoropyridin-2-yl)-2-methylpiperazine-l-carbonyl)-5-methylp henyl)propylcarbamate (50 mg, 0.07 mmol) in CH ₃ OH (2 mL) was added HC1 (4 in dioxane, 2 mL). The mixture was stirred at rt for 2 h. The resulting mixture was concentrated and the residue was purified by prep-HPLC to give (,S)-2-(4-(4-(3-aminopropyl)-5-(4-(5-fluoropyridin-2-yl)-2-m ethylpiperazine-l-carbonyl)- 2-methylbenzyl)piperazin-l-yl)benzonitrile trifluoroacetate salt 1-116 (50 mg, 0.07 mmol, 84%) as a white solid. ESI-MS (EI ⁺ , m/z): 570.2 [M+H] ⁺ . ¹ H- MR (500 MHz, MeOD)5: 8.02 (d, J= 3.0 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.64-7.67 (t, J= 8.5 Hz, 1H), 7.40-7.49 (m, 3H), 7.22-7.26 (m, 2H), 6.88-6.90 (dd, Ji = 3.0 Hz, J ₂ = 9.0 Hz, 1H), 4.95 (s, 1H), 4.28-4.68 (m, 3H), 4.02-4.15 (m, 2H), 3.36-3.68 (m, 9H), 2.79-3.28 (m, 6H), 2.56 (s, 3H), 2.03 (s, 2H), 1.22-1.42 (m, 3H).

Example 123. Synthesis of (R)-2-(4-(4-(3-aminopropyl)-5-(4-(5-fluoropyridin-2-yl)-2- methylpiperazine-l-carbonyl)-2-methylbenzyl)piperazin-l-yl)b enzonitrile trifluoroacetate salt, 1-99

1-99 Synthetic scheme:

Procedures and characterization:

[00865] The procedure for (R)-2-(4-(4-(3-aminopropyl)-5-(4-(5-fluoropyridin-2-yl)-2- methylpiperazine-l-carbonyl)-2-methylbenzyl)piperazin-l-yl)b enzonitrile tnfluoroacetate salt I- 99 was same as example 122.

Analysis was performed following Method A. Separation was performed following Method C.

[00866] ESI-MS (EI ⁺ , m/z): 570.2 [M+H] ⁺ . ¾- MR (500 MHz, MeOD)5: 8.02 (d, J= 3.0 Hz, IH), 7.71 (d, J= 7.5 Hz, IH), 7.64-7.67 (t, J= 8.0 Hz, IH), 7.40-7.51 (m, 3H), 7.22-7.26 (m, 2H), 6.91 (d, J= 8.5 Hz, IH), 4.95 (s, IH), 4.28-4.68 (m, 3H), 4.02-4.15 (m, 2H), 3.36-3.67 (m, 9H), 2.80-3.25 (m, 6H), 2.56 (s, 3H), 2.03 (s, 2H), 1.21-1.42 (m, 3H).

Example 124. Synthesis of (S)-2-(4-(2-(3-aminopropyl)-5-((4-(2-cyanophenyl)piperazin-l - yl)methyl)-4-methylbenzoyl)-3-methylpiperazin-l-yl)benzonitr ile trifluoroacetate salt, I- 101

1-101

Synthetic scheme:

Procedures and characterization:

[00867] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: (S)-2-(3-methylpiperazin-l-yl)benzonitrile

[00868] To a solution of 2-fluorobenzonitrile (500 mg, 4.13 mmol) and (S)-2-methylpiperazine (826 mg, 8.26 mmol) in CH ₃ CN (20 mL) was added K ₂ C0 ₃ (1.14 g, 8.26 mmol). The mixture was stirred at 80 °C for 5 h. The resulting mixture was concentrated and the residue was diluted with EtOAc (200 mL), washed with water (50mL x 2) and brine (50mL). The organic phase was dried and concentrated. The residue was purified by column chromatography on silica to give (S)-2-(3- methylpiperazin-l-yl)benzonitrile (500 mg, 2.48 mmol, 60%) as a yellow liquid. ESI-MS (EI ⁺ , m/z): 202.2 [M+H] ⁺ . Step 2: (S)-tert-b tyl 3-(4-bromo-2-(4-(2-cyanophenyl)-2-methylpiperazine-l-carbony l)-5- methylphenyl)propylcarbamate

[00869] The procedure for (S)-tert-buty\ 3-(4-bromo-2-(4-(2-cyanophenyl)-2- methylpiperazine-l-carbonyl)-5-methylphenyl)propylcarbamate was same as example 122.

Step 3: (S)-tert-buty\ 3-(2-(4-(2-cyanophenyl)-2-methylpiperazine-l-carbonyl)-5-met hyl-4- vinylphenyl)propylcarbamate

[00870] The procedure for (^-tert-butyl 3-(2-(4-(2-cyanophenyl)-2-methylpiperazine-l- carbonyl)-5-methyl-4-vinylphenyl)propylcarbamate was same as example 122.

Step 4: (S)-tert-buty\ 3-(2-(4-(2-cyanophenyl)-2-methylpiperazine-l-carbonyl)-4-for myl-5- methylphenyl)propylcarbamate

[00871] The procedure for (^-tert-butyl 3-(2-(4-(2-cyanophenyl)-2-methylpiperazine-l- carbonyl)-4-formyl-5-methylphenyl)propylcarbamate was same as example 122.

Step 5: (S)-tert-buty\ 3-(2-(4-(2-cyanophenyl)-2-methylpiperazine-l-carbonyl)-4-((4 -(2- cyanophenyl)piperazin-l-yl)methyl)-5-methylphenyl)propylcarb amate

[00872] The procedure for The procedure for (^-tert-butyl 3-(2-(4-(2-cyanophenyl)-2- methylpiperazine-l-carbonyl)-4-formyl-5-methylphenyl)propylc arbamate was same as example

122.

Step 6: (S)-2-(4-(2-(3-aminopropyl)-5-((4-(2-cyanophenyl)piperazin-l -yl)methyl)-4- methylbenzoyl)-3-methylpiperazin-l-yl)benzonitrile trifluoroacetate salt, 1-101

To a solution of (S)-tert-butyl 3-(2-(4-(2-cyanophenyl)-2-methylpiperazine-l-carbonyl)-4- formyl-5-methylphenyl)propylcarbamate (90 mg, 0.13 mmol) in CH3OH (4mL) was added HC1 (4 in dioxane, 6 mL). The mixture was stirred at rt for 2 h. The resulting mixture was concentrated and the residue was purified by prep-HPLC to give (,S)-2-(4-(2-(3-aminopropyl)-5- ((4-(2-cyanophenyl)piperazin-l-yl)methyl)-4-methylbenzoyl)-3 -methylpiperazin-l- yl)benzonitrile trifluoroacetate salt 1-101 (65.8 mg, 0.095 mmol, 70%) as a white solid.

[00873] ESI-MS (EI ⁺ , m/z): 576.2 [M+H] ⁺ , ¾- MR (500 MHz, MeOD)5: 7.62-7.72 (m, 4H), 7.42-7.52 (m, 2H), 7.16-7.26 (m, 4H), 4.59-5.09 (m, 1H), 4.56 (s, 2H), 3.37-4.53 (m, 11H), 2.59- 3.26 (m, 6H), 2.56 (s, 3H), 1.99-2.10 (m, 2H), 1.43-1.63 (m, 3H).

Example 125. Synthesis of (R)-2-(4-(2-(3-aminopropyl)-5-((4-(2-cyanophenyl)piperazin-l - yl)methyl)-4-methylbenzoyl)-3-methylpiperazin-l-yl)benzonitr ile trifluoroacetate salt, 1-81

1-81

Synthetic scheme:

Procedures and characterization:

[00874] The procedure for (R)-tert-bu y\ 3-(2-(4-(2-cyanophenyl)-2-methylpiperazine-l- carbonyl)-4-formyl-5-methylphenyl)propylcarbamate was same as example 124.

[00875] Analysis was performed following Method A. Separation was performed following Method C.

Step 6: (R)-2-(4-(2-(3-aminopropyl)-5-((4-(2-cyanophenyl)piperazin-l -yl)methyl)-4- methylbenzoyl)-3-methylpiperazin-l-yl)benzonitrile trifluoroacetate salt, 1-81

To a solution of (R)-tert-buty\ 3-(2-(4-(2-cyanophenyl)-2-methylpiperazine-l-carbonyl)-4- formyl-5-methylphenyl)propylcarbamate (50 mg, 0.074 mmol) in CH3OH (2 mL) was added HCl (4 in dioxane, 4 mL). The mixture was stirred at rt for 2h. The resulting mixture was concentrated and the residue was purified by prep-HPLC to give (R)-2-(4-(2-(3-aminopropyl)-5- ((4-(2-cyanophenyl)piperazin-l-yl)methyl)-4-methylbenzoyl)-3 -methylpiperazin-l- yl)benzonitrile trifluoroacetate salt 1-81 (38.2 mg, 0.055 mmol, 62%) as a white solid. ESI-MS (EI ⁺ , m/z): 576.3 [M+H] ⁺ . ¹ H- MR (500 MHz, MeOD)5: 7.62-7.72 (m, 4H), 7.42-7.52 (m, 2H), 7.16-7.26 (m, 4H), 4.59-5.10 (m, 1H), 4.56 (s, 2H), 3.37-4.54 (m, 11H), 2.60-3.26 (m, 6H), 2.56 (s, 3H), 1.99-2.06 (m, 2H), 1.43-1.63 (m, 3H).

Example 126. Synthesis of 2-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2-fluoro-4 - methylbenzoyl)piperazin-l- l)benzonitrile, 1-147

1-147

Synthetic scheme:

34% for two steps

Procedures and characterization:

[00876] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: 5-Bromo-2-fluoro-4-methylbenzoic acid [00877] To a solution of 2-fluoro-4-methylbenzoic acid (2 g, 12.99 mmol) in CF ₃ COOH (50mL) was added NBS (6.9 g, 38.97 mmol). The mixture was stirred at 80 °C for 8 h. The resulting mixture was poured into water (300 mL) and stirred for 20 min at rt. The precipitate was collected by filtration and dried to give 5-bromo-2-fluoro-4-methylbenzoic acid (2 g, crude) as a white solid. ESI-MS (EI ⁺ , m/z): 232.9 [M+H] ⁺ .

Step 2: 2-Fluoro-5-formyl-4-methylbenzoic acid

[00878] To a solution of 5-bromo-2-fluoro-4-methylbenzoic acid (1.8 g, crude) in dry THF (60mL) at -78 °C was added «-BuLi (2.5 Min hexane, 7.7 mL, 19.3 mmol). After the mixture was stirred at -78 °C for 1 h, DMF (2.4mL, 30.88mmol) was added and the mixture was stirred at -78 °C for 1 h. The reaction mixture was quenched with saturated aqueous H4CI solution (10 mL) and acidified with 5 HCl until the pH of the mixture was 3. The resulting mixture was diluted with EtOAc (200mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S04, filtered and concentrated. The residue was purified by trituration with EtOAc (lOmL) to give 2-fluoro-5-formyl-4-methylbenzoic acid (530 mg, 2.91 mmol, 34%) as a white solid. ESI-MS (EI ⁺ , m/z): 183.1 [M+H] ⁺ .

Step 4: 2-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-2-fluoro-4 - methylbenzoyl)piperazin-l-yl)benzonitrile, 1-147

[00879] To a solution of 2-(4-(2-fluoro-5-formyl-4-methylbenzoyl)piperazin-l-yl)benzo nitrile (100 mg, 0.28 mmol) and 2-(piperazin-l-yl)benzonitrile (63 mg, 0.34 mmol) in ethanol (10 mL) was added NaBFLCN (53 mg, 0.84 mmol) and a catalytic amount of AcOH. The mixture was stirred at room temperature overnight. The resulting mixture was concentrated and the residue was purified by prep-HPLC to give 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2-fluoro- 4-methylbenzoyl)piperazin-l-yl)benzonitrile 1-147 (13.7 mg, 0.026 mmol, 9%) as a white solid. ESI-MS (EI ⁺ , m/z): 523.3 [M+H] ⁺ . ¹ H- MR (500 MHz, CDC1 ₃ )5: 7.45-7.60 (m, 4H), 7.36 (d, J= 7.0 Hz, 1H), 6.98-7.08 (m, 4H), 6.92 (d, J= 10.5 Hz, 1H), 4.01-4.03 (t, J= 3.5 Hz, 2H), 3.58 (s, 2H), 3.51 (s, 2H), 3.17-3.27 (m, 8H), 2.66-2.67 (t, J= 4.0 Hz, 4H), 2.40 (s, 3H).

Example 127. Synthesis of 2-(4-(3-(4-(2-Cyanophenyl)piperazin-l-yl)-6-methyl-lH-indole -5- carbonyl)piperazin-l-yl)benzonitrile, 1-63

1-63

Synthetic scheme:

Procedures and characterization:

[00880] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: Methyl 4-amino-5-iodo-2-methylbenzoate [00881] To a solution of methyl 4-amino-2-methylbenzoate (5.8 g, 33.2 mmol), NaI0 ₄ (2.9 g, 13.2 mmol) in DMF (40 mL) was added I ₂ (6.8 g, 26.6 mmol). The mixture was stirred for 2 h at 50 °C. The mixture was poured onto ice-water and the solid was filtered to afford methyl 4-amino- 5-iodo-2-methylbenzoate as an off-white solid (6.3 g, 21.6 mmol, 65%). ESI-MS (EI ⁺ , m/z): 291.9 [M+H] ⁺ .

Step 2: Methyl 4-acetamido-5-iodo-2-methylbenzoate

[00882] To a solution of methyl methyl 4-amino-5-iodo-2-methylbenzoate (6.3 g, 21.6 mmol), pyridine (2.0 mL, 30 mmol) in THF (60 mL) was added acetyl chloride (1.8 mL, 26 mmol) at 0 °C. The mixture was stirred for 4 h at rt. The mixture was poured onto ice-water and the solid was filtered to afford methyl 4-acetamido-5-iodo-2-methylbenzoate as an off-white solid (6.0 g, 18 mmol, 83%). ESI-MS (EI ⁺ , m/z): 304.0 [M+H] ⁺ .

Step 3: Methyl 4-acetamido-2-methyl-5-((trimethylsilyl)ethynyl)benzoate

[00883] To a solution of methyl 4-acetamido-5-iodo-2-methylbenzoate (6.0 g, 18 mmol), Cul (342 mg, 1.8 mmol), Et ₃ N (5.4 g, 54 mmol), and Pd(PPh ₃ ) ₂ Cl ₂ (504 mg, 0.72 mmol) in DCM (100 mL) was added ethynyltrimethylsilane (5.3 g, 54 mmol) at 0 °C. The mixture was stirred for 17 h at rt. The mixture was extracted with DCM, the organic layer was washed with aq. NH ₄ C1, brine and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE =1/9) to afford methyl 4-acetamido-2-methyl-5-((trimethylsilyl)ethynyl)benzoate as a dark solid (4.9 g, 16.2 mmol, 90%). ESI-MS (EI ⁺ , m/z): 304.0 [M+H] ⁺ .

Step 4: Methyl 6-methyl-lH-indole-5-carboxylate

[00884] To a solution of methyl 4-acetamido-2-methyl-5-((trimethylsilyl)ethynyl)benzoate (4.9 g, 16.2 mmol) in dry THF (100 mL) was added TBAF (10.3 g, 39.4 mmol). The mixture was stirred for 17 h at 80 °C. The mixture was extracted with EtOAc, the organic layer was washed with aq. H ₄ C1, brine and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE =1/8) to afford methyl 6-methyl-lH-indole-5-carboxylate as a yellow solid (2.7 g, 14.3 mmol, 87%). ESI-MS (EI ⁺ , m/z): 190.1 [M+H] ⁺ .

Step 5: Methyl 3-iodo-6-methyl-lH-indole-5-carboxylate

[00885] To a solution of methyl 6-methyl-lH-indole-5-carboxylate (2.7 g, 14.3 mmol) in dry DMF (60 mL) was added KOH (2.0 g, 5.7 mmol) and the reaction mixture was stirred at 30 °C for 10 min. I ₂ (3.6 g, 14.3 mmol) was added and the mixture was stirred for 3 h at 30 °C. The mixture was poured onto ice-water and the solid was filtered to afford methyl 3-iodo-6-methyl-lH-indole- 5-carboxylate as a pink solid (4.3 g, 13.6 mmol, 95%). ESI-MS (EI ⁺ , m/z): 315.9 [M+H] ⁺ .

Step 6: Methyl 3-iodo-6-methyl-l-tosyl-lH-indole-5-carboxylate

[00886] To a solution of methyl methyl 3-iodo-6-methyl-lH-indole-5-carboxylate (4.3 g, 13.6 mmol), 50% NaOH (5.4 g, 136 mmol), and TEBAC (308 mg, 1.36 mmol) in dry DCM (100 mL) was added TsCl (3.9 g, 20.4 mmol) and the reaction mixture was stirred at rt for 17 h. The mixture was extracted with DCM, the organic layer was washed with aq. H ₄ C1, brine and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE =1/6) to afford methyl 3- iodo-6-methyl-l-tosyl-lH-indole-5-carboxylate as a pink solid (4.5 g, 9.6 mmol, 70%). ESI-MS (EI ⁺ , m/z): 469.9 [M+H] ⁺ .

Step 7: Methyl 3-(4-(2-cyanophenyl)piperazin-l-yl)-6-methyl-l-tosyl-lH-indo le-5- carboxylate

[00887] To a solution of methyl 3-iodo-6-methyl-l-tosyl-lH-indole-5-carboxylate (1.5 g, 3.2 mmol), 2-(piperazin-l-yl)benzonitrile (720 g, 3.8 mmol), CS2CO3 (3.1 g, 9.6 mmol), and Brettphos (164 mg, 0.32 mmol) in dry toluene (60 mL) was added Pd(OAc) ₂ (160 mg, 0.64 mmol). The mixture was stirred at 100 °C for 17 h. The mixture was extracted with EtOAc, the organic layer was washed with aq. H4CI, brine and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE =1/5) to afford methyl 3-(4-(2-cyanophenyl)piperazin-l-yl)-6- methyl-l-tosyl-lH-indole-5-carboxylate as a yellow solid (400 mg, 0.76 mmol, 23%). ESI-MS (EI ⁺ , m/z): 529.3 [M+H] ⁺ .

Step 8: Methyl 3-(4-(2-cyanophenyl)piperazin-l-yl)-6-methyl-lH-indole-5-car boxylate

[00888] To a solution of methyl 3-(4-(2-cyanophenyl)piperazin-l-yl)-6-methyl-l-tosyl-lH- indole-5-carboxylate (400 mg, 0.76 mmol) in dry THF (10 mL) was added TBAF (420 mg, 1.6 mmol). The mixture was stirred for 17 h at 80 °C. The mixture was extracted with EtOAc, the organic layer was washed with aq. H4CI, brine and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE =1/5) to afford methyl 3-(4-(2-cyanophenyl)piperazin-l- yl)-6-methyl-lH-indole-5-carboxylate as a white solid (200 mg, 0.53 mmol, 69%). ESI-MS (EI ⁺ , m/z): 375.2 [M+H] ⁺ .

Step 9: 3-(4-(2-Cyanophenyl)piperazin-l-yl)-6-methyl-lH-indole-5-car boxylic acid

[00889] To a solution of methyl 3-(4-(2-cyanophenyl)piperazin-l-yl)-6-methyl-lH-indole-5- carboxylate (200 mg, 0.76 mmol) in dry DCM (10 mL) was added 17% BBr ₃ (3 mL, 5.3 mmol) at -70 °C. The mixture was stirred for 17 h at rt. 1 MHO was added and the reaction mixture was stirred at rt for 10 min. MeOH was added and the mixture was concentrated. The crude product was purified by prep-HPLC (Boston C18 21 *250mm ΙΟμπι, Mobile phase: A: 0.1 % trifluoroacetic acid; B: acetonitrile) to afford 3-(4-(2-cyanophenyl)piperazin-l-yl)-6-methyl-lH-indole-5- carboxylic acid as a yellow solid (30 mg, 0.083 mmol, 11%). ESI-MS (EI ⁺ , m/z): 361.1 [M+H] ⁺ . Step 10: 2-(4-(3-(4-(2-Cyanophenyl)piperazin-l-yl)-6-methyl-lH-indole -5- carbonyl)piperazin-l-yl)benzonitrile, 1-63

[00890] To a solution of 3-(4-(2-cyanophenyl)piperazin-l-yl)-6-methyl-lH-indole-5- carboxylic acid (30 mg, 0.083 mmol), 2-(piperazin-l-yl)benzonitrile (31 mg, 0.16 mmol) in DMF (5 mL) was added HATU (50 mg, 0.13 mmol), and Et ₃ N (0.1 mL, 0.6 mmol). The mixture was stirred at rt for 17 h. The solution was purified by prep-HPLC (Boston CI 8 21 *250mm ΙΟμπι, Mobile phase: A: 0.1 % trifluoroacetic acid; B: acetonitrile) to afford 2-(4-(3-(4-(2- cyanophenyl)piperazin- 1 -yl)-6-m ethyl- lH-indole-5-carbonyl)piperazin- 1 -yl)benzonitrile 1-63 (13.6 mg, 0.025 mmol, 31%) as a white solid. ESI-MS (EI ⁺ , m/z): 530.0 [M+H] ⁺ . ¾ NMR (500 MHz, CDC1 ₃ ) δ 8.72 (s, 1H), 7.70 (s, 1H), 7.63 (d, J= 7.5 Hz, 1H), 7.59 (d, J= 7.0 Hz, 2H), 7.52 (t, J= 7.5 Hz, 1H), 7.29 (s, 1H), 7.15 (m, 2H), 7.07 (m 2H), 4.32 (m, 1H), 3.82 (m, 3H), 3.65 (m, 6H), 3.50 (m, 2H), 3.36 (m, 1H), 3.26 (m, 1H), 3.11 (m, 2H), 2.42 (s, 3H).

Example 128. Synthesis of 2-(4-(3-(4-(2-Cyanophenyl)piperazin-l-yl)-l,6-dimethyl-lH- indole-5-carbonyl)piperazin-l-yl)benzonitrile, 1-62

1-62

Synthetic scheme:

Procedures and characterization:

[00891] Analysis was performed following Method A.

Step 1 : 2-(4-(3-(4-(2-Cyanophenyl)piperazin-l-yl)-l,6-dimethyl-lH-in dole-5- carbonyl)piperazin-l-yl)benzonitrile, 1-62

[00892] To a solution of 2-(4-(3-(4-(2-cyanophenyl)piperazin-l-yl)-6-methyl-lH-indole -5- carbonyl)piperazin-l-yl)benzonitrile (50 mg, 0.09 mmol) in dry DMF (5 mL) was added 60% NaH (5.2 mg, 0.13 mmol) at 0 °C and the reaction mixture was stirred for 10 min. Mel (20 mg, 0.13 mmol) was added and the reaction mixture was stirred for 2 h at rt. The mixture was extracted with DCM, the organic layer was washed with aq. NH4CI, brine and concentrated. The crude product was purified by chromatography (silica, EtOAc/PE =1/1) to afford 2-(4-(3-(4-(2- Cyanophenyl)piperazin-l-yl)-l,6-dimethyl-lH-indole-5-carbony l)piperazin-l-yl)benzonitrile I- 62 as a yellow solid (38 mg, 0.07 mmol, 77%). ESI-MS (EI ⁺ , m/z): 544.2 [M+H] ⁺ .

Example 129. Synthesis of 2-(4-(6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-lH-indole- 4- carbonyl)piperazin-l-yl)benzonitrile, 1-203

1-203

Synthetic scheme:

Procedures and characterization:

[00893] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 6-Bromo-l-tosyl-lH-indole-4-carboxylic acid

[00894] To a solution of 6-bromo-lH-indole-4-carboxylic acid (2.0 g, 8.33 mmol) in DMF (20mL) at 0 °C was slowly added NaH (60% in mineral oil, 417mg, 10.4mmol). After the mixture was stirred at 0 °C for 1 h, TsCl (833 mg, 20.83 mmol) was added and the mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with saturated aqueous NH ₄ C1 solution (10 mL) and acidified with 5 MHCl until the pH of the mixture was 3. The resulting mixture was diluted with EtOAc (200mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S04, filtered and concentrated to give 6-bromo-l-tosyl-lH-indole-4-carboxylic acid (2.6 g, 6.6 mmol, 79%) as a yellow solid. ESI-MS (EI+, m/z): 394.0 [M+H] ⁺ .

Step 2: 2-(4-(6-Bromo-l-tosyl-lH-indole-4-carbonyl)piperazin-l-yl)be nzonitrile

[00895] To a solution of 6-bromo-l-tosyl-lH-indole-4-carboxylic acid (1 g, 2.54 mmol) and 2- (piperazin-l-yl)benzonitrile (522 mg, 2.80 mmol) in DMF (10 mL) was added HATU (1.06 g, 2.80 mmol) and DIPEA (2.0 mL, 12.7 mmol). The mixture was stirred at room temperature for 4 h. The resulting mixture was diluted with EtOAc (300mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S04, filtered and concentrated. The residue was purified by column chromatography on silica to give 2-(4-(6-bromo-l-tosyl-lH-indole-4- carbonyl)piperazin-l-yl)benzonitrile (1.0 g, 1.77 mmol, 69.9%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 563.1 [M+H] ⁺ .

Step 3: 2-(4-(l-Tosyl-6-vinyl-lH-indole-4-carbonyl)piperazin-l-yl)be nzonitrile

[00896] To a solution of 2-(4-(6-bromo-l-tosyl-lH-indole-4-carbonyl)piperazin-l- yl)benzonitrile (1.0 g, 1.77 mmol) and vinyltrifluoroboric acid potassium (715 mg, 5.34 mmol) in CH ₃ CN(40 mL) and H ₂ O(10 mL) was added Pd(dppf)Cl ₂ (130 mg, 0.18 mmol) and K ₂ C0 ₃ (491 mg, 3.56 mmol). The mixture was stirred at 80 °C for 12 h. The resulting mixture was diluted with EtOAc (200mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica to give 2-(4-(l-tosyl-6-vinyl-lH-indole-4-carbonyl)piperazin-l- yl)benzonitrile (0.85 g, 1.66 mmol, 94%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 511.1 [M+H] ⁺ . Step 4: 2-(4-(6-Formyl-l-tosyl-lH-indole-4-carbonyl)piperazin-l-yl)b enzonitrile

[00897] To a solution of 2-(4-(l-tosyl-6-vinyl-lH-indole-4-carbonyl)piperazin-l- yl)benzonitrile (0.8 g, 1.56 mmol) in acetone (40 mL) and H ₂ 0 (40 mL) was added Potassium osmate(VI) dihydrate (29.4 mg, 0.08 mmol), MO (9.3 mg, 0.08 mmol) and NaI0 ₄ (1.0 g, 4.68 mmol). The mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with EtOAc (200mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica to give 2-(4-(6-formyl-l-tosyl-lH-indole-4-carbonyl)piperazin-l- yl)benzonitrile(480 mg, 0.93 mmol, 53%) as a white solid. ESI-MS (EI ⁺ , m/z): 513.2 [M+H] ⁺ . Step 5: 2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-l-tosyl-lH -indole-4- carbonyl)piperazin-l-yl)benzonitrile

[00898] To a solution of 2-(4-(6-formyl-l-tosyl-lH-indole-4-carbonyl)piperazin-l- yl)benzonitrile (200 mg, 0.39 mmol) and 2-(piperazin-l-yl)benzonitrile (80 mg, 0.43 mmol) in dichloroethane (10 mL) was added a catalytic amount of AcOH and NaBH ₃ CN (74 mg, 1.17 mmol). The mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated and the residue was purified by column chromatography on silica to give 2-(4-(6-((4- (2-cyanophenyl)piperazin- 1 -yl)methyl)- 1 -tosyl- lH-indole-4-carbonyl)piperazin- 1 -yl)benzonitrile (400 mg, crude) as a white solid. ESI-MS (EI ⁺ , m/z): 684.2 [M+H] ⁺ .

Step 6: 2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-lH-indole- 4-carbonyl)piperazin- l-yl)benzonitrile, 1-203 [00899] To a solution of 2-(4-(6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-l-tosyl-lH - indole-4-carbonyl)piperazin-l-yl)benzonitrile (350 mg, crude) in THF (5 mL) was added TBAF (1 in THF, 2.55 mL, 2.55 mmol). The mixture was stirred at 70 °C for 5 h. The resulting mixture was diluted with EtOAc (200mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S04, filtered and concentrated. The residue was purified by prep-HPLC to give 2-(4-(6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-lH-indole- 4- carbonyl)piperazin-l-yl)benzonitrile 1-203 (128 mg, 0.24 mmol, 48% for two steps) as a white solid. ESI-MS (EI ⁺ , m/z): 530.3 [M+H] ⁺ . ¹ H- MR (500 MHz, CDC1 ₃ )5: 8.40 (s, 1H), 7.44-7.59 (m, 4H), 7.42 (s, 1H), 7.21 (d, J = 1.0 Hz, 1H), 6.97-7.07 (m, 4H), 6.55 (s, 1H), 4.10 (d, J = 2.0 Hz, 2H), 3.59-3.69 (m, 4H), 3.11-3.31 (m, 8H), 2.68-2.70 (t, J= 5.5 Hz, 4H).

Example 130. Synthesis of 2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-lH-indole- 4- carbonyl)piperazin-l-yl)benzonitrile, 1-365

1-365

Synthetic scheme:

Procedures and characterization:

[00900] The procedure for 2-(4-(6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-lH-indole- 4- carbonyl)piperazin-l-yl)benzonitrile was same as example 129.

[00901] Analysis was performed following Method A. Separation was performed following Method D.

Step 7: 2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-l-methyl-l H-indole-4- carbonyl)piperazin-l-yl)benzonitrile, 1-365

[00902] To a solution of 2-(4-(6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-lH-indole- 4- carbonyl)piperazin-l-yl)benzonitrile (84 mg, 0.16 mmol) in THF (15mL) at 0 °C was slowly added NaH (60% in mineral oil, 417 mg, 10.4 mmol). After the mixture was stirred at 0 °C for 1 h, CH ₃ I (12 uL, 0.19 mmol) was added and the mixture was stirred continuely at 0 °C for 1 h. The reaction mixture was quenched with saturated aqueous H4CI solution (5 mL). The resulting mixture was diluted with EtOAc (lOOmL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S04, filtered and concentrated. The residue was purified by prep-HPLC to give 2-(4-(6-((4-(2-cyanophenyl)piperazin-l-yl)m ethyl)- 1 -methyl- 1 H-indole-4- carbonyl)piperazin-l-yl)benzonitrile 1-365 (50.3 mg, 0.09 mmol, 47%) as a white solid.

[00903] ESI-MS (EI ⁺ , m/z): 544.2 [M+H] ⁺ . ¹ H-NMR (500 MHz, CDC1 ₃ )5: 7.69 (s, 1H), 7.49- 7.61 (m, 4H), 7.23 (d, 7= 2.5 Hz, 1H), 7.12-7.16 (m, 2H), 7.02-7.08 (m, 3H), 6.51 (d, 7= 3.0 Hz, 1H), 4.39 (s, 2H), 4.09 (s, 2H), 3.83 (s, 3H), 3.70 (d, 7= 9.5 Hz, 2H), 3.43-3.56 (m, 6H), 3.32 (s, 2H), 3.11-3.14 (m, 4H).

Example 131. Synthesis of 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-lH-indole- 7- carbonyl)piperazin-l-yl)be

1-171

Synthetic scheme:

Procedures and characterization:

[00904] The procedure for 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-l-tosyl-lH - indole-7-carbonyl)piperazin-l-yl)benzonitrile was same as example 129.

[00905] Analysis was performed following Method B. Separation was performed following Method D. Step 6: 2-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-lH-indole- 7-carbonyl)piperazin- l-yl)benzonitrile, 1-171

[00906] To a solution of 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-l-tosyl-lH - indole-7-carbonyl)piperazin-l-yl)benzonitrile (1.4 g, crude) in THF (5 mL) was added TBAF (1 in THF, 10.3 mL, 10.3 mmol). The mixture was stirred at 70 °C for 5 h. The resulting mixture was diluted with EtOAc (200mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S04, filtered and concentrated. The residue was purified by prep- HPLC to give 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-lH-indole- 7- carbonyl)piperazin-l-yl)benzonitrile 1-171 (200 mg, 0.37 mmol, 20% for two steps) as a white solid. ESI-MS (EI ⁺ , m/z): 530.3 [M+H] ⁺ . ¾- MR (500 MHz, CDC1 ₃ )5: 9.08 (s, 1H), 7.68 (s, 1H), 7.23 (dd, Ji = 1.5 Hz, J ₂ = 7.5 Hz, 1H), 7.44-7.55 (m, 3H), 7.30 (s, 1H), 7.27-7.28 (t, J= 2.5 Hz, 1H), 6.96-7.08 (m, 4H), 6.55-6.56 (t, J = 2.5 Hz, 1H), 4.01 (s, 4H), 3.70 (s, 2H), 3.21-3.26 (m, 8H), 2.70 (d, J= 4.5 Hz, 4H).

Example 132. Synthesis of 2-(4-(5-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-l-methyl- lH-indole-7-carbonyl)piperazin-l-yl)benzonitrile trifluoroacetate salt, 1-170

TFA

1-170

Synthetic scheme:

TFA

Procedures and characterization:

[00907] Analysis was performed following Method A. Separation was performed following Method C.

Step 1 : 2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-l-methyl-l H-indole-4- carbonyl)piperazin-l-yl)benzonitrile trifluoroacetate salt, 1-170

[00908] To a solution of 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-lH-indole- 7- carbonyl)piperazin-l-yl)benzonitrile (150 mg, 0.28 mmol) in THF (20mL) at 0 °C was slowly added NaH (60% in mineral oil, 417mg, 10.4mmol). After the mixture was stirred at 0 °C for lh, CH ₃ I (19 uL, 0.31 mmol) was added and the mixture was stirred at 0 °C for lh. The reaction mixture was quenched with saturated aqueous H4CI solution (10 mL). The resulting mixture was diluted with EtOAc (lOOmL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S04, filtered and concentrated. The residue was purified by prep-HPLC to give 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-l-methyl-l H-indole-7- carbonyl)piperazin-l-yl)benzonitrile trifluoroacetate salt 1-170 (94.3 mg, 0.14 mmol, 51%) as a white solid. [00909] ESI-MS (EI ⁺ , m/z): 544.2 [M+H] ^{+ 1} H- MR (500 MHz, CDC1 ₃ )5: 7.69 (s, 1H), 7.57- 7.59 (m, 2H), 7.50-7.55 (m, 2H), 7.20 (s, 1H), 7.12-7.55 (m, 2H), 7.06-7.09 (m, 3H), 6.57 (d, J= 3.0 Hz, 1H), 4.33-4.43 (m, 3H), 3.80 (s, 3H), 3.61-3.77 (m, 4H), 3.38-3.55 (m, 6H), 3.22-3.27 (m, 1H), 3.09-3.17 (m, 4H).

Example 133. Synthesis of 2-(4-((3,5-dimethyl-6-(4-(pyridazin-3-yl)piperazine-l- carbonyl)pyridin-2-yl)methyl)piperazin- l-yl)benzonitrile, 1-117

1-117

Synthetic scheme:

Procedures and characterization:

[00910] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: terf-Butyl 4-(pyridazin-3-yl)piperazine-l-carboxylate

[00911] A mixture of 3-chloropyridazine (1 g, 8.73 mmol), tert-butyl piperazine-l-carboxylate (1.626 g, 8.73 mmol), and K ₂ C0 ₃ (2.413 g, 17.46 mmol) in NMP (10 mL) was stirred at 120 °C for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/20) to afford tert- butyl 4-(pyridazin-3-yl)piperazine-l-carboxylate (709 mg, 2.68 mmol, 31%) as a yellow oil. ESI- MS (EI+, m/z): 265.4 [M+H] ⁺ .

Step 2: 3-(Piperazin-l-yl)pyridazine

[00912] A mixture of tert-butyl 4-(pyridazin-3-yl)piperazine-l-carboxylate (750 mg, 2.84 mmol) in HCI/dioxane (5 mL) was stirred at rt for 2 h. The reaction mixture was concentrated to give crude product 3-(piperazin-l-yl)pyridazine (460 mg) as yellow solid. ESI-MS (EI ⁺ , m/z): 165.2 [M+H] ⁺ .

Step 3: 2-(4-((3,5-Dimethyl-6-(4-(pyridazin-3-yl)piperazine-l-carbon yl)pyridin-2- yl)methyl)piperazin-l-yl)benzonitrile, 1-117

[00913] ESI-MS (EI ⁺ , m/z): 497.2 [M+H] ⁺ . ¾- MR(500 MHz, CDCb) δ 8.62 (d, J = 4.0 Hz, 1H), 7.55(dd, J= 8.0, 1.5 Hz, 1H), 7.47 (dt, J = 9.0, 1.5 Hz, 1H), 7.38 (s, 1H), 7.25 (t, J = 4.5 Hz, 2H), 6.98 (q, J = 6.9 Hz, 3H), 3.98 (t, J = 5.0 Hz, 2H), 3.84 - 3.65 (m, 6H), 3.43 (t, J = 5.0 Hz, 2H), 3.20 (t, J = 4.5 Hz, 4H), 2.70 (t, J = 4.5 Hz, 4H), 2.44 (s, 3H), 2.33 (s, 3H).

Example 134. Synthesis of (3-((4-(2-Chlorophenyl)piperazin-l-yl)methyl)-4- methoxyphenyl)(4-(5-fluoropyridin-2-yl)piperazin-l-yl)methan one, 1-305

1-305

Synthetic scheme:

Procedures and characterization:

[00914] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: tert-Butyl 4-(5-fluoropyridin-2-yl)piperazine-l-carboxylate [00915] A solution of tert-butyl piperazine-l-carboxylate (5 g, 26.85 mmol), 2-bromo-5- fluoropyridine (4.7 g, 26.85 mmol), t-BuONa (5.16 g, 53.7 mmol), BINAP (1.67 g, 2.685 mmol), and Pd ₂ (dba)3 (1.23 mg, 1.34 mmol) in dry toluene (80 mL) was stirred under N ₂ at 80 °C for 16 h. The reaction mixture was concentrated and the mixture was purified by chromatography (silica, EtOAc/PE =1/5) to afford tert-butyl 4-(5-fluoropyridin-2-yl)piperazine-l-carboxylate (7 g, 24.88 mmol, 93%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 282.1 [M+H] ⁺ .

Step 2: l-(5-Fluoropyridin-2-yl)piperazine

[00916] A mixture of tert-butyl 4-(5-fluoropyridin-2-yl)piperazine-l-carboxylate (7.4 g, 26.3 mmol) in HCl/dioxane (40 mL) was stirred at rt for 16 h. The reaction mixture was concentrated to give crude product l-(5-fluoropyridin-2-yl)piperazine (6 g) as yellow solid. ESI-MS (EI ⁺ , m/z): 182.1 [M+H] ⁺ .

Step 3: 5-(4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl)-2-methoxyb enzaldehyde

[00917] A mixture of 3-formyl-4-methoxybenzoic acid (270 mg, 1.5 mmol), l-(5- fluoropyridin-2-yl)piperazine (407 mg, 2.25 mmol), HATU (741 mg, 1.95 mmol), and DIPEA(969 mg, 7.5 mmol) in DMF (6 mL) was stirred at rt for 16 h. The mixture was purified by chromatography (silica, EtOAc/PE =1/5) to afford 5-(4-(5-fluoropyridin-2-yl)piperazine-l- carbonyl)-2-methoxybenzaldehyde (353 mg, 1.03 mmol, 69%) as yellow solid. ESI-MS (EI ⁺ , m/z): 344.1 [M+H] ⁺ .

Step 4: (3-((4-(2-Chlorophenyl)piperazin-l-yl)methyl)-4-methoxypheny l)(4-(5- fluoropyridin-2-yl)piperazin-l-yl)methanone, 1-305

[00918] A solution of 5-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2- methoxybenzaldehyde (137 mg, 0.4 mmol), l-(2-chlorophenyl)piperazine (94 mg, 0.48 mmol) in EtOH (3 mL) and HO Ac (1 drop) was stirred at rt for 2 h. NaBH ₃ CN (50 mg, 0.8 mmol) was added and the reaction mixture was stirred at rt for 14 h. The mixture was purified by prep-HPLC to afford (3-((4-(2-chlorophenyl)piperazin-l-yl)methyl)-4-methoxypheny l)(4-(5-fluoropyridin-2- yl)piperazin-l-yl)methanone 1-305 (42 mg, 0.04 mmol, 20%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 524.2 [M+H] ⁺ . ¹ H- MR (500 MHz, CDC1 ₃ ) δ 8.06 (d, J= 3.0 Hz, 1H), 7.55 (d, J= 2.1 Hz, 1H), 7.39 (dd, J= 8.4, 2.2 Hz, 1H), 7.34 (dd, J= 7.9, 1.5 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.21 (td, J = 8.0, 1.5 Hz, 1H), 7.04 (dd, J = 8.1, 1.4 Hz, 1H), 6.96 (td, J = 7.7, 1.5 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 9.2, 3.2 Hz, 1H), 3.89 - 3.66 (m, 9H), 3.52 (s, 4H), 3.09 (s, 4H), 2.71 (s, 4H). Example 135. Synthesis of 2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5- difluoropicolinoyl)piperazin-l-yl)benzonitrile, 1-186

1-186

Synthetic scheme:

Procedures and characterization:

[00919] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 2-Cyano-3,5-difluoropyridine 1-oxide

[00920] To a solution of 3,5-difluoropicolinonitrile (500 mg, 3.6 mmol) in TFA (5 mL) was added 30% H2O2 (1 mL) at 0 °C and the reaction mixture was stirred for 3 h at 80 °C. The residue was dissolved in EtOAc (20 mL) and washed with aq. Na2S ₂ 04. The organic layer was concentrated to afford 2-cyano-3,5-difluoropyridine 1-oxide (450 mg, 2.8 mmol, 80%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 157.1 [M+H] ⁺ . Step 2: 6-Chloro-3,5-difluoropicolinonitrile

[00921] A solution of 2-cyano-3,5-difluoropyridine 1-oxide (400 mg, 2.56 mmol) in POCh (10 mL) was stirred for 17 h at 80 °C. The mixture was cooled to rt, and poured onto ice-water. The residue was dissolved in EtOAc (20 mL) and washed with aq. NaHCCb. The organic layer was concentrated. The crude product was purified by chromatography (silica, EtOAc/PE =1/6) to afford 6-chloro-3,5-difluoropicolinonitrile as a yellow solid (250 mg, 1.2 mmol, 55%).

Step 3: Methyl 6-chloro-3,5-difluoropicolinate

[00922] To a solution of 6-chloro-3,5-difluoropicolinonitrile (250 mg, 1.43 mmol) in MeOH (15 mL) was added 4 HCl/dioxane (15 mL). The reaction mixture was stirred for 17 h at 80 °C. The mixture was concentrated. The crude product was purified by chromatography (silica, EtOAc/PE =1/6) to afford 6-chloro-3,5-difluoropicolinonitrile as a yellow solid (270 mg, 1.3 mmol, 90%). ESI-MS (EI ⁺ , m/z): 208.2 [M+H] ⁺ .

Step 4: Methyl 3,5-difluoro-6-vinylpicolinate

[00923] To a solution of 6-chloro-3,5-difluoropicolinonitrile (270 mg, 1.3 mmol) in MeCN (15 mL) and water (1.5 mL) was added potassium vinyltrifluoroborate (350 mg, 2.6 mmol), K2CO3 (538 mg, 3.9 mmol), and Pd(dppf)Cl2 (95 mg, 0.13 mmol). The reaction mixture was stirred for 3 h at 80 °C. The mixture was concentrated and the crude product was purified by chromatography (silica, EtOAc/PE =1/10) to afford methyl 3,5-difluoro-6-vinylpicolinate as a yellow oil (200 mg, 1.0 mmol, 77%). ESI-MS (EI ⁺ , m/z): 200.1 [M+H] ⁺ .

Step 5: Methyl 3,5-difluoro-6-formylpicolinate

[00924] To a solution of methyl 3,5-difluoro-6-vinylpicolinate (200 mg, 1.0 mmol) in acetone (20 mL) and water (10 mL) was added MO, K ₂ 0s0 ₄ .H ₂ 0, NaI0 ₄ (642 mg, 3.0 mmol). The mixture was stirred for 17 h at rt. The mixture was dissolved in EtOAc (20 mL) and washed with aq. Na ₂ SC"3 and the organic layer was concentrated. The crude product was purified by chromatography (silica, EtOAc/PE =1/1) to afford methyl 3,5-difluoro-6-formylpicolinate as a yellow oil (90 mg, 0.45 mmol, 45%).

Step 6: Methyl 6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5-difluoropico linate

[00925] A solution of methyl 3,5-difluoro-6-formylpicolinate (50 mg, 0.25 mmol), 2- (piperazin-l-yl)benzonitrile (70 mg, 0.37 mmol) in EtOH (5 mL) was stirred at rt for 1 h. Then cat. HOAc and NaB¾CN (32 mg, 0.5 mmol) were added and the reaction mixture was stirred at rt for 17 h. The solvent was concentrated and extracted with EtOAc (20 mL). The organic layer was washed with aq. H4CI, brine, dried over MgS0 ₄ and concentrated to afford crude methyl 6- ((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5-difluoropicoli nate as a brown oil (70 mg). ESI-MS (EI ⁺ , m/z): 373.3 [M+H] ⁺ .

Step 7: 6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5-difluoropico linic acid

[00926] To a solution of crude methyl 6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5- difluoropicolinate (500 mg, 1.3 mmol) in THF (10 mL) and water (5 mL) was added NaOH (157 mg, 3.9 mmol). The mixture was stirred at rt for 17 h. The solvent was concentrated and extracted with Et ₂ 0 (10 mL), the aqueous layer was acidified with aqueousl M HC1 solution and then extracted with EtOAc (20 mL). The organic layer was washed with aq. H4CI, brine, dried over MgS0 ₄ and concentrated to afford crude 6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5- difluoropicolinic acid as a white solid (300 mg, 0.83 mmol, 64%). ESI-MS (EI ⁺ , m/z): 359.1 [M+H] ⁺ .

Step 8: 2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5-difluo ropicolinoyl)piperazin- l-yl)benzonitrile, 1-186

[00927] To a solution of crude 6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5- difluoropicolinic acid (100 mg, 0.28 mmol) and 2-(piperazin-l-yl)benzonitrile (78 mg, 0.42 mmol) in DMF (3 mL) was added HATU (160 mg, 0.42 mmol) and Et ₃ N (0.3 mL, 2.0 mmol). The mixture was stirred at rt for 17 h. The solution was purified by prep-HPLC (Boston CI 8 21 *250mm ΙΟμπι, Mobile phase: A: 0.1 % trifluoroacetic acid; B: acetonitrile) to afford 2-(4-(6-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-3,5-difluoropicolinoyl)pi perazin-l-yl)benzonitrile 1-186 (24.3 mg, 0.046 mmol, 16%) as a white solid. ESI-MS (EI ⁺ , m/z): 528.3 [M+H] ⁺ . ¾ NMR (500 MHz, CDC1 ₃ ) δ 7.52 (dd, J = 7.5, 1.5 Hz, 1H), 7.43 (m, 3H), 7.25 (t, J = 8.5 Hz, 1H), 6.97 (m, 4H), 4.05 - 3.95 (m, 2H), 3.79 (m, 2H), 3.55 - 3.47 (m, 2H), 3.28 - 3.20 (m, 2H), 3.16 (m, 6H), 2.80 - 2.62 (m, 4H).

Example 136. Synthesis of 2-(4-((3,5-Difluoro-6-(4-(5-fluoropyridin-2-yl)piperazine-l- carbonyl)pyridin-2-yl)methyl)piperazin- l-yl)benzonitrile, I- 172

1-172

The procedure was same as Example 112.

[00928] Analysis was performed following Method B. Separation was performed following Method D.

[00929] ESI-MS (EI ⁺ , m/z): 522.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 8.05 (d, J= 3.0 Hz, 1H), 7.56 (dd, J = 7.5, 1.5 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.30 (m, 2H), 7.00 (m, 2H), 4.02 - 3.91 (m, 2H), 3.88 (m, 2H), 3.66 - 3.58 (m, 2H), 3.57 - 3.51 (m, 2H), 3.50 - 3.43 (m, 2H), 3.27 - 3.15 (m, 4H), 2.83 - 2.73 (m, 4H).

Example 137. Synthesis of 2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5- difluoropicolinoyl)piperazin-l-yl)nicotinonitrile, 1-153

1-153

The procedure was same as Example 112.

[00930] Analysis was performed following Method B. Separation was performed following Method D.

[00931] ESI-MS (EI+, m/z): 529.2 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 8.37 (dd, J = 5.0, 2.0 Hz, 1H), 7.81 (dd, J= 7.5, 2.0 Hz, 1H), 7.54 (d, J= 6.5 Hz, 1H), 7.47 (t, J= 7.5 Hz, 1H), 7.32 (t, J= 8.5 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.84 (dd, J= 7.5, 5.0 Hz, 1H), 4.07 - 3.93 (m, 2H), 3.92 - 3.79 (m, 4H), 3.78 - 3.68 (m, 2H), 3.57 - 3.49 (m, 2H), 3.29 - 3.18 (m, 4H), 2.79 (m, 4H).

Example 138. Synthesis of 3-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5- difluoropicolinoyl)piperazin-l-yl)pyridazine-4-carbonitrile, 1-369

1-369

The procedure was same as Example 133.

[00932] Analysis was performed following Method B. Separation was performed following Method D.

[00933] ESI-MS (EI ⁺ , m/z): 530.2 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 8.88 (d, J= 5.0 Hz, 1H), 7.56 - 7.50 (m, 2H), 7.50 - 7.44 (m, 1H), 7.34 (t, J= 8.5 Hz, 1H), 7.05 - 6.94 (m, 2H), 4.05 (dd, J = 6.5, 3.5 Hz, 2H), 3.99 (m, 2H), 3.89 (m, 4H), 3.65 - 3.55 (m, 2H), 3.29 - 3.19 (m, 4H), 2.83 - 2.72 (m, 4H).

Example 139. Synthesis of 4-(4-(6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5- difluoropicolinoyl)piperazin-l-yl)-2,5-difluorobenzonitrile, 1-143

1-143

The procedure was same as Example 133.

[00934] Analysis was performed following Method B. Separation was performed following Method D.

[00935] ESI-MS (EI ⁺ , m/z): 564.2 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.55 (d, J= 7.5 Hz, 1H), 7.48 (t, J= 8.0 Hz, 1H), 7.33 (t, J= 8.5 Hz, 1H), 7.23 (m, 1H), 7.00 (m, 2H), 6.69 (m, 1H), 4.05 - 3.96 (m, 2H), 3.90 (m, 2H), 3.61 - 3.51 (m, 2H), 3.44 - 3.34 (m, 2H), 3.33 - 3.18 (m, 6H), 2.86 - 2.72 (m, 4H). Example 140. Synthesis of 2-[4-({3,5-dichloro-6-[4-(2-cyanophenyl)piperazine-l- carbonyl] pyridin-2-yl}methyl)piperazin- 1-yl] benzonitrile, 1-159

Procedures and characterization:

[00936] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: methyl 3,5-dichloro-6-methylpicolinate

[00937] To a solution of 2-bromo-3,5-dichloro-6-methylpyridine (2.0 g, 8.3 mmol) in MeOH (50 mL) was added Pd(dppf)Cl ₂ (303.7 mg, 0.4 mmol) and NaOAc(3.4 g, 4.23 mmol). The reaction mixture was stirred for 17 h under CO at 90 °C. The solution was diluted with water (50 mL) and extracted with DCM (100 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum and the crude product was purified by chromatography (silica, EtOAc/PE =1/10) to afford methyl 3,5-dichloro-6-methylpicolinate (360 mg, 1.63 mmol, 19%) as a yellow oil. ESI-MS (EI+, m/z): 220 [M+2] ⁺ .

Step 2: methyl 6-(bromomethyl)-3,5-dichloropicolinate

[00938] To a solution of methyl 3,5-dichloro-6-methylpicolinate (360 mg, 1.51 mmol) in CC1 ₄ (10 mL) was added NBS (268.9 mg, 1.51 mmol) and dibenzoyl peroxide (366.1 mg, 0.15 mmol). The reaction mixture was stirred for 17 h at 80 °C. The solution was diluted with water (30 mL) and extracted with EtOAc (50 mL x 3). The organic phase was dried (Na ₂ S04), filtered and concentrated in vacuum and the crude product was purified by chromatography (silica, EtOAc/PE =1/10) to afford methyl methyl 6-(bromomethyl)-3,5-dichloropicolinate (270 mg,0.90 mmol, 60 %) as pale oil. ESI-MS (EI+, m/z): 298 [M+H] ⁺ .

Step 3: methyl 3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)pico linate

[00939] To a solution of methyl 6-(bromomethyl)-3,5-dichloropicolinate (270 mg, 0.91 mmol) in DMF (20 mL) was added 2-(piperazin-l-yl)benzonitrile (170.55 mg, 0.91 mmol) and K2CO3 (377.9 mg, 0.73 mmol). The reaction mixture was stirred for 17 h at 45 °C. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum and the crude product was purified by chromatography (silica, EtOAc/PE =1/10) to afford methyl 3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l- yl)methyl)picolinate (205 mg, 0.50 mmol, 55%) as a yellow solid. ESI-MS (EI+, m/z): 405 [M+H] ⁺ .

Step 4: 3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)pico linic acid

[00940] To a solution of methyl 3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l- yl)methyl)picolinate (205 mg, 0.50 mmol) in MeOH (10 mL) was added LiOHH ₂ 0 (63.08 mg, 1.53 mmol) and H ₂ 0 (1 mL). The reaction mixture was stirred for 17 h at 45 °C. The solution was diluted with 1M HC1 (10 mL), water (20 mL) and extracted with DCM (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum to afford 3,5-dichloro-6-((4-(2- cyanophenyl)piperazin-l-yl)methyl)picolinic acid (180 mg, 0.46 mmol, 90%) as a white solid. ESI-MS (EI+, m/z): 391 [M+H] ⁺ .

Step 5: 2-(4-(3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l-yl)methy l)picolinoyl)piperazin- l-yl)benzonitrile, 1-159

[00941] To a solution of 3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)pico linic acid (90 mg, 0.23 mmol) in DMF (10 mL) was added HATU (114.0 mg, 0.30 mmol), DIPEA (89.4 mg, 0.69 mmol), and 2-(piperazin-l-yl)benzonitrile (43.1 mg, 0.23 mmol). The mixture was stirred for 17 h at rt. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phase was dried (Na ₂ S04), filtered and concentrated in vacuum, the crude product was purified by prep-HPLC to afford 2-(4-(3,5-dichloro-6-((4-(2- cyanophenyl)piperazin-l-yl)methyl)picolinoyl)piperazin-l-yl) benzonitrile 1-159 (20.5 mg, 0.03 mmol, 15%) as a white solid. ESI-MS (EI+, m/z): 560 [M+H] ⁺ . 1H MR (500 MHz, DMSO) δ 8.38 (s, 1H), 7.67-7.74 (m, 2H), 7.55-7.61 (m, 2H), 7.15-7.19 (m, 3H), 7.6-06-7.08 (m, 1H), 3.85 (s, 2H), 3.79 (s, 2H), 3.35 (s, 2H), 3.34 (s, 2H), 3.12 (s, 6H), 2.68 (s, 4H).

Example 141. Synthesis of 2-[4-({3,5-dichloro-6-[4-(5-fluoropyridin-2-yl)piperazine-l- carbonyl] pyridin-2-yl}methyl)piperazin- 1-yl] benzonitrile, 1-158

1-158

S nthetic scheme:

Procedures and characterization: [00942] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: methyl 3,5-dichloro-6-methylpicolinate

[00943] To a solution of 2-bromo-3,5-dichloro-6-methylpyridine (2.0 g, 8.3 mol) in MeOH (20 mL) was added Pd(dppf)Cl ₂ (303.8 g, 0.42 mol) and NaOAc (2.04 g, 24.9 mmol). The solution was stirred for 17 h at 90 °C under CO. The solution was diluted with water (600 mL) and extracted with EtOAc (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum and the crude product was purified by chromatography (silica, EtOAc/PE =1/20) to afford methyl 3,5-dichloro-6-methylpicolinate (360 mg, 1.65mmol, 19%) as a yellow oil. ESI-MS (EI+, m/z): 219 [M+H] ⁺ .

Step 2: methyl 6-(bromomethyl)-3,5-dichloropicolinate

[00944] To a solution of methyl 3,5-dichloro-6-methylpicolinate (360 mg, 1.65 mmol) in dry CC1 ₄ (10 mL) was added BS (268.9 mg, 1.51 mmol) and dibenzoyl peroxide (366.1 mg,0.15 mmol). The mixture was stirred at 80 °C for 17 h. The solution was diluted with water (600 mL) and extracted with EtOAc (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum, the crude product was purified by chromatography (silica, EtOAc/PE =1/10) to afford methyl 6-(bromomethyl)-3,5-dichloropicolinate (270 mg, 0.90 mmol, 60%) as a pale oil. ESI-MS (EI+, m/z): 297 [M+H] ⁺ .

Step 3: methyl 3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)pico linate

[00945] To a solution of methyl 6-(bromomethyl)-3,5-dichloropicolinate (270 mg, 0.91 mmol) in DMF (10 mL) was added K ₂ C0 ₃ (377.9 mg, 2.73 mmol) and 2-(piperazin-l-yl)benzonitrile (170.55 mg, 0.91 mmol). The mixture was stirred for 17 h at 45 °C. A solution of 1- methylcyclobutanecarbaldehyde was added and stirred at rt for 17 h. The solution was diluted with water (600 mL) and extracted with EtOAc (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum and the crude product was purified by chromatography (silica, EtOAc/PE =1/10) to afford methyl 3,5-dichloro-6-((4-(2- cyanophenyl)piperazin-l-yl)methyl)picolinate (205 mg, 0.50mmol, 55%) as a yellow oil. ESI-MS (EI+, m/z): 406 [M+H] ⁺ .

Step 4: 3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)pico linic acid

[00946] To a solution of methyl 3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l- yl)methyl)picolinate (205 mg, 0.51 mmol) in MeOH (10 mL) was added LiOHH ₂ 0 (63.8 mg, 1.53 mmol) and H ₂ 0 (1 mL). The mixture was stirred for 17 h at 40 °C. The solution was concentrated in vacuum to afford the crude. The crude was diluted with 1M HC1 (20 mL) and extracted with DCM (100 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum to afford 3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l- yl)methyl)picolinic acid (180 mg, 0.46 mmol, 90%) as yellow solid. ESI-MS (EI+ +, m/z): 391 [M+H] ⁺ .

Step 5: 2 2-(4-((3,5-dichloro-6-(4-(5-fluoropyridin-2-yl)piperazine-l- carbonyl)pyridin-2- yl)methyl)piperazin-l-yl)benzonitrile, 1-158

[00947] To a solution of 3,5-dichloro-6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)pico linic acid (90 mg, 0.23 mmol) in DMF (10 mL) was added HATU (114.1 mg, 0.30 mmol) , DIPEA (0.2 mL, 0.92 mmol), and l-(5-fluoropyridin-2-yl)piperazine (50.1 mg, 0.23 mmol). The mixture was stirred for 17 h at rt. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phase was dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuum, and the crude product purified by CHIRAL-HPLC to give 2-(4-(2,4-dimethyl-5-(4-(6-methylpyridin-2- yl)piperazine-l-carbonyl)benzyl)piperidin-l-yl)benzonitrile 1-158 (15 mg, 0.027 mmol, 20 %) as a white solid. ESI-MS (EI+, m/z): 555[M+H]+. 1H MR (500 MHz, DMSO) δ 8.38 (s, 1H), 8.09- 8.10 (m, 1H), 7.67-7.69 (m, 1H), 7.53-7.58 (m, 2H), 7.06-7.13 (m, 2H), 6.88-6.90 (m, 1H), 3.75- 3.78(m, 4H), 3.54-3.56 (m, 2H), 3.43-3.46 (m, 2H), 3.28-3.23 (m, 2H), 3.11 (s, 4H), 3.62-3.64 (m, 4H), 1.89-1.90 (m, 2H).

Example 142. Synthesis of l-(2-Chlorophenyl)-4-{[5-methyl-6-(4-phenylpiperazine-l- carbonyl)pyridin-2-yl]methyl}piperazine, 1-267

1-267

Synthetic scheme:

Procedures and characterization:

[00948] Analysis was performed following Method A. Separation was performed following Method C.

Step 1: 2-Chloro-6-iodo-3-methylpyridine

[00949] To a solution of 2-dimethylaminoethanol (10.5 g, 1 17 mmol) in hexane (60 mL) cooled at 0 °C, under a nitrogen atmosphere, was added dropwise «-BuLi (94 mL of a 2.5 M solution in hexanes, 234 mmol). After 1 h at 0 °C, the reaction medium was cooled at -78°C and a solution of 2-chloro-3-methylpyridine (5.0 g, 39 mmol) in hexane (40 mL) was added dropwise. After 2 h at this temperature, a solution of iodine (40 g, 156 mmol) in tetrahydrofuran (60 mL) was added dropwise at -78 °C. The reaction medium was allowed to warm slowly at room temperature and stirred overnight. The reaction mixture was then cooled to 0 °C and H ₂ 0 (100 ml) was added dropwise, separated the organic phase, the aqueous was further extracted with EtOAc (2 x 100 mL), combined the extracts and washed with brine (100 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated, purified by silica gel chromatography (PE / EtOAc=10/l) to afford 2- chloro-6-iodo-3-methylpyridine (4.9 g, 19.4 mmol, 50%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 254.0 [M+H] ⁺ .

Step 2: 2-Chloro-3-methyl-6-vinyl pyridine

[00950] A mixture of 2-chloro-6-iodo-3-methylpyridine (4.6 g, 18 mmol), potassium trifluoro(vinyl)borate (4.8 g, 36 mmol), Pd(dppf)Cl ₂ (1.3 g, 1.8 mmol), K ₂ C0 ₃ (5 g, 36 mmol) in MeCN (80 mL) and H ₂ 0 (20 mL) was stirred at 80 °C for 16 h. Then H ₂ 0 (100 mL) and EtOAc (100 mL) were added and separated the organic phase, the aqueous was further extracted with EtOAc (2 x 100 mL), combined the extracts and washed with brine (100 mL), dried over anhydrous Na ₂ S04, filtered and concentrated, purified by silica gel chromatography (PE / EtOAc= 10/ 1-3/1) to afford 2-chloro-3-methyl-6-vinylpyridine (2.3 g, 15 mmol, 83%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 154.0 [M+H] ⁺ .

Step 3: 6-Chloro-5-methylpicolinaldehyde

[00951] A mixture of 2-chloro-3-methyl-6-vinylpyridine (2.1 g, 14 mmol), K ₂ 0s0 ₄ 2H ₂ 0 (51 mg, 0.70 mmol), MO (3.3 g, 28 mmol), NaI0 ₄ (9.0 g, 42 mmol) in acetone (50 mL) and H ₂ 0 (50 mL) was stirred at rt for 16 h. The reaction mixture was quenched with sat. Na ₂ S0 ₃ (50 mL), and

EtOAc (200 mL) was added and the organic phase separated, the aqueous was further extracted with EtOAc (200 mL), the extracts were combined and washed with brine (200 mL), dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated to afford 6-chloro-5-methylpicolinaldehyde (1.9 g, 12 mmol, 87%) as a yellow solid. ESI-MS (EI ⁺ , m/z): 156.0 [M+H] ⁺ .

Step 4: l-((6-Chloro-5-methylpyridin-2-yl)methyl)-4-(2-chlorophenyl) piperazine

[00952] A mixture of 6-chloro-5-methylpicolinaldehyde (1.3 g, 8.38 mmol) and l-(2- chlorophenyl)piperazine (2.0 g, 10.1 mmol) in EtOH (30 mL) was stirred at rt for 1 h, then

NaBH ₃ CN (1.0 g, 16.8 mmol) was added and the mixture was stirred at rt overnight. The reaction mixture was concentrated and purified by silica gel chromatography (PE / EtOAc= 10/ 1-3/1) to afford l-((6-chloro-5-methylpyridin-2-yl)methyl)-4-(2-chlorophenyl) piperazine (2.4 g, 7.16 mmol, 85%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 336.0 [M+H] ⁺ .

Step 5: 6-((4-(2-Chlorophenyl)piperazin-l-yl)methyl)-3-methylpicolin onitrile

[00953] A mixture of l-((6-chloro-5-methylpyridin-2-yl)methyl)-4-(2-chlorophenyl) piperazine

(600 mg, 1.79 mmol), Pd(t-Bu ₃ P) ₂ (92 mg, 0.18 mmol), Zn(CN) ₂ (415 mg, 3.58 mmol), Zn (107 mg, 1.79 mmol) in dioxane (20 mL) was stirred at 110 °C for 17 h. The reaction mixture was cooled and concentrated and the residue was purified by silica gel chromatography (PE /

EtOAc=10/l~3/l) to afford 6-((4-(2-chlorophenyl)piperazin-l-yl)methyl)-3- methylpicolinonitrile(270 mg, 0.83 mmol, 46%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 327.0

[M+H] ⁺ .

Step 6: 6-((4-(2-Chlorophenyl)piperazin-l-yl)methyl)-3-methylpicolin ic acid

[00954] A mixture of 6-((4-(2-chlorophenyl)piperazin-l-yl)methyl)-3-methylpicolin onitrile (270 mg, 0.83 mmol) in HC1 (6 M, 15 mL) was stirred at 100 °C for 17 h. The reaction mixture was cooled, H ₂ 0 (20 mL) and EtOAc (20 mL) was added and the organic phase separated , the aqueous was further extracted with EtOAc (2 x 20 mL), the extracts combined and washed with brine (20 mL), dried over anhydrous Na ₂ S04, filtered and concentrated to afford 6-((4-(2- chlorophenyl)piperazin-l-yl)methyl)-3-methylpicolinic acid (110 mg, 0.32 mmol, 38%) as a yellow oil. ESI-MS (EI ⁺ , m/z): 346.0 [M+H] ⁺ .

Step 7: l-(2-Chlorophenyl)-4-{[5-methyl-6-(4-phenylpiperazine-l-carb onyl)pyridin-2- yl] methyl} piperazine, 1-267

[00955] A mixture of 6-((4-(2-chlorophenyl)piperazin-l-yl)methyl)-3-methylpicolin ic acid (110 mg, 0.32 mmol), 1-phenylpiperazine (78 mg, 0.48 mmol), HATU (146 mg, 0.38 mmol) and DIPEA (83 mg, 0.64 mmol) in DMF (5 mL) was stirred at rt for 24 h. The reaction mixture was filtered and purified by prep-HPLC to afford l-(2-chlorophenyl)-4-{[5-methyl-6-(4- phenylpiperazine-l-carbonyl)pyridin-2-yl]methyl}piperazine 1-267 (61.5 mg, 0.13 mmol, 26%) as a white solid. ESI-MS (EI ⁺ , m/z): 490.0 [M+H] ⁺ . ¾ MR (500 MHz, CDCh) δ 7.70 (d, J = 7.0 Hz, 1H), 7.49 (d, J= 7.5 Hz, 1H), 7.39-7.34 (m, 3H), 7.25 (t, J= 7.5 Hz, 1H), 7.17 (d, J= 8.0 Hz, 2H), 7.12-7.02 (m, 3H), 4.41 (br, 2H), 4.12 (br, 2H), 3.79 (br, 2H), 3.53-3.29 (m, 10H), 2.39 (s, 3H).

Example 143. Synthesis of 2-(4-{[5-Methyl-6-(4-phenylpiperazine-l-carbonyl)pyridin-2- yl]methyl}piperazin-l-yl)benzonitrile, 1-230

1-230

Synthetic scheme:

Procedures and characterization:

[00956] Analysis was performed following Method A. Separation was performed following Method D. Step 1: 2-(4-{[5-methyl-6-(4-phenylpiperazine-l-carbonyl)pyridin-2-y l]methyl}piperazin-l- yl)benzonitrile, 1-230

[00957] A mixture of l-(2-chlorophenyl)-4-{[5-methyl-6-(4-phenylpiperazine-l- carbonyl)pyridin-2-yl]methyl}piperazine (30 mg, 0.061 mmol), Pd(t-Bu ₃ P) ₂ (16 mg, 0.031 mmol), Zn(CN) ₂ (14 mg, 0.12 mmol) and Zn (7 mg, 0.12 mmol) in dioxane (5 mL) was irradiated in the microwave at 160 °C for 3 h. The reaction mixture was cooled, filtered and purified by prep-HPLC to afford 2-(4-{[5-methyl-6-(4-phenylpiperazine-l-carbonyl)pyridin-2-y l]methyl}piperazin-l- yl)benzonitrile 1-230 (14.6 mg, 0.030 mmol, 50%) as a white solid. ESI-MS (EI ⁺ , m/z): 481.0 [M+H] ⁺ . ¹ H MR (500 MHz, CDC1 ₃ ) δ 7.60-7.55 (m, 2H), 7.51-7.47 (m, 1H), 7.29-7.25 (m, 3H), 7.04-7.00 (m, 2H), 6.91 (dd, J = 8.0 Hz, 17.5 Hz, 3H ), 3.99 (t, J = 5.0 Hz, 2H), 3.85 (br, 2H), 3.42-.3.28 (m, 8H), 3.14 (t, J= 5.0 Hz, 2H), 2.83 (br, 4H), 2.62 (s, 3H).

Example 144. Synthesis of 2-(4-((5-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2,6 - dimethylpyridin-3-yl)methyl)piperazin-l-yl)benzonitrile, 1-187

1-187

Synthetic scheme:

Procedures and characterization:

[00958] Analysis was performed following Method A. Separation was performed following Method D.

Step 1: ethyl 5-formyl-2,6-dimethylnicotinate

[00959] DIBAL-H (4.8mL, 4.8 mmmol, 1M in toluene) was added dropwise to a solution of diethyl 2,6-dimethylpyridine-3,5-dicarboxylate (lg, 4 mmol) in toluene (60 mL) at -78 °C. The resulted solution was stirred at -78 °C for 1 h. The mixture was quenched with Na ₂ S04 IOH2O. The mixture was filtered and concentrated to obtain a residue. The residue was purified by chromatography (silica, EtOAc/PE =1/2) to afford ethyl 5-formyl-2,6-dimethylnicotinate (115 mg, 0.56 mmol, 14%) as yellow oil. ESI-MS (EI+, m/z): 208.1 [M+H] ⁺ .

Step 2: ethyl 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnico tinate

[00960] NaBH ₃ CN (122mg, 1.93 mmol) and CH3COOH (2 drops) were added to a solution of ethyl 5-formyl-2,6-dimethylnicotinate (200 mg, 0.97 mmol) and 2-(piperazin-l-yl)benzonitrile (181 mg, 0.97 mmol) in ethanol (10 mL). The mixture was stirred at 25 °C for 2h. The mixture was poured into water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na ₂ S0 ₄ and concentrated to obtain a crude product. The crude product purified by chromatography (silica, EtOAc/PE =1/3) to afford ethyl 5-((4-(2-cyanophenyl)piperazin-l- yl)methyl)-2,6-dimethylnicotinate(265 mg, 0.97 mmol, 73%) as yellow solid. ESI-MS (EI+, m/z): 379.1 [M+H] ⁺ .

Step 3: 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnico tinic acid

[00961] L1OH H2O (88.2 mg, 2.1 mmol) was added to a solution of ethyl 5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnicotinate (265 mg, 0.7 mmol) in THF (15 mL). The mixture was stirred at 25 °C for 18 h. The mixture was acidified with IN HCl until pH = 6. The mixture was poured into water and extracted with EtOAc (50 mL). The organic layer was dried over Na ₂ S04 and concentrated to afford 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6- dimethylnicotinic acid (220 mg, 0.63 mmol, 90%) as a yellow solid. ESI-MS (EI+, m/z): 351.1 [M+H]+.

Step 4: 2-(4-((5-(4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl)-2,6 -dimethylpyridin-3- yl)methyl)piperazin-l-yl)benzonitrile, 1-187

[00962] HATU (144.4 mg, 0.38 mmol) and DIPEA(80mg, 0.62 mmol) were added to a solution of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnico tinic acid (110 mg, 0.31 mmol) and l-(5-fluoropyridin-2-yl)piperazine (68 mg, 0.38 mmol) in DMF (5 ml). The mixture was stirred at 25 °C for 18 h. The mixture was purified by prep-HPLC to afford 2-(4-((5-(4-(5- fluoropyridin-2-yl)piperazine-l-carbonyl)-2,6-dimethylpyridi n-3-yl)methyl)piperazin-l- yl)benzonitrile 1-187 (64 mg, 0.12 mmol, 40%) as a white solid. ESI-MS (EI+, m/z): 514.1 [M+H] ⁺ . 1H NMR (500 MHz, DMSO) δ 8.07-8.08 (s, 1H), 7.57-7.59 (d, 1Η),7.47-7.52 (m, 2H), 7.29-7.36 (m, 1H), 7.00-7.05 (m, 2H), 6.66-6.68 (m, 1H), 3.97 (s, 2H), 3.56-3.59 (d, 4H), 3.40- 3.47(d, 4H),3.22-3.23 (s, 4H), 2.68-2.70 (s, 4H), 2.63 (s, 3H), 2.54 (s, 3H).

Example 145. Synthesis of 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6- dimethylnicotinoyl)piperazin- l-yl)benzonitrile, 1-188

1-188

Synthetic scheme:

Procedures and characterization:

[00963] The synthesis of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnico tinic acid was same as example 133.

[00964] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6- dimethylnicotinoyl)piperazin- l-yl)benzonitrile, 1-188

[00965] HATU(144.4 mg, 0.38 mmol) and DIPEA (80mg, 0.62 mmol) were added to a solution of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnico tinic acid (110 mg, 0.31 mmol) and l-(5-fluoropyridin-2-yl)piperazine (68 mg, 0.38 mmol) in DMF (5 ml). The mixture was stirred at 25 °C for 18 h. The mixture was purified by prep-HPLC to afford 2-(4-(5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnicotinoyl)pi perazin-l-yl)benzonitrile 1-188 (25.8 mg, 0.05 mmol, 16%) as a white solid. ESI-MS (EI+, m/z): 520.3[M+H] ⁺ . 1H MR (500 MHz, DMSO) δ 7.48-7.63 (m, 5H), 7.10-7.13 (t, 1Η),7.01-7.06 (m, 3H), 4.12 (s, 1H), 4.02 (s, 1H), 3.51-3.57 (d, 4H), 3.13-3.30 (m, 8H), 2.70 (s, 4H), 2.62 (s, 3H), 2.55 (s, 3H).

Example 146. Synthesis of 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6- dimethylnicotinoyl)piperazin-l-yl)nicotinonitrile, 1-154

1-154

Synthetic scheme:

Procedures and characterization:

[00966] The synthesis of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnico tinic acid was same as example 133.

[00967] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6- dimethylnicotinoyl)piperazin-l-yl)nicotinonitrile, 1-154

[00968] HATU (141 mg, 0.37 mmol) and DIPEA (80mg, 0.62 mmol) were added to a solution of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnico tinic acid (110 mg, 0.31 mmol) and 2-(piperazin-l-yl)nicotinonitrile (59 mg, 0.31 mmol) in DMF (5 ml). The mixture was stirred at 25°C for 2h. The mixture was purified by prep-HPLC to afford 2-(4-(5-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnicotinoyl)pi perazin-l-yl)nicotinonitrile 1-154 (84 mg, 0.16 mmol, 51%) as a white solid. ESI-MS (EI+, m/z): 521.2 [M+H] ⁺ . IH MR (500 MHz, DMSO) δ 8.39-8.40 (d, IH), 7.83-7.85 (d, IH), 7.57-7.59 (d, IH), 7.48-7.52 (t, 2H), 7.29 (s, IH), 7.01-7.04 (t, 2H), 6.87-6.89 (m, IH), 4.01 (s, 2H), 3.81 (s, 2H), 3.63 (s, 2H), 3.56 (s, 2H), 3.45-3.47 (t, 2H), 3.23-3.24 (t, 4H), 2.69-2.71 (t, 4H), 2.62 (s, 3H), 2.55 (s, 3H).

Example 147. Synthesis of 3-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6- dimethylnicotinoyl)piperazin-l-yl)pyridazine-4-carbonitrile, 1-366

1-366

Synthetic scheme:

Procedures and characterization:

[00969] The synthesis of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnico tinic acid was same as example 133. [00970] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 3-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6- dimethylnicotinoyl)piperazin-l-yl)pyridazine-4-carbonitrile, 1-366

[00971] HATU (129 mg, 0.34 mmol) and DIPEA (75 mg, 0.58 mmol) were added to a solution of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnico tinic acid (100 mg, 0.29 mmol) and 3-(piperazin-l-yl)pyridazine-4-carbonitrile (55 mg, 0.29 mmol) in DMF (5 ml). The mixture was stirred at 25 °C for 2h. The mixture was purified by prep-HPLC to afford 3-(4-(5-((4-(2- cyanophenyl)piperazin- 1 -yl)methyl)-2,6-dimethylnicotinoyl)piperazin- 1 -yl)pyridazine-4- carbonitrile 1-366 (50 mg, 0.096 mmol, 34%) as a white solid. ESI-MS (EI+, m/z): 522.3[M+H] ⁺ . 1H MR (500 MHz, DMSO) δ 8.92-8.93 (d, 1H), 7.55-7.59 (m, 2H), 7.49-7.52 (m, 2H), 7.01- 7.04 (t, 2H), 4.07 (s, 2H), 3.95 (s, 2H), 3.78 (s, 2H), 3.57 (s, 2H), 3.52-3.53 (t, 2H), 3.24 (s, 4H), 2.69-2.71 (t, 4H), 2.63 (s, 3H), 2.55 (s, 3H).

Example 148. Synthesis of 4-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6- dimethylnicotinoyl)piperazin-l-yl)-2,5-difluorobenzonitrile, 1-100

1-100

Synthetic scheme:

Procedures and characterization:

[00972] The synthesis of 5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6-dimethylnico tinic acid was same as example 133.

[00973] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 2-(4-(5-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-2,6- dimethylnicotinoyl)piperazin-l-yl)-4,5-difluorobenzonitrile, 1-100

[00974] The procedure was as similar as for Example 145. ESI-MS (EI+, m/z): 556.3[M+H] ⁺ . IH NMR (500 MHz, DMSO) δ 7.58-7.59 (d, IH), 7.49-7.52 (t, IH), 7.46(s, IH), 7.24-7.29(m, IH), 7.00-7.05(t, 2H), 6.67-6.71(t, IH), 4.02 (s, 2H), 3.57 (s, 2H), 3.46-3.47 (d, 2H), 3.34 (s, 2H), 3.23(s, 4H),3.18(s,2H), 2.69 (S, 4H), 2.63 (s, 3H), 2.54 (s, 3H).

Example 149. Synthesis of 2-(4-(6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5- dimethylpicolinoyl)piperazin-l- l)nicotinonitrile, 1-156

1-156

Synthetic scheme:

Procedures and characterization:

[00975] Analysis was performed following Method B. Separation was performed following Method D.

Step 1: 6-Bromo-3,5-dimethylpicolinaldehyde

[00976] To a solution of 2,6-dibromo-3,5-dimethylpyridine (1.0 g, 3.77 mmol) in toluene (30 mL) was added «-BuLi (1.5 mL, 3.77 mmol) dropwise at -78 °C. After 1 h, DMF (358 mg, 4.9 mmol) was added to the mixture for an additional 1 h. The mixture was adjusted to pH = 3-4 using HC1 and extracted with EtOAc (50 mL x 3) and the organic layers were concentrated and purified by chromatography (silica, EtOAc/PE =1/10) to afford 6-bromo-3,5-dimethylpicolinaldehyde (242 mg, 1.13 mmol, 30%) as a white solid. ESI-MS (EI ⁺ , m/z): 214.1 [M+H] ⁺ .

Step 2: 2-(4-((6-Bromo-3,5-dimethylpyridin-2-yl)methyl)piperazin-l-y l)benzonitrile

[00977] A mixture of 6-bromo-3,5-dimethylpicolinaldehyde (500 mg, 2.35 mmol) and 2- (piperazin-l-yl)benzonitrile (439 mg, 2.35 mmol) in AcOH (0.1 mL) and ethanol (10 mL) was heated to 40 °C for 2 h. The mixture was cooled to rt. NaC BH ₃ (296 mg, 4.69 mmol) was added. After 10 h of stirring at 20 °C, the mixture was quenched with water and purified by prep-HPLC to afford 2-(4-((6-bromo-3,5-dimethylpyridin-2-yl)methyl)piperazin-l-y l)benzonitrile (190 mg, 0.49 mmol, 21%). ESI-MS (EI ⁺ , m/z): 385.1 [M+H] ⁺ .

Step 3: Methyl 6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5-dimethylpico linate

[00978] A mixture of 2-(4-((6-bromo-3,5-dimethylpyridin-2-yl)methyl)piperazin-l- yl)benzonitrile (100 mg, 0.26 mmol), CH ₃ COONa (64 mg, 0.78 mmol) and Pd(dppf)Cl ₂ (10 mg, 0.01 mmol) in MeOH (15 mL) was stirred at 90 °C under CO (1 MPa) for 16 h. The mixture was washed with water and extracted with EtOAc (40 mL x 3) to afford methyl 6-((4-(2- cyanophenyl)piperazin-l-yl)methyl)-3,5-dimethylpicolinate (57 mg, 0.16 mmol, 60%). ESI-MS (EI ⁺ , m/z): 365.2 [M+H] ⁺ .

Step 4: 6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5-dimethylpico linic acid

[00979] A mixture of methyl 6-((4-(2-cyanophenyl)piperazin-l-yl)methyl)-3,5- dimethylpicolinate (600 mg, 1.65 mmol) and NaOH (2 N, 5 mL) in THF (5 mL) and MeOH (5 mL) was stirred at rt for 4 h. The mixture was adjusted to pH = 3-4 and extracted with EtOAc (50 mL x 3). The organice layer was concentrated to give 6-((4-(2-cyanophenyl)piperazin-l- yl)methyl)-3,5-dimethylpicolinic acid (520 mg, 1.49 mmol, 90%) as a brown solid. ESI-MS (EI, m/z): 349 [M-H]\

Step 5: 2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5- dimethylpicolinoyl)piperazin-l-yl)nicotinonitrile, 1-156

[00980] ESI-MS (EI ⁺ , m/z): 521.3 [M+H] ⁺ . ¾NMR (500 MHz, CDC1 ₃ ) δ 8.43 - 8.30 (m, 1H), 7.79 (dd, 7= 7.6, 1.6 Hz, 1H), 7.54 (d, 7= 7.8 Hz, 1H), 7.46 (t, 7= 7.9 Hz, 1H), 7.36 (s, 1H), 6.98 (dd, 7= 7.7, 4.9 Hz, 2H), 6.81 (dd, 7= 7.5, 4.8 Hz, 1H), 4.04 - 3.93 (m, 2H), 3.87 - 3.76 (m, 2H), 3.69 (m, 4H), 3.48 - 3.36 (m, 2H), 3.20 (s, 4H), 2.70 (s, 4H), 2.43 (s, 3H), 2.33 (s, 3H).

Example 150. Synthesis of 2-(4-((6-(4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl)-3,5 - dimethylpyridin-2-yl)methyl)piperazin-l-yl)benzonitrile 2,2,2-trifluoroacetate, 1-157

1-157

Procedures and characterization:

[00981] Analysis was performed following Method A. Separation was performed following Method C.

[00982] The procedure was the same as Example 133.

2-(4-((6-(4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl)-3,5 -dimethylpyridin-2- yl)methyl)piperazin-l-yl)benzonitrile 2,2,2-trifluoroacetate, 1-157: ESI-MS (EI ⁺ , m/z): 514.2 [M+H] ⁺ . ¾ NMR (500 MHz, CDCb) δ 8.06 (s, 1H), 7.66 - 7.32 (m, 4H), 7.23 - 7.06 (m, 2H), 6.72 (d, J= 6.9 Hz, 1H), 4.44 (s, 2H), 3.96 (s, 4H), 3.67 (s, 4H), 3.59 - 3.26 (m, 8H), 2.36 (d, J = 23.3 Hz, 6H).

Example 151. Synthesis of 2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5- dimethylpicolinoyl)piperazin- l- l)benzonitrile, I- 173

1-173

Procedures and characterization:

[00983] The procedure was same as Example [00984] Analysis was performed following Method B. Separation was performed following Method D.

2-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5-dimeth ylpicolinoyl)piperazin-l- yl)benzonitrile, 1-173: ESI-MS (EI ⁺ , m/z): 520.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 7.58 (dd, 7= 7.6, 1.4 Hz, 1H), 7.52 (dd, 7= 15.9, 7.5 Hz, 2H), 7.48 - 7.43 (m, 1H), 7.36 (s, 1H), 7.09 - 7.03 (m, 2H), 6.98 (t, 7 = 8.6 Hz, 2H), 4.08 - 4.00 (m, 2H), 3.71 (s, 2H), 3.51 - 3.43 (m, 2H), 3.34 - 3.29 (m, 2H), 3.19 (s, 6H), 2.74 - 2.63 (m, 4H), 2.43 (s, 3H), 2.33 (s, 3H).

Example 152. Synthesis of 3-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5- dimethylpicolinoyl)piperazin-l- l)pyridazine-4-carbonitrile, 1-151

1-151

Procedures and characterization:

[00985] Analysis was performed following Method A. Separation was performed following Method D.

[00986] The procedure was same as Example 133.

3-(4-(6-((4-(2-Cyanophenyl)piperazin-l-yl)methyl)-3,5-dimeth ylpicolinoyl)piperazin-l- yl)pyridazine-4-carbonitrile 1-151: ESI-MS (EI ⁺ , m/z): 522.3 [M+H] ⁺ . ¾ MR (500 MHz, CDCb) δ 8.86 (d, 7 = 4.9 Hz, 1H), 7.57 - 7.43 (m, 3H), 7.38 (s, 1H), 6.98 (dd, 7 = 7.8, 5.1 Hz, 2H), 4.01 (ddd, 7 = 9.6, 7.1, 4.0 Hz, 4H), 3.89 - 3.80 (m, 2H), 3.71 (s, 2H), 3.56 - 3.46 (m, 2H), 3.20 (s, 4H), 2.70 (s, 4H), 2.44 (s, 3H), 2.34 (s, 3H).

Generic Method for Amide Couplings using HATTJ

Example 153. Synthesis of 2-[4-({5-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-243

1-243

[00987] 5-{[4-(2-Cyanophenyl)piperazin-l-yl]methyl}-2,4-dimethylbenz oic acid [Intermediate C] (100 mg, 0.29 mmol) and HATU (131 mg, 0.34 mmol) were suspended in DMF (5 ml) and stirred at room temperature for 30 min. 2-(Piperazin-l-yl)benzonitrile [Amine 72] (59 mg, 0.31 mmol) and DIPEA (150 μΐ, 0.86 mmol) were then added and the reaction was stirred for 18 hours. The reaction was partitioned between DCM (20 ml) and water (20 ml). The aqueous layer was extracted with DCM (20 ml). The combined organics were reduced in vacuo then the residue was purified using UV Directed High pH Prep HPLC. The fractions containing product were combined and concentrated in vacuo to yield the title compound as a white solid (101 mg, 68 %).

1H NMR (500 MHz, Chloroform-d) δ 7.58 (dd, J = 7.7, 1.5 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.48 - 7.44 (m, 1H), 7.13 (s, 1H), 7.07 (td, J = 0.8 Hz, 1H), 7.05 - 7.01 (m, 2H), 7.00 - 6.96 (m, 2H), 4.14 - 3.93 (m, 2H), 3.57 - 3.42 (m, 4H), 3.26 (t, J = 5.0 Hz, 2H), 3.23 - 3.16 (m, 4H), 3.15 - 3.06 (m, 2H), 2.71 - 2.61 (m, 4H), 2.36 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.49 min (ES+) (M+H)+ 519.3

Generic Method for Reductive Aminations using NaBHYOAcb

Example 154. Synthesis of 2-[4-(5-{[4-(3-Chloropyridin-2-yl)piperazin-l-yl]methyl}-2,4 - dimethylbenzoyl)piperazin-l-yl]benzonitrile, 1-133

1-133 [00988] 2-[4-(5-Formyl-2,4-dimethylbenzoyl)piperazin-l-yl]benzonitri le [Intermediate H] (28 mg, 0.08 mmol) and l-(3-chloropyridin-2-yl)piperazine [Amine 78] (17 mg, 0.09 mmol) were dissolved in DCM (1 ml). NaBH(OAc) ₃ (50 mg, 0.24 mmol) was added and the reaction mixture was stirred overnight. The reaction was quenched with water. The quenched reaction was partitioned between DCM (10 ml) and water (10 ml). The organics were washed with water, sat aq NaHC0 ₃ , dried (MgS0 ₄ ), filtered and concentrated in vacuo. The residue was purified via basic UV directed prep HPLC. The fractions containing product were concentrated in vacuo to yield the title compound as a white solid (17 mg, 38 %).

1H MR (500 MHz, DMSO-d6) δ 8.21 (dd, J = 4.7, 1.6 Hz, 1H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.73 (dd, J = 7.7, 1.5 Hz, 1H), 7.61 (td, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.12 - 7.09 (m, 2H), 6.99 (dd, J = 7.8, 4.7 Hz, 1H), 3.89 - 3.79 (m, 2H), 3.57 - 3.44 (m, 2H), 3.36 (s, 2H), 3.29 - 2.98 (m, 8H), 2.58 - 2.53 (m, 4H), 2.34 (s, 3H), 2.21 (s, 3H).

LCMS Method 6 - Tr = 4.55 min (ES+) (M+H)+ 529.3 / 531.2

Example 155. Synthesis of 2-[4-({2-Cyano-3-[4-(6-methylpyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-310

1-310

[00989] 2-Cyano-3-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}benzoic acid [Intermediate 34] (40 mg, 0.12 mmol) and l-(6-methylpyridin-2-yl)piperazine [Amine 3] (22.5 mg, 0.13 mmol) were suspended in DMF (1 ml) then HATU (52.7 mg, 0.14 mmol) was added and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with DCM (10 ml) and water (10 ml). The organics were separated and concentrated in vacuo. The residue was purified by UV- Directed High pH preparative HPLC. The fractions containing product were combined and concentrated in vacuo to give the title compound as a yellow solid (28 mg, 46%). 1H NMR (500 MHz, DMSO-d6) δ 7.77 (t, J = 7.7 Hz, 1H), 7.70 (d, J = 7.7 Hz, 2H), 7.62 - 7.57 (m, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.45 (t, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 3.78 (s, 4H), 3.61 (s, 2H), 3.48 (s, 2H), 3.17 (s, 4H), 2.67 - 2.64 (m, 4H), 2.53 - 2.52 (m, 2H), 2.30 (s, 3H).

LCMS Method 7 - Tr = 1.59 min (ES+) (M+H)+ 506.2

Example 156. Synthesis of 2-{4-[4-Methyl-3-(4-phenylpiperazine-l- carbonyl)benzoyl]piperazin-l-yl}benzonitrile, 1-303

1-303

[00990] To a suspension of 4-methyl-3-(4-phenylpiperazine-l-carbonyl)benzoic acid [Intermediate 41] (24 mg, 0.075 mmol) and HATU (31 mg, 0.082 mmol) in DMF (1 ml) was added DIPEA (40 μΐ, 0.224 mmol) and the resultant solution was stirred at room temperature for 30 min. 2-(Piperazin-l-yl)benzonitrile [Amine 72] (14 mg, 0.075 mmol) was then added and the reaction was stirred overnight. The crude reaction mixture was directly submitted for open access preparative HPLC (basic pH). The fractions containing product were combined and then concentrated in vacuo, then freeze-dried overnight to afford the title compound as a white powder (10 mg, 26%).

1H NMR (500 MHz, Chloroform-i ) δ 7.60 (dd, J = 7.7, 1.5 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.39 (dd, J = 7.8, 1.7 Hz, 1H), 7.35 - 7.25 (m, 7H), 7.08 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.96 - 6.88 (m, 3H), 4.17 (s, 1H), 3.91 (s, 3H), 3.61 (s, 2H), 3.52 - 3.42 (m, 2H), 3.39 - 3.01 (m, 8H), 2.38 (s, 3H).

LCMS Method 7 - Tr = 3.45 min (ES+) (M+H)+ 494

Example 157. Synthesis of 2-{4-[2-Methyl-5-(4-phenylpiperazine-l- carbonyl)benzoyl]piperazin-l-yl}benzonitrile, 1-285

1-285

[00991] The title compound was prepared according to the generic method in Example 153 using 3-[4-(2-cyanophenyl)piperazine-l-carbonyl]-4-methylbenzoic acid [Intermediate 42] (40.92 mg, 0.12 mmol) and 1-phenylpiperazine [Amine 71] (19 mg, 0.12 mmol) to yield a tan solid (10 mg, 16%).

1H NMR (500 MHz, Chloroform-i ) δ 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.39 (dd, J = 7.8, 1.8 Hz, 1H), 7.35 - 7.26 (m, 4H), 7.07 (td, J = 7.6, 0.9 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.95 - 6.88 (m, 3H), 4.14 - 3.85 (m, 4H), 3.68 (s, 2H), 3.41 (s, 2H), 3.30 - 3.02 (m, 8H), 2.38 (s, 3H).

LCMS Method 7 - Tr = 3.46 min (ES+) (M+H)+ 494

Example 158. Synthesis of 2-(4-{5-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-2- methylbenzoyl}piperazin-l-yl)benzonitrile, 1-284

1-284

[00992] The title compound was prepared according to the generic method in Example 153 using 3-[4-(2-cyanophenyl)piperazine-l-carbonyl]-4-methylbenzoic acid [Intermediate 42] (37.32 mg, 0.11 mmol) and 2-(piperazin-l-yl)benzonitrile [Amine 72] (20 mg, 0.11 mmol) to yield an off-white powder (14 mg, 24%).

1H NMR (500 MHz, Chloroform-i ) δ 7.59 (dd, J = 7.7, 1.3 Hz, 2H), 7.54 - 7.49 (m, 2H), 7.39 (dd, J= 7.8, 1.7 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.1 1 - 7.05 (m, 2H), 7.01 (dd, J= 8.2, 4.1 Hz, 2H), 4.24 - 3.83 (m, 4H), 3.80 - 3.56 (m, 2H), 3.52 - 3.42 (m, 2H), 3.36 - 3.00 (m, 8H), 2.38 (s, 3H). LCMS Method 7 - Tr = 3.41 min (ES+) (M+H)+ 519

Example 159. Synthesis of 2-{4-[(5-{[4-(2-Chlorophenyl)piperazin-l-yl] methylphenyl)methyl] -3-oxopiperazin- 1-yl} benzonitrile, 1-241

1-241

[00993] l-{[3-(Chloromethyl)-4-methylphenyl]methyl}-4-(2-chloropheny l)piperazine

[Intermediate 44] (30 mg, 0.09 mmol) and 2-(3-oxopiperazin-l-yl)benzonitrile [Amine 74] (20.7 mg, 0.1 mmol) were suspended in DMF (900 μΐ) then sodium hydride (60% dispersion in mineral oil) (4.6 mg, 0.12 mmol) was added and the reaction was stirred at ambient temperature for 1.5 hours. The reaction mixture was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a pale yellow crystalline solid (8.5 mg, 18 %).

1H MR (500 MHz, DMSO-d6) δ 7.75 (d, J = 8.0 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.25 (q, J = 7.9 Hz, 2H), 7.20 - 7.16 (m, 2H), 7.13 (d, J = 9.2 Hz, 1H), 7.01 (t, J = 8.4 Hz, 2H), 6.99 - 6.94 (m, 1H), 5.68 (s, 2H), 4.71 (s, 2H), 4.12 - 4.08 (m, 2H), 3.61 - 3.58 (m, 2H), 3.50 (s, 2H), 2.89 (s, 4H), 2.54 (s, 4H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.63 min (ES+) (M+H ⁺ ) 514.3/516.3

Example 160. Synthesis of 2-(4-{l-[4-(2-Chlorophenyl)piperazin-l-yl]-2,3-dihydro-lH- indene-4-carbonyl}piperazin-l-yl)benzonitrile, 1-240

1-240

[00994] l-[4-(2-Chlorophenyl)piperazin-l-yl]-2,3-dihydro-lH-indene-4 -carboxylic acid [Intermediate 49] (65 mg, 0.18 mmol) and HATU (80 mg, 0.21 mmol) were dissolved in DMF (lml). DIPEA (100 μΐ, 0.56 mmol) was added and the reaction was stirred for 30 min. 2-(Piperazin- l-yl)benzonitrile [Amine 72] (40 mg, 0.21 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was purified by UV Direct High pH Prep HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a yellow glassy solid (55.0 mg, 55 %).

1H MR (250 MHz, DMSO-d6, 353K) δ 7.68 (dd, J = 7.7, 1.5 Hz, 1H), 7.61 (ddd, J = 9.1, 7.5, 1.7 Hz, 1H), 7.45 - 7.08 (m, 8H), 7.02 (td, J = 7.8, 1.6 Hz, 1H), 4.41 (t, J = 6.9 Hz, 1H), 3.74 - 3.54 (m, 4H), 3.26 - 3.16 (m, 4H), 3.03 - 2.54 (m, 10H), 2.20 - 2.07 (m, 2H).

LCMS Method 7 - Tr = 2.58 min (ES+) (M+H)+ 526.3 / 528.3

Example 161. Synthesis of l-(2-Chlorophenyl)-4-{4-[4-(5-fluoropyridin-2-yl)piperazine- l- carbonyl]-2,3-dihydro-lH-inden-l-yl}piperazine, 1-239

1-239

[00995] l-[4-(2-Chlorophenyl)piperazin-l-yl]-2,3-dihydro-lH-indene-4 -carboxylic acid [Intermediate 49] (65 mg, 0.18 mmol) and HATU (75 mg, 0.20 mmol) were dissolved in DMF (lml). DIPEA (200 μΐ, 1.1 mmol) was added and the reaction mixture was stirred for 30min. l-(5- Fluoropyridin-2-yl)piperazine trihydrochloride [Amine 57] (57 mg, 0.20 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was purified by UV-Directed High pH Prep HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as an off white glassy solid (60.5 mg, 61 %).

1H MR (250 MHz, DMSO-d6) δ 8.09 (d, J = 3.1 Hz, 1H), 7.54 - 7.24 (m, 5H), 7.22 - 7.12 (m, 2H), 7.02 (td, J = 7.8, 1.6 Hz, 1H), 6.86 (dd, J = 9.2, 3.3 Hz, 1H), 4.40 (t, J = 6.9 Hz, 1H), 3.66 - 3.40 (m, 8H), 3.02 - 2.65 (m, 7H), 2.65 - 2.54 (m, 3H), 2.19 - 2.06 (m, 2H).

LCMS Method 7 - Tr = 2.44 min (ES+) (M+H)+ 520.3 / 522.3 Example 162. Synthesis of 2-(4-{l-[4-(2-Cyanophenyl)piperazin-l-yl]-2,3-dihydro-lH- indene-4-carbonyl}piperazin-l-yl)benzonitrile, 1-238

1-238

[00996] l-[4-(2-Chlorophenyl)piperazin-l-yl]-2,3-dihydro-lH-indene-4 -carboxylic acid [Intermediate 50] (65 mg, 0.0.19 mmol) and HATU (75 mg, 0.20 mmol) were dissolved in DMF (lml). DIPEA (100 μΐ, 0.56 mmol) was added and the reaction mixture was stirred for 30 min. 2- (Piperazin-l-yl)benzonitrile [Amine 72] (37 mg, 0.20 mmol) was added and the reaction mixture was stirred for 3 hours. The reaction mixture was purified by UV-Directed High pH Prep HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as an off white glassy solid (61.1 mg, 60 %).

1H MR (250 MHz, DMSO-d6) δ 7.72 - 7.53 (m, 4H), 7.42 (d, J = 7.4 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.24 - 7.02 (m, 5H), 4.42 (t, J = 6.8 Hz, 1H), 3.81 - 3.48 (m, 4H), 3.21 (dd, 8H), 2.98 - 2.57 (m, 6H), 2.13 (q, J = 7.2 Hz, 2H).

LCMS Method 7 - Tr = 2.36 min (ES+) (M+H)+ 517.4

Example 163. Synthesis of 2-(4-{4-[4-(5-Fluoropyridin-2-yl)piperazine-l-carbonyl]-2,3- dihydro-lH-inden-l-yl}piperazin-l-yl)benzonitrile, 1-237

1-237

[00997] l-[4-(2-Cyanophenyl)piperazin-l-yl]-2,3-dihydro-lH-indene-4- carboxylic acid [Intermediate 50] (65 mg, 0.19 mmol) and HATU (75 mg, 0.20 mmol) were dissolved in DMF (lml). DIPEA (200 μΐ, 1.12 mmol) was added and the reaction mixture was stirred for 30 min. 1- (5-Fluoropyridin-2-yl)piperazine trihydrochloride [Amine 57] (55 mg, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by UV-Directed High pH Prep HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as an off white glassy solid (47.8 mg, 48 %). 1H NMR (250 MHz, DMSO-d6) δ 8.09 (d, J = 3.0 Hz, 1H), 7.67 - 7.38 (m, 4H), 7.31 (t, J = 7.4 Hz, 1H), 7.22 - 7.13 (m, 2H), 7.07 (t, J = 7.5 Hz, 1H), 6.86 (dd, J = 9.3, 3.4 Hz, 1H), 4.41 (t, J = 6.9 Hz, 1H), 3.70 - 3.44 (m, 8H), 3.26 - 3.17 (m, 4H), 2.96 - 2.57 (m, 6H), 2.12 (q, J = 7.2 Hz, 2H).

LCMS Method 7 - Tr = 2.20 min (ES+) (M+H)+ 511.4

Example 164. Synthesis of 2-(4-{3-[4-(2-Cyanophenyl)-2-oxopiperazine-l-carbonyl]-4- methylbenzoyl}piperazin-l-yl)benzonitrile, 1-217

1-217

[00998] 5-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-2-methylbenzoic acid [Intermediate 38] (20 mg, 0.06 mmol) was suspended in tetrahydrofuran (500 μΐ) then DIPEA (21.9 μΐ, 0.13 mmol) was added followed by the addition of SOCl ₂ (5.01 μΐ, 0.07 mmol, 1 :4 solution in THF) then the reaction was stirred for 1 hour. Further 2-(3-oxopiperazin-l-yl)benzonitrile [Amine 74] (12.7 mg, 0.06 mmol) was added followed by the addition of 1.0 mg DMAP then the reaction was stirred for an additional hour. The reaction was partitioned between DCM (10.0 ml) and sat aq NaHCCb (10.0 ml), then the organics were dried over Na ₂ S04, filtered and concentrated in vacuo. The residue was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a pale yellow glass (19.6 mg, 63%).

1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.21 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.73 (dd, J = 7.8, 1.6 Hz, 2H), 7.66 - 7.59 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.16 - 7.09 (m, 2H), 4.28 (t, J = 5.5 Hz, 2H), 3.73 (d, J = 71.6 Hz, 6H), 3.20 (s, 4H), 2.54 (s, 3H). LCMS Method 7 - Tr = 3.23 min (ES+) (M+H ⁺ ) 533.2

Example 165. Synthesis of 2-{4-[(3-{[4-(2-Cyanophenyl)-2-oxopiperazin-l-yl] methylphenyl)methyl]piperazin-l-yl}benzonitrile, 1-205

1-205

[00999] 2-(4-{[3-(Chloromethyl)-4-methylphenyl]methyl}piperazin-l-yl )benzonitrile

[Intermediate 52] (27 mg, 0.08 mmol) was dissolved in DMF (900 μΐ) then 2-(3-oxopiperazin-l- yl)benzonitrile [Amine 74] (19.18 mg, 0.1 mmol) was added followed by the addition of sodium hydride [60% dispersion] (60%, 4.29 mg, 0.11 mmol) then the reaction was stirred at ambient temperature for 2 hours The reaction mixture was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a pale yellow crystalline solid (5.1 mg, 13%).

1H MR (500 MHz, DMSO-d6) δ 7.74 (d, J = 8.1 Hz, 1H), 7.68 - 7.65 (m, 1H), 7.57 - 7.52 (m, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.19 (s, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 9.0 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 5.68 (s, 2H), 4.70 (s, 2H), 4.12 - 4.05 (m, 2H), 3.62 - 3.55 (m, 2H), 3.51 (s, 2H), 3.06 (s, 4H), 2.53 (s, 4H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.36 min (ES+) (M+H ⁺ ) 504.2

Example 166. Synthesis of 2-[4-(3-{[4-(2-Cyanophenyl)-2-oxopiperazin-l-yl]methyl}-4- methylbenzoyl)piperazin-l-yl]benzonitrile, 1-198

1-198 [001000] Step 1. 2-{4-[3-(Hydroxymethyl)-4-methylbenzoyl]piperazin-l-yl}benzo nitrile [Intermediate 53] (29 mg, 0.09 mmol) was dissolved in dichloromethane (800 μΐ) then DIPEA (19.58 μΐ, 0.11 mmol) was added followed by the addition of thionyl chloride (7.53 μΐ, 0.1 mmol) then the reaction was stirred for 20 mins. A further aliquot of thionyl chloride (4 μΐ, 0.05 mmol) was required to fully convert the alcohol to the chloride. The reaction was partitioned between DCM (5.0 ml) and water (5.0 ml) then the organics were separated and concentrated to give crude 2-{4-[3-(chloromethyl)-4-methylbenzoyl]piperazin-l-yl}benzon itrile.

[001001] Step 2. The crude 2-{4-[3-(chloromethyl)-4-methylbenzoyl]piperazin-l- yl}benzonitrile was dissolved in DMF (1.0 ml) then 2-(3-oxopiperazin-l-yl)benzonitrile [Amine 74] (19.14 mg, 0.1 mmol) was added followed by the addition of sodium hydride [60% dispersion in mineral oil] (4.15 mg, 0.1 mmol) and the reaction was stirred at ambient temperature for 1 hour. The reaction was partitioned between DCM (5 ml) and sat aq NaHCCb (5 ml) then the organics were separated and concentrated in vacuo. The residue was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a pale yellow glass (9.8 mg, 21%).

1H MR (500 MHz, DMSO-d6) δ 7.75 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 7.7, 1.5 Hz, 1H), 7.46 (ddd, 1H), 7.35 - 7.28 (m, 3H), 7.28 - 7.23 (m, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.96 (dt, J = 7.1, 3.3 Hz, 2H), 5.69 (s, 2H), 4.73 (s, 2H), 4.17 - 4.08 (m, 2H), 3.82 - 3.46 (m, 6H), 3.09 (s, 4H), 2.36 (s, 3H).

LCMS Method 7 - Tr = 3.32 min (ES+) (M+H ⁺ ) 519.3

Example 167. Synthesis of 2-[4-({3-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-4- methylphenyl}methyl)-3-oxopiperazin-l-yl]benzonitrile, 1-197

1-197

[001002] 5-{[4-(2-Cyanophenyl)-2-oxopiperazin-l-yl]methyl}-2-methylbe nzoic acid [Intermediate 57] (35 mg, 0.1 mmol) and 2-(piperazin-l-yl)benzonitrile [Amine 72] (18.5 μΐ, 0.11 mmol) were suspended in anhydrous DMF (0.8 ml) then HATU (45.7 mg, 0.12 mmol) was added and the reaction was stirred at ambient temperature for 1 hour. The reaction mixture was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a pale yellow glass (15.2 mg, 27%). 1H MR (500 MHz, DMSO-d6) δ 7.74 (ddd, J = 8.0 Hz, 1H), 7.72 (dd, J = 7.8, 1.5 Hz, 1H), 7.56 (ddd, J = 9.0, 7.9, 1.6 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.28 (t, J = 6.7 Hz, 1H), 7.24 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.19 (s, 1H), 7.15 - 7.10 (m, 2H), 6.95 (ddd, 1H), 5.68 (s, 2H), 4.69 (d, J = 18.8 Hz, 2H), 4.09 (t, 2H), 3.83 (s, 2H), 3.63 (t, 2H), 3.20 (s, 2H), 3.02 (s, 2H), 2.24 (s, 3H).

LCMS Method 7 - Tr = 3.32 min (ES+) (M+H ⁺ ) 519.3

Example 168. Synthesis of 2-[4-({4-Methyl-3-[4-(6-methylpyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)-3-oxopiperazin- 1-yl] benzonitrile, 1-196

1-196

[001003] 5-{[4-(2-Cyanophenyl)-2-oxopiperazin-l-yl]methyl}-2-methylbe nzoic acid [Intermediate 57] (35 mg, 0.1 mmol) and l-(6-methylpyridin-2-yl)piperazine [Amine 3] (19.5 mg, 0.11 mmol) were suspended in DMF (anhydrous) (0.8 ml) then HATU (45.7 mg, 0.12 mmol) was added and the reaction was stirred at ambient temperature for 1 hour. The reaction mixture was purified by UV-Direct High pH preparative HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a pale yellow glass (15.7 mg, 29%). 1H MR (500 MHz, DMSO-d6) δ 7.74 (d, J = 8.0 Hz, 1H), 7.42 (dd, J = 8.3, 7.4 Hz, 1H), 7.33 - 7.30 (m, 2H), 7.29 (t, J = 6.8 Hz, 1H), 7.25 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.17 (s, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.57 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 7.2 Hz, 1H), 5.67 (s, 2H), 4.68 (s, 2H), 4.09 (t, J = 5.3 Hz, 2H), 3.78 - 3.70 (m, 2H), 3.63 (t, 2H), 3.58 (t, 2H), 3.39 (s, 2H), 3.23 (s, 2H), 2.29 (s, 3H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.02 min (ES+) (M+H ⁺ ) 509.3 Example 169. Synthesis of 2-{4-[(5-{[4-(2-Cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylphenyl)methyl]piperazin-l-yl}benzonitrile, 1-184

1-184

[001004] A pressure tube was charged with l,5-bis(chloromethyl)-2,4-dimethylbenzene (Y. Wang and Y. Xi, Journal of the Chilean Chemical Society, 2013, 58 (4), 2196-9), (60.9 mg, 0.3 mmol) and a solution of 2-(piperazin-l-yl)benzonitrile [Amine 72] (112.3 mg, 0.6 mmol) and DIPEA (0.157 ml, 0.9 mmol) in acetonitrile (2 ml). The tube was sealed and the mixture stirred at 100 °C overnight. The resulting solution was purified by low pH preparative HPLC and further purified by high pH preparative HPLC to yield the title product as a cream solid. (94.1 mg, 62%). 1H MR (500 MHz, Methanol-d4) δ 7.68 - 7.49 (m, 2H), 7.27 - 6.98 (m, 3H), 3.74 - 3.52 (m, 2H), 3.28 - 3.11 (m, 4H), 2.83 - 2.61 (m, 4H), 2.54 - 2.29 (m, 3H).

LCMS Method 7 - Tr = 1.73 min (ES+) (M+H)+ 505.3

Example 170. Synthesis of 2-[4-({5-[4-(2-Cyano-4-fluorophenyl)piperazine-l-carbonyl]-2 ,4- dimethylphenyl}methyl)piperazin-l-yl]-5-fluorobenzonitrile, 1-180

1-180

[001005] 5-{[4-(2-Cyano-4-fluorophenyl)piperazin-l-yl]methyl}-2,4-dim ethylbenzoic acid [Intermediate 58] (50 mg, 0.14 mmol), 5-fluoro-2-(piperazin-l-yl)benzonitrile [Amine 5] (30.72 mg, 0.15 mmol), HATU (62.1 mg, 0.16 mmol) and DIPEA (71 μΐ, 0.41 mmol) were suspended in DMF (1 ml) then the reaction was stirred for 16 hours at room temperature. The reaction was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and the solvents removed in vacuo to yield the title compound (27 mg, 35%). 1H NMR (500 MHz, Chloroform-d) δ 7.30 (dd, J = 7.7, 3.0 Hz, 1H), 7.27 - 7.26 (m, 1H), 7.25 - 7.18 (m, 2H), 7.11 (s, 1H), 7.04 (s, 1H), 7.02 (dd, J = 9.1, 4.5 Hz, 1H), 6.98 (d, J = 4.6 Hz, 1H), 4.03 (s, 2H), 3.57 - 3.44 (m, 4H), 3.22 - 3.16 (m, 2H), 3.16 - 3.08 (m, 4H), 3.06 - 2.98 (m, 2H), 2.70 - 2.61 (m, 4H), 2.36 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.68 min (ES+) (M+H)+ 555.3

Example 171. Synthesis of 2-[4-({2,4-Dimethyl-5-[4-(pyridazin-3-yl)piperazine-l- carbonyl]phenyl}methyl)piperazin-l-yl]-5-fluorobenzonitrile, 1-161

1-161

[001006] 5-{[4-(2-Cyano-4-fluorophenyl)piperazin-l-yl]methyl}-2,4-dim ethylbenzoic acid [Intermediate 58] (48 mg, 0.13 mmol) and HATU (59 mg, 0.16 mmol) were suspended in DMF (1 ml). 3-(Piperazin-l-yl)pyridazine [Amine 1] (23.6 mg, 0.14 mmol) then DIPEA (68 μΐ, 0.39 mmol) was added and the reaction mixture was stirred for 18 hours at room temperature. The reaction was then partitioned between water (10 ml) and DCM (10 ml). The DCM was separated and the water extracted with DCM (2 x 10 ml). The combined organics were concentrated in vacuo to give a brown oil. The oil was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and concentrated in vacuo to yield the title compound (37 mg, 55%).

1H NMR (500 MHz, Chloroform-d) δ 8.63 (dd, J = 4.5, 1.1 Hz, 1H), 7.24 (dd, J = 5.0, 4.1 Hz, 2H), 7.20 (ddd, J = 9.0, 7.9, 3.0 Hz, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 6.98 (dd, J = 9.1, 4.6 Hz, 1H), 6.94 (dd, J = 9.3, 1.1 Hz, 1H), 4.00 - 3.92 (m, 2H), 3.75 - 3.64 (m, 4H), 3.54 - 3.48 (m, 2H), 3.46 - 3.38 (m, 2H), 3.16 - 3.07 (m, 4H), 2.69 - 2.60 (m, 4H), 2.36 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 1.59 min (ES+) (M+H)+ 514.3 Example 172. Synthesis of 2-[4-(5-{[4-(2-Cyanophenyl)piperazin-l-yl] methylphenoxy)piperidin-l-yl]benzonitrile, 1-160

1-160

[001007] 2-(4-Hydroxypiperidin-l-yl)benzonitrile [Intermediate 59] (92%, 50 mg, 0.23 mmol) and 2-{4-[(3-hydroxy-4-methylphenyl)methyl]piperazin-l-yl}benzon itrile [Intermediate 77] (69.9 mg, 0.23 mmol) were suspended in toluene (5 ml) under a nitrogen atmosphere. CMBP (68.62 μΐ, 0.26 mmol) was added and the reaction was stirred at 100 °C for 48 hours. The reaction was then cooled to room temperature and concentrated in vacuo. The resultant brown oil was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and concentrated in vacuo then purified by UV-Directed Low pH preparative HPLC. The fractions containing product were combined and the solvents removed in vacuo to yield the title compound (24 mg, 21%).

1H MR (500 MHz, Chloroform-d) δ 7.56 (td, J = 7.7, 1.5 Hz, 2H), 7.50 - 7.45 (m, 2H), 7.11 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 7.02 - 6.97 (m, 3H), 6.89 (s, 1H), 6.83 (d, J = 7.5 Hz, 1H), 4.64 - 4.59 (m, 1H), 3.55 (s, 2H), 3.43 (ddd, J = 11.8, 8.8, 3.1 Hz, 2H), 3.28 - 3.18 (m, 6H), 2.71 - 2.63 (m, 4H), 2.24 (s, 3H), 2.22 - 2.04 (m, 4H).

LCMS Method 7 - Tr = 3.04 min (ES+) (M+H)+ 492.3

Example 173. Synthesis of 2-[4-({6-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-3,5- dimethylpyrazin-2-yl} methyl)piperazin- 1-yl] benzonitrile, 1-140

1-140

[001008] Lithium 6-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-3,5-dimethylpyra zine-2- carboxylate [Intermediate 62] (50 mg, 0.122 mmol) and 2-(piperazin-l-yl)benzonitrile [Amine 72] (22.84 mg, 0.12 mmol) were suspended in dry DMF (1 ml) under nitrogen, then DIPEA (65 μΐ _^ , 0.366 mmol) and HATU (51 mg, 0.134 mmol) were added and the reaction was stirred at room temperature overnight. The reaction was purified by UV-Directed High pH preparative HPLC to yield the title compound as pale beige crystalline solid (14.1 mg, 22%).

1H MR (500 MHz, Methanol-d4) δ 7.74 - 7.68 (m, 1H), 7.68 - 7.63 (m, 2H), 7.63 - 7.56 (m, 1H), 7.32 - 7.27 (m, 1H), 7.26 - 7.18 (m, 2H), 7.18 - 7.12 (m, 1H), 4.79 (s, 2H), 4.07 - 4.01 (m, 2H), 3.89 - 3.68 (m, 4H), 3.68 - 3.50 (m, 4H), 3.49 - 3.33 (m, 4H), 3.24 - 3.17 (m, 2H), 2.65 (s, 3H), 2.60 (s, 3H).

LCMS Method 7 - Tr = 2.27 min (ES+) (M+H)+ 521.3

Example 174. Synthesis of 2-[4-({5-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)-3-oxopiperazin-l-yl]benzonitrile, 1-139

1-139

[001009] 5-{[4-(2-Cyanophenyl)-2-oxopiperazin-l-yl]methyl}-2,4-dimeth ylbenzoic acid [Intermediate 82] (35 mg, 0.1 mmol) and HATU (44 mg, 0.12 mmol) were suspended in DMF (1 ml) and stirred at room temperature for 30 min. 2-(Piperazin-l-yl)benzonitrile [Amine 72] (20 mg, 0.11 mmol) and DIPEA (50 μΐ, 0.29 mmol) were then added and the reaction was stirred for a further 16 hours. The reaction was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and the solvents removed in vacuo to yield the title compound (30 mg, 57%).

1H MR (500 MHz, Chloroform-d) δ 7.59 - 7.55 (m, 2H), 7.46 (td, J = 8.3, 1.6 Hz, 1H), 7.32 (td, J = 7.6, 7.0, 1.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.09 - 7.03 (m, 4H), 6.95 (d, J = 8.2 Hz, 1H), 4.88 (s, 2H), 4.82 - 4.70 (m, 2H), 4.16 - 3.85 (m, 4H), 3.65 - 3.52 (m, 2H), 3.52 - 3.41 (m, 2H), 3.29 - 3.14 (m, 2H), 3.13 - 3.02 (m, 2H), 2.33 (s, 3H), 2.30 (s, 3H).

LCMS Method 7 - Tr = 3.46 min (ES+) (M+H)+ 533.3 Example 175. Synthesis of 2-{4-[(lS or R)-l-[4-(2-Cyanophenyl)piperazin-l-yl]-2,3-dihydro- lH-indene-4-carbonyl]piperazin-l-yl}benzonitrile, 1-137 and

2-{4-[(lR or S)-l-[4-(2-cyanophenyl)piperazin-l-yl]-2,3-dihydro-lH-indene -4- carbonyl]piperazin-l-yl}benzonitrile, 1-136

I-136 I-137

[001010] (2-(4- { 1 -[4-(2-Cyanophenyl)piperazin- 1 -yl ]-2, 3 -dihydro- 1 H-indene-4- carbonyl}piperazin-l-yl)benzonitrile was dissolved to 15 mg/ml in ethanol and was then purified by chiral HPLC. Combined fractions of peak 1 at 9.572 min were then evaporated to near dryness using a rotary evaporator, transferred into final vessels with DCM, which was removed under a stream of nitrogen at 40 °C before being stored in a vacuum oven at 40 °C and 5 mbar for 4 hours to afford the title compound as a colourless glass.

Separation Conditions:

Column Details: Lux Al (21.2mm x 250mm, 5um)

Column Temperature: Ambient

Flow Rate: 21 ml/min

Detector Wavelength: 220 nm

Injection Volume: 1000 μΐ (15 mg)

Isocratic Conditions: 40:60 HEPTANE :EtOH (0.1% v/v H ₃ )

The stereochemistry was arbitrarily assigned

1H MR (500 MHz, DMSO-d6) δ 7.73 (dd, J = 7.7, 1.5 Hz, 1H), 7.69 (dd, J = 7.7, 1.5 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.40 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.19 - 7.12 (m, 2H),7.09 (t, J = 7.5 Hz, 1H), 4.42 (t, J = 6.9 Hz, 1H), 3.94 - 3.73 (m, 2H), 3.46 - 3.39 (m, 2H), 3.27 - 2.98 (m, 8H), 2.94 - 2.67 (m, 4H), 2.60 - 2.55 (m, 2H), 2.11 (q, J = 7.3 Hz, 2H).

LCMS Method 6 - Tr = 4.02 min (ES+) (M+H)+ 517.4 [001011] (2-(4- { 1 - [4-(2-Cyanophenyl)piperazin- 1 -yl] -2,3 -dihydro- 1 H-indene-4- carbonyl}piperazin-l-yl)benzonitrile Peak 2 at 12.4 min

The stereochemistry was arbitrarily assigned

1H NMR (500 MHz, DMSO-d6) δ 7.75 - 7.67 (m, 2H), 7.66 - 7.56 (m, 2H), 7.40 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.20 - 7.12 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 4.42 (t, J = 7.1 Hz, 1H), 3.95 - 3.64 (m, 2H), 3.47 - 3.38 (m, 2H), 3.27 - 3.03 (m, 8H), 2.96 - 2.67 (m, 4H), 2.62 - 2.54 (m, 2H), 2.11 (q, J = 7.3 Hz, 2H).

LCMS Method 6 - Tr = 4.02 min (ES+) (M+H)+ 517.4

Example 176. Synthesis of 2-[4-(5-{[4-(2-Cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]benzoic acid, 1-131

1-131

[001012] 5-{[4-(2-Cyanophenyl)piperazin-l-yl]methyl}-2,4-dimethylbenz oic acid [Intermediate C] (200 mg, 0.57 mmol) was suspended in DCM (10 ml) and the reaction was cooled in a ice-bath. Oxalyl chloride (55 μΐ, 0.64 mmol) and DMF (5 ul, 0.07 mmol) were added and the reaction mixture was stirred for 1 hour. 2-(Piperazin-l-yl)benzoic acid (128.55 mg, 0.62 mmol) was added and the reaction was stirred at room temperature for 1 hour. The reaction was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and the solvents removed in vacuo to yield the title compound as an off-white solid (133mg, 41%).

1H NMR (250 MHz, DMSO-d6) δ 7.95 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 6.6 Hz, 1H), 7.65 - 7.55 (m, 3H), 7.35 (dt, J = 8.1, 4.0 Hz, 1H), 7.22 - 7.01 (m, 4H), 4.01 - 3.73 (m, 2H), 3.52 (s, 2H), 3.22 - 3.06 (m, 8H), 3.06 - 2.87 (m, 2H), 2.68 - 2.55 (m, 4H), 2.35 (s, 3H), 2.23 (s, 3H).

LCMS Method 6 - Tr = 2.23 min (ES+) (M+H)+ 538.4 Example 177. Synthesis of 2-[4-({5-[4-(2-Cyano-4,5-difluorophenyl)piperazine-l-carbony l]- 2,4-dimethylphenyl}methyl)piperazin-l-yl]-4,5-difluorobenzon itrile, 1-129

1-129

[001013] 5-{[4-(2-Cyano-4,5-difluorophenyl)piperazin-l-yl]methyl}-2,4 -dimethylbenzoic acid [Intermediate 63] (45 mg, 0.12 mmol) and HATU (53 mg, 0.14 mmol) were suspended in DMF (1 ml) and stirred at room temperature for 15 min. 4,5-Difluoro-2-(piperazin-l- yl)benzonitrile dihydrochloride [Amine 6] (43 mg, 0.13 mmol) and DIPEA (61 μΐ, 0.35 mmol) were then added and the reaction stirred at room temperature for 1 hour. The reaction was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and the solvents removed in vacuo to yield the title compound as a white solid (26 mg, 37%).

1H MR (500 MHz, Chloroform-d) δ 7.44 - 7.39 (m, 1H), 7.39 - 7.34 (m, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 6.84 (dd, J = 11.5, 6.8 Hz, 1H), 6.79 (dd, J = 11.9, 6.8 Hz, 1H), 4.07 - 3.99 (m, 2H), 3.59 - 3.42 (m, 4H), 3.25 - 3.17 (m, 2H), 3.19 - 3.11 (m, 4H), 3.10 - 3.01 (m, 2H), 2.69 - 2.61 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H)

LCMS Method 7 - Tr = 2.86 min (ES+) (M+H)+ 591.3

Example 178. Synthesis of 2-[4-({5-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]-4,5-difluorobenzonitri le, 1-128

1-128

[001014] 5 - { [4-(2-Cyano-4, 5 -difluorophenyl)piperazin- 1 -yljmethyl } -2,4-dimethylb enzoic acid [Intermediate 63] (45 mg, 0.12 mmol) and HATU (53 mg, 0.14 mmol) were suspended in Ν,Ν-dimethylformamide (1 ml) and stirred at room temperature for 15 min. 2-(Piperazin-l- yl)benzonitrile [Amine 72] (24 mg, 0.13 mmol) and DIPEA (61 μΐ, 0.35 mmol) were then added and the reaction was stirred at room temperature for 1 hour. The reaction was purified by UV- Directed High pH preparative HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a white powdery solid (21.0 mg, 31%).

1H MR (500 MHz, Chloroform-d) δ 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.39 - 7.34 (m, 1H), 7.11 (s, 1H), 7.07 (td, J = 7.6, 0.8 Hz, 1H), 7.04 (s, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.79 (dd, J = 12.0, 6.8 Hz, 1H), 4.07 - 4.01 (m, 2H), 3.58 - 3.45 (m, 4H), 3.29 - 3.23 (m, 2H), 3.16 - 3.07 (m, 6H), 2.68 - 2.61 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.71 min (ES+) (M+H ⁺ ) 555.3

Example 179. Synthesis of 2-[4-(5-{[l-(2-Cyanophenyl)piperidin-4-yl]oxy}-2,4- dimethylbenzoyl)piperazin- 1-yl] benzonitrile, 1-114

1-114

[001015] 2-[4-(5-Hydroxy-2,4-dimethylbenzoyl)piperazin-l-yl]benzonitr ile [Intermediate 66] (25 mg, 0.07 mmol) and 2-(4-hy droxypiperi din- 1-yl )benzonitrile [Intermediate 59] (16 mg, 0.07 mmol) were suspended in toluene (5 ml) under nitrogen. CMBP (23 μΐ, 0.09 mmol) was added and the reaction was stirred at 100 °C for 18 hours. The reaction was concentrated in vacuo. The residue was partitioned between DCM (20 ml) and water (20 ml). The organics were separated and the aqueous phase extracted with DCM (2 x 20 ml). The combined organics were concentrated in vacuo. The residue was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and the solvents removed in vacuo to yield the title compound as a white solid (37 mg, 93%).

1H MR (500 MHz, Chloroform-d) δ 7.62 - 7.54 (m, 2H), 7.54 - 7.45 (m, 2H), 7.10 - 7.06 (m, 1H), 7.05 - 6.97 (m, 4H), 6.70 (s, 1H), 4.53 - 4.45 (m, 1H), 4.11 - 3.95 (m, 2H), 3.53 - 3.33 (m, 4H), 3.32 - 3.04 (m, 6H), 2.23 (s, 6H), 2.21 - 1.99 (m, 4H). LCMS Method 7 - Tr = 4.44 min (ES+) (M+H)+ 520.3

Example 180. Synthesis of 4-(2-Cyanophenyl)-l-({5-[4-(2-cyanophenyl)piperazine-l- carbonyl]-2,4 dimethylphenyljmethyl)- piperazin-l-ium-l-olate formate, 1-92

1-92

[001016] 3-Chloroperoxybenzoic acid (7.2 mg, 0.042 mmol) was dissolved in acetone (0.7 ml) and added in one portion to 2-[4-({5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile [1-243] (20.5 mg, 0.04 mmol) in acetone (0.8 ml) at 20 °C. The resulting solution was stirred for 40 minutes then left to stand overnight. The reaction was purified by UV-Directed High pH preparative HPLC to yield the title compound as the formate salt and as a colourless glass (19.7 mg 86%).

1H MR (500 MHz, Methanol-d4) δ 8.22 (s, 1H), 7.72 - 7.57 (m, 4H), 7.47 (s, 1H), 7.33 (s, 1H), 7.31 - 7.25 (m, 1H), 7.25 - 7.11 (m, 3H), 4.83 - 4.63 (d, 2H), 4.19 - 3.94 (m, 2H), 3.94 - 3.82 (m, 2H), 3.72 - 3.59 (m, 2H), 3.59 - 3.40 (m, 6H), 3.33 - 3.27 (m, 2H), 3.26 - 3.10 (m, 2H), 2.59 (s, 3H), 2.36 (s, 3H).

LCMS Method 7 - Tr = 2.52 min (ES+) (M+H)+ 535.3

Example 181. Synthesis of 2-(4-{3-[4-(2-Cyanophenyl)piperazin-l-yl]-l-oxo-2,3-dihydro- lH-isoindole-5-carbonyl}piperazin-l-yl)benzonitrile, 1-79

1-79

[001017] 2-[4-(3-Chloro-l-oxo-2,3-dihydro-lH-isoindole-5-carbonyl)pip erazin-l- yljbenzonitrile [Intermediate 70] (60 mg, 0.16 mmol) was stirred with dry acetonitrile (1 ml) and a solution of 2-(piperazin-l-yl)benzonitrile [Amine 72] (59 mg, 0.32 mmol) and DIPEA (137 μΐ) in acetonitrile (1 ml) was added at 0 °C. After stirring overnight at 20 °C the mixture was concentrated in vacuo and the residue was purified by UV-Directed High pH preparative HPLC to yield the title product as a white solid (5.2 mg, 6% yield).

1H MR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.80 - 7.75 (m, 1H), 7.73 (dd, J = 7.7, 1.5 Hz, 1H), 7.69 (dd, J = 7.7, 1.5 Hz, 1H), 7.66 - 7.56 (m, 4H), 7.25 - 7.05 (m, 4H), 5.76 (s, 1H), 5.61 (s, 1H), 3.85 (s, 2H), 3.51 (s, 2H), 3.27 (s, 2H), 3.20 - 3.10 (m, 6H), 2.82 - 2.70 (m, 2H), 2.58 - 2.53 (m, 2H).

LCMS Method 7 - Tr = 3.12 min (ES+) (M+H)+ 532.3

Example 182. Synthesis of 2-(4-{[5-(4-{2-[Imino(methyl)oxo- ⁶ -sulfanyl]phenyl}piperazine- l-carbonyl)-2,4-dimethylphenyl]methyl}piperazin-l-yl)benzoni trile, 1-72

1-72

[001018] tert-Butyl N-({2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]phenyl} (methyl)oxo- ⁶ -sulfanylidene)carbamate [Intermediate 74] (180 mg, 0.268 mmol) was suspended in HC1 (4M in 1,4-dioxane, 4 ml) and subjected to sonication for 30 min then stirred for 1 hour at room temperature. The reaction was concentrated to dryness and then redissolved in methanol and loaded onto an SCX-2 column. The column was washed with 1 : 1 DCM/MeOH (30 ml) then 7N ¼ in MeOH (30 ml) was eluted through the column and this fraction concentrated in vacuo to afford the title compound as a viscous yellow oil (150 mg, 98%).

lH MR (500 MHz, Chloroform-d) δ 8.05 (dd, J = 7.9, 1.5 Hz, 1H), 7.59 (td, J = 7.9, 1.6 Hz, 1H), 7.55 (dd, J = 7.8, 1.5 Hz, 1H), 7.46 (td, J = 8.2, 1.6 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.13 (s, 1H), 7.04 (s, 1H), 6.99 (t, J = 7.6 Hz, 2H), 3.42 (s, 7H), 3.38 - 2.68 (m, 10H), 2.69 - 2.61 (m, 4H), 2.36 (s, 3H), 2.31 (s, 3H).

LCMS Method 7 - Tr = 1.95 min (ES+) (M+H)+ 571

Example 183. Synthesis of 2-(4-{5-[4-(2-Cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylbenzenecarbothioyl}piperazin-l-yl)benzonitrile, 1-58

1-58

[001019] 5-[4-(2-Cyanophenyl)piperazine-l-carbothioyl]-2,4-dimethylbe nzoic acid [Intermediate 71] (56 mg, 0.15 mmol), 2-(piperazin-l-yl)benzonitrile [Amine 72] (27 μΐ, 0.16 mmol) and HATU (67 mg, 0.18 mmol) were suspended in anhydrous DMF (1 ml) then the reaction was stirred at ambient temperature for 18 hours. The reaction was partitioned between DCM (10 ml) and water (5 ml) then the organics were separated and concentrated in vacuo. The residue was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a pale yellow glass (21.4 mg, 26%). 1H MR (500 MHz, Chloroform-d) δ 7.59 (td, J = 7.7, 1.5 Hz, 2H), 7.55 - 7.48 (m, 2H), 7.13 - 7.05 (m, 3H), 7.01 (s, 2H), 6.99 (s, 1H), 5.05 (d, J = 11.8 Hz, 1H), 4.24 (s, 1H), 4.08 (s, 1H), 3.98 - 3.89 (m, 1H), 3.75 (d, J = 12.9 Hz, 1H), 3.69 - 3.59 (m, 1H), 3.49 (ddd, J = 23.6, 16.5, 10.5 Hz, 3H), 3.33 - 3.26 (m, 2H), 3.22 (ddd, J = 11.5, 7.4, 3.2 Hz, 2H), 3.06 (d, J = 29.9 Hz, 3H), 2.32 (s, 3H), 2.27 (s, 3H). LCMS Method 7 - Tr = 3.94 min (ES+) (M+H ⁺ ) 549.2

Example 184. Synthesis of 2-(4-{[5-(4-{2-[(R or S)-Imino(methyl)oxo- ⁶ - sulfanyl]phenyl}piperazine-l-carbonyl)-2,4-dimethylphenyl]me thyl}piperazin-l- yl)benzonitrile, 1-37 and

2-(4-{[5-(4-{2-[(S or R)-Imino(methyl)oxo- ⁶ -sulfanyl]phenyl}piperazine-l-carbonyl)-2,4- dimethylphenyl]methyl}piperazin-l-yl)benzonitrile, 1-36

I-36 I-37

[001020] 2-(4-{[5-(4-{2-[Imino(methyl)oxo- ⁶ -sulfanyl]phenyl}piperazine-l-carbonyl)- 2,4-dimethylphenyl]methyl} piperazin-l-yl)benzonitrile was dissolved to 15 mg/ml in ethanol and was then purified by chiral HPLC. Combined fractions of peak 1 at 8.17min were then evaporated to near dryness using a rotary evaporator, transferred into final vessels with DCM, which was removed under a stream of nitrogen at 40 °C before being stored in a vacuum oven at 40 °C and 5 mbar for 16 hours. The yellow gum was dissolved in 4: 1 acetonitrile / water (2 ml) and lyophilised, followed by oven drying at 40 °C to obtain the title compound as a straw coloured powder (55 mg, 36%).

Separation conditions:

Column Details: Lux CI (21.2mm x 250mm, 5um)

Column Temperature: Ambient

Flow Rate: 21 ml/min

Detector Wavelength: 210 nm

Injection Volume: 700 μΐ (10.5 mg)

Isocratic Conditions: 40:60 HEPTANE :EtOH (0.1% v/v NH3) The stereochemistry was arbitrarily assigned

lH MR (500 MHz, Chloroform-d) δ 8.05 (dd, J = 7.9, 1.5 Hz, 1H), 7.58 (td, J = 7.8, 1.5 Hz, 1H), 7.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.46 (td, J = 8.2, 1.6 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.13 (s, 1H), 7.04 (s, 1H), 7.01 - 6.96 (m, 2H), 3.58 - 3.36 (m, 7H), 3.37 - 2.67 (m, 10H), 2.67 - 2.55 (m, 4H), 2.36 (s, 3H), 2.31 (s, 3H).

LCMS Method 7 - Tr = 1.95 min (ES+) (M+H)+ 571.2

2-(4-{[5-(4-{2-[Imino(methyl)oxo- ⁶ -sulfanyl]phenyl}piperazine-l-carbonyl)-2,4- dimethylphenyl] methyl} piperazin-l-yl)benzonitrile peak 2 at 10.11 min

The stereochemistry was arbitrarily assigned

lH MR (500 MHz, Chloroform-d) δ 8.05 (dd, J = 7.9, 1.5 Hz, 1H), 7.58 (td, J = 7.8, 1.5 Hz, 1H), 7.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.46 (td, J = 8.2, 1.6 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.13 (s, 1H), 7.04 (s, 1H), 7.01 - 6.95 (m, 2H), 3.56 - 3.38 (m, 7H), 3.37 - 2.69 (m, 10H), 2.69 - 2.59 (m, 4H), 2.36 (s, 3H), 2.31 (s, 3H).

LCMS Method 7 - Tr = 1.96 min (ES+) (M+H)+ 571.2

Example 185. Synthesis of 2-[4-({5-[(2S)-4-{2-[Imino(methyl)oxo- ⁶ -sulfanyl]phenyl}-2- methylpiperazine-l-carbonyl]-2,4-dimethylphenyl}methyl)piper azin-l-yl]benzonitrile, 1-29

1-29

[001021] The title compound was prepared according to the generic method in Example 153 using 5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4-dimethylbenz oic acid [Intermediate C] (124.12 mg, 0.36 mmol) and imino(methyl){2-[(3S)-3-methylpiperazin-l-yl]phenyl}- ⁶ - sulfanone [Amine 30] (90 mg, 0.36 mmol) to yield an off-white powder (30 mg, 14%).

1H VT- MR (250 MHz, DMSO-d6) δ 8.05 - 7.98 (m, 1H), 7.67 - 7.50 (m, 4H), 7.42 - 7.32 (m, 1H), 7.18 - 7.02 (m, 4H), 4.06 - 3.93 (m, 1H), 3.54 (s, 2H), 3.44 - 3.24 (m, 5H), 3.24 - 3.06 (m, 7H), 2.81 - 2.57 (m, 6H), 2.39 - 2.33 (m, 3H), 2.28 - 2.22 (m, 3H), 1.44 - 1.34 (m, 3H).

LCMS Method 7 - Tr = 2.00 & 2.02 min (ES+) (M+H)+ 585.2 Example 186. Synthesis of 2-[4-({5-[3-(Hydroxymethyl)-4-phenylpiperazine-l-carbonyl]- 2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-16

1-16

[001022] 5-{[4-(2-Cyanophenyl)piperazin-l-yl]methyl}-2,4-dimethylbenz oic acid (35 mg, 0.1 mmol) [Intermediate C], (l-phenylpiperazin-2-yl)methanol [Amine 56] (21.18 mg, 0.11 mmol) and HATU (45.7 mg, 0.12 mmol) were suspended in anhydrous DMF (0.9 ml) then the reaction was stirred at ambient temperature for 18 hours. The reaction mixture was purified by UV-Directed High pH preparative HPLC. The fractions containing product were combined and reduced in vacuo to yield the title compound as a white crystalline solid (27.4 mg, 51%).

1H MR (500 MHz, DMSO-d6) δ 7.68 (d, J = 7.3 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.20 (t, J = 7.4 Hz, 2H), 7.17 - 7.11 (m, 1H), 7.11 - 7.04 (m, 3H), 6.89 (d, J = 6.1 Hz, 2H), 6.73 (t, J = 7.2 Hz, 1H), 4.77 - 4.53 (m, 1H), 4.34 (d, J = 151.8 Hz, 1H), 3.85 (s, 1H), 3.62 - 3.44 (m, 4H), 3.34 (s, 2H), 3.22 (d, J = 9.7 Hz, 1H), 3.13 (s, 5H), 2.92 (s, 1H), 2.57 (s, 4H), 2.34 (d, J = 3.8 Hz, 3H), 2.18 (s, 3H).

1H VT- MR (250 MHz, DMSO-d6, 353K) δ 7.63 (dd, J = 7.6, 1.6 Hz, 1H), 7.61 - 7.52 (m, 1H), 7.25 - 7.11 (m, 3H), 7.11 - 7.02 (m, 3H), 6.91 (d, J = 8.0 Hz, 2H), 6.75 (t, J = 7.2 Hz, 1H), 4.34 (s, 2H), 3.71 (s, 3H), 3.53 (s, 2H), 3.48 - 3.26 (m, 5H), 3.23 - 3.13 (m, 4H), 2.65 - 2.56 (m, 4H), 2.35 (s, 3H), 2.21 (s, 3H).

LCMS Method 7 - Tr = 2.31 min (ES+) (M+H ⁺ ) 524.2

Example 187. Synthesis of 2-[4-(5-{[(3S or R)-3-[(2-Cyanophenyl)amino]pyrrolidin-l- yl]methyl}-2,4-dimethylbenzoyl)piperazin-l-yl]benzonitrile, 1-15 and

2-[4-(5-{[(3R or S)-3-[(2-Cyanophenyl)amino]pyrrolidin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin- 1-yl] benzonitrile, 1-14

I-14 I-15

[001023] 2-{4-[5-({3-[(2-Cyanophenyl)amino]pyrrolidin-l-yl}methyl)-2, 4- dimethylbenzoyl]piperazin-l-yl}benzonitrile [1-55] was dissolved to 22 mg/ml in methanol and was then purified by chiral HPLC. Combined fractions of peak 1 at 6.728 min were then evaporated to near dryness using a rotary evaporator, transferred into final vessels with DCM, which was removed under a stream of nitrogen at 40 °C before being stored in a vacuum oven at 40 °C and 5 mbar for 16 hours to yield a yellow oil. The oil was then lyophilised for 16 hrs to give the title compound as a white solid (13 mg).

Separation Conditions:

Column Details: Lux Al (21.2mm x 250mm, 5um)

Column Temperature: Ambient

Flow Rate: 21 ml/min

Detector Wavelength: 220 nm

Injection Volume: 1000 μΐ (15 mg)

Isocratic Conditions: 40:60 HEPTANE :EtOH (0.1% v/v H3)

The stereochemistry was arbitrarily assigned

1H MR (500 MHz, Chloroform-d) δ 7.58 (dd, J = 7.7, 1.5 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.38 -

7.29 (m, 2H), 7.14 - 6.99 (m, 4H), 6.66 - 6.57 (m, 2H), 4.73 (d, J = 7.2 Hz, 1H), 4.11 - 3.94 (m, 3H), 3.59 (s, 2H), 3.51 - 3.40 (m, 2H), 3.33 - 3.19 (m, 2H), 3.14 - 3.00 (m, 2H), 2.88 - 2.69 (m, 2H), 2.56 (d, J = 8.2 Hz, 1H), 2.52 - 2.40 (m, 1H), 2.36 (s, 4H), 2.28 (s, 3H), 1.71 (s, 1H).

LCMS (LCMS Method 7) Tr = 2.53 min (ES+) (M+H)+ 519.2

2-{4-[5-({3-[(2-Cyanophenyl)amino]pyrrolidin-l-yl}methyl)-2, 4-dimethylbenzoyl]piperazin-l- yl}benzonitrile 1-55 peak 2 at 9.789 min

The stereochemistry was arbitrarily assigned

1H MR (500 MHz, Chloroform-d) δ 7.58 (dd, J = 7.7, 1.5 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.38 -

7.30 (m, 2H), 7.14 - 6.99 (m, 4H), 6.66 - 6.57 (m, 2H), 4.73 (d, J = 7.0 Hz, 1H), 4.11 - 3.94 (m, 3H), 3.59 (s, 2H), 3.51 - 3.41 (m, 2H), 3.34 - 3.18 (m, 2H), 3.14 - 3.01 (m, 2H), 2.90 - 2.71 (m, 2H), 2.56 (d, J = 7.4 Hz, 1H), 2.53 - 2.40 (m, 1H), 2.39 - 2.24 (m, 7H), 1.70 (s, 1H).

LCMS Method 7 - Tr = 2.54 min (ES+) (M+H)+ 519.2

Example 188. Synthesis of 2-(4-{[5-(4-{2-[Imino(methyl)oxo- ⁶ -sulfanyl]pyridin-3- yl}piperazine-l-carbonyl)-2,4-dimethylphenyl]methyl}piperazi n-l-yl)benzonitrile, 1-13

1-13

[001024] 5-{[4-(2-Cyanophenyl)piperazin-l-yl]methyl}-2,4-dimethylbenz oic acid [Intermediate C] (40 mg, 0.116 mmol) was dissolved in DCM (1 ml) then oxalyl chloride (10 μΐ, 0.116 mmol) was added followed by DMF (10 μΐ) and the reaction was stirred at room temperature for 30 min. Imino(methyl)[3-(piperazin-l-yl)pyridin-2-yl]- ⁶ -sulfanone hydrochloride [Amine 32] (32 mg, 0.116 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. DCM (3 ml) and water (3 ml) were added to the reaction mixture and the phases separated. The organics were concentrated in vacuo and the residue was then purified by preparative HPLC (basic pH). The fractions containing product were lyophilised to afford the title compound as a white solid (2 mg, 3%).

1H NMR (500 MHz, Chloroform-d) δ 8.52 (dd, J = 4.8, 1.8 Hz, 1H), 8.36 (dd, J = 7.8, 1.8 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.27 - 7.24 (m, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 7.00 - 6.97 (m, 2H), 4.13 - 3.90 (m, 2H), 3.54 - 3.43 (m, 4H), 3.42 - 3.31 (m, 5H), 3.26 - 3.13 (m, 6H), 3.06 - 2.93 (m, 1H), 2.68 - 2.62 (m, 4H), 2.36 (s, 3H), 2.30 (s, 3H).

LCMS Method 6 - Tr = 3.50 min (ES+) (M+H)+ 350

Example 189. Synthesis of 2-[4-({5-[(2S)-4-{2-[(R or S)-Imino(methyl)oxo- ⁶ - sulfanyl]phenyl}-2-methylpiperazine-l-carbonyl]-2,4-dimethyl phenyl}methyl)piperazin-l- yl]benzonitrile, 1-12 and 2-[4-({5-[(2S)-4-{2-[(S or R)-Imino(methyl)oxo- ⁶ -sulfanyl]phenyl}-2-methylpiperazine-l- carbonyl]-2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitr ile, I-ll

1-11 1-12

20mg of a mixture of diastereoisomers, 2-(4-{[5-(4-{2-[Imino(methyl)oxo- ⁶ - sulfanyl] phenyl }piperazine- 1 -carbonyl)-2,4-dimethylphenyl]methyl } piperazin- 1 -yl)benzonitrile, was separated using achiral HPLC. Combined fractions of peakl at 14.1 min were then evaporated to near dryness using a rotary evaporator yield 1-12, and the combined fractions of peak2 at 15.0 min were then evaporated to near dryness using a rotary evaporator yield I-l l . The solids were dissolved in 4: 1 acetonitrile / water (2 ml) and Lyophilised, followed by oven drying at 40°C to obtain the title compounds as a white powders (3 mg, 15%)

Separation conditions:

Column Details: Waters Sunfire (19mm x 100mm, lOOum) column

Column Temperature: Ambient

Flow Rate: 20 ml/min

Gardient Conditions: Solvent A - Water + 0.1% formic acid

Solvent B - Acetonitrile + 0.1% formic acid.

2-[4-({5-[(2S)-4-{2-[(R or S)-Imino(methyl)oxo- ⁶ -sulfanyl]phenyl}-2-methylpiperazine-l- carbonyl]-2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitr ile peak 1 at 14.1 min

The stereochemistry was arbitrarily assigned

1H NMR (250 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.02 (dd, J = 7.9, 1.5 Hz, 1H), 7.70 - 7.46 (m, 4H), 7.43 - 7.27 (m, 1H), 7.20 - 6.99 (m, 4H), 4.05 - 3.87 (m, 1H), 3.54 (s, 2H), 3.42 - 3.28 (m, 4H), 3.27 - 3.07 (m, 8H), 2.88 - 2.54 (m, 6H), 2.35 (s, 3H), 2.23 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). LCMS Method 7 - Tr = 2.01 min (ES+) (M+H)+ 585.2 2-[4-({5-[(2S)-4-{2-[(S or R)-Imino(methyl)oxo- ⁶ -sulfanyl]phenyl}-2-methylpiperazine-l- carbonyl]-2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitr ile peak 2 at 15.0 min

The stereochemistry was arbitrarily assigned

1H NMR (250 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.01 (dd, J = 7.9, 1.5 Hz, 1H), 7.69 - 7.45 (m, 4H), 7.44 - 7.30 (m, 1H), 7.22 - 7.00 (m, 4H), 4.11 - 3.96 (m, 1H), 3.54 (s, 2H), 3.42 - 3.27 (m, 5H), 3.25 - 3.08 (m, 6H), 2.80 - 2.57 (m, 7H), 2.35 (s, 3H), 2.25 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H). LCMS Method 7 - Tr = 2.03 min (ES+) (M+H)+ 585.2

Example 190. Synthesis of 2-[(3S)-4-({5-[(2S)-4-{2-[Imino(methyl)oxo- ⁶ -sulfanyl]phenyl}- 2-methylpiperazine-l-carbonyl]-2,4-dimethylphenyl}methyl)-3- methylpiperazin-l- yl]benzonitrile, I- 10

1-10

[001025] The title compound was prepared according to the generic method in Example 153 using 2,4-dimethyl-5-{[(2S)-2-methyl-4-phenylpiperazin-l-yl]methyl }benzoic acid

[Intermediate 76] (124.12 mg, 0.36 mmol) and imino(methyl){2-[(3S)-3-methylpiperazin-l- yl]phenyl}- ⁶ -sulfanone [Amine 6] (90 mg, 0.36 mmol) to yield an off-white glass (30 mg, 14%). 1H NMR (250 MHz, DMSO-d6) δ 8.05 - 7.96 (m, 1H), 7.69 - 7.49 (m, 4H), 7.43 - 7.30 (m, 1H), 7.19 - 6.99 (m, 4H), 4.09 - 3.90 (m, 2H), 3.42 - 3.09 (m, 10H), 2.96 - 2.58 (m, 7H), 2.41 - 2.32 (m, 4H), 2.26 - 2.20 (m, 3H), 1.52 (s, 1H), 1.45 - 1.33 (m, 3H), 1.25 - 1.15 (m, 3H).

LCMS Method 7 - Tr = 2.10 min (ES+) (M+H)+ 599

Example 191. Synthesis of 2-[4-({5-[(3S or R)-3-[(2-Cyanophenyl)amino]pyrrolidine-l- carbonyl]-2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitr ile, 1-7 and

2-[4-({5-[(3R or S)-3-[(2-Cyanophenyl)amino]pyrrolidine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-6

I-6 I-7

[001026] 2-{4-[(5-{3-[(2-Cyanophenyl)amino]pyrrolidine-l-carbonyl}-2, 4- dimethylphenyl)methyl]piperazin-l-yl}benzonitrile [1-51] was dissolved to 19 mg/ml in methanol and was then purified by chiral HPLC. Combined fractions of peak 1 at 6.680 min were then evaporated to near dryness using a rotary evaporator, transferred into final vessels with DCM, which was removed under a stream of nitrogen at 40 °C before being stored in a vacuum oven at 40 °C and 5 mbar for 16 hours to yield a yellow oil. The oil was then lyophilised for 16 hours to give the title compound as a white solid (8 mg, 80%).

Separation Conditions:

Column Details: Lux Al (21.2mm x 250mm, 5um)

Column Temperature: Ambient

Flow Rate: 21 ml/min

Detector Wavelength: 220 nm

Injection Volume: 1000 μΐ (19 mg)

Isocratic Conditions: 40:60 HEPTANE :EtOH (0.1% v/v H3)

The stereochemistry was arbitrarily assigned

1H MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.8, 1.7 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.39 - 7.33 (m, 1H), 7.16 (d, J = 15.0 Hz, 1H), 7.07 - 6.95 (m, 3H), 6.79 - 6.56 (m, 2H), 4.54 (dd, J = 34.4, 6.1 Hz, 1H), 4.26 - 4.03 (m, 2H), 3.97 - 3.74 (m, 1H), 3.72 - 3.56 (m, 1H), 3.55 - 3.29 (m, 3H), 3.25 - 3.18 (m, 2H), 3.18 - 3.10 (m, 2H), 2.72 - 2.58 (m, 4H), 2.32 (dd, J = 28.3, 12.9 Hz, 7H), 2.11 - 1.95 (m, 1H).

LCMS Method 7 - Tr = 2.47 min (ES+) (M+H)+ 519.2

[001027] 2-{4-[(5-{3-[(2-cyanophenyl)amino]pyrrolidine-l-carbonyl}-2, 4- dimethylphenyl)methyl]piperazin-l-yl}benzonitrile [1-51] peak 2 at 8.108 min

The stereochemistry was arbitrarily assigned

1H MR (500 MHz, Chloroform-d) δ 7.58 - 7.52 (m, 1H), 7.50 - 7.40 (m, 2H), 7.39 - 7.32 (m, 1H), 7.16 (d, J = 15.0 Hz, 1H), 7.07 - 6.93 (m, 3H), 6.80 - 6.54 (m, 2H), 4.54 (dd, J = 34.3, 6.2 Hz, 1H), 4.26 - 3.29 (m, 7H), 3.26 - 3.08 (m, 4H), 2.64 (dt, J = 17.0, 4.1 Hz, 4H), 2.48 - 2.26 (m, 7H), 2.08 - 1.97 (m, 1H).

LCMS Method 7 - Tr = 2.47 min (ES+) (M+H)+ 519.2

[001028] The following compounds were synthesised from the indicated acid [Intermediate Acid] and amine [Intermediate Amine] using the method described in Example 153 for [1-243] to afford the final compounds.

Example 192. Synthesis of 2-[4-({4-methyl-3-[4-(pyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-327

1-327

[001029] Prepared using the HATU generic method with Intermediate A and Amine 83. 1H MR (500 MHz, Chloroform-d) δ 8.21 - 8.17 (m, 1H), 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.29 - 7.26 (m, 1H), 7.21 - 7.18 (m, 2H), 7.01 - 6.97 (m, 2H), 6.69 - 6.65 (m, 2H), 3.98 - 3.92 (m, 2H), 3.67 - 3.62 (m, 2H), 3.56 (s, 2H), 3.53 - 3.47 (m, 2H), 3.41 - 3.33 (m, 2H), 3.25 - 3.19 (m, 4H), 2.68 - 2.62 (m, 4H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 2.48 min

m/z value = 481

Example 193. Synthesis of 2-[4-({4-methyl-3-[4-(6-methylpyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-326

1-326

[001030] Prepared using the HATU generic method with Intermediate A and Amine 3. 1H MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.42 - 7.38 (m, 1H), 7.29 - 7.26 (m, 1H), 7.21 - 7.18 (m, 2H), 7.01 - 6.96 (m, 2H), 6.54 (d, J = 7.3 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 3.97 - 3.91 (m, 2H), 3.65 - 3.60 (m, 2H), 3.56 (s, 2H), 3.53 - 3.45 (m, 2H), 3.41 - 3.32 (m, 2H), 3.25 - 3.19 (m, 4H), 2.69 - 2.62 (m, 4H), 2.38 (s, 3H), 2.32 (s, 3H). LCMS Method 7 - Tr = 2.68 min

m/z value = 495

Example 194. Synthesis of 2-(4-{[4-methyl-3-(4-phenylpiperazine-l- carbonyl)phenyl]methyl}piperazin-l- l)benzonitrile, 1-325

1-325

[001031] Prepared using the HATU generic method with Intermediate A and Amine 71. 1H MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.30 - 7.26 (m, 3H), 7.21 - 7.18 (m, 2H), 7.01 - 6.97 (m, 2H), 6.95 - 6.89 (m, 3H), 4.05 - 3.91 (m, 2H), 3.62 - 3.51 (m, 2H), 3.41 (s, 2H), 3.31 - 3.24 (m, 2H), 3.24 - 3.19 (m, 4H), 3.15 - 3.02 (m, 2H), 2.69 - 2.60 (m, 4H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 3.23 min

m/z value = 480

Example 195. Synthesis of 2-[4-({4-methyl-3-[(2S)-2-methyl-4-(pyridin-2-yl)piperazine- l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-321

1-321

[001032] Prepared using the HATU generic method with Intermediate A and Amine 65. 1H MR (250 MHz, DMSO-d6) δ 8.15 - 8.06 (m, 1H), 7.69 - 7.48 (m, 3H), 7.32 - 7.22 (m, 2H), 7.20 - 7.12 (m, 2H), 7.07 (td, J = 7.5, 1.0 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 6.67 - 6.59 (m, 1H), 4.28 - 4.04 (m, 2H), 3.59 (s, 2H), 3.38 - 3.08 (m, 6H), 3.01 - 2.75 (m, 3H), 2.65 - 2.56 (m, 4H), 2.24 (s, 3H), 1.21 (d, J = 6.5 Hz, 3H).

LCMS Method 7 - Tr = 2.49 min

m/z value = 495

Example 196. Synthesis of 2-[4-({4-methyl-3-[(2S)-2-methyl-4-phenylpiperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-320

1-320

[001033] Prepared using the HATU generic method with Intermediate A and Amine 66. 1H MR (250 MHz, DMSO-d6) δ 7.69 - 7.50 (m, 2H), 7.31 - 7.11 (m, 6H), 7.07 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 7.9 Hz, 2H), 6.79 (t, J = 7.3 Hz, 1H), 3.69 - 3.41 (m, 4H), 3.32 (s, 1H), 3.24 - 3.15 (m, 4H), 3.01 - 2.64 (m, 4H), 2.63 - 2.56 (m, 4H), 2.24 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H). LCMS Method 7 - Tr = 3.38 min

m/z value = 494

Example 197. Synthesis of 2-[4-({4-methyl-3-[4-(4-methylpyrimidin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-317

1-317

[001034] Prepared using the HATU generic method with Intermediate A and Amine 14. 1H MR (500 MHz, DMSO-d6) δ 8.23 (d, J = 4.9 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.31 - 7.24 (m, 2H), 7.19 - 7.14 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 6.56 (d, J = 4.9 Hz, 1H), 3.89 - 3.80 (m, 2H), 3.78 - 3.65 (m, 4H), 3.56 (s, 2H), 3.25 - 3.18 (m, 2H), 3.18 - 3.11 (m, 4H), 2.60 - 2.54 (m, 4H), 2.28 (s, 3H), 2.23 (s, 3H).

LCMS Method 7 - Tr = 2.08 min

m/z value = 496

Example 198. Synthesis of 2-[4-({3-[4-(3-cyanophenyl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-316

1-316

[001035] Prepared using the HATU generic method with Intermediate A and Amine 68.

1H MR (500 MHz, DMSO-d6) δ 7.69 (dd, J = 7.7, 1.5 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.43 - 7.38

(m, 1H), 7.36 (s, 1H), 7.31 - 7.25 (m, 3H), 7.22 - 7.14 (m, 3H), 7.09 (t, J = 7.5 Hz, 1H), 3.80 (s,

2H), 3.57 (s, 2H), 3.36 (d, J = 5.1 Hz, 2H), 3.28 (s, 2H), 3.19 (s, 2H), 3.17 - 3.12 (m, 4H), 2.56 (s,

4H), 2.23 (s, 3H).

LCMS Method 7 - Tr = 2.33 min

m/z value = 505

Example 199. Synthesis of 2-[4-({3-[(2S)-4-(2-cyanophenyl)-2-methylpiperazine-l- carbonyl]-4-methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-315

1-315

[001036] Prepared using the HATU generic method with Intermediate A and Amine 9.

1H MR (500 MHz, DMSO-d6) δ 7.73 (dd, J = 7.6, 1.4 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.60

(q, J = 8.5, 7.9 Hz, 2H), 7.30 - 7.24 (m, 2H), 7.17 (dd, J = 17.6, 8.3 Hz, 4H), 7.08 (t, J = 7.5 Hz,

1H), 4.90 (s, 1H), 4.55 (s, 1H), 3.64 - 3.38 (m, 4H), 3.26 (s, 1H), 3.15 (s, 4H), 3.02 (s, 1H), 2.85

(s, 1H), 2.56 (s, 4H), 2.26 (s, 2H), 2.19 (s, 1H), 1.52 - 1.27 (m, 3H).

LCMS Method 5 - Tr = 2.48 min

m/z value = 519, 521

Example 200. Synthesis of 2-{4-[(4-methyl-3-{4-[6-(propan-2-yl)pyridin-2-yl]piperazine -l- carbonyl}phenyl)methyl] piperazin- 1-yl} benzonitrile, 1-314

1-314

[001037] Prepared using the HATU generic method with Intermediate A and Amine 64. 1H MR (500 MHz, DMSO-d6) δ 7.69 (dd, J = 7.7, 1.5 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.49 - 7.43 (m, 1H), 7.26 (t, J = 6.9 Hz, 2H), 7.17 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 3.80 (s, 2H), 3.59 (s, 2H), 3.56 (s, 2H), 3.44 (s, 2H), 3.25 (s, 2H), 3.15 (s, 4H), 2.81 (p, J = 6.9 Hz, 1H), 2.56 (s, 4H), 2.22 (s, 3H), 1.15 (d, J = 6.9 Hz, 6H).

LCMS Method 5 - Tr = 2.07 min

m/z value = 523

Example 201. Synthesis of 2-[4-({3-[4-(4-fluorophenyl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-302

1-302

[001038] Prepared using the HATU generic method with Intermediate A and Amine 58. 1H MR (500 MHz, DMSO-d6) δ 7.69 (dd, J = 7.7, 1.5 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.30 - 7.24 (m, 2H), 7.17 - 7.13 (m, 2H), 7.11 - 7.02 (m, 3H), 7.00 - 6.94 (m, 2H), 3.80 (t, J = 4.9 Hz, 2H), 3.56 (s, 2H), 3.29 - 3.25 (m, 2H), 3.19 - 3.10 (m, 6H), 3.05 - 2.95 (m, 2H), 2.58 - 2.52 (m, 4H), 2.22 (s, 3H).

LCMS Method 5 - Tr = 2.42 min

m/z value = 498

Example 202. Synthesis of 2-[4-({3-[4-(3-chlorophenyl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-299

1-299

[001039] Prepared using the HATU generic method with Intermediate A and Amine 61. lH MR (500 MHz, DMSO-d6) 7.69 (dd, J = 7.7, 1.5 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.31 - 7.25 (m, 2H), 7.22 (t, J = 8.1 Hz, 1H), 7.18 - 7.14 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 2.1 Hz, 1H), 6.92 (dd, J = 8.4, 2.1 Hz, 1H), 6.82 (dd, J = 7.8, 1.4 Hz, 1H), 3.79 (s, 2H), 3.57 (s, 2H), 3.31 - 3.26 (m, 4H), 3.15 (d, J = 4.4 Hz, 6H), 2.56 (s, 4H), 2.23 (s, 3H).

LCMS Method 7 - Tr = 2.65 min

m/z value = 514, 516

Example 203. Synthesis of 2-[4-({3-[4-(5-fluoro-4-methylpyrimidin-2-yl)piperazine-l- carbonyl]-4-methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-291

1-291

[001040] Prepared using the HATU generic method with Intermediate A and Amine 54.

1H MR (500 MHz, DMSO-d6) 8.30 (d, J = 1.7 Hz, 1H), 7.68 (dd, J = 7.7, 1.6 Hz, 1H), 7.61 -

7.55 (m, 1H), 7.30 - 7.23 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.08 (t, J = 8.0 Hz, 1H), 3.78 (s, 4H),

3.62 (t, J = 5.2 Hz, 2H), 3.55 (s, 2H), 3.22 (s, 2H), 3.15 (s, 4H), 2.55 (s, 4H), 2.30 (d, J = 2.5 Hz,

3H), 2.22 (s, 3H).

LCMS Method 6 - Tr = 2.4 min

m/z value = 514

Example 204. Synthesis of 2-[4-({3-[4-(2-cyanophenyl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-289

1-289

[001041] Prepared using the HATU generic method with Intermediate A and Amine 72. 1H NMR (500 MHz, DMSO-d6) 7.73 (dd, J = 7.7, 1.6 Hz, 1H), 7.69 (dd, J = 7.7, 1.6 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.31 - 7.25 (m, 2H), 7.22 - 7.18 (m, 2H), 7.18 - 7.12 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 3.86 (s, 2H), 3.57 (s, 2H), 3.24 (s, 2H), 3.19 - 3.13 (m, 4H), 3.08 (d, J = 24.3 Hz, 2H), 2.57 (s, 4H), 2.53 (d, J = 1.9 Hz, 2H), 2.25 (s, 3H).

LCMS Method 6 - Tr = 2.33 min

m/z value = 505

Example 205. Synthesis of 2-[4-({4-methyl-3-[4-(4-methyl-l,3-thiazol-2-yl)piperazine-l - carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-278

1-278

[001042] Prepared using the HATU generic method with Intermediate A and Amine 62. lH MR (500 MHz, DMSO-d6) 7.69 (dd, J = 7.7, 1.6 Hz, 1H), 7.61 - 7.56 (m, 1H), 7.30 - 7.23 (m, 2H), 7.19 - 7.17 (m, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.11 - 7.06 (m, 1H), 6.42 (d, J = 1.1 Hz, 1H), 3.78 (d, J = 32.6 Hz, 2H), 3.55 (s, 2H), 3.48 (s, 2H), 3.33 (d, J = 4.0 Hz, 2H), 3.27 (d, J = 4.3 Hz, 2H), 3.18 - 3.11 (m, 4H), 2.56 (s, 4H), 2.22 (s, 3H), 2.13 (d, J = 0.9 Hz, 3H).

LCMS Method 6 - Tr = 1.77 min

m/z value = 501

Example 206. Synthesis of 6-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl] methylbenzoyl)piperazin-l-yl]pyridine-2-carbonitrile, 1-274

1-274

[001043] Prepared using the HATU generic method with Intermediate A and Amine 67.

1H MR (500 MHz, Chloroform-d) δ 7.58 - 7.54 (m, 2H), 7.50 - 7.46 (m, 1H), 7.30 (s, 1H), 7.24

- 7.19 (m, 2H), 7.02 (d, J = 7.1 Hz, 1H), 7.01 - 6.98 (m, 2H), 6.86 (d, J = 8.7 Hz, 1H), 3.94 (s,

2H), 3.73 - 3.67 (m, 2H), 3.66 - 3.52 (m, 4H), 3.38 (s, 2H), 3.31 - 3.18 (m, 4H), 2.78 - 2.57 (m,

4H), 2.32 (s, 3H).

LCMS Method 6 - Tr = 2.31 min

m/z value = 506

Example 207. Synthesis of 2-[4-({3-[4-(5-chloropyridin-2-yl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-273

1-273

[001044] Prepared using the HATU generic method with Intermediate A and Amine 60. 1H NMR (500 MHz, Chloroform-d) δ 8.12 - 8.10 (m, 1H), 7.57 - 7.53 (m, 1H), 7.50 - 7.43 (m, 2H), 7.29 (d, J = 7.5 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.02 - 6.96 (m, 2H), 6.64 - 6.58 (m, 1H), 3.96 - 3.90 (m, 2H), 3.65 - 3.54 (m, 4H), 3.51 - 3.43 (m, 2H), 3.40 - 3.32 (m, 2H), 3.28 - 3.19 (m, 4H), 2.74 - 2.61 (m, 4H), 2.32 (s, 3H).

LCMS Method 6 - Tr = 2.45 min

m/z value = 515, 517

Example 208. Synthesis of 6-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl] methylbenzoyl)piperazin-l-yl]pyridine-3-carbonitrile, 1-271

1-271

[001045] Prepared using the HATU generic method with Intermediate A and Amine 69. 1H NMR (500 MHz, Chloroform-d) δ 8.42 - 8.41 (m, 1H), 7.65 (dd, J = 9.0, 2.3 Hz, 1H), 7.55 (dd, J = 7.6, 1.5 Hz, 1H), 7.50 - 7.45 (m, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.22 (d, J = 7.9 Hz, 2H), 7.04 - 6.97 (m, 2H), 6.63 (d, J = 9.0 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.83 - 3.77 (m, 2H), 3.69 - 3.56 (m, 4H), 3.42 - 3.33 (m, 2H), 3.32 - 3.19 (m, 4H), 2.75 - 2.59 (m, 4H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 2.11 min

m/z value = 506

Example 209. Synthesis of 2-[4-({4-methyl-3-[4-(5-methylpyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-261

1-261

[001046] Prepared using the HATU generic method with Intermediate A and Amine 63. 1H MR (500 MHz, Chloroform-d) δ 8.02 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.51

- 7.44 (m, 1H), 7.34 (dd, J = 8.6, 2.4 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.21 (d, J = 5.2 Hz, 2H), 7.02

- 6.98 (m, 2H), 6.61 (d, J = 8.6 Hz, 1H), 3.94 (t, 2H), 3.63 - 3.53 (m, 4H), 3.48 - 3.40 (m, 2H), 3.40 - 3.34 (m, 2H), 3.29 - 3.17 (m, 4H), 2.77 - 2.59 (m, 4H), 2.32 (s, 3H), 2.20 (s, 3H).

LCMS Method 7 - Tr = 1.46 min

m/z value = 495

Example 210. Synthesis of 2-[4-({3-[4-(5-methoxypyridin-2-yl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-259

1-259

[001047] Prepared using the HATU generic method with Intermediate A and Amine 59. 1H MR (500 MHz, Chloroform-d) δ 7.93 (d, J = 3.0 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.50

- 7.45 (m, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.22 - 7.18 (m, 2H), 7.17 (dd, J = 9.1, 3.1 Hz, 1H), 7.01

- 6.97 (m, 2H), 6.66 (d, J = 9.1 Hz, 1H), 3.95 (t, J = 5.0 Hz, 2H), 3.79 (s, 3H), 3.62 - 3.56 (m, 2H), 3.54 - 3.48 (m, 2H), 3.41 - 3.34 (m, 4H), 3.25 - 3.20 (m, 4H), 2.71 - 2.64 (m, 4H), 2.32 (s, 3H). LCMS Method 7 - Tr = 1.74 min

m/z value = 511

Example 211. Synthesis of 2-[4-({3-[4-(5-fluoro-6-methylpyridin-2-yl)piperazine-l- carbonyl]-4-methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-255

1-255

[001048] Prepared using the HATU generic method with Intermediate A and Amine 36. 1H MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.28 - 7.26 (m, 1H), 7.22 - 7.15 (m, 3H), 7.02 - 6.96 (m, 2H), 6.45 (dd, J = 8.9, 2.5 Hz, 1H), 3.97 - 3.91 (m, 2H), 3.61 - 3.51 (m, 4H), 3.44 - 3.33 (m, 4H), 3.26 - 3.19 (m, 4H), 2.69 - 2.62 (m, 4H), 2.36 (d, J = 3.0 Hz, 3H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 2.45 min

m/z value = 513

Example 212. Synthesis of 2-[4-({3-[4-(4,6-dimethylpyrimidin-2-yl)piperazine-l-carbony l]- 4-methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-253

1-253

[001049] Prepared using the HATU generic method with Intermediate A and Amine 10. 1H MR (500 MHz, DMSO-d6) δ 7.69 (dd, J = 7.7, 1.6 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.31 - 7.22 (m, 2H), 7.19 - 7.13 (m, 2H), 7.09 (t, 1H), 6.45 (s, 1H), 3.89 - 3.78 (m, 2H), 3.78 - 3.64 (m, 4H), 3.56 (s, 2H), 3.26 - 3.18 (m, 2H), 3.18 - 3.12 (m, 4H), 2.60 - 2.54 (m, 4H), 2.23 (s, 9H).

LCMS Method 7 - Tr = 2.18 min

m/z value = 510

Example 213. Synthesis of 6-[(3S)-4-(5-{[4-(2-cyanophenyl)piperazin-l-yl] methylbenzoyl)-3-methylpiperazin-l-yl]pyridine-2-carbonitril e, 1-251

1-251

[001050] Prepared using the HATU generic method with Intermediate A and Amine 37. 1H MR (250 MHz, DMSO-d6) δ 7.68 (dd, J = 8.8, 7.2 Hz, 1H), 7.63 (dd, J = 7.7, 1.5 Hz, 1H), 7.56 (ddd, J = 9.1, 7.4, 1.7 Hz, 1H), 7.32 - 7.21 (m, 2H), 7.19 - 7.09 (m, 4H), 7.08 (ddd, J = 7.5, 0.9 Hz, 1H), 4.28 - 3.99 (m, 3H), 3.62 - 3.55 (m, 2H), 3.37 - 3.15 (m, 8H), 2.65 - 2.55 (m, 4H), 2.23 (s, 3H), 1.26 - 1.10 (m, 3H).

LCMS Method 7 - Tr = 2.45 min

m/z value = 520

Example 214. Synthesis of 2-[4-({4-methyl-3-[4-(pyrimidin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-248

1-248

[001051] Prepared using the HATU generic method with Intermediate A and Amine 38. 1H MR (500 MHz, Chloroform-d) δ 8.32 (d, J = 4.7 Hz, 2H), 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.49 - 7.45 (m, 1H), 7.30 - 7.26 (m, 1H), 7.23 - 7.18 (m, 2H), 7.02 - 6.97 (m, 2H), 6.54 (t, J = 4.7 Hz, 1H), 3.98 - 3.88 (m, 4H), 3.80 - 3.73 (m, 2H), 3.59 - 3.54 (m, 2H), 3.35 - 3.29 (m, 2H), 3.25 - 3.18 (m, 4H), 2.69 - 2.64 (m, 4H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 1.99 min

m/z value = 482

Example 215. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2- methylbenzoyl)piperazin-l-yl]pyrimidine-4-carbonitrile, 1-244

1-244

[001052] Prepared using the HATU generic method with Intermediate A and Amine 15. 1H MR (500 MHz, Chloroform-d) δ 8.47 (d, J = 4.7 Hz, 1H), 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.47 (td, J = 7.9, 7.5, 1.6 Hz, 1H), 7.29 (dd, J = 7.8, 1.6 Hz, 1H), 7.23 - 7.19 (m, 2H), 7.02 - 6.97 (m, 2H), 6.81 (d, J = 4.7 Hz, 1H), 4.00 - 3.94 (m, 2H), 3.94 - 3.87 (m, 2H), 3.81 - 3.72 (m, 2H), 3.57 (s, 2H), 3.40 - 3.29 (m, 2H), 3.25 - 3.19 (m, 4H), 2.70 - 2.63 (m, 4H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 5.07 min

m/z value = 507

Example 216. Synthesis of 2-[4-({3-[4-(5-fluoropyrimidin-2-yl)piperazine-l-carbonyl]-4 - methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-235

1-235

[001053] Prepared using the HATU generic method with Intermediate A and Amine 39.

1H MR (500 MHz, Chloroform-d) δ 8.21 (s, 2H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.49 - 7.45 (m,

1H), 7.28 (dd, J = 7.8, 1.6 Hz, 1H), 7.22 - 7.19 (m, 2H), 7.01 - 6.97 (m, 2H), 3.92 - 3.88 (m, 4H),

3.73 - 3.67 (m, 2H), 3.59 - 3.54 (m, 2H), 3.34 - 3.29 (m, 2H), 3.24 - 3.20 (m, 4H), 2.68 - 2.63

(m, 4H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 2.2 min

m/z value = 500

Example 217. Synthesis of 2-[4-({4-methyl-3-[4-(l-methyl-lH-imidazol-2-yl)piperazine-l - carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-222

1-222

[001054] Prepared using the HATU generic method with Intermediate A and Amine 16. 1H MR (500 MHz, Chloroform-d) δ 7.57 (dd, J = 7.6, 1.4 Hz, 1H), 7.49 (dt, J = 9.0, 7.5, 1.6 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.23 - 7.20 (m, 2H), 7.04 - 6.98 (m, 2H), 6.81 (d, J = 1.5 Hz, 1H), 6.71 (d, J = 1.4 Hz, 1H), 4.10 - 4.00 (m, 1H), 3.99 - 3.88 (m, 1H), 3.64 - 3.56 (m, 2H), 3.54 (s, 3H), 3.48 - 3.38 (m, 2H), 3.31 - 3.23 (m, 4H), 3.20 - 3.12 (m, 2H), 3.09 - 2.99 (m, 2H), 2.72 - 2.63 (m, 4H), 2.35 (s, 3H).

LCMS Method 7 - Tr = 1.16 min

m/z value = 484

Example 218. Synthesis of 2-[4-({4-methyl-3-[4-(pyridazin-3-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-220

1-220

[001055] Prepared using the HATU generic method with Intermediate A and Amine 1. 1H NMR (500 MHz, Chloroform-d) δ 8.63 (dd, J = 4.5, 1.2 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.28 (dd, J = 7.8, 1.6 Hz, 3H), 7.27 - 7.22 (m, 3H), 7.24 - 7.17 (m, 2H), 7.02 - 6.95 (m, 2H), 6.94 (dd, J = 9.3, 1.2 Hz, 1H), 4.03 - 3.93 (m, 2H), 3.78 - 3.71 (m, 2H), 3.67 (s, 2H), 3.57 (d, J = 9.1 Hz, 2H), 3.46 - 3.36 (m, 2H), 3.30 - 3.16 (m, 4H), 2.73 - 2.60 (m, 4H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 1.36 min

m/z value = 482 Example 219. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl] methylbenzoyl)piperazin- - l]-6-methylpyridine-3-carbonitrile, 1-214

1-214

[001056] Prepared using the HATU generic method with Intermediate A and Amine 44. 1H NMR (500 MHz, Chloroform-d) δ 7.67 (d, J = 7.8 Hz, 1H), 7.56 - 7.53 (m, 1H), 7.49 - 7.44 (m, 1H), 7.29 - 7.26 (m, 1H), 7.22 - 7.18 (m, 2H), 7.02 - 6.96 (m, 2H), 6.68 (d, J = 7.8 Hz, 1H), 3.99 - 3.95 (m, 2H), 3.81 - 3.76 (m, 2H), 3.63 - 3.58 (m, 2H), 3.58 - 3.53 (m, 2H), 3.43 - 3.38 (m, 2H), 3.25 - 3.20 (m, 4H), 2.69 - 2.63 (m, 4H), 2.44 (s, 3H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 2.38 min

m/z value = 520

Example 220. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl] methylbenzoyl)piperazin-l-yl]-5-fluoropyridine-3-carbonitril e, 1-212

1-212

[001057] Prepared using the HATU generic method with Intermediate A and Amine 46. 1H NMR (500 MHz, Chloroform-d) δ 8.27 (d, J = 3.0 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.49 - 7.45 (m, 1H), 7.30 - 7.27 (m, 1H), 7.22 - 7.18 (m, 2H), 7.01 - 6.96 (m, 2H), 4.01 - 3.97 (m, 2H), 3.69 - 3.64 (m, 2H), 3.59 - 3.54 (m, 2H), 3.53 - 3.46 (m, 2H), 3.46 - 3.39 (m, 2H), 3.25 - 3.19 (m, 4H), 2.69 - 2.63 (m, 4H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 2.35 min

m/z value = 524 Example 221. Synthesis of 2-[4-({4-methyl-3-[3-oxo-4-(pyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-207

1-207

[001058] Prepared using the HATU generic method with Intermediate A and Amine 8. 1H MR (500 MHz, DMSO-d6) 8.43 (d, J = 33.0 Hz, 1H), 7.93 - 7.79 (m, 2H), 7.70 - 7.66 (m, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.34 - 7.19 (m, 4H), 7.14 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 4.44 (s, 1H), 4.15 (s, 1H), 3.98 (s, 3H), 3.56 (s, 2H), 3.52 (d, J = 5.6 Hz, 1H), 3.14 (s, 4H), 2.56 (s, 4H), 2.23 (d, J = 12.5 Hz, 3H).

LCMS Method 7 - Tr = 1.76 min

m/z value = 495

Example 222. Synthesis of 5-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2- methylbenzoyl)piperazin-l-yl]-2-cyclopropyl-l,3-oxazole-4-ca rbonitrile, 1-177

1-177

[001059] Prepared using the HATU generic method with Intermediate A and Amine 21. 1H NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 8.0, 1.5 Hz, 1H), 7.50 - 7.44 (m, 1H), 7.29 (dd, J = 7.8, 1.6 Hz, 1H), 7.24 - 7.19 (m, 1H), 7.17 (d, J = 1.4 Hz, 1H), 7.03 - 6.96 (m, 2H), 4.02 - 3.89 (m, 2H), 3.58 (d, J = 10.2 Hz, 4H), 3.42 (d, J = 11.2 Hz, 4H), 3.24 - 3.20 (m, 4H), 2.67 - 2.62 (m, 4H), 2.31 (s, 3H), 1.92 - 1.84 (m, 1H), 1.02 - 0.98 (m, 4H).

LCMS Method 7 - Tr = 2.24 min

m/z value = 536 Example 223. Synthesis of 2-[4-({3-[4-(2-methanesulfonylphenyl)piperazine-l-carbonyl]- 4- methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-176

1-176

[001060] Prepared using the HATU generic method with Intermediate A and Amine 55. 1H MR (500 MHz, DMSO-d6) 7.91 (dd, J = 7.9, 1.5 Hz, 1H), 7.72 (td, J = 8.0, 1.6 Hz, 1H), 7.67 (dd, J = 7.7, 1.5 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.58 (ddd, 1H), 7.44 (ddd, 1H), 7.30 - 7.23 (m, 2H), 7.19 (s, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 3.70 (d, J = 114.5 Hz, 2H), 3.56 (d, J = 3.2 Hz, 2H), 3.38 (s, 3H), 3.32 (s, 2H), 3.18 - 3.11 (m, 4H), 3.05 (s, 2H), 2.90 (d, J = 34.9 Hz, 2H), 2.56 (s, 4H), 2.26 (s, 3H).

LCMS Method 7 - Tr = 2.15 min

m/z value = 558

Example 224. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(6-methylpyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-294

1-294

[001061] Prepared using the HATU generic method with Intermediate C and Amine 3. lH MR (500 MHz, DMSO-d6) 7.70 (dd, J = 7.7, 1.5 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.47 - 7.41 (m, 1H), 7.15 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 4.6 Hz, 3H), 6.62 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 3.75 (s, 2H), 3.58 (s, 2H), 3.51 (s, 2H), 3.40 (t, J = 5.0 Hz, 2H), 3.25 (s, 2H), 3.14 (s, 4H), 2.57 (s, 4H), 2.35 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H).

LCMS Method 7 - Tr = 1.57 min

m/z value = 509 Example 225. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(5-methyl-l,3-thiazol-2-yl)piperazi ne-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-293

1-293

[001062] Prepared using the HATU generic method with Intermediate C and Amine 4.

1H MR (500 MHz, DMSO-d6) 7.70 (dd, J = 7.7, 1.5 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.16 (d, J =

8.3 Hz, 1H), 7.10 (d, J = 6.2 Hz, 3H), 6.84 (d, J = 1.3 Hz, 1H), 3.77 (d, J = 24.7 Hz, 2H), 3.50 (s,

2H), 3.28 (s, 4H), 3.13 (s, 4H), 2.56 (s, 4H), 2.53 (d, J = 1.9 Hz, 2H), 2.34 (s, 3H), 2.26 (d, J = 1.1

Hz, 3H), 2.18 (s, 3H).

LCMS Method 7 - Tr = 1.96 min

m/z value = 515

Example 226. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(pyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-290

1-290

[001063] Prepared using the HATU generic method with Intermediate C and Amine 83. lH MR (500 MHz, DMSO-d6) 8.14 - 8.10 (m, 1H), 7.70 (dd, J = 7.6, 1.5 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.15 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 5.0 Hz, 3H), 6.84 (d, J = 8.7 Hz, 1H), 6.67 (dd, J = 6.9, 5.0 Hz, 1H), 3.75 (s, 2H), 3.60 (s, 2H), 3.51 (s, 2H), 3.43 (s, 2H), 3.26 (s, 2H), 3.14 (s, 4H), 2.57 (s, 4H), 2.35 (s, 3H), 2.19 (s, 3H).

LCMS Method 7 - Tr = 1.53 min

m/z value = 495 Example 227. Synthesis of 2-[4-({5-[(2S)-4-(2-cyanophenyl)-2-methylpiperazine-l- carbonyl]-2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitr ile, 1-262

1-262

[001064] Prepared using the HATU generic method with Intermediate C and Amine 9.

1H MR (250 MHz, DMSO-d6, 353K) δ 7.72 - 7.50 (m, 4H), 7.24 - 7.02 (m, 6H), 3.55 (s, 2H),

3.51 - 3.29 (m, 3H), 3.24 - 3.16 (m, 4H), 3.00 - 2.81 (m, 2H), 2.65 - 2.57 (m, 4H), 2.37 (s, 3H),

2.23 (s, 3H), 1.40 (d, J = 6.7 Hz, 3H).

(2 protons are missing, under the water peak.)

LCMS Method 7 - Tr = 2.63 min

m/z value = 533

Example 228. Synthesis of 2-[4-({5-[4-(4,6-dimethylpyrimidin-2-yl)piperazine-l-carbony l]- 2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-254

1-254

[001065] Prepared using the HATU generic method with Intermediate C and Amine 10. 1H MR (500 MHz, DMSO-d6) δ 7.69 (dd, J = 7.7, 1.6 Hz, 1H), 7.62 - 7.56 (m, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.11 - 7.06 (m, 3H), 6.45 (s, 1H), 3.88 - 3.77 (m, 2H), 3.77 - 3.68 (m, 2H), 3.68 - 3.63 (m, 2H), 3.51 (s, 2H), 3.26 - 3.19 (m, 2H), 3.16 - 3.10 (m, 4H), 2.60 - 2.54 (m, 4H), 2.35 (s, 3H), 2.23 (s, 6H), 2.19 (s, 3H).

LCMS Method 7 - Tr = 2.31 min

m/z value = 524 Example 229. Synthesis of 2-[4-({5-[4-(5-fluoro-6-methylpyridin-2-yl)piperazine-l- carbonyl]-2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitr ile, 1-252

1-252

[001066] Prepared using the HATU generic method with Intermediate C and Amine 36. 1H MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.18 (t, J = 8.8 Hz, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 7.01 - 6.95 (m, 2H), 6.44 (dd, J = 8.9, 2.4 Hz, 1H), 3.97 - 3.89 (m, 2H), 3.58 - 3.47 (m, 4H), 3.44 - 3.33 (m, 4H), 3.24 - 3.15 (m, 4H), 2.69 - 2.62 (m, 4H), 2.37 - 2.35 (m, 6H), 2.28 (s, 3H).

LCMS Method 7 - Tr = 2.57 min

m/z value = 527

Example 230. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(pyrimidin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-247

1-247

[001067] Prepared using the HATU generic method with Intermediate C and Amine 38. 1H MR (500 MHz, Chloroform-d) δ 8.33 - 8.30 (m, 2H), 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.53 (t, J = 4.7 Hz, 1H), 3.97 - 3.92 (m, 2H), 3.91 - 3.86 (m, 2H), 3.80 - 3.71 (m, 2H), 3.56 - 3.48 (m, 2H), 3.37 - 3.29 (m, 2H), 3.23 - 3.16 (m, 4H), 2.68 - 2.61 (m, 4H), 2.37 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.14 min

m/z value = 496 Example 231. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(4-methylpyrimidin-2-yl)piperazine- l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-246

1-246

[001068] Prepared using the HATU generic method with Intermediate C and Amine 14. 1H MR (500 MHz, Chloroform-d) δ 8.17 (d, J = 5.0 Hz, 1H), 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 7.00 - 6.97 (m, 2H), 6.42 (d, J = 5.0 Hz, 1H), 3.94 (s, 2H), 3.91 - 3.85 (m, 2H), 3.81 - 3.71 (m, 2H), 3.56 - 3.46 (m, 2H), 3.37 - 3.28 (m, 2H), 3.24 - 3.16 (m, 4H), 2.72 - 2.61 (m, 4H), 2.36 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.27 min

m/z value = 510

Example 232. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]pyrimidine-4-carbonitrile, 1-245

1-245

[001069] Prepared using the HATU generic method with Intermediate C and Amine 15. 1H MR (500 MHz, Chloroform-d) δ 8.47 (d, J = 4.7 Hz, 1H), 7.55 (dd, J = 8.1, 1.6 Hz, 1H), 7.47 (td, J = 8.1, 1.6 Hz, 1H), 7.13 (s, 1H), 7.06 (s, 1H), 6.99 (t, J = 7.5 Hz, 2H), 6.80 (d, J = 4.7 Hz, 1H), 3.93 (dd, J = 33.7, 5.1 Hz, 4H), 3.76 (s, 2H), 3.51 (s, 2H), 3.34 (s, 2H), 3.24 - 3.16 (m, 4H), 2.70 - 2.61 (m, 4H), 2.37 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 5.48 min

m/z value = 521 Example 233. Synthesis of 6-[(3S)-4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)-3-methylpiperazin-l-yl]pyridine-2-carbonitr ile, 1-236

1-236

[001070] Prepared using the HATU generic method with Intermediate C and Amine 37. 1H MR (500 MHz, Chloroform-d) δ 7.57 - 7.51 (m, 2H), 7.49 - 7.44 (m, 1H), 7.12 (s, 1H), 7.05 (s, 1H), 7.01 - 6.96 (m, 3H), 6.81 (d, J = 8.0 Hz, 1H), 5.15 - 4.59 (m, 1H), 4.34 - 4.00 (m, 2H), 3.60 - 3.46 (m, 2H), 3.46 - 3.25 (m, 2H), 3.24 - 3.15 (m, 4H), 3.15 - 2.75 (m, 2H), 2.69 - 2.61 (m, 4H), 2.37 (s, 3H), 2.34 - 2.17 (m, 3H), 1.37 - 1.14 (m, 3H).

LCMS Method 7 - Tr = 2.55 min

m/z value = 534

Example 234. Synthesis of 2-[4-({5-[4-(5-fluoropyrimidin-2-yl)piperazine-l-carbonyl]-2 ,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-234

1-234

[001071] Prepared using the HATU generic method with Intermediate C and Amine 39. 1H MR (500 MHz, Chloroform-d) δ 8.20 (s, 2H), 7.55 (d, J = 7.6 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 7.01 - 6.96 (m, 2H), 3.92 - 3.84 (m, 4H), 3.74 - 3.66 (m, 2H), 3.55 - 3.47 (m, 2H), 3.36 - 3.29 (m, 2H), 3.22 - 3.17 (m, 4H), 2.68 - 2.63 (m, 4H), 2.37 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.32 min

m/z value = 514 Example 235. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l- l ridine-3-carbonitrile 1-242

1-242

[001072] Prepared using the HATU generic method with Intermediate C and Amine 73. 1H NMR (500 MHz, Chloroform-d) δ 8.36 (dd, J = 4.8, 2.0 Hz, 1H), 7.80 (dd, J = 7.6, 2.0 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.50 - 7.42 (m, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 7.02 - 6.95 (m, 2H), 6.83 (dd, J = 7.6, 4.8 Hz, 1H), 4.04 - 3.92 (m, 2H), 3.85 - 3.73 (m, 2H), 3.66 - 3.55 (m, 2H), 3.55 - 3.46 (m, 2H), 3.47 - 3.40 (m, 2H), 3.24 - 3.15 (m, 4H), 2.70 - 2.61 (m, 4H), 2.36 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.3 min

m/z value = 520

Example 236. Synthesis of 2-[4-({5-[4-(2-chlorophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-228

1-228

[001073] Prepared using the HATU generic method with Intermediate C and Amine 82. 1H NMR (500 MHz, Chloroform-d) 5 7.55 (dd, J = 7.6, 1.4 Hz, 1H), 7.46 (td, J = 8.2, 1.6 Hz, 1H), 7.37 (dd, J = 7.9, 1.5 Hz, 1H), 7.23 (td, J = 8.0, 1.5 Hz, 1H), 7.14 (s, 1H), 7.04 (s, 1H), 7.03 - 7.00 (m, 2H), 7.00 - 6.96 (m, 2H), 4.04 - 3.98 (m, 2H), 3.56 - 3.48 (m, 2H), 3.48 - 3.42 (m, 2H), 3.22 - 3.16 (m, 4H), 3.16 - 3.09 (m, 2H), 3.00 - 2.89 (m, 2H), 2.69 - 2.62 (m, 4H), 2.36 (s, 3H), 2.30 (s, 3H).

LCMS Method 7 - Tr = 2.82 min m/z value = 528, 530

Example 237. Synthesis of 2-[4-({5-[4-(2-fluorophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-277

1-277

[001074] Prepared using the HATU generic method with Intermediate C and Amine 40. 1H MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.6, 1.4 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.13 (s, 1H), 7.08 - 6.91 (m, 7H), 3.99 (t, J = 4.7 Hz, 2H), 3.56 - 3.47 (m, 2H), 3.47 - 3.41 (m, 2H), 3.22 - 3.18 (m, 4H), 3.18 - 3.14 (m, 2H), 3.04 - 2.94 (m, 2H), 2.69 - 2.62 (m, 4H), 2.36 (s, 3H), 2.30 (s, 3H).

LCMS Method 7 - Tr = 2.62 min

m/z value = 512

Example 238. Synthesis of 2-[4-({5-[4-(2-methoxyphenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-226

1-226

[001075] Prepared using the HATU generic method with Intermediate C and Amine 41. 1H MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.7, 1.4 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.14 (s, 1H), 7.05 - 6.96 (m, 4H), 6.95 - 6.86 (m, 3H), 4.03 - 3.98 (m, 2H), 3.86 (s, 3H), 3.57 - 3.47 (m, 2H), 3.47 - 3.41 (m, 2H), 3.24 - 3.17 (m, 4H), 3.17 - 3.11 (m, 2H), 3.01 - 2.90 (m, 2H), 2.69 - 2.62 (m, 4H), 2.35 (s, 3H), 2.30 (s, 3H).

LCMS Method 7 - Tr = 2.45 min

m/z value = 524 Example 239. Synthesis of 2-[4-({5-[4-(3-chloropyridin-2-yl)piperazine-l-carbonyl]-2,4 - dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-225

1-225

[001076] Prepared using the HATU generic method with Intermediate C and Amine 78. 1H NMR (500 MHz, Chloroform-d) δ 8.18 (dd, J = 4.8, 1.6 Hz, 1H), 7.61 (dd, J = 7.7, 1.6 Hz, 1H), 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.14 (s, 1H), 7.04 (s, 1H), 7.00 - 6.96 (m, 2H), 6.88 (dd, J = 7.7, 4.8 Hz, 1H), 4.06 - 3.91 (m, 2H), 3.56 - 3.46 (m, 2H), 3.46 - 3.37 (m, 4H), 3.33 - 3.22 (m, 2H), 3.22 - 3.16 (m, 4H), 2.72 - 2.61 (m, 4H), 2.36 (s, 3H), 2.30 (s, 3H).

LCMS Method 7 - Tr = 2.5 min

m/z value = 529, 531

Example 240. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(4-methyl-l,3-oxazol-2-yl)piperazin e-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-244

1-244

[001077] Prepared using the HATU generic method with Intermediate C and Amine 43.

1H NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.9, 1.4 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.11 (s,

1H), 7.04 (s, 1H), 7.01 - 6.95 (m, 3H), 3.94 - 3.87 (m, 2H), 3.63 - 3.54 (m, 2H), 3.55 - 3.45 (m,

2H), 3.43 - 3.31 (m, 4H), 3.23 - 3.15 (m, 4H), 2.67 - 2.62 (m, 4H), 2.36 (s, 3H), 2.27 (s, 3H), 2.05

(d, J = 1.3 Hz, 3H).

LCMS Method 7 - Tr = 1.89 min

m/z value = 499 Example 241. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(l-methyl-lH-imidazol-2-yl)piperazi ne- l-carbonyl]phenyl}methyl)piperazin-l-yl]benzonitrile, 1-223

1-223

[001078] Prepared using the HATU generic method with Intermediate C and Amine 16. lH MR (500 MHz, Chloroform-d) δ 7.54 (dd, J = 8.0, 1.5 Hz, 1H), 7.46 (td, J = 8.1, 1.6 Hz, 1H), 7.12 (s, 1H), 7.03 (s, 1H), 7.02 - 6.96 (m, 2H), 6.78 (d, J = 1.4 Hz, 1H), 6.68 (d, J = 1.4 Hz, 1H), 4.12 - 4.00 (m, 1H), 3.94 - 3.80 (m, 1H), 3.54 - 3.46 (m, 5H), 3.45 - 3.38 (m, 2H), 3.25 - 3.17 (m, 4H), 3.15 - 3.06 (m, 2H), 3.05 - 2.94 (m, 2H), 2.72 - 2.60 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H). LCMS Method 7 - Tr = 1.29 min

m/z value = 498

Example 242. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(pyridazin-3-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-221

1-221

[001079] Prepared using the HATU generic method with Intermediate C and Amine 1. 1H NMR (500 MHz, Chloroform-d) δ 8.63 (dd, J = 4.5, 1.1 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.46 (td, J = 8.5, 7.5, 1.6 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.13 (s, 1H), 7.06 (s, 1H), 7.01 - 6.96 (m, 2H), 6.94 (dd, J = 9.3, 1.2 Hz, 1H), 4.01 - 3.89 (m, 2H), 3.69 (d, J = 25.1 Hz, 4H), 3.52 (s, 2H), 3.47 - 3.37 (m, 2H), 3.27 - 3.14 (m, 4H), 2.69 - 2.61 (m, 4H), 2.37 (s, 3H), 2.29 (s, 3H). LCMS Method 7 - Tr = 1.51 min

m/z value = 496 Example 243. Synthesis of 2-[4-({5-[4-(5-fluoro-4-methylpyrimidin-2-yl)piperazine-l- carbonyl]-2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitr ile, 1-219

1-219

[001080] Prepared using the HATU generic method with Intermediate C and Amine 54. 1H MR (500 MHz, DMSO-d6) 8.29 (d, J = 1.7 Hz, 1H), 7.68 (dd, J = 7.7, 1.5 Hz, 1H), 7.61 - 7.55 (m, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.10 - 7.05 (m, 3H), 3.74 (d, J = 28.3 Hz, 4H), 3.61 (s, 2H), 3.49 (s, 2H), 3.22 (s, 2H), 3.12 (s, 4H), 2.55 (s, 4H), 2.33 (s, 3H), 2.30 (d, J = 2.4 Hz, 3H), 2.17 (s, 3H).

LCMS Method 7 - Tr = 2.56 min

m/z value = 528

Example 244. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(2-methylphenyl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-216

1-216

[001081] Prepared using the HATU generic method with Intermediate C and Amine 42. 1H MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.21 - 7.13 (m, 3H), 7.06 - 6.96 (m, 5H), 4.07 - 3.88 (m, 2H), 3.55 - 3.46 (m, 2H), 3.44 - 3.38 (m, 2H), 3.25 - 3.15 (m, 4H), 3.05 - 2.91 (m, 2H), 2.88 - 2.73 (m, 2H), 2.74 - 2.60 (m, 4H), 2.36 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H).

LCMS Method 7 - Tr = 2.87 min

m/z value = 508 Example 245. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin- 1-yl] -6-methylpyridine-3-carbonitrile, 1-215

1-215

[001082] Prepared using the HATU generic method with Intermediate C and Amine 44. 1H MR (500 MHz, Chloroform-d) δ 7.66 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 7.01 - 6.96 (m, 2H), 6.67 (d, J = 7.8 Hz, 1H), 4.00 - 3.94 (m, 2H), 3.81 - 3.75 (m, 2H), 3.63 - 3.56 (m, 2H), 3.55 - 3.46 (m, 2H), 3.45 - 3.39 (m, 2H), 3.24 - 3.17 (m, 4H), 2.69 - 2.62 (m, 4H), 2.44 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.52 min

m/z value = 534

Example 246. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]-5-fluoropyridine-3-carbonitr ile, 1-213

1-213

[001083] Prepared using the HATU generic method with Intermediate C and Amine 46. 1H MR (500 MHz, Chloroform-d) δ 8.26 (d, J = 3.0 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.49 - 7.44 (m, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 6.99 (dd, J = 7.8, 6.0 Hz, 2H), 4.01 - 3.95 (m, 2H), 3.66 (s, 2H), 3.49 (d, J = 13.7 Hz, 6H), 3.23 - 3.17 (m, 4H), 2.69 - 2.62 (m, 4H), 2.36 (s, 3H), 2.29 (s, 3H). LCMS Method 7 - Tr = 2.49 min

m/z value = 538

Example 247. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(6-methylpyrazin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-211

1-211

[001084] Prepared using the HATU generic method with Intermediate C and Amine 17. 1H NMR (500 MHz, Chloroform-d) δ 7.94 (s, 1H), 7.79 (s, 1H), 7.55 (dd, J = 7.6, 1.4 Hz, 1H), 7.46 (td, J = 8.3, 1.6 Hz, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 7.01 - 6.95 (m, 2H), 3.99 - 3.90 (m, 2H), 3.75 - 3.66 (m, 2H), 3.58 - 3.45 (m, 4H), 3.45 - 3.35 (m, 2H), 3.25 - 3.14 (m, 4H), 2.69 - 2.62 (m, 4H), 2.37 (s, 6H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.16 min

m/z value = 510

Example 248. Synthesis of 3-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin- 1-yl] pyrazine-2-car bonitrile, 1-210

1-210

[001085] Prepared using the HATU generic method with Intermediate C and Amine 18. 1H NMR (500 MHz, Chloroform-d) δ 8.29 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.50 - 7.43 (m, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 7.02 - 6.95 (m, 2H), 3.98 (d, J = 5.0 Hz, 2H), 3.88 (s, 2H), 3.70 (s, 2H), 3.51 (s, 2H), 3.45 (s, 2H), 3.25 - 3.15 (m, 4H), 2.73 - 2.61 (m, 4H), 2.37 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.24 min

m/z value = 521

Example 249. Synthesis of 2-[4-({2,4-dimethyl-5-[4-(pyrazin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-209

1-209

[001086] Prepared using the HATU generic method with Intermediate C and Amine 19. 1H NMR (500 MHz, Chloroform-d) δ 8.16 (d, J = 1.3 Hz, 1H), 8.09 - 8.06 (m, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.55 (dd, J = 7.6, 1.5 Hz, 1H), 7.46 (td, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 7.01 - 6.95 (m, 2H), 4.02 - 3.90 (m, 2H), 3.78 - 3.67 (m, 2H), 3.58 - 3.47 (m, 4H), 3.45 - 3.36 (m, 2H), 3.25 - 3.14 (m, 4H), 2.71 - 2.62 (m, 4H), 2.37 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.01 min

m/z value = 496

Example 250. Synthesis of 2-[4-({2,4-dimethyl-5-[3-oxo-4-(pyridin-2-yl)piperazine-l- carbonyl] phenyl} methyl)piperazin- 1-yl] benzonitrile, 1-208

1-208

[001087] Prepared using the HATU generic method with Intermediate C and Amine 8.

1H NMR (500 MHz, DMSO-d6) 8.44 (d, J = 26.7 Hz, 1H), 7.93 - 7.80 (m, 2H), 7.69 (dd, J =

7.7, 1.6 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.23 (s, 1H), 7.21 - 7.11 (m, 3H), 7.09 (t, J = 7.5 Hz, 1H),

4.44 (s, 1H), 4.16 (s, 1H), 3.98 (s, 3H), 3.53 (d, J = 9.8 Hz, 3H), 3.13 (s, 4H), 2.58 (s, 4H), 2.36

(d, J = 5.0 Hz, 3H), 2.20 (d, J = 12.8 Hz, 3H).

LCMS Method 7 - Tr = 1.95 min

m/z value = 509

Example 251. Synthesis of 2-[4-({5-[4-(3-methoxypyridin-2-yl)piperazine-l-carbonyl]-2, 4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-199

1-199

[001088] Prepared using the HATU generic method with Intermediate C and Amine 47. 1H NMR (500 MHz, Chloroform-d) δ 7.85 (dd, J = 4.9, 1.3 Hz, 1H), 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.14 (s, 1H), 7.06 (dd, J = 7.9, 1.2 Hz, 1H), 7.03 (s, 1H), 7.00 - 6.96 (m, 2H), 6.87 (dd, J = 7.9, 4.9 Hz, 1H), 3.97 (d, J = 15.8 Hz, 2H), 3.85 (s, 3H), 3.56 - 3.43 (m, 4H), 3.43 - 3.25 (m, 4H), 3.24 - 3.16 (m, 4H), 2.70 - 2.62 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 1.99 min

m/z value = 525

Example 252. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]-5-fluorobenzonitrile, 1-182

1-182

[001089] Prepared using the HATU generic method with Intermediate C and Amine 5.

1H NMR (500 MHz, Chloroform-d) δ 7.56 - 7.53 (m, 1H), 7.49 - 7.44 (m, 1H), 7.30 (dd, J = 7.7,

3.0 Hz, 1H), 7.25 - 7.22 (m, 1H), 7.12 (s, 1H), 7.04 (s, 1H), 7.04 - 6.97 (m, 3H), 4.12 - 3.94 (m,

2H), 3.55 - 3.45 (m, 4H), 3.24 - 3.14 (m, 6H), 3.07 - 2.99 (m, 2H), 2.70 - 2.62 (m, 4H), 2.36 (s,

3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.61 min

m/z value = 537

Example 253. Synthesis of 5-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin- 1-yl] -2-methyl- 1 ,3-oxazole-4-carbonitrile, 1-179

1-179

[001090] Prepared using the HATU generic method with Intermediate C and Amine 20. lH MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.47 (td, J = 7.9, 1.6 Hz, 1H),

7.10 (s, 1H), 7.05 (s, 1H), 7.02 - 6.95 (m, 2H), 4.01 - 3.88 (m, 2H), 3.64 - 3.57 (m, 2H), 3.54 -

3.48 (m, 2H), 3.48 - 3.37 (m, 4H), 3.24 - 3.17 (m, 4H), 2.68 - 2.62 (m, 4H), 2.37 (s, 3H), 2.33 (s,

3H), 2.27 (s, 3H).

LCMS Method 7 - Tr = 2.13 min

m/z value = 524

Example 254. Synthesis of 5-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin- 1- l -2- l r l- 1 3- x z l -4- r nitrile, 1-178

1-178

[001091] Prepared using the HATU generic method with Intermediate C and Amine 21. 1H MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.8, 1.5 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 7.03 - 6.96 (m, 2H), 3.98 - 3.87 (m, 2H), 3.62 - 3.54 (m, 2H), 3.54 - 3.48 (m, 2H), 3.48 - 3.37 (m, 4H), 3.24 - 3.16 (m, 4H), 2.68 - 2.62 (m, 4H), 2.36 (s, 3H), 2.27 (s, 3H), 1.93 - 1.83 (m, 1H), 1.02 - 0.96 (m, 4H).

LCMS Method 7 - Tr = 2.37 min

m/z value = 550

Example 255. Synthesis of 2-[4-({5-[4-(2-methanesulfonylphenyl)piperazine-l-carbonyl]- 2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-175

1-175

[001092] Prepared using the HATU generic method with Intermediate C and Amine 55. lH MR (500 MHz, DMSO-d6) 7.91 (dd, J = 7.9, 1.5 Hz, 1H), 7.71 (ddd, 1H), 7.68 (dd, J = 7.7, 1.5 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.58 (ddd, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.11 (s, 1H), 7.10 - 7.06 (m, 2H), 3.83 (s, 2H), 3.51 (s, 2H), 3.39 (s, 3H), 3.33 (s, 2H), 3.13 (s, 4H), 3.05 (s, 2H), 2.89 (d, J = 23.7 Hz, 2H), 2.57 (s, 4H), 2.34 (s, 3H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.26 min

m/z value = 572

Example 256. Synthesis of 3-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]pyridazine-4-carbonitrile, 1-165

1-165

[001093] Prepared using the HATU generic method with Intermediate C and Amine 11. 1H MR (500 MHz, DMSO-d6) δ 8.95 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 4.9 Hz, 1H), 7.69 (dd, J = 7.7, 1.5 Hz, 1H), 7.59 (td, 1H), 7.19 - 7.06 (m, 4H), 3.92 - 3.77 (m, 4H), 3.73 - 3.59 (m, 2H), 3.52 (s, 2H), 3.41 - 3.36 (m, 2H), 3.20 - 3.09 (m, 4H), 2.61 - 2.54 (m, 4H), 2.35 (s, 3H), 2.21 (s, 3H). LCMS Method 6 - Tr = 4.93 min

m/z value = 521

Example 257. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]benzamide, 1-141

1-141

[001094] Prepared using the HATU generic method with Intermediate C and Amine 23. 1H NMR (500 MHz, Chloroform-d) δ 9.09 (s, 1H), 8.14 (dd, J = 7.8, 1.7 Hz, 1H), 7.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.25 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 7.05 (s, 1H), 7.01 - 6.95 (m, 2H), 5.80 - 5.69 (m, 1H), 4.13 - 3.88 (m, 2H), 3.51 (s, 2H), 3.49 - 3.40 (m, 2H), 3.22 - 3.17 (m, 4H), 3.16 - 3.06 (m, 2H), 3.00 - 2.82 (m, 2H), 2.68 - 2.62 (m, 4H), 2.37 (s, 3H), 2.30 (s, 3H).

LCMS Method 7 - Tr = 2.07 min

m/z value = 537

Example 258. Synthesis of 4-chloro-2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2 ,4- dimethylbenzoyl)piperazin-l-yl]-5-fluorobenzonitrile, 1-138

1-138

[001095] Prepared using the HATU generic method with Intermediate C and Amine 48.

1H NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.36 (d,

J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.06 (d, J = 6.3 Hz, 1H), 7.04 (s, 1H), 7.01 - 6.96 (m, 2H), 4.10 -

3.95 (m, 2H), 3.49 (s, 4H), 3.24 - 3.17 (m, 6H), 3.08 - 3.01 (m, 2H), 2.69 - 2.62 (m, 4H), 2.36 (s,

3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.86 min

m/z value = 571, 573 Example 259. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]benzene-l-sulfonamide, 1-120

1-120

[001096] Prepared using the HATU generic method with Intermediate C and Amine 2. 1H NMR (500 MHz, DMSO-d6) 7.86 (dd, J = 7.9, 1.5 Hz, 1H), 7.68 (dd, J = 7.7, 1.5 Hz, 1H), 7.62 - 7.53 (m, 3H), 7.36 - 7.31 (m, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.08 (dd, J = 8.3, 6.0 Hz, 3H), 6.95 (s, 2H), 3.86 (s, 2H), 3.51 (s, 2H), 3.36 (s, 2H), 3.13 (s, 4H), 2.99 (s, 2H), 2.84 (d, J = 22.6 Hz, 2H), 2.56 (s, 4H), 2.33 (s, 3H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.21 min

m/z value = 573

Example 260. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperaz -l-yl]-4,5-difluorobenzonitrile, 1-130

1-130

[001097] Prepared using the HATU generic method with Intermediate C and Amine 6. lH MR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.9, 1.3 Hz, 1H), 7.47 (td, J = 8.1, 1.6 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.12 (s, 1H), 7.05 (s, 1H), 7.01 - 6.96 (m, 2H), 6.84 (dd, J = 11.5, 6.8 Hz, 1H), 4.03 (d, J = 21.2 Hz, 2H), 3.58 - 3.43 (m, 4H), 3.24 - 3.15 (m, 6H), 3.10 - 3.02 (m, 2H), 2.70 - 2.62 (m, 4H), 2.36 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.66 min

m/z value = 555

Example 261. Synthesis of 2-(4-{[5-(4-{2-[imino(methyl)oxo- ⁶ -sulfanyl]phenyl}piperazine- l-carbonyl)-2,4-dimethylphenyl]methyl}piperazin-l-yl)benzoni trile, 1-91

1-91

[001098] Prepared using the HATU generic method with Intermediate C and Amine 24. lH MR (500 MHz, Chloroform-d) δ 8.05 (dd, J = 7.9, 1.5 Hz, 1H), 7.59 (td, J = 7.9, 1.6 Hz, 1H),

7.55 (dd, J = 7.8, 1.5 Hz, 1H), 7.46 (td, J = 8.2, 1.6 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.13 (s, 1H),

7.04 (s, 1H), 6.99 (t, J = 7.6 Hz, 2H), 3.42 (s, 7H), 3.38 - 2.68 (m, 10H), 2.69 - 2.61 (m, 4H), 2.36

(s, 3H), 2.31 (s, 3H).

LCMS Method 7 - Tr = 1.95 min

m/z value = 571

Example 262. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]-5-fluoro-6-methylpyridine-3- carbonitrile, 1-80

1-80

[001099] Prepared using the HATU generic method with Intermediate C and Amine 45. lH MR (250 MHz, Chloroform-d) δ 7.57 - 7.48 (m, 1H), 7.46 (s, 1H), 7.43 (s, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 7.02 - 6.94 (m, 2H), 4.01 - 3.92 (m, 2H), 3.70 - 3.61 (m, 2H), 3.55 - 3.48 (m, 2H), 3.48 - 3.37 (m, 4H), 3.25 - 3.15 (m, 4H), 2.71 - 2.61 (m, 4H), 2.43 (d, 3H), 2.36 (s, 3H), 2.28 (s, 3H).

LCMS Method 7 - Tr = 2.7 min

m/z value = 552

Example 263. Synthesis of 2-[4-({5-[4-(3,4-difluorophenyl)-3-oxopiperazine-l-carbonyl] -2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-76

1-76

[001100] Prepared using the HATU generic method with Intermediate C and Amine 49. 1H MR (250 MHz, DMSO-d6) δ 7.69 (dd, J = 7.6, 1.4 Hz, 1H), 7.63 - 7.54 (m, 1H), 7.53 - 7.40 (m, 1H), 7.32 - 7.01 (m, 6H), 4.37 (s, 1H), 4.06 - 3.58 (m, 4H), 3.59 - 3.44 (m, 3H), 3.20 - 3.04 (m, 4H), 2.64 - 2.52 (m, 4H), 2.35 (s, 3H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.31 min

m/z value = 544

Example 264. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]-N-methylbenzamide, 1-78

1-78

[001101] Prepared using the HATU generic method with Intermediate C and Amine 25. 1H NMR (500 MHz, Chloroform-d) δ 8.12 (dd, J = 7.8, 1.7 Hz, 1H), 7.55 (dd, J = 7.7, 1.6 Hz, 1H), 9.15 - 9.08 (m, 1H), 7.50 - 7.45 (m, 1H), 7.43 (td, J = 7.7, 1.7 Hz, 1H), 7.23 (td, J = 7.7, 1.0 Hz, 1H), 7.17 - 7.10 (m, 2H), 7.06 (s, 1H), 7.03 - 6.94 (m, 2H), 4.09 - 3.86 (m, 2H), 3.57 - 3.36 (m, 4H), 3.25 - 3.16 (m, 4H), 3.14 - 3.04 (m, 2H), 3.02 (d, J = 4.9 Hz, 3H), 2.97 - 2.81 (m, 2H), 2.71 - 2.60 (m, 4H), 2.37 (s, 3H), 2.31 (s, 3H).

LCMS Method 7 - Tr = 2.16 min

m/z value = 551

Example 265. Synthesis of 2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]-N,N-dimethylbenzamide, 1-77

1-77

[001102] Prepared using the HATU generic method with Intermediate C and Amine 26. lH MR (250 MHz, DMSO-d6) δ 7.63 (dd, J = 7.7, 1.5 Hz, 1H), 7.60 - 7.52 (m, 1H), 7.38 - 7.28 (m, 1H), 7.17 - 7.03 (m, 7H), 3.76 - 3.29 (m, 6H), 3.21 - 3.16 (m, 4H), 2.87 - 2.67 (m, 4H), 2.64 - 2.56 (m, 4H), 2.35 (s, 3H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.28 min

m/z value = 565

Example 266. Synthesis of 2-(4-{[2,4-dimethyl-5-(4-phenylpiperazine-l- carbonyl)phenyl]methyl}piperazin-l-yl)benzonitrile, 1-68

1-68

[001103] Prepared using the HATU generic method with Intermediate C and Amine 71. 1H MR (500 MHz, DMSO-d6) δ 7.70 (dd, J = 7.7, 1.5 Hz, 1H), 7.59 (td, 1H), 7.26 - 7.19 (m, 2H), 7.15 (d, J = 8.3 Hz, 1H), 7.12 - 7.06 (m, 3H), 6.96 (d, J = 8.3 Hz, 2H), 6.82 (t, J = 7.2 Hz, 1H), 3.87 - 3.72 (m, 2H), 3.51 (s, 2H), 3.31 - 3.26 (m, 2H), 3.26 - 3.19 (m, 2H), 3.18 - 3.10 (m, 4H), 3.10 - 3.01 (m, 2H), 2.60 - 2.54 (m, 4H), 2.35 (s, 3H), 2.20 (s, 3H).

LCMS Method 6 - Tr = 4.58 min

m/z value = 494

Example 267. Synthesis of 3-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]pyridine-2-carbonitrile, 1-67

1-67

[001104] Prepared using the HATU generic method with Intermediate C and Amine 12. 1H MR (500 MHz, DMSO-d6) δ 8.33 - 8.30 (m, 1H), 7.72 - 7.66 (m, 2H), 7.65 - 7.56 (m, 2H), 7.15 (d, J = 8.4 Hz, 1H), 7.12 - 7.06 (m, 3H), 3.88 - 3.82 (m, 2H), 3.51 (s, 2H), 3.39 - 3.34 (m, 4H), 3.20 - 3.08 (m, 6H), 2.60 - 2.53 (m, 4H), 2.35 (s, 3H), 2.21 (s, 3H).

LCMS Method 6 - Tr = 4.06 min

m/z value = 520

Example 268. Synthesis of 2-(4-{[2,4-dimethyl-5-(2-phenylmorpholine-4- carbonyl)phenyl]methyl}piperazin-l-yl)benzonitrile, 1-70

1-70

[001105] Prepared using the HATU generic method with Intermediate C and Amine 50. 1H MR (250 MHz, DMSO-d6) δ 7.64 (dd, J = 7.7, 1.4 Hz, 1H), 7.57 (ddd, J = 9.0, 7.5, 1.7 Hz, 1H), 7.45 - 7.18 (m, 5H), 7.16 - 7.03 (m, 4H), 4.60 - 3.89 (m, 3H), 3.77 - 3.56 (m, 2H), 3.56 - 3.45 (m, 2H), 3.23 - 3.04 (m, 6H), 2.62 - 2.54 (m, 4H), 2.34 (s, 3H), 2.22 (s, 3H). LCMS Method 7 - Tr = 2.52 min

m/z value = 495

Example 269. Synthesis of 2-(4-{[2,4-dimethyl-5-({2-oxo-l,2-dihydrospiro[indole-3,4'- piperidine]-l'-yl}carbonyl)phenyl]methyl}piperazin-l-yl)benz onitrile, 1-74

1-74

[001106] Prepared using the HATU generic method with Intermediate C and Amine 27. 1H MR (500 MHz, Chloroform-d) δ 7.94 - 7.81 (m, 1H), 7.54 (dd, J = 7.7, 1.6 Hz, 1H), 7.49 - 7.43 (m, 1H), 7.34 - 7.26 (m, 1H), 7.25 - 7.18 (m, 2H), 7.07 - 7.03 (m, 2H), 7.01 - 6.94 (m, 2H), 6.91 - 6.87 (m, 1H), 4.47 - 4.31 (m, 1H), 4.17 - 3.97 (m, 1H), 3.92 - 3.81 (m, 1H), 3.62 - 3.41 (m, 3H), 3.23 - 3.15 (m, 4H), 2.70 - 2.62 (m, 4H), 2.41 - 2.27 (m, 6H), 1.98 (s, 2H), 1.83 - 1.67 (m, 2H).

LCMS Method 7 - Tr = 2.24 min

m/z value = 534

Example 270. Synthesis of 2-[4-({5-[4-(benzenesulfonyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-73

1-73

[001107] Prepared using the HATU generic method with Intermediate C and Amine 28. 1H NMR (500 MHz, Chloroform-d) δ 7.78 - 7.71 (m, 2H), 7.64 - 7.59 (m, 1H), 7.58 - 7.52 (m, 3H), 7.50 - 7.45 (m, 1H), 7.04 - 6.95 (m, 4H), 4.05 - 3.70 (m, 2H), 3.56 - 3.39 (m, 2H), 3.35 (s, 2H), 3.26 - 3.02 (m, 6H), 3.01 - 2.82 (m, 2H), 2.67 - 2.55 (m, 4H), 2.33 (s, 3H), 2.15 (s, 3H). LCMS Method 6 - Tr = 2.36 min

m/z value = 558

Example 271. Synthesis of tert-butyl N-{2-[4-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}- 2,4-dimethylbenzoyl)piperazin-l-yl]ethyl}carbamate, 1-71

1-71

[001108] Prepared using the HATU generic method with Intermediate C and Amine 29. 1H NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 8.1, 1.6 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.07 (s, 1H), 7.02 (s, 1H), 7.01 - 6.96 (m, 2H), 4.91 (s, 1H), 3.93 - 3.73 (m, 2H), 3.55 - 3.44 (m, 2H), 3.30 - 3.15 (m, 8H), 2.68 - 2.61 (m, 4H), 2.59 - 2.45 (m, 4H), 2.39 - 2.28 (m, 5H), 2.26 (s, 3H), 1.45 (s, 9H).

LCMS Method 7 - Tr = 1.6 min

m/z value = 561

Example 272. Synthesis of l-(5-{[4-(2-cyanophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)-4-phenylpiperidine-4-carboxamide, 1-49

1-49

[001109] Prepared using the HATU generic method with Intermediate C and Amine 13. 1H NMR (500 MHz, DMSO-d6) δ 7.70 (dd, J = 7.7, 1.6 Hz, 1H), 7.60 (td, 1H), 7.41 - 7.37 (m, 2H), 7.37 - 7.03 (m, 9H), 4.40 - 4.15 (m, 1H), 3.57 - 3.42 (m, 2H), 3.29 - 2.98 (m, 8H), 2.62 - 2.54 (m, 4H), 2.50 - 2.38 (m, 2H), 2.33 (s, 3H), 2.15 (s, 2H), 1.91 - 1.56 (m, 2H).

LCMS Method 6 - Tr = 3.81 min

m/z value = 536

Example 273. Synthesis of 2-[4-({5-[5-(2-cyanophenyl)-octahydropyrrolo[3,4-c]pyrrole-2 - carbonyl]-2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitr ile, 1-57

1-57

[001110] Prepared using the HATU generic method with Intermediate C and Amine 51. 1H NMR (500 MHz, Chloroform-d) δ 7.54 (dd, J = 7.7, 1.5 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.35 (ddd, J = 8.8, 7.2, 1.7 Hz, lH), 7.13 (s, 1H), 7.02 (s, 1H), 7.00 - 6.95 (m, 2H), 6.75 - 6.70 (m, 1H), 6.65 (d, J = 8.6 Hz, 1H), 3.97 (dd, J = 12.8, 7.8 Hz, 1H), 3.89 - 3.80 (m, 2H), 3.73 (dd, J = 12.8, 4.7 Hz, 1H), 3.56 (dd, J = 10.1, 4.8 Hz, 1H), 3.54 - 3.45 (m, 4H), 3.22 - 3.14 (m, 5H), 3.13 - 2.98 (m, 2H), 2.64 (t, J = 4.7 Hz, 4H), 2.34 (s, 3H), 2.28 (s, 3H).

LCMS Method 7 - Tr = 4.4 min

m/z value = 545

Example 274. Synthesis of 2-{4-[(5-{3-[(2-cyanophenyl)amino]pyrrolidine-l-carbonyl}-2, 4- dimethylphenyl)methyl]piperazin-l-yl}benzonitrile, 1-51

1-51 [001111] Prepared using the HATU generic method with Intermediate C and Amine 52. 1H NMR (500 MHz, Chloroform-d) δ 7.55 (dt, J = 7.8, 1.6 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.38 - 7.33 (m, 1H), 7.16 (d, J = 15.1 Hz, 1H), 7.05 - 6.95 (m, 3H), 6.78 - 6.56 (m, 2H), 4.55 (dd, J = 34.0, 6.3 Hz, 1H), 4.25 - 3.87 (m, 2H), 3.84 - 3.64 (m, 1H), 3.63 - 3.26 (m, 4H), 3.19 (t, J = 6.7 Hz, 2H), 3.14 (dq, J = 11.5, 5.0 Hz, 2H), 2.70 - 2.58 (m, 4H), 2.40 (d, J = 17.8 Hz, 1H), 2.34 (d, J = 11.6 Hz, 3H), 2.29 (d, J = 14.4 Hz, 3H), 2.09 - 1.96 (m, 1H).

LCMS Method 7 - Tr = 2.42 min

m/z value = 519

Example 275. Synthesis of 2-{4-[(5-{3-[(2-cyanophenyl)amino]azetidine-l-carbonyl}-2,4- dimethylphenyl)methyl]piperazin-l-yl}benzonitrile, 1-56

1-56

[001112] Prepared using the HATU generic method with Intermediate C and Amine 53. 1H NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.47 (ddd, J = 8.3, 7.5, 1.7 Hz, 1H), 7.42 (dd, J = 7.7, 1.4 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.23 (s, 1H), 7.04 (s, 1H), 7.01 - 6.95 (m, 2H), 6.76 (td, J = 7.6, 0.8 Hz, 1H), 6.41 (d, J = 8.4 Hz, 1H), 4.89 (d, J = 5.4 Hz, 1H), 4.66 - 4.57 (m, 1H), 4.42 - 4.28 (m, 2H), 4.09 - 4.02 (m, 1H), 3.88 - 3.80 (m, 1H), 3.57 - 3.45 (m, 2H), 3.24 - 3.12 (m, 4H), 2.64 (t, J = 4.8 Hz, 4H), 2.39 (s, 3H), 2.35 (s, 3H).

LCMS Method 7 - Tr = 2.38 min

m/z value = 505

Example 276. Synthesis of 2-[4-({5-[4-(2-cyanophenyl)-3-oxopiperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-38

1-38

[001113] Prepared using the HATU generic method with Intermediate C and Amine 7. 1H NMR (250 MHz, DMSO-d6) 5 8.12 (dd, J = 7.9, 1.5 Hz, 1H), 7.87 - 7.77 (m, 1H), 7.72 - 7.48 (m, 4H), 7.21 (s, 1H), 7.16 - 7.00 (m, 3H), 4.75 - 4.43 (m, 2H), 4.30 - 4.15 (m, 2H), 4.09 - 3.79 (m, 2H), 3.54 (s, 2H), 3.22 - 3.13 (m, 4H), 2.65 - 2.56 (m, 4H), 2.38 (s, 3H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 1.83 min

m/z value = 533

Example 277. Synthesis of 2-(4-{[5-(4-{2-[(R)-imino(methyl)oxo- ⁶ - sulfanyl]phenyl}piperazine-l-carbonyl)-2,4-dimethylphenyl]me thyl}piperazin-l- yl)benzonitrile, 1-37

1-37

[001114] Prepared using the HATU generic method with Intermediate C and Amine 35. The stereochemistry was arbitrarily assigned.

1H MR (500 MHz, Chloroform-d) δ 8.05 (dd, J = 7.9, 1.5 Hz, 1H), 7.58 (td, J = 7.8, 1.6 Hz, 1H), 7.55 (dd, J = 7.7, 1.4 Hz, 1H), 7.46 (td, J = 8.2, 1.6 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.13 (s, 1H), 7.04 (s, 1H), 7.02 - 6.95 (m, 2H), 3.56 - 3.39 (m, 7H), 3.40 - 2.68 (m, 10H), 2.69 - 2.59 (m, 4H), 2.36 (s, 3H), 2.31 (s, 3H). LCMS Method 7 - Tr = 3.66 min

m/z value = 571

Example 278. Synthesis of 2-(4-{[5-(4-{2-[(S)-imino(methyl)oxo- ⁶ - sulfanyl]phenyl}piperazine-l-carbonyl)-2,4-dimethylphenyl]me thyl}piperazin-l- yl)benzonitrile, 1-36

1-36

[001115] Prepared using the HATU generic method with Intermediate C and Amine 34. The stereochemistry was arbitrarily assigned.

1H NMR (500 MHz, Chloroform-d) δ 8.05 (dd, J = 7.9, 1.5 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.49 - 7.44 (m, 1H), 7.40 - 7.31 (m, 2H), 7.13 (s, 1H), 7.04 (s, 1H), 7.01 - 6.94 (m, 2H), 3.58 - 3.39 (m, 7H), 3.37 - 3.03 (m, 7H), 3.03 - 2.71 (m, 3H), 2.71 - 2.61 (m, 4H), 2.36 (s, 3H), 2.31 (s, 3H). LCMS Method 7 - Tr = 3.66 min

m/z value = 571

Example 279. Synthesis of 2-[4-({5-[(2S)-4-{2-[imino(methyl)oxo- ⁶ -sulfanyl]phenyl}-2- methylpiperazine-l-carbonyl]-2,4-dimethylphenyl}methyl)piper azin-l-yl]benzonitrile, 1-29

1-29

[001116] Prepared using the HATU generic method with Intermediate C and Amine 30. 1H NMR (250 MHz, DMSO-d6) δ 8.05 - 7.98 (m, 1H), 7.67 - 7.50 (m, 4H), 7.42 - 7.32 (m, 1H), 7.18 - 7.02 (m, 4H), 4.06 - 3.93 (m, 1H), 3.54 (s, 2H), 3.44 - 3.24 (m, 5H), 3.24 - 3.06 (m, 7H), 2.81 - 2.57 (m, 6H), 2.39 - 2.33 (m, 3H), 2.28 - 2.22 (m, 3H), 1.44 - 1.34 (m, 3H). LCMS Method 7 - Tr = 2.00, 2.03 min

m/z value = 585

Example 280. Synthesis of 2-[4-({5-[3-(hydroxymethyl)-4-phenylpiperazine-l-carbonyl]-2 ,4- dimethylphenyl}methyl)piperazin-l- l]benzonitrile, 1-16

1-16

[001117] Prepared using the HATU generic method with Intermediate C and Amine 56. 1H NMR (500 MHz, DMSO-d6) 7.68 (d, J = 7.3 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.20 (t, J = 7.4 Hz, 2H), 7.17 - 7.11 (m, 1H), 7.11 - 7.04 (m, 3H), 6.89 (d, J = 6.1 Hz, 2H), 6.73 (t, J = 7.2 Hz, 1H), 4.77 - 4.53 (m, 1H), 4.34 (d, J = 151.8 Hz, 1H), 3.85 (s, 1H), 3.62 - 3.44 (m, 4H), 3.34 (s, 2H), 3.22 (d, J = 9.7 Hz, 1H), 3.13 (s, 5H), 2.92 (s, 1H), 2.57 (s, 4H), 2.34 (d, J = 3.8 Hz, 3H), 2.18 (s, 3H).

LCMS Method 7 - Tr = 2.31 min

m/z value = 524

Example 281. Synthesis of 2-[4-({5-[4-(2-methanesulfonylpyridin-3-yl)piperazine-l- carbonyl]-2,4-dimethylphenyl}methyl)piperazin-l-yl]benzonitr ile, 1-18

1-18

[001118] Prepared using the HATU generic method with Intermediate C and Amine 31. 1H NMR (500 MHz, Chloroform-d) δ 8.56 (dd, J = 4.8, 1.9 Hz, 1H), 8.37 (dd, J = 7.8, 1.9 Hz, 1H), 7.55 (dd, J = 7.9, 1.6 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.29 - 7.26 (m, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 7.01 - 6.96 (m, 2H), 4.12 - 3.91 (m, 2H), 3.54 - 3.33 (m, 6H), 3.29 (s, 3H), 3.26 - 3.13 (m, 6H), 2.68 - 2.61 (m, 4H), 2.36 (s, 3H), 2.30 (s, 3H).

LCMS Method 7 - Tr = 2.18 min

m/z value = 573

Example 282. Synthesis of 2-(4-{[5-(4-{3-[imino(methyl)oxo- ⁶ -sulfanyl]pyridin-2- yl}piperazine-l-carbonyl)-2,4-dimethylphenyl]methyl}piperazi n-l-yl)benzonitrile, 1-4

1-4

[001119] Prepared using the HATU generic method with Intermediate C and Amine 33. 1H NMR (500 MHz, Chloroform-d) δ 8.52 (dd, J = 4.8, 1.8 Hz, 1H), 8.36 (dd, J = 7.8, 1.8 Hz, 1H), 7.55 (dd, J = 7.8, 1.6 Hz, 1H), 7.49 - 7.44 (m, 1H), 7.26 - 7.24 (m, 1H), 7.13 (s, 1H), 7.04 (s, 1H), 7.01 - 6.96 (m, 2H), 4.14 - 3.92 (m, 2H), 3.58 - 3.43 (m, 4H), 3.43 - 3.31 (m, 5H), 3.27 - 3.13 (m, 6H), 3.06 - 2.94 (m, 1H), 2.72 - 2.58 (m, 4H), 2.36 (s, 3H), 2.30 (s, 3H).

LCMS Method 6 - Tr = 1.88 min

m/z value = 572

Example 283. Synthesis of 2-[4-(5-{[4-(2-chlorophenyl)piperazin-l-yl] methylbenzoyl)piperazin-l-yl]benzonitrile, 1-329

1-329

[001120] Prepared using the HATU generic method with Intermediate B and Amine 72. 1H NMR (500 MHz, Chloroform-d) δ 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.51 (t, 1H), 7.34 (dd, J = 7.9, 1.4 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.25 - 7.15 (m, 3H), 7.11 - 7.00 (m, 3H), 6.97 (t, J = 7.3 Hz, 1H), 4.19 - 3.93 (m, 2H), 3.69 - 3.41 (m, 4H), 3.32 - 3.23 (m, 2H), 3.22 - 2.95 (m, 6H), 2.84 - 2.47 (m, 3H), 2.33 (s, 3H).

LCMS Method 7 - Tr = 2.54 min

m/z value = 514, 516

Example 284. Synthesis of 2-[(3S)-4-(5-{[4-(2-chlorophenyl)piperazin-l-yl] methylbenzoyl)-3-methylpiperazin-l-yl]benzonitrile, 1-328

1-328

[001121] Prepared using the HATU generic method with Intermediate B and Amine 9. 1H MR (250 MHz, DMSO-d6, 353K) 5 7.68 (dd, J = 7.7, 1.6 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.37 (dd, J = 7.9, 1.5 Hz, 1H), 7.33 - 7.09 (m, 7H), 7.02 (td, J = 7.6, 1.6 Hz, 1H), 3.58 (s, 2H), 3.40 (s, 3H), 3.03 (s, 7H), 2.93 (d, J = 11.4 Hz, 1H), 2.64 - 2.55 (m, 4H), 2.27 (s, 3H), 1.42 (d, J = 6.7 Hz, 3H).

LCMS Method 7 - Tr = 2.69 min

m/z value = 528, 530

Example 285. Synthesis of l-(5-{[4-(2-chlorophenyl)piperazin-l-yl]methyl}-2- methylbenzoyl)-4-[6-(propan-2-yl)pyridin-2-yl]piperazine, 1-313

1-313 [001122] Prepared using the HATU generic method with Intermediate B and Amine 64. 1H NMR (500 MHz, DMSO-d6) 7.49 - 7.44 (m, 1H), 7.39 (dd, J = 7.9, 1.4 Hz, 1H), 7.27 (q, J = 8.1 Hz, 3H), 7.18 - 7.12 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 7.3 Hz, 1H), 3.73 (s, 2H), 3.58 (s, 2H), 3.55 (s, 2H), 3.45 (s, 2H), 3.25 (s, 2H), 2.98 (s, 4H), 2.81 (dt, J = 13.7, 7.0 Hz, 1H), 2.54 (s, 4H), 2.22 (s, 3H), 1.15 (d, J = 6.9 Hz, 6H).

LCMS Method 5 - Tr = 2.34 min

m/z value = 532, 534

Example 286. Synthesis of 4-(5-{[4-(2-chlorophenyl)piperazin-l-yl]methyl}-2- methylbenzoyl)-l-phenylpiperazin-2-one, 1-218

1-218

[001123] Prepared using the HATU generic method with Intermediate B and Amine 70. 1H MR (500 MHz, DMSO-d6) 7.37 (ddt, J = 24.4, 17.1, 8.6 Hz, 6H), 7.31 - 7.25 (m, 4H), 7.16 - 7.11 (m, 1H), 7.03 (td, J = 7.7, 1.5 Hz, 1H), 4.38 (s, 1H), 3.97 (d, J = 56.1 Hz, 1H), 3.84 (d, J = 5.2 Hz, 1H), 3.68 (s, 1H), 3.55 (t, J = 6.3 Hz, 4H), 2.97 (s, 4H), 2.54 (s, 4H), 2.25 (d, J = 5.9 Hz, 3H).

LCMS Method 7 - Tr = 2.21 min

m/z value = 503, 505

Example 287. Synthesis of 4-(5-{[4-(2-chlorophenyl)piperazin-l-yl] methylbenzoyl)-l-(pyridin-2- l i erazin-2-one 1-206

1-206

[001124] Prepared using the HATU generic method with Intermediate B and Amine 8. 1H MR (500 MHz, DMSO-d6) 8.44 (dd, J = 32.0, 4.1 Hz, 1H), 7.93 - 7.79 (m, 2H), 7.39 (dd, J = 7.9, 1.5 Hz, 1H), 7.33 - 7.19 (m, 5H), 7.13 (d, J = 8.2 Hz, 1H), 7.05 - 6.99 (m, 1H), 4.44 (s, 1H), 4.16 (t, J = 5.4 Hz, 1H), 3.98 (s, 3H), 3.55 (s, 2H), 3.53 - 3.49 (m, 1H), 2.97 (s, 4H), 2.53 (d, J = 8.6 Hz, 4H), 2.23 (d, J = 12.1 Hz, 3H).

LCMS Method 7 - Tr = 1.97 min

m/z value = 504, 506

Example 288. Synthesis of l-(5-{[4-(2-chlorophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)-4-(6-methylpyridin-2-yl)piperazine, 1-296

1-296

[001125] Prepared using the HATU generic method with Intermediate D and Amine 3.

1H MR (500 MHz, DMSO-d6) 7.46 - 7.42 (m, 1H), 7.40 (dd, J = 7.9, 1.4 Hz, 1H), 7.30 - 7.25

(m, 1H), 7.14 (dd, J = 8.1, 1.3 Hz, 1H), 7.09 (s, 2H), 7.06 - 7.01 (m, 1H), 6.62 (d, J = 8.5 Hz, 1H),

6.54 (d, J = 7.3 Hz, 1H), 3.74 (s, 2H), 3.58 (s, 2H), 3.50 (s, 2H), 3.40 (s, 2H), 3.25 (s, 2H), 2.97 (s,

4H), 2.58 - 2.52 (m, 4H), 2.35 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H).

LCMS Method 7 - Tr = 1.78 min

m/z value = 518, 520

Example 289. Synthesis of l-(5-{[4-(2-chlorophenyl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)-4-(5-methyl-l,3-thiazol-2-yl)piperazine, 1-295

1-295

[001126] Prepared using the HATU generic method with Intermediate D and Amine 4. lH MR (500 MHz, DMSO-d6) 7.40 (dd, J = 7.9, 1.4 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.17 - 7.13 (m, 1H), 7.10 (d, J = 4.7 Hz, 2H), 7.06 - 7.01 (m, 1H), 6.85 (d, J = 1.3 Hz, 1H), 3.77 (d, J = 52.7 Hz, 2H), 3.49 (s, 2H), 3.43 (s, 2H), 3.27 (s, 4H), 2.97 (s, 4H), 2.53 (d, J = 1.9 Hz, 4H), 2.34 (s, 3H), 2.26 (d, J = 1.2 Hz, 3H), 2.18 (s, 3H).

LCMS Method 7 - Tr = 2.2 min

m/z value = 524, 526

Example 290. Synthesis of 2-[4-({3-[4-(5-fluoro-4-methylpyrimidin-2-yl)piperazine-l- carbonyl]-4-methylphenyl}methyl)piperazin-l-yl]pyridine-3-ca rbonitrile, 1-304

1-304

[001127] Prepared using the HATU generic method with Intermediate F and Amine 54. 1H NMR (500 MHz, DMSO-d6) 8.40 (dd, J = 4.8, 1.9 Hz, 1H), 8.32 (d, J = 1.7 Hz, 1H), 8.06 (dd, J = 7.6, 1.9 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.16 (s, 1H), 6.92 (dd, J = 7.6, 4.8 Hz, 1H), 3.78 (s, 4H), 3.61 (dt, J = 13.9, 5.0 Hz, 6H), 3.54 (s, 2H), 3.22 (s, 2H), 2.53 (d, J = 1.9 Hz, 4H), 2.32 (d, J = 2.4 Hz, 3H), 2.22 (s, 3H).

LCMS Method 5 - Tr = 2.25 min

m/z value = 515

Example 291. Synthesis of 2-[4-({3-[4-(4-fluorophenyl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]pyridine-3-carbonitrile, 1-300

1-300

[001128] Prepared using the HATU generic method with Intermediate F and Amine 58. 1H NMR (500 MHz, DMSO-d6) 8.41 (dd, J = 4.8, 1.9 Hz, 1H), 8.07 (dd, J = 7.6, 1.9 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.16 (s, 1H), 7.07 (t, J = 8.9 Hz, 2H), 7.01 - 6.96 (m, 2H), 6.93 (dd, J = 7.6, 4.8 Hz, 1H), 3.80 (t, J = 5.0 Hz, 2H), 3.63 - 3.57 (m, 4H), 3.54 (s, 2H), 3.28 (d, J = 4.9 Hz, 2H), 3.20 - 3.12 (m, 2H), 3.00 (d, J = 18.5 Hz, 2H), 2.53 (m, J = 1.9 Hz, 4H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.26 min

m/z value = 499

Example 292. Synthesis of 2-[4-({3-[4-(3-chlorophenyl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]pyridine-3-carbonitrile, 1-297

1-297

[001129] Prepared using the HATU generic method with Intermediate F and Amine 61. 1H NMR (500 MHz, DMSO-d6) 8.40 (dd, J = 4.8, 1.9 Hz, 1H), 8.07 (dd, J = 7.6, 1.9 Hz, 1H), 7.31 - 7.20 (m, 3H), 7.16 (s, 1H), 6.97 (t, J = 2.1 Hz, 1H), 6.92 (dt, J = 8.3, 4.1 Hz, 2H), 6.82 (dd, J = 7.7, 1.6 Hz, 1H), 3.84 - 3.75 (m, 2H), 3.63 - 3.57 (m, 4H), 3.54 (s, 2H), 3.28 (dd, J = 9.6, 4.7 Hz, 4H), 3.12 (s, 2H), 2.53 (s, 4H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.53 min

m/z value = 515, 517

Example 293. Synthesis of 2-[4-({3-[4-(6-cyanopyridin-2-yl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]pyridine-3-carbonitrile, 1-286

1-286

[001130] Prepared using the HATU generic method with Intermediate F and Amine 67. 1H NMR (500 MHz, DMSO-d6) 8.40 (dd, J = 4.8, 1.9 Hz, 1H), 8.06 (dd, J = 7.6, 1.9 Hz, 1H), 7.73 (dd, J = 8.9, 7.2 Hz, 1H), 7.31 - 7.22 (m, 3H), 7.21 - 7.15 (m, 2H), 6.92 (dd, J = 7.6, 4.8 Hz, 1H), 3.77 (s, 2H), 3.69 (s, 2H), 3.65 - 3.58 (m, 4H), 3.54 (s, 2H), 3.51 (d, J = 4.9 Hz, 2H), 3.25 (s, 2H), 2.54 - 2.52 (m, 4H), 2.23 (s, 3H).

LCMS Method 6 - Tr = 2.17 min

m/z value = 507

Example 294. Synthesis of 2-[4-({3-[(2S)-4-(2-cyanophenyl)-2-methylpiperazine-l- carbonyl]-4-methylphenyl}methyl)piperazin-l-yl]pyridine-3-ca rbonitrile, 1-276

1-276

[001131] Prepared using the HATU generic method with Intermediate F and Amine 9. 1H MR (500 MHz, Chloroform-d) δ 8.35 - 8.31 (m, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.22 (d, J = 10.0 Hz, 2H), 7.11 - 6.98 (m, 2H), 6.74 (s, 1H), 3.84 - 2.39 (m, 17H), 2.35 (s, 2H), 2.28 (s, 1H), 1.58 (d, J = 6.8 Hz, 3H).

LCMS Method 6 - Tr = 2.36 min

m/z value = 520

Example 295. Synthesis of 2-[4-({3-[4-(2-cyanophenyl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]pyridine-3-carbonitrile, 1-275

1-275

[001132] Prepared using the HATU generic method with Intermediate F and Amine 72. 1H NMR (500 MHz, DMSO-d6) 8.40 (dd, J = 4.8, 1.9 Hz, 1H), 8.05 (dd, J = 7.6, 1.9 Hz, 1H), 7.73 (dd, J = 7.7, 1.6 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.33 - 7.25 (m, 2H), 7.23 - 7.12 (m, 3H), 6.92 (dd, J = 7.6, 4.8 Hz, 1H), 3.85 (t, J = 5.0 Hz, 2H), 3.64 - 3.58 (m, 4H), 3.55 (s, 2H), 3.24 (s, 2H), 3.08 (d, J = 20.8 Hz, 2H), 2.55 - 2.52 (m, 6H), 2.24 (s, 3H).

LCMS Method 6 - Tr = 2.23 min

m/z value = 506

Example 296. Synthesis of 2-[4-({3-[4-(5-fluoro-6-methylpyridin-2-yl)piperazine-l- carbonyl]-4-methylphenyl}methyl)piperazin-l-yl]pyridine-3-ca rbonitrile, 1-256

1-256

[001133] Prepared using the HATU generic method with Intermediate F and Amine 36. 1H NMR (500 MHz, Chloroform-d) δ 8.32 (dd, J = 4.8, 2.0 Hz, 1H), 7.74 (dd, J = 7.6, 2.0 Hz, 1H), 7.28 (d, J = 1.7 Hz, 1H), 7.22 - 7.16 (m, 3H), 6.72 (dd, J = 7.6, 4.8 Hz, 1H), 6.44 (dd, J = 8.9, 2.4 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.76 - 3.70 (m, 4H), 3.54 (d, J = 5.3 Hz, 4H), 3.44 - 3.33 (m, 4H), 2.62 - 2.55 (m, 4H), 2.36 (d, J = 3.0 Hz, 3H), 2.31 (s, 3H).

LCMS Method 7 - Tr = 2.31 min

m/z value = 514

Example 297. Synthesis of 2-[4-({3-[(2S)-4-(6-cyanopyridin-2-yl)-2-methylpiperazine-l- carbonyl]-4-methylphenyl}methyl)piperazin-l-yl]pyridine-3-ca rbonitrile, 1-250

1-250

[001134] Prepared using the HATU generic method with Intermediate F and Amine 37. 1H NMR (250 MHz, DMSO-d6) δ 8.38 (dd, J = 4.8, 1.9 Hz, 1H), 7.97 (dd, J = 7.6, 1.9 Hz, 1H), 7.69 (dd, J = 8.8, 7.2 Hz, 1H), 7.32 - 7.21 (m, 2H), 7.17 - 7.09 (m, 3H), 6.87 (dd, J = 7.6, 4.8 Hz, 1H), 4.27 - 3.98 (m, 3H), 3.70 - 3.63 (m, 4H), 3.56 (s, 2H), 3.41 - 3.15 (m, 4H), 2.58 - 2.53 (m, 4H), 2.22 (s, 3H), 1.18 (d, J = 6.5 Hz, 3H).

LCMS Method 7 - Tr = 2.3 min

m/z value = 521

Example 298. Synthesis of l-(3-chloropyridin-2-yl)-4-({4-methyl-3-[4-(pyridin-2- yl)piperazine-l-carbonyl]phenyl}methyl)piperazine, 1-324

1-324

[001135] Prepared using the HATU generic method with Intermediate E and Amine 83. 1H NMR (500 MHz, Chloroform-d) δ 8.21 - 8.18 (m, 1H), 8.17 (dd, J = 4.7, 1.6 Hz, 1H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.32 - 7.28 (m, 1H), 7.22 - 7.18 (m, 2H), 6.84 - 6.79 (m, 1H), 6.69 - 6.65 (m, 2H), 3.98 - 3.91 (m, 2H), 3.64 (s, 2H), 3.56 (s, 2H), 3.52 - 3.47 (m, 2H), 3.42 - 3.32 (m, 6H), 2.66 - 2.55 (m, 4H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 2.47 min

m/z value = 491, 493

Example 299. Synthesis of l-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl] methylbenzoyl)-4-(6-methylpyridin-2-yl)piperazine, 1-323

1-323

[001136] Prepared using the HATU generic method with Intermediate E and Amine 3. 1H NMR (500 MHz, Chloroform-d) δ 8.17 (dd, J = 4.7, 1.6 Hz, 1H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 7.42 - 7.38 (m, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 7.6 Hz, 2H), 6.83 - 6.80 (m, 1H), 6.54 (d, J = 7.3 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 3.96 - 3.92 (m, 2H), 3.64 - 3.59 (m, 2H), 3.56 (s, 2H), 3.53 - 3.46 (m, 2H), 3.42 - 3.32 (m, 6H), 2.65 - 2.56 (m, 4H), 2.39 (s, 3H), 2.32 (s, 3H). LCMS Method 7 - Tr = 2.49 min

m/z value = 505, 507

Example 300. Synthesis of l-(3-chloropyridin-2-yl)-4-{[4-methyl-3-(4-phenylpiperazine- l- carbonyl)phenyl] methyljpiperazine, 1-322

1-322

[001137] Prepared using the HATU generic method with Intermediate E and Amine 71. 1H NMR (500 MHz, Chloroform-d) δ 8.17 (dd, J = 4.7, 1.6 Hz, 1H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 7.28 (s, 3H), 7.20 (d, J = 7.6 Hz, 2H), 6.92 (dd, J = 13.5, 7.6 Hz, 3H), 6.81 (dd, J = 7.7, 4.8 Hz, 1H), 3.98 (s, 2H), 3.56 (d, J = 5.9 Hz, 2H), 3.39 (d, J = 18.3 Hz, 6H), 3.28 (s, 2H), 3.08 (d, J = 18.0 Hz, 2H), 2.65 - 2.57 (m, 4H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 3.47 min

m/z value = 490, 492

Example 301. Synthesis of (2S)-l-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl] methylbenzoyl)-2-methyl- -(pyridin-2-yl)piperazine, 1-319

1-319

[001138] Prepared using the HATU generic method with Intermediate E and Amine 65. 1H NMR (250 MHz, DMSO-d6) δ 8.18 (dd, J = 4.7, 1.6 Hz, 1H), 8.12 - 8.07 (m, 1H), 7.72 (dd, J = 7.8, 1.6 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.29 - 7.21 (m, 2H), 7.13 (s, 1H), 6.98 - 6.91 (m, 1H), 6.78 (d, J = 8.6 Hz, 1H), 6.66 - 6.59 (m, 1H), 4.23 - 4.03 (m, 2H), 3.56 (s, 2H), 3.36 - 3.07 (m, 6H), 2.97 - 2.75 (m, 3H), 2.61 - 2.53 (m, 4H), 2.23 (s, 3H), 1.20 (d, J = 6.7 Hz, 3H).

LCMS Method 7 - Tr = 2.55 min

m/z value = 505, 507 Example 302. Synthesis of (2S)-l-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl] methylbenzoyl)-2-methyl- -phenylpiperazine, 1-318

1-318

[001139] Prepared using the HATU generic method with Intermediate E and Amine 66. 1H MR (250 MHz, DMSO-d6) δ 8.18 (dd, J = 4.7, 1.6 Hz, 1H), 7.72 (dd, J = 7.7, 1.6 Hz, 1H), 7.28 - 7.12 (m, 5H), 6.98 - 6.89 (m, 3H), 6.85 - 6.73 (m, 1H), 3.60 - 3.46 (m, 4H), 3.36 - 3.28 (m, 5H), 2.97 - 2.56 (m, 8H), 2.24 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H).

LCMS Method 7 - Tr = 3.41 min

m/z value = 504, 506

Example 303. Synthesis of l-(3-chloropyridin-2-yl)-4-({3-[4-(4-fluorophenyl)piperazine -l- carbonyl]-4-methylphenyl}methyl)piperazine, 1-301

1-301

[001140] Prepared using the HATU generic method with Intermediate E and Amine 58. 1H NMR (500 MHz, DMSO-d6) 8.21 (dd, J = 4.7, 1.6 Hz, 1H), 7.79 (dd, J = 7.8, 1.6 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.16 (s, 1H), 7.10 - 7.03 (m, 2H), 7.02 - 6.93 (m, 3H), 3.80 (t, J = 5.0 Hz, 2H), 3.54 (s, 2H), 3.27 (m, J = 11.5, 5.9 Hz, 6H), 3.21 - 3.11 (m, 2H), 3.00 (d, J = 17.9 Hz, 2H), 2.58 - 2.52 (m, 4H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.39 min

m/z value = 508, 510 Example 304. Synthesis of l-({3-[4-(3-chlorophenyl)piperazine-l-carbonyl]-4- methylphenyl}methyl)-4-(3-chloropyridin-2-yl)piperazine, 1-298

1-298

[001141] Prepared using the HATU generic method with Intermediate E and Amine 61. 1H NMR (500 MHz, DMSO-d6) 8.21 (dd, J = 4.7, 1.6 Hz, 1H), 7.79 (dd, J = 7.8, 1.6 Hz, 1H), 7.31 - 7.19 (m, 3H), 7.16 (s, 1H), 7.02 - 6.95 (m, 2H), 6.92 (dd, J = 8.3, 2.1 Hz, 1H), 6.82 (dd, J = 7.8, 1.4 Hz, 1H), 3.78 (s, 2H), 3.54 (s, 2H), 3.28 (dt, J = 9.8, 4.5 Hz, 8H), 3.12 (s, 2H), 2.57 - 2.52 (m, 4H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.62 min

m/z value = 524, 526

Example 305. Synthesis of 2-[4-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl] methylbenzoyl)piperazin- - l]-5-fluoro-4-methylpyrimidine, 1-292

1-292

[001142] Prepared using the HATU generic method with Intermediate E and Amine 54. 1H MR (500 MHz, DMSO-d6) 8.30 (d, J = 1.7 Hz, 1H), 8.20 (dd, J = 4.7, 1.6 Hz, 1H), 7.77 (dd, J = 7.8, 1.6 Hz, 1H), 7.29 - 7.22 (m, 2H), 7.16 (s, 1H), 6.98 (dd, J = 7.8, 4.7 Hz, 1H), 3.77 (s, 4H), 3.62 (s, 2H), 3.53 (s, 2H), 3.26 (d, J = 10.9 Hz, 4H), 3.22 (s, 2H), 2.52 (d, J = 1.8 Hz, 4H), 2.31 (d, J = 2.5 Hz, 3H), 2.21 (s, 3H).

LCMS Method 5 - Tr = 2.34 min

m/z value = 524, 526

Example 306. Synthesis of 2-[4-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl]methyl}-2- methylbenzoyl)piperazin-l-yl]benzonitrile, 1-288

1-288

[001143] Prepared using the HATU generic method with Intermediate E and Amine 72. 1H NMR (500 MHz, DMSO-d6) 8.21 (dd, J = 4.7, 1.6 Hz, 1H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.73 (dd, J = 7.7, 1.6 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.32 - 7.24 (m, 2H), 7.23 - 7.11 (m, 3H), 6.99 (dd, J = 7.8, 4.7 Hz, 1H), 3.85 (t, J = 4.8 Hz, 2H), 3.55 (s, 2H), 3.26 (s, 6H), 3.08 (d, J = 23.4 Hz, 2H), 2.55 - 2.52 (m, 6H), 2.24 (s, 3H).

LCMS Method 6 - Tr = 2.32 min

m/z value = 515, 517

Example 307. Synthesis of 6-[4-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl] methylbenzoyl)piperazin-l-yl]pyridine-2-carbonitrile, 1-287

1-287

[001144] Prepared using the HATU generic method with Intermediate E and Amine 67.

1H NMR (500 MHz, DMSO-d6) 8.21 (dd, J = 4.7, 1.6 Hz, 1H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H),

7.73 (dd, J = 8.9, 7.2 Hz, 1H), 7.32 - 7.22 (m, 3H), 7.22 - 7.16 (m, 2H), 6.99 (dd, J = 7.8, 4.7 Hz,

1H), 3.77 (s, 2H), 3.69 (s, 2H), 3.54 (s, 2H), 3.54 - 3.49 (m, 2H), 3.26 (s, 6H), 2.53 (d, J = 1.8 Hz,

4H), 2.23 (s, 3H).

LCMS Method 6 - Tr = 2.27 min

m/z value = 516, 518

Example 308. Synthesis of l-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl]methyl}-2- methylbenzoyl)-4-(4-methyl-l,3-thiazol-2-yl)piperazine, 1-279

1-279

[001145] Prepared using the HATU generic method with Intermediate E and Amine 62.

1H NMR (500 MHz, DMSO-d6) 8.20 (dd, J = 4.7, 1.6 Hz, 1H), 7.77 (dd, J = 7.8, 1.6 Hz, 1H),

7.30 - 7.22 (m, 2H), 7.17 (s, 1H), 6.98 (dd, J = 7.8, 4.7 Hz, 1H), 6.42 (d, J = 1.1 Hz, 1H), 3.78 (d,

J = 49.0 Hz, 2H), 3.53 (s, 2H), 3.47 (s, 4H), 3.32 (d, J = 6.1 Hz, 4H), 3.25 (s, 6H), 2.21 (s, 3H),

2.13 (d, J = 0.8 Hz, 3H).

LCMS Method 6 - Tr = 1.73 min

m/z value = 511, 513

Example 309. Synthesis of 2-[(3S)-4-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl] methylbenzoyl)-3-methylpiperazin-l-yl]benzonitrile, 1-277

1-277

[001146] Prepared using the HATU generic method with Intermediate E and Amine 9. 1H MR (500 MHz, DMSO-d6) δ 8.21 (d, J = 3.2 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.74 (dd, J = 7.7, 1.5 Hz, 1H), 7.63 (s, 1H), 7.31 - 7.13 (m, 5H), 6.99 (dd, J = 7.8, 4.7 Hz, 1H), 3.80 - 3.35 (m, 9H), 3.29 - 3.17 (m, 6H), 3.09 - 2.80 (m, 2H), 2.26 (s, 2H), 2.19 (s, 1H), 1.45 (d, J = 6.5 Hz, 2H), 1.34 (s, 1H).

LCMS Method 7 - Tr = 2.51 min

m/z value = 529, 531

Example 310. Synthesis of l-(3-chloropyridin-2-yl)-4-({3-[4-(5-chloropyridin-2- yl)piperazine-l-carbonyl]-4-methylphenyl}methyl)piperazine, 1-272

1-272

[001147] Prepared using the HATU generic method with Intermediate E and Amine 60. lH MR (500 MHz, Chloroform-d) δ 8.17 (dd, J = 4.7, 1.6 Hz, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 7.45 (dd, J = 9.0, 2.6 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.22 - 7.19 (m, 2H), 6.82 (dd, J = 7.7, 4.8 Hz, 1H), 6.60 (d, J = 9.0 Hz, 1H), 3.96 - 3.89 (m, 2H), 3.64 - 3.53 (m, 4H), 3.50 - 3.44 (m, 2H), 3.43 - 3.32 (m, 6H), 2.68 - 2.56 (m, 4H), 2.31 (s, 3H).

LCMS Method 6 - Tr = 2.43 min

m/z value = 525, 528

Example 311. Synthesis of l-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl]methyl}-2- methylbenzoyl)-4-(5-methylpyridin-2-yl)piperazine, 1-260

1-260

[001148] Prepared using the HATU generic method with Intermediate E and Amine 63. 1H NMR (500 MHz, Chloroform-d) δ 8.16 (dd, J = 4.7, 1.6 Hz, 1H), 8.03 - 8.01 (m, 1H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 7.34 (dd, J = 8.6, 2.3 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.21 (s, 1H), 7.19 (s, 1H), 6.81 (dd, J = 7.7, 4.8 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H), 3.97 - 3.91 (m, 2H), 3.65 - 3.51 (m, 4H), 3.49 - 3.30 (m, 8H), 2.63 (s, 4H), 2.31 (s, 3H), 2.20 (s, 3H).

LCMS Method 7 - Tr = 1.41 min

m/z value = 505, 507

Example 312. Synthesis of l-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl] methylbenzoyl)-4-(5-methoxypyridin-2-yl)piperazine, 1-258

1-258

[001149] Prepared using the HATU generic method with Intermediate E and Amine 59. lH MR (500 MHz, Chloroform-d) δ 8.16 (dd, J = 4.7, 1.6 Hz, 1H), 7.93 (d, J = 3.0 Hz, 1H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.19 (s, 1H), 7.16 (dd, J = 9.1, 3.1 Hz, 1H), 6.81 (dd, J = 7.7, 4.8 Hz, 1H), 6.66 (d, J = 9.1 Hz, 1H), 3.98 - 3.92 (m, 2H), 3.79 (s, 3H), 3.63 - 3.54 (m, 2H), 3.53 - 3.47 (m, 2H), 3.37 (s, 8H), 2.69 - 2.56 (m, 4H), 2.31 (s, 3H).

LCMS Method 7 - Tr = 1.74 min

m/z value = 521

Example 313. Synthesis of l-(3-chloropyridin-2-yl)-4-({3-[4-(5-fluoro-6-methylpyridin- 2- yl)piperazine-l-carbonyl]-4-methylphenyl}methyl)piperazine, 1-257

1-257

[001150] Prepared using the HATU generic method with Intermediate E and Amine 36. 1H NMR (500 MHz, Chloroform-d) δ 8.17 (dd, J = 4.7, 1.7 Hz, 1H), 7.56 (dd, J = 7.7, 1.7 Hz, 1H), 7.29 (dd, J = 7.9, 1.5 Hz, 1H), 7.21 - 7.16 (m, 3H), 6.81 (dd, J = 7.7, 4.8 Hz, 1H), 6.44 (dd, J = 8.9, 2.4 Hz, 1H), 3.97 - 3.91 (m, 2H), 3.59 - 3.52 (m, 4H), 3.38 (d, J = 12.6 Hz, 8H), 2.65 - 2.57 (m, 4H), 2.36 (d, J = 3.0 Hz, 3H), 2.31 (s, 3H).

LCMS Method 7 - Tr = 2.45 min

m/z value = 523, 525

Example 314. Synthesis of 6-[(3S)-4-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl] methylbenzoyl)-3-methylpiperazin-l-yl]pyridine-2-carbonitril e, 1-249

1-249

[001151] Prepared using the HATU generic method with Intermediate E and Amine 37. 1H NMR (250 MHz, DMSO-d6) 5 8.18 (dd, J = 4.7, 1.6 Hz, 1H), 7.75 - 7.64 (m, 2H), 7.31 - 7.20 (m, 2H), 7.17 - 7.09 (m, 3H), 6.94 (dd, J = 7.8, 4.7 Hz, 1H), 4.08 (d, J = 13.3 Hz, 3H), 3.59 - 3.51 (m, 2H), 3.37 - 3.11 (m, 8H), 2.56 (d, J = 4.9 Hz, 4H), 2.22 (s, 3H), 1.27 - 1.14 (m, 3H).

LCMS Method 7 - Tr = 3.16 min

m/z value = 530, 532

Example 315. Synthesis of 4-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)-l-(pyridin-2-yl)piperazin-2-one, 1-33

1-33

[001152] Prepared using the HATU generic method with Intermediate G and Amine 8.

1H NMR (500 MHz, Chloroform-d) δ 8.41 (d, J = 27.6 Hz, 1H), 8.16 (dd, J = 4.7, 1.6 Hz, 1H),

7.97 (dd, J = 59.0, 8.0 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 7.21 - 7.02

(m, 3H), 6.81 (dd, J = 7.7, 4.7 Hz, 1H), 4.63 (s, 1H), 4.29 - 4.19 (m, 1H), 4.16 - 4.00 (m, 3H),

3.67 - 3.57 (m, 1H), 3.51 (s, 2H), 3.42 - 3.27 (m, 4H), 2.66 - 2.56 (m, 4H), 2.37 (s, 3H), 2.29 (d,

J = 13.0 Hz, 3H).

LCMS Method 7 - Tr = 3.87 min

m/z value = 519, 521

Example 316. Synthesis of 3-[4-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl]methyl}-2,4 - dimethylbenzoyl)piperazin-l-yl]pyridazine, 1-32

1-32

[001153] Prepared using the HATU generic method with Intermediate G and Amine 1. 1H NMR (500 MHz, Chloroform-d) δ 8.63 (dd, J = 4.5, 1.2 Hz, 1H), 8.16 (dd, J = 4.7, 1.7 Hz, 1H), 7.56 (dd, J = 7.7, 1.7 Hz, 1H), 7.25 - 7.21 (m, 1H), 7.14 (s, 1H), 7.05 (s, 1H), 6.93 (dd, J = 9.3, 1.2 Hz, 1H), 6.81 (dd, J = 7.7, 4.8 Hz, 1H), 3.96 (s, 2H), 3.75 - 3.61 (m, 4H), 3.55 - 3.46 (m, 2H), 3.46 - 3.39 (m, 2H), 3.38 - 3.29 (m, 4H), 2.64 - 2.56 (m, 4H), 2.37 (s, 3H), 2.29 (s, 3H). LCMS Method 7 - Tr = 1.5 min

m/z value = 506, 508

Example 317. Synthesis of 2-[4-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl]methyl}-2,4 - dimethylbenzoyl)-2-oxopiperazin-l-yl]benzonitrile, 1-30

1-30

[001154] Prepared using the HATU generic method with Intermediate G and Amine 7.

1H NMR (500 MHz, Chloroform-d) δ 8.16 (d, J = 4.1 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.69 (t, J

= 7.6 Hz, 1H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.19

(s, 1H), 7.06 (s, 1H), 6.81 (dd, J = 7.7, 4.8 Hz, 1H), 4.74 - 4.10 (m, 3H), 3.90 - 3.59 (m, 3H), 3.51

(s, 2H), 3.43 - 3.26 (m, 4H), 2.70 - 2.54 (m, 4H), 2.37 (s, 3H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 2.03 min

m/z value = 543, 545

[001155] The following compounds were synthesised from the indicated aldehyde [Intermediate Aldehyde] and amine [Intermediate Amine] using the method described in Example 154 to afford the final compounds.

Example 318. Synthesis of 2-[4-({3-[4-(5-fluoropyridin-2-yl)piperazine-l-carbonyl]-4- methylphenyl}methyl)piperazin-l-yl]benzonitrile, 1-312

1-312

[001156] Prepared by reductive amination of Intermediate J with Amine 72 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, DMSO-d6) δ 8.16 - 8.09 (m, 1H), 7.69 (dd, J = 7.7, 1.4 Hz, 1H), 7.61 - 7.57 (m, 1H), 7.54 (td, J = 8.7, 3.1 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.18 - 7.13 (m, 2H), 7.09 (t, J = 7.5 Hz, 1H), 6.89 (dd, J = 9.3, 3.4 Hz, 1H), 3.76 (s, 2H), 3.58 - 3.53 (m, 4H), 3.39 - 3.37 (m, 2H), 3.26 - 3.25 (m, 2H), 3.17 - 3.13 (m, 4H), 2.58 - 2.54 (m, 4H), 2.22 (s, 3H).

LCMS Method 5 - Tr = 2.22 min

m/z value = 499

Example 319. Synthesis of l-(3-chloropyridin-2-yl)-4-({3-[4-(5-fluoropyridin-2- yl)piperazine-l-carbonyl]-4-methylphenyl}methyl)piperazine, 1-311

1-311

[001157] Prepared by reductive amination of Intermediate J with Amine 78 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, DMSO-d6) 8.21 (dd, J = 4.7, 1.6 Hz, 1H), 8.11 (d, J = 3.1 Hz, 1H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.54 (td, J = 8.7, 3.2 Hz, 1H), 7.27 (q, J = 8.0 Hz, 2H), 7.16 (s, 1H), 6.99 (dd, J = 7.8, 4.7 Hz, 1H), 6.90 (dd, J = 9.3, 3.3 Hz, 1H), 3.77 (s, 2H), 3.55 (d, J = 7.5 Hz, 4H), 3.39 (d, J = 4.8 Hz, 2H), 3.26 (s, 6H), 2.53 (s, 4H), 2.22 (s, 3H).

LCMS Method 5 - Tr = 2.15 min

m/z value = 509, 511

Example 320. Synthesis of 2-[4-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl]methyl}-2,4 - dimethylbenzoyl)piperazin-l-yl]benzene-l-sulfonamide, 1-17

[001158] Prepared by reductive amination of Intermediate K with Amine 78 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, DMSO-d6) 8.20 (dd, J = 4.7, 1.6 Hz, 1H), 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.56 (d, J = 6.9 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.09 (s, 2H), 6.98 (dd, J = 7.8, 4.7 Hz, 1H), 6.96 (s, 2H), 3.87 (s, 2H), 3.49 (s, 2H), 3.37 (s, 2H), 3.24 (s, 4H), 2.99 (s, 2H), 2.87 (s, 2H), 2.53 (s, 4H), 2.33 (s, 3H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.2 min

m/z value = 583, 585

Example 321. Synthesis of 2-[4-(5-{[4-(3-cyanopyridin-2-yl)piperazin-l-yl]methyl}-2,4- dimethylbenzoyl)piperazin-l-yl]benzene-l-sulfonamide, 1-28

1-28

[001159] Prepared by reductive amination of Intermediate K with Amine 73 using the sodium triacetoxyborohydride generic method. 1H NMR (500 MHz, DMSO-d6) 8.39 (dd, J = 4.8, 1.9 Hz, 1H), 8.05 (dd, J = 7.6, 1.9 Hz, 1H), 7.86 (dd, J = 7.9, 1.5 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.57 - 7.53 (m, 1H), 7.36 - 7.31 (m, 1H), 7.08 (s, 2H), 6.95 (s, 2H), 6.91 (dd, J = 7.6, 4.8 Hz, 1H), 3.86 (s, 2H), 3.61 - 3.55 (m, 4H), 3.48 (s, 2H), 3.36 (s, 2H), 2.99 (s, 2H), 2.85 (s, 2H), 2.52 (s, 4H), 2.33 (s, 3H), 2.22 (s, 3H).

LCMS Method 7 - Tr = 2.05 min

m/z value = 574

Example 322. Synthesis of 2-[4-(5-{[4-(3-chloropyridin-2-yl)piperazin-l-yl]methyl}-2,4 - dimethylbenzoyl)piperazin-l-yl]pyridine-3-carbonitrile, 1-132

1-132

[001160] Prepared by reductive amination of Intermediate L with Amine 78 using the sodium triacetoxyborohydride generic method.

1H MR (500 MHz, DMSO-d6) δ 8.43 (dd, J = 4.8, 1.9 Hz, 1H), 8.21 (dd, J = 4.7, 1.6 Hz, 1H), 8.11 (dd, J = 7.6, 1.9 Hz, 1H), 7.78 (dd, J = 7.8, 1.6 Hz, 1H), 7.15 - 7.07 (m, 2H), 7.05 - 6.91 (m, 2H), 3.81 (s, 2H), 3.71 (s, 2H), 3.55 (s, 2H), 3.49 (s, 2H), 3.25 (s, 4H), 2.59 - 2.53 (m, 4H), 2.35 (s, 3H), 2.20 (s, 3H). (2 protons missing, under water peak)

LCMS Method 6 - Tr = 4.37 min

m/z value = 530, 532

Example 323. Synthesis of 2-[4-({5-[4-(3-cyanopyridin-2-yl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]pyridine-3-carbonitrile , 1-134

1-134 [001161] Prepared by reductive amination of Intermediate L with Amine 73 using the sodium triacetoxyborohydride generic method.

1H MR (500 MHz, DMSO-d6) δ 8.45 - 8.38 (m, 2H), 8.13 - 8.03 (m, 2H), 7.13 - 7.08 (m, 2H), 7.01 - 6.88 (m, 2H), 3.85 - 3.67 (m, 4H), 3.62 - 3.57 (m, 4H), 3.54 (s, 2H), 3.49 (s, 2H), 2.54 - 2.52 (m, 4H), 2.34 (s, 3H), 2.20 (s, 3H). (2 protons missing, under water peak).

LCMS Method 6 - Tr = 4.01 min

m/z value = 521

Example 324. Synthesis of 2-[4-({5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]pyridine-3-carbonitrile , 1-135

1-135

[001162] Prepared by reductive amination of Intermediate H with Amine 73 using the sodium triacetoxyborohydride generic method.

1H MR (500 MHz, DMSO-d6) δ 8.40 (dd, J = 4.8, 1.9 Hz, 1H), 8.06 (dd, J = 7.6, 1.9 Hz, 1H), 7.73 (dd, J = 7.7, 1.5 Hz, 1H), 7.61 (td, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.12 - 7.09 (m, 2H), 6.92 (dd, J = 7.6, 4.8 Hz, 1H), 3.89 - 3.79 (m, 2H), 3.63 - 3.56 (m, 4H), 3.49 (s, 2H), 3.37 - 3.34 (m, 2H), 3.25 - 3.01 (m, 4H), 2.53 (d, J = 1.9 Hz, 4H), 2.34 (s, 3H), 2.21 (s, 3H). LCMS Method 6 - Tr = 4.21 min

m/z value = 520

Example 325. Synthesis of 2-[4-(2,4-dimethyl-5-{[4-(pyridazin-3-yl)piperazin-l- yl] methyl} benzoyl)piperazin- 1-yl] benzonitrile, I- 183

1-183 [001163] Prepared by reductive amination of Intermediate H with Amine 1 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, Chloroform-d) δ 8.56 (dd, J = 4.5, 1.1 Hz, 1H), 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.18 (dd, J = 9.3, 4.5 Hz, 1H), 7.12 (s, 1H), 7.09 - 6.99 (m, 3H), 6.87 (dd, J = 9.3, 1.2 Hz, 1H), 4.08 - 3.99 (m, 2H), 3.66 - 3.60 (m, 4H), 3.47 (d, J = 16.9 Hz, 4H), 3.26 (t, J = 5.0 Hz, 2H), 3.14 - 3.06 (m, 2H), 2.60 - 2.52 (m, 4H), 2.37 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 1.91 min

m/z value = 496

Example 326. Synthesis of 2-[4-({5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]-5-fluorobenzonitrile, 1-181

1-181

[001164] Prepared by reductive amination of Intermediate H with Amine 5 using the sodium triacetoxyborohydride generic method.

1H MR (500 MHz, Chloroform-d) δ 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.26 - 7.24 (m, 1H), 7.20 (ddd, J = 9.0, 7.8, 3.0 Hz, 1H), 7.12 (s, 1H), 7.07 (td, J = 7.6, 0.8 Hz, 1H), 7.05 - 7.00 (m, 2H), 6.97 (dd, J = 9.1, 4.6 Hz, 1H), 4.08 - 3.99 (m, 2H), 3.57 - 3.43 (m, 4H), 3.29 - 3.23 (m, 2H), 3.16 - 3.07 (m, 6H), 2.69 - 2.62 (m, 4H), 2.36 (s, 3H), 2.29 (s, 3H).

LCMS Method 7 - Tr = 2.61 min

m/z value = 537

Example 327. Synthesis of 2-[4-({5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzamide, 1-142

1-142

[001165] Prepared by reductive amination of Intermediate H with Amine 23 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, Chloroform-d) δ 9.59 - 9.47 (m, 1H), 8.15 (dd, J = 8.1, 1.7 Hz, 1H), 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.48 - 7.43 (m, 1H), 7.24 - 7.19 (m, 2H), 7.11 (s, 1H), 7.09 - 7.04 (m, 2H), 7.01 (d, J = 8.2 Hz, 1H), 5.75 - 5.63 (m, 1H), 4.07 - 4.00 (m, 2H), 3.57 - 3.43 (m, 4H), 3.29 - 3.22 (m, 2H), 3.14 - 3.06 (m, 2H), 3.04 - 2.97 (m, 4H), 2.74 - 2.49 (m, 4H), 2.37 (s, 3H), 2.30 (s, 3H).

LCMS Method 7 - Tr = 2.16 min

m/z value = 537

Example 328. Synthesis of 3-[4-({5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]pyridazine-4-carbonitri le, 1-126

1-126

[001166] Prepared by reductive amination of Intermediate H with Amine 11 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, DMSO-d6) δ 8.91 (d, J = 4.9 Hz, 1H), 7.98 (d, J = 4.9 Hz, 1H), 7.73 (dd, J = 7.7, 1.4 Hz, 1H), 7.62 (td, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.18 - 7.09 (m, 3H), 3.91 - 3.77 (m, 2H), 3.73 - 3.64 (m, 4H), 3.51 (s, 2H), 3.27 - 3.17 (m, 2H), 3.14 - 3.01 (m, 2H), 2.60 - 2.54 (m, 4H), 2.35 (s, 3H), 2.21 (s, 3H). (2 protons missing under water peak).

LCMS Method 6 - Tr = 3.74 min

m/z value = 521

Example 329. Synthesis of 2-[4-({5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]benzene-l-sulfonamide, 1-125

1-125

[001167] Prepared by reductive amination of Intermediate H with Amine 2 using the sodium triacetoxyborohydride generic method.

1H MR (500 MHz, DMSO-d6) δ 7.85 (d, J = 7.8 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.59 (dt, J = 16.2, 7.9 Hz, 3H), 7.34 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.16 - 7.08 (m, 3H), 6.91 (s, 2H), 3.88 - 3.79 (m, 2H), 3.51 (s, 2H), 3.41 - 3.35 (m, 2H), 3.27 - 3.19 (m, 2H), 3.13 - 2.99 (m, 2H), 2.99 - 2.91 (m, 4H), 2.62 - 2.53 (m, 4H), 2.36 (s, 3H), 2.21 (s, 3H).

LCMS Method 6 - Tr = 3.84 min

m/z value = 573

Example 330. Synthesis of 2-[4-(5-{[4-(2-methanesulfonylphenyl)piperazin-l-yl]

2,4-dimethylbenzoyl)piperazin-l-yl]benzonitrile, 1-124

1-124

[001168] Prepared by reductive amination of Intermediate H with Amine 24 using the sodium triacetoxyborohydride generic method.

1H MR (500 MHz, DMSO-d6) δ 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.74 - 7.67 (m, 2H), 7.64 - 7.57 (m, 2H), 7.41 (t, J = 7.7 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.16 - 7.08 (m, 3H), 3.88 - 3.79 (m, 2H), 3.51 (s, 2H), 3.41 (s, 3H), 3.39 - 3.35 (m, 2H), 3.27 - 3.17 (m, 2H), 3.15 - 3.00 (m, 2H), 3.00 - 2.93 (m, 4H), 2.63 - 2.53 (m, 4H), 2.36 (s, 3H), 2.21 (s, 3H).

LCMS Method 6 - Tr = 4.04 min

m/z value = 572 Example 331. Synthesis of 3-[4-({5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]pyrazine-2-carbonitrile , 1-123

1-123

[001169] Prepared by reductive amination of Intermediate H with Amine 18 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, DMSO-d6) δ 8.44 (d, J = 2.2 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 7.73 (dd, J = 7.7, 1.5 Hz, 1H), 7.65 - 7.58 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.11 (s, 2H), 3.84 (s, 2H), 3.74 - 3.68 (m, 4H), 3.49 (s, 2H), 3.23 (s, 2H), 3.06 (s, 2H), 2.57 - 2.52 (m, 4H), 2.34 (s, 3H), 2.21 (s, 3H). (2 protons missing under water peak).

LCMS Method 6 - Tr = 4.1 min

m/z value = 521

Example 332. Synthesis of 2-[4-(2,4-dimethyl-5-{[2-(trifluoromethyl)-5H,6H,7H,8H- imidazo[l,2-a]pyrazin- -yl]methyl}benzoyl)piperazin-l-yl]benzonitrile, 1-122

1-122

[001170] Prepared by reductive amination of Intermediate H with Amine 81 using the sodium triacetoxyborohydride generic method.

1H MR (500 MHz, DMSO-d6) δ 7.75 - 7.69 (m, 2H), 7.61 (t, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.17 - 7.10 (m, 3H), 4.01 (t, J = 5.4 Hz, 2H), 3.88 - 3.80 (m, 2H), 3.72 - 3.59 (m, 4H), 3.26 - 3.18 (m, 2H), 3.14 - 2.99 (m, 2H), 2.91 - 2.81 (m, 2H), 2.53 (d, J = 1.9 Hz, 2H), 2.33 (s, 3H), 2.22 (s, 3H). LCMS Method 7 - Tr = 3.47 min

m/z value = 523 Example 333. Synthesis of 2-(4-{2,4-dimethyl-5-[(4-phenylpiperazin-l- yl)methyl]benzoyl}piperazin-l-yl)benzonitrile, 1-69

1-69

[001171] Prepared by reductive amination of Intermediate H with Amine 71 using the sodium triacetoxyborohydride generic method.

lH MR (500 MHz, DMSO-d6) δ 7.73 (dd, J = 7.7, 1.5 Hz, 1H), 7.64 - 7.57 (m, 1H), 7.23 - 7.16 (m, 3H), 7.14 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 2.8 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 6.77 (t, J = 7.2 Hz, 1H), 3.89 - 3.80 (m, 2H), 3.48 (s, 2H), 3.39 - 3.33 (m, 2H), 3.26 - 3.19 (m, 2H), 3.15 - 3.10 (m, 4H), 3.10 - 3.02 (m, 2H), 2.54 - 2.52 (m, 4H), 2.34 (s, 3H), 2.21 (s, 3H).

LCMS Method 6 - Tr = 4.58 min

m/z value = 494

Example 334. Synthesis of 3-[4-({5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)piperazin-l-yl]pyridine-2-carbonitrile , 1-66

1-66

[001172] Prepared by reductive amination of Intermediate H with Amine 12 using the sodium triacetoxyborohydride generic method.

1H MR (500 MHz, DMSO-d6) a 8.27 (dd, J = 4.4, 1.2 Hz, 1H), 7.73 (dd, J = 7.7, 1.5 Hz, 1H), 7.69 - 7.56 (m, 3H), 7.20 (d, J = 8.3 Hz, 1H), 7.17 - 7.07 (m, 3H), 3.90 - 3.79 (m, 2H), 3.52 (s, 2H), 3.38 - 3.33 (m, 2H), 3.26 - 3.16 (m, 6H), 3.16 - 2.92 (m, 2H), 2.62 - 2.55 (m, 4H), 2.35 (s, 3H), 2.21 (s, 3H).

LCMS Method 6 - Tr = 4.04 min m/z value = 520

Example 335. Synthesis of 2-(4-{5-[(4-{2-[imino(methyl)oxo- ⁶ -sulfanyl]phenyl}piperazin-l- yl)methyl]-2,4-dimethylbenzoyl}piperazin-l-yl)benzonitrile, 1-72

1-72

[001173] Prepared by reductive amination of Intermediate H with Amine 80 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, Chloroform-d) δ 8.01 (dd, J = 7.9, 1.5 Hz, 1H), 7.58 (dd, J = 7.7, 1.5 Hz, 1H), 7.55 (td, J = 7.9, 1.6 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.41 (dd, J = 8.0, 1.0 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.13 (s, 1H), 7.08 - 6.99 (m, 3H), 4.10 - 3.97 (m, 2H), 3.50 (d, J = 13.3 Hz, 4H), 3.44 (s, 3H), 3.30 - 3.22 (m, 2H), 3.17 - 2.97 (m, 7H), 2.81 - 2.45 (m, 4H), 2.37 (s, 3H), 2.29 (s, 3H). LCMS Method 7 - Tr = 2.04 min

m/z value = 571

Example 336. Synthesis of 2-(4-{2,4-dimethyl-5-[(2-phenylmorpholin-4- yl)methyl]benzoyl}piperazin-l-yl)benzonitrile, 1-52

1-52

[001174] Prepared by reductive amination of Intermediate H with Amine 50 using the sodium triacetoxyborohydride generic method.

1H MR (500 MHz, Chloroform-d) δ 7.59 (dd, J = 7.7, 1.6 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.35 - 7.27 (m, 4H), 7.25 - 7.15 (m, 1H), 7.13 - 7.05 (m, 2H), 7.04 (s, 1H), 7.03 - 6.90 (m, 1H), 4.50 (dd, J = 10.2, 2.3 Hz, 1H), 4.19 - 3.70 (m, 4H), 3.53 - 3.37 (m, 4H), 3.31 - 3.15 (m, 2H), 3.15 - 3.01 (m, 1H), 3.01 - 2.89 (m, 1H), 2.89 - 2.78 (m, 1H), 2.72 (d, J = 11.2 Hz, 1H), 2.37 (s, 3H), 2.33 - 2.23 (m, 4H), 2.18 - 2.06 (m, 1H).

LCMS Method 6 - Tr = 2.48 min

m/z value = 495

Example 337. Synthesis of 2-{4-[5-({3-[(2-cyanophenyl)amino]pyrrolidin-l-yl}methyl)-2, 4- dimethylbenzoyl]piper

1-55

[001175] Prepared by reductive amination of Intermediate H with Amine 52 using the sodium triacetoxyborohydride generic method.

lH MR (500 MHz, Chloroform-d) δ 7.58 (dd, J = 7.7, 1.5 Hz, 1H), 7.51 (td, J = 8.3, 1.6 Hz, 1H), 7.38 - 7.28 (m, 2H), 7.06 (td, J = 7.6, 0.9 Hz, 2H), 7.03 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.66 - 6.57 (m, 2H), 4.73 (d, J = 7.1 Hz, 1H), 4.10 - 3.95 (m, 3H), 3.59 (s, 2H), 3.51 - 3.40 (m, 2H), 3.25 (s, 2H), 3.16 - 2.99 (m, 2H), 2.88 - 2.72 (m, 2H), 2.56 (d, J = 7.8 Hz, 1H), 2.46 (s, 1H), 2.36 (s, 3H), 2.35 - 2.30 (m, 1H), 2.28 (s, 3H), 1.70 (s, 1H).

LCMS Method 7 - Tr = 2.45 min

m/z value = 519

Example 338. Synthesis of 2-{4-[5-({3-[(2-cyanophenyl)amino]azetidin-l-yl}methyl)-2,4- dimethylbenzoyl]piperaz -l-yl}benzonitrile, 1-54

1-54

[001176] Prepared by reductive amination of Intermediate H with Amine 53 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, Chloroform-d) δ 7.58 (dd, J = 7.7, 1.6 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.39 (dd, J = 7.7, 1.5 Hz, 1H), 7.37 - 7.33 (m, 1H), 7.10 (s, 1H), 7.07 (td, J = 7.6, 0.8 Hz, 1H), 7.03 (s, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.72 - 6.67 (m, 1H), 6.49 (d, J = 8.4 Hz, 1H), 4.77 (d, J = 6.3 Hz, 1H), 4.22 - 4.13 (m, 1H), 4.11 - 3.96 (m, 2H), 3.86 - 3.73 (m, 2H), 3.61 (d, J = 9.1 Hz, 2H), 3.52 - 3.43 (m, 2H), 3.30 - 3.22 (m, 2H), 3.14 - 3.05 (m, 2H), 3.03 - 2.89 (m, 2H), 2.31 (s, 3H), 2.28 (s, 3H).

LCMS Method 7 - Tr = 2.45 min

m/z value = 505

Example 339. Synthesis of 2-[5-({5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl} methyl)-octahy dropyrrolo [3,4-c] pyrrol-2-yl] benzonitrile, 1-53

1-53

[001177] Prepared by reductive amination of Intermediate H with Amine 51 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, Chloroform-d) δ 7.59 (dd, J = 7.7, 1.6 Hz, 1H), 7.51 (ddd, J = 8.3, 7.6, 1.6 Hz, 1H), 7.45 (dd, J = 7.8, 1.6 Hz, 1H), 7.35 (ddd, J = 8.8, 7.3, 1.7 Hz, 1H), 7.10 - 7.04 (m, 2H), 7.02 - 6.98 (m, 2H), 6.78 - 6.73 (m, 1H), 6.72 (d, J = 8.6 Hz, 1H), 4.01 (s, 2H), 3.70 (s, 2H), 3.55 (s, 2H), 3.47 (t, J = 4.5 Hz, 2H), 3.41 - 3.31 (m, 2H), 3.24 (t, J = 4.5 Hz, 2H), 3.16 - 3.02 (m, 2H), 2.97 - 2.85 (m, 2H), 2.73 - 2.62 (m, 2H), 2.56 - 2.45 (m, 2H), 2.31 (s, 3H), 2.28 (s, 3H).

LCMS Method 7 - Tr = 4.59 min

m/z value = 545

Example 340. Synthesis of 2-{3-[({5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylphenyl}methyl)amino]pyrrolidin-l-yl}benzonitrile, 1-50

1-50

[001178] Prepared by reductive amination of Intermediate H with Amine 75 using the sodium triacetoxyborohydride generic method.

1H NMR (500 MHz, Chloroform-d) δ 7.58 (dd, J = 7.7, 1.5 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.43 (dd, J = 7.8, 1.3 Hz, 1H), 7.32 (ddd, J = 8.8, 7.2, 1.7 Hz, 1H), 7.14 (s, 1H), 7.07 (td, J = 7.6, 0.9 Hz, 1H), 7.04 - 6.99 (m, 2H), 6.69 - 6.60 (m, 2H), 4.03 (d, J = 34.6 Hz, 2H), 3.89 - 3.69 (m, 4H), 3.66 - 3.57 (m, 1H), 3.56 - 3.42 (m, 4H), 3.25 (t, J = 5.0 Hz, 2H), 3.14 - 3.04 (m, 2H), 2.33 (s, 3H), 2.28 (s, 3H), 2.23 - 2.14 (m, 1H), 1.96 - 1.88 (m, 1H), 1.45 - 1.22 (m, 1H).

LCMS Method 7 - Tr = 2.53 min

m/z value = 519

Example 341. Synthesis of 2-(4-{2,4-Dimethyl-5-[4-(pyridazin-3-yl)piperazine-l- carbonyl]benzenesulfonyl}piperazin-l-yl)benzonitrile, 1-330

1-330

[001179] 2-(Piperazin-l-yl)benzonitrile hydrochloride [Intermediate 68] (90 mg, 0.4 mmol) and sulphonyl chloride (100 mg, 0.4 mmol) were dissolved in ethyl acetate (5 ml) then DIPEA (0.175 ml, 1 mmol) was added under nitrogen atmosphere and stirred for 40 minutes. The reaction was concentrated in vacuo to yield ethyl bis(propan-2-yl)azanium 5-{[4-(2- cyanophenyl)piperazin-l -yl]sulfonyl}-2,4-dimethylbenzoate as a pale yellow semi-solid (280 mg, 100%).

[001180] Crude ethylbis(propan-2-yl)azanium 5-{[4-(2-cyanophenyl)piperazin-l- yl]sulfonyl}-2,4-dimethylbenzoate (0.2 mmol) was dissolved in anhydrous DMF (2 ml) under nitrogen atmosphere. DIPEA (107 μΐ, 0.6 mmol), 3-(piperazin-l-yl)pyridazine (32.8 mg, 0.2 mmol) and HATU (83.7 mg, 0.22 mmol) were added and the reaction mixture was stirred at rt for 90 minutes. The reaction was purified by preparative HPLC [Generic UV-Directed low pH prep method] to yield the title compound as a white solid (20.9 mg, 19%).

[001181] 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 4.5 Hz, 1H), 7.73 (dd, J = 7.7, 1.6 Hz, 1H), 7.68 (s, 1H), 7.66 - 7.59 (m, 1H), 7.50 (d, J = 9.5 Hz, 1H), 7.46 (s, 1H), 7.35 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 3.81 (s, 4H), 3.58 (s, 3H), 3.22 (s, 9H), 2.62 (s, 3H), 2.32 (s, 3H).

LCMS Method 7 - Tr = 2.61 min (ES ⁺ ) (M+H ⁺ ) 546.2

Example 342. Synthesis of 2-(4-{5-[4-(2-cyanophenyl)piperazine-l-carbonyl]-2,4- dimethylbenzenesulfonyl}piperidin-l-yl)benzonitrile, 1-331

1-331

[001182] 5-{[l-(2-cyanophenyl)piperidin-4-yl]sulfonyl}-2,4-dimethylbe nzoic acid [Intermediate 87] (6.6 mg, 0.017 mmol) in DMF (anhydrous, 0.2 mL) under nitrogen was treated with 2-(piperazin-l-yl)benzonitrile hydrochloride (3.7 mg, 0.017 mmol), HATU (6.9 mg, 0.018 mmol) and DIPEA (8.9 μΕ, 0.050 mmol) added and the reaction mixture stirred at rt for 5 minutes when all had dissolved giving a yellow solution then the reaction was allowed to stand overnight. The reaction was purified by preparative HPLC [Generic UV-Directed low pH prep method] to yield the title compound as a pale yellow gum (2.9 mg, 31%).

[001183] 1H NMR (500 MHz, Methanol-d4) δ 7.77 (s, 1H), 7.66 (dd, J = 7.7, 1.4 Hz, 1H), 7.60 (dd, J = 7.6, 1.5 Hz, 2H), 7.58 - 7.52 (m, 1H), 7.34 (s, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.15 (dt, J = 7.5, 3.5 Hz, 2H), 7.08 (td, J = 7.6, 0.9 Hz, 1H), 4.72 - 4.46 (m, 2H), 4.21 - 3.89 (m, 2H), 3.65 - 3.34 (m, 5H), 3.23 - 2.97 (m, 4H), 2.56 (s, 3H), 2.41 (s, 3H), 2.26 - 2.13 (m, 1H), 2.05 - 1.97 (m, 1H), 1.97 - 1.74 (m, 2H).

LCMS Method 7 - Tr = 4.01 min, (ES ⁺ ) (M+H ⁺ ) 568.2 Example 343. Synthesis of 2-(4-(5-(4-(2-Cyanophenyl)piperazin-l-yl)-2,6- dimethylnicotinoyl)piperaz -l-yl)benzonitrile, 1-333

1-333

Synthetic scheme:

Procedures and characterization:

The analysis method was following Method B and the separation method was following Method D.

Step 1 : 2-(4-(5-Bromo-2,6-dimethylpyridin-3-yl)piperazin-l-yl)benzon itrile

[001184] The procedure for 2-(4-(5-bromo-2,6-dimethylpyridin-3-yl)piperazin-l- yl)benzonitrile was same as for Example 23. ESI-MS (EI+, m/z): 371.0 [M+H] ⁺ .

Step 2: 2-(4-(2,6-Dimethyl-5-vinylpyridin-3-yl)piperazin-l-yl)benzon itrile

[001185] To a solution of 2-(4-(5-bromo-2,6-dimethylpyridin-3-yl)piperazin-l- yl)benzonitrile (400 mg, 1.08 mmol) and vinyltrifluoroboric acid potassium(434 mg, 3.24 mmol) in CH ₃ CN (20 mL) and H ₂ 0 (4 mL) was added Pd(dppf)Cl ₂ (88.2 mg, 0.11 mmol) and K ₂ C0 ₃ (298 mg, 2.16 mmol). The mixture was stirred at 80 °C for 16 h. The resulting mixture was diluted with EtOAc (200mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S04, filtered and concentrated to give 2-(4-(2,6-dimethyl-5-vinylpyridin-3- yl)piperazin-l-yl)benzonitrile (340 mg, crude) which was used for the next step directly. ESI-MS (EI+, m/z): 319.1 [M+H] ⁺ .

Step 3: 2-(4-(5-Formyl-2,6-dimethylpyridin-3-yl)piperazin-l-yl)benzo nitrile

[001186] To a solution of 2-(4-(2,6-dimethyl-5-vinylpyridin-3-yl)piperazin-l-yl)benzon itrile (290 mg, crude) in acetone (30 mL) and H ₂ 0 (6 mL) was added Potassium osmate(VI) dihydrate (15.14 mg, 45.54 umol), MO (10.67 mg, 91.08 umol) and NaI0 ₄ (194 mg, 0.91 mmol). The mixture was stirred at rt for 16h. The resulting mixture was diluted with EtOAc (200mL), and washed with water (50mL x 2) and brine (50mL). The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by column chromatography on silica to give 2- (4-(5-formyl-2,6-dimethylpyridin-3-yl)piperazin-l-yl)benzoni trile (220 mg, 0.69 mmol, 75.39%) as a yellow solid. ESI-MS (EI+, m/z): 321.0 [M+H] ⁺ .

Step 4: 5-(4-(2-Cyanophenyl)piperazin-l-yl)-2,6-dimethylnicotinic acid

[001187] To a solution of 2-(4-(5-formyl-2,6-dimethylpyridin-3-yl)piperazin-l- yl)benzonitrile (200 mg, 0.62 mmol) in CH ₃ CN (15 mL) and water (3 mL) was added NaC10 ₂ (226 mg, 2.5 mmol), NaH ₂ P0 ₄ (150 mg, 1.25 mmol) and H ₂ 0 ₂ (84.9 mg, 2.5 mmol). The mixture was stirred at rt for 2h, then quenched with Na ₂ S0 ₃ , diluted with EA(200 mL), and washed with water(50 mL) and brine(50 mL). The organic phase was dried and concentrated to give 5-(4-(2- cyanophenyl)piperazin-l-yl)-2,6-dimethylnicotinic acid (190 mg, crude) as a white solid. ESI-MS (EI+, m/z): 336.9 [M+H] ⁺ .

Step 5: 2-(4-(5-(4-(2-Cyanophenyl) piperazin-l-yl)-2,6-dimethylnicotinoyl)piperazin-l- yl)benzonitrile, 1-333

[001188] Followed the amide coupling HATU method to obtain 2-(4-(5-(4-(2- cyanophenyl)piperazin- 1 -yl)-2,6-dimethylnicotinoyl)piperazin- 1 -yl)benzonitrile, 1-333. ESI-MS (EI+, m/z): 506.0 [M+H] ⁺ . ¾- MR (500 MHz, CD ₃ OD)5: 7.47-7.55 (m, 4H), 7.37 (s, 1H), 7.09- 7.14 (m, 2H), 6.99-7.05 (m, 2H), 3.91 (d, J= 3.5 Hz, 2H), 3.42 (d, J= 3.0 Hz, 2H), 3.20-3.28 (m, 5H), 3.04-3.06 (m, 7H), 2.47 (s, 3H), 2.35 (s, 3H).

Example 344. Synthesis of l-(2-Cyanophenyl)-N-(2,4-dimethyl-5-(4-(2- sulfamoylphenyl)piperazine-l-carbonyl)phenyl)piperidine-4-ca rboxamide, 1-332

1-332

Synthetic scheme:

³ 1-332

Procedures and characterization:

The analysis method was following Method B and the separation method was following Method D.

Step 1: Methyl l-(2-cyanophenyl)piperidine-4-carboxylate

[001189] A mixture of methyl piperidine-4-carboxylate (1.50 g, 10.48 mmol), 2- fluorobenzonitrile (1.27 g, 10.48 mmol) and K ₂ C0 ₃ (3.62 g, 26.20 mmol) in DMSO (15.00 mL) was kept stirring at 120 °C for 2 h. The mixture was diluted with EtOAc (200 mL), washed with water (50 mL x 3) and brine (40 mL). The organic layer was dried over Na ₂ S0 ₄ for 20 mins, filtered and concentrated under vacuum. The residue was purified by CombiFlash ^® (UV 254, silica gel, 40 g, EA/PE from 20%~70%) to give the product methyl l-(2-cyanophenyl)piperidine-4- carboxylate (1.98 g, 8.11 mmol, 77.39% yield) as yellow solid. ESI-MS (EI ⁺ , m/z): 245.2 [M+H] Step 2: l-(2-Cyanophenyl)piperidine-4-carboxylic acid

[001190] A mixture of methyl l-(2-cyanophenyl)piperidine-4-carboxylate (500.00 mg, 2.05 mmol), LiOH-HiO (490.98 mg, 20.50 mmol), THF (20.00 mL) and water (20.00 mL) was kept stirring at 50 °C for 2 h. The mixture was adjusted to pH 4 with sat. Na ₂ C03 aqueous solution and extracted with EtOAc (30 mL x 3). The organic layer was washed with water (15 mL x 2) and brine (15 mL). The organic layer was dried over Na ₂ S0 ₄ for 20 mins, filtered and concentrated under vacuum to give the product l-(2-cyanophenyl)piperidine-4-carboxylic acid (400.00 mg, 1.74 mmol, 84.74% yield) as a yellow solid. ESI-MS (EI ⁺ , m/z): 368.1 [M+H] ⁺ . ¾ MR (500 MHz, OMSO-d ₆ ) δ 12.30 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 3.44 (d, J= 12.1 Hz, 2H), 2.90 - 2.81 (m, 2H), 2.42 (tt, J = 10.9, 3.9 Hz, 1H), 1.96 (dd, J= 13.1, 2.7 Hz, 2H), 1.79 - 1.67 (m, 2H).

Step 3: l-(2-Cyanophenyl)-N-(2,4-dimethyl-5-(4-(2-sulfamoylphenyl)pi perazine-l- carbonyl)phenyl)piperidine-4-carboxamide

[001191] Followed the amide coupling EDCI/HOBT method to give the product l-(2- cyanophenyl)-N-[2,4-dimethyl-5-[4-(2-sulfamoylphenyl)piperaz ine-l- carbonyl]phenyl]piperidine-4-carboxamide 1-332 as a white solid. ESI-MS (EI ⁺ , m/z): 601.4 [M+H] ⁺ . ¾NMR (500 MHz, OMSO-d ₆ ) δ 7.96 (d, J= 7.8 Hz, 1H), 7.66 (d, J= 7.6 Hz, 2H), 7.56 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 60.2 Hz, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H),

6.81 (s, 1H), 6.43 (s, 1H), 4.79 (s, 2H), 4.03 - 3.70 (m, 2H), 3.49 - 3.36 (m, 4H), 2.91 (s, 2H),

2.82 - 2.73 (m, 4H), 2.45 - 2.36 (m, 1H), 2.07 (s, 3H), 2.03 (s, 3H), 1.79 (d, J = 11.6 Hz, 2H), 1.57 (dd, J = 20.7, 11.2 Hz, 2H).

Example 345: (S)-4-(4-(5-(4-(2-Cyanophenyl) piperazin-l-ylsulfonyl)-2, 4-dimethylb

3-methylpiperazin-l-yl)-2 5-difluorobenzonitrile, 1-343

1-343 Synthetic scheme:

Procedures and characterization:

[001192] The analysis method was following Method B and the separation method was following Method D.

(S)-4-(4-(5-(4-(2-Cyanophenyl)piperazin-l-ylsulfonyl)-2,4-di methylbenzoyl)-3- methylpiperazin-l-yl)-2,5-difluorobenzonitrile, 1-343:

The procedure was as similar as that of Example 66.

ESI-MS (EI ⁺ , m/z): 619.2[M+H] ⁺ . ¾ MR (500 MHz, OMSO-d ₆ ) δ 7.74-7.81 (m, 1 H), 7.59- 7.61 (d, J= 7.7 Hz, 1 H), 7.52-7.56 (t, 1 H), 7.23-7.29 (m, 2 H), 7.09-7.12 (t, 1 H), 7.02-7.04 (d, J = 8.3 Hz, 1 H), 6.63-6.72 (m, l H), 4.68-5.12 (m, 1 H), 2.99-3.65 (m, 14 H), 2.67 (s, 3 H), 2.35- 2.43 (m, 3 H), 1.28-1.51 (m, 3 H).

Example 346: AlphaLISA Ultra pS6Kl assay Table 12: Key Reagents/Supplies

[001193] Assay Protocol: 1. Seed MCF-7 cells in Corning 3701 plate and incubate for 20-24 hour. 12,000-16,000 cells will be seeded in 36 μΐ. medium per well.

2. Change the culture medium with fresh medium and incubate for another 2 hours.

3. Add 12 μL· (4X) compounds into the cell plate by HAMILTON. Final DMSO concentration is 0.5%. Incubate for 2 hours.

4. Aspirate 38 by HAMILTON, 10 rest per well.

5. Add 10 μL 2X lysis buffer using HAMILTON; total volume in wells is 20 μL·. Allow cells to shake for 30 min. Cover plate by plastic foil and store plate at -80 °C up to analysis.

6. Thaw cell lysate at RT and transfer 10 ul lysate to assay plate (Optiplate-384).

7. Add 5 ul acceptor beads into assay plate and incubation for 2 hours

8. Add 5 ul donor beads and incubation for 2 hours

9. Count the plate by EnSpire Multimode Plate Reader

Example 347: AlphaLISA Ultra pAKT assay Table 13: Key Reagents/Supplies

[001194] Assay Protocol:

1. MCF-7 cells in Corning 3701 plate and incubate for 20-24 hour. 16,000-20,000 cells will be seeded in 36 μΕ medium per well.

2. Change the culture medium with fresh medium and incubate for another 2 hours. 3. Add 12 μL· (4X) compounds into the cell plate by HAMILTON. Final DMSO concentration is 0.5%. Incubate for 2 hours.

4. Aspirate 38 by HAMILTON, 10 rest per well.

5. Add 10 μL 2X lysis buffer using HAMILTON; total volume in wells is 20 μL·. Allow cells to shake for 30 min. Cover plate by plastic foil and store plate at -80 °C up to analysis.

6. Thaw cell lysate at RT and transfer 10 ul lysate to assay plate (Optiplate-384).

7. Add 5 ul acceptor beads into assay plate and incubation for 2 hours

8. Add 5 ul donor beads and incubation for 2 hours

9. Count the plate by EnSpire Multimode Plate Reader

Example 348: Radioactive Glucose Uptake in MCF-7 Cells

[001195] Assay Protocol

1. Seed approximately 12,000 MCF-7 cells cultured without insulin per well in 96-well plates (BIOCOAT, #356690) and let the cells sit in hood for 30 min. (Cell culture medium: DMEM+10% FBS).

2. Put the cell culture plates in TC incubator (5% C0 ₂ , 37°C) and incubate overnight.

3. Take out the cell plates and wash with prewarmed KRH buffer (37°C) three times using BioTek plate washer. (KRH buffer preparation: 136 mM NaCl, 4.7 mM KCl, 1.25 mM MgCb, 1.2mM CaCl ₂ , 20 mM HEPES, 0.1 mg/ml sodium pyruvate, 0.1%BS A, pH 7.4).

4. Compound preparation and treatment:

a) Add 12 ul compound stock in 100% DMSO to the first column of Echo LDV plate b) Serially dilute the compound solution in 100% DMSO (4 uL+8uL DMSO) using Bravo for 9 doses

c) Dispense 350 nL compounds using Echo to the working plate. For HPE dispense 350 nL 3.3 mM NV5440; for ZPE dispense 350 nL DMSO

d) i) Without compound preincubation condition, dispense 116 uL KRH buffer containing tritiated 2-deoxy-D-glucose (3H-2DG) and 2-deoxy-D-glucose (2DG) to the working plate and mix.

ii) With compound preincubation condition, dispense 110 uL KRH buffer only to the working plates and mix

e) Keep the compound working plate at 37°C incubator until use 5. Discard the KRH buffer (cells were kept in KRH buffer for 10-15 min before 2-DG addition) and transfer 100 uL compound working solution out to the cell culture plate using Bravo. Incubate for 20mins at 37°C. (2DG final at 0.2mM, 3H-2DG at lOuCi/mL).

6. Add prewarmed 50uL KRH buffer (37°C) containing 60mM cold 2DG to the wells to stop the 2DG uptake using Multidrop combi

7. Wash the cells with prewarmed PBS three times using BioTek plate washer

8. Add 50uL lysis buffer (0.1 M NaOH ) into the assay plate to lyse the cells using Bravo and shake at 800 rpm for 30 min.

9. Mix and transfer 20 uL lysate to a new white plate (Corning, #3610) and add 200uL MicroScint-20 using Bravo

10. Shake the plate at 1000 rpm for 30 min and count in a MicroBeta plate reader.

Example 349: ATP/Rotenone Assay

[001196] Assay Protocol

Day 1: Plate cells in Corning 96-Well Clear Bottom Black Polystyrene Microplates (corning 3340) in Glucose-free DMEM + 10% dFBS

- 80 uL/well

- 25,000 cells/well for 293 T

- 10,000 cells/well for MCF7

Day 2:

Glucose DR to establish glucose ECso

1. lh pre-treat with lOuM Rotenone

add 1 OuL if 9x (90uM) rotenone to each well (freshly made 1 OmM stock diluted 1 : 11 lx in glucose-free DMEM.

2. Stimulate with glucose for 15 min

Make glucose DR at lOx concentration in glucose-free DMEM

Add lOuL per well and incubate at 37°C for 15min

3. Reconstitute and Measure

Remove plate, immediately add 1 OOuL of reconstituted Celltiter-Glo reagent (Promega; G7570) per well

Shake plate covered for lOmin at room temperature Let plate sit for 2-5 min, read luminescence

- Calculate EC50 for glucose (usually -lmM for 293T cells and ~0.25mM for MCF-7 cells).

Determine Compound ICsos

1. lh pre-treat Rotenone/compound solution

Make 9X (90uM) rotenone: lOmM stock of Rotenone fresh - dilute 1 : 11 IX in Glucose- free DMEM).

Make compound dilution series in DMSO then dilute 1 : 111 in 90uM rotenone in glucose-free media

Add lOuL of 9X rotenone/compound solutions per well

2. Stimulate with glucose for 15 min

Make glucose DR at lOx concentration in glucose-free DMEM

Add lOuL per well and incubate at 37°C for 15min

3. Reconstitute and Measure

Remove plate, immediately add 1 OOuL of reconstituted Celltiter-Glo reagent (Promega; G7570) per well

Shake plate covered for lOmin at room temperature

Let plate sit for 2-5 min, read luminescence

Calculate IC50 for compounds

[001197] Table 14 shows the inhibitory activity (IC50) of selected compounds of this invention in the pS6Kl, pAKT, and glucose uptake assays. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as "A" provided inhibitory activity (IC50) of 0.01-1 μΜ; compounds designated as "B" provided inhibitory activity (IC50) of 1-3 μΜ; compounds designated as "C" provided inhibitory activity (IC50) of 3-10 μΜ; compounds designated as "D" provided inhibitory activity (IC50) >1 μΜ; compounds designated as "E" provided inhibitory activity (IC50) >3 μΜ and compounds designated as "F" provided inhibitory activity (IC50) >10 μΜ.

Table 14: Assay Data for Exemplary Compounds Compound pS6Kl in MCF7 pAKT in MCF7 Glucose uptake in MCF7: Number ICso (μΜ) ICso (μΜ) ICso (μΜ)

1-1 A F NA

1-2 B F B

1-4 A F NA

1-6 B F NA

1-7 A F NA

1-8 A F NA

1-9 B F NA

1-10 A F NA

1-11 A F NA

1-12 A F NA

1-13 A F NA

1-14 B F NA

1-15 B F NA

1-16 A E NA

1-17 A F NA

1-18 A F NA

1-19 B F NA

1-20 B F NA

1-21 A F A

1-22 C F NA

1-23 C F NA

1-24 A F F

1-25 A F NA

1-26 B F NA

1-27 C F NA

1-28 A F NA

1-29 A F NA

1-30 C F NA

1-31 A F NA

1-32 B F NA

1-33 A F NA

1-36 A D A

1-37 A F NA

1-38 A F NA

1-39 A E NA

1-40 A F NA

1-41 B F F Compound pS6Kl in MCF7 pAKT in MCF7 Glucose uptake in MCF7: Number ICso (μΜ) ICso (μΜ) ICso (μΜ)

1-42 B F NA

1-43 B F NA

1-44 A F NA

1-45 C F F

1-46 B F B

1-47 A F NA

1-48 B F NA

1-49 B F NA

1-50 B F NA

1-51 B F NA

1-52 C F NA

1-53 A F NA

1-54 B F NA

1-55 B F NA

1-56 A F NA

1-57 B F NA

1-58 B F NA

1-59 C F NA

1-60 A F NA

1-61 A F NA

1-62 C F NA

1-63 C F NA

1-64 C F NA

1-65 A F NA

1-66 A F NA

1-67 A F NA

1-68 A F NA

1-69 A F NA

1-70 C F NA

1-71 C F NA

1-72 B F NA

1-73 A F NA

1-74 B F NA

1-76 C F NA

1-77 A F NA

1-78 A F NA

1-79 A F NA Compound pS6Kl in MCF7 pAKT in MCF7 Glucose uptake in MCF7: Number ICso (μΜ) ICso (μΜ) ICso (μΜ)

1-80 B F NA

1-81 B F C

1-82 B F NA

1-83 A F NA

1-84 B F A

1-85 B F NA

1-86 A F A

1-87 B F NA

1-88 C F F

1-89 A F NA

1-90 A F A

1-91 A F NA

1-92 B F NA

1-95 C F NA

1-96 C F NA

1-97 B F NA

1-98 A F A

1-99 C F F

1-100 C F NA

1-101 B F NA

1-102 C F B

1-103 B F A

1-104 A F A

1-105 B F NA

1-106 A F NA

1-107 A F NA

1-108 A F NA

1-109 A F NA

1-110 B F C

1-111 A F NA

1-112 A F NA

1-113 A F A

1-114 B F NA

1-115 A F NA

1-116 C F NA

1-117 C F NA

1-118 A F NA Compound pS6Kl in MCF7 pAKT in MCF7 Glucose uptake in MCF7: Number ICso (μΜ) ICso (μΜ) ICso (μΜ)

1-119 A F NA

1-120 A F A

1-122 C F NA

1-123 B F NA

1-124 B F NA

1-125 B F NA

1-126 B F NA

1-128 B F NA

1-129 C F NA

1-130 A F A

1-131 C F NA

1-132 A F NA

1-133 A F NA

1-134 A F NA

1-135 A F NA

1-136 C F NA

1-137 A F NA

1-138 A F NA

1-139 C F NA

1-140 C F NA

1-141 A F NA

1-142 B F NA

1-143 C F NA

1-144 C F NA

1-145 B F NA

1-146 C F NA

1-147 A F NA

1-148 B F NA

1-149 A F NA

1-150 B F NA

1-151 C F B

1-152 B F NA

1-153 C F NA

1-154 B F NA

1-155 B F NA

1-156 A F NA

1-157 B F NA Compound pS6Kl in MCF7 pAKT in MCF7 Glucose uptake in MCF7: Number ICso (μΜ) ICso (μΜ) ICso (μΜ)

1-158 B F NA

1-159 A F A

1-160 C F NA

1-161 B F NA

1-165 A F NA

1-168 C F F

1-169 C F NA

1-170 C F NA

1-171 C F NA

1-172 C F NA

1-173 A F A

1-174 B F NA

1-175 A F NA

1-176 B F NA

1-177 B F NA

1-178 B F NA

1-179 C F NA

1-180 B F NA

1-181 A F NA

1-182 A F A

1-183 C F NA

1-184 B F NA

1-185 B F NA

1-186 B F NA

1-187 B F NA

1-188 A F NA

1-189 B F NA

1-190 B F NA

1-191 B F NA

1-192 B F B

1-193 C F NA

1-195 C F F

1-196 C F NA

1-197 C F NA

1-198 C F NA

1-199 A F NA

1-200 A E NA Compound pS6Kl in MCF7 pAKT in MCF7 Glucose uptake in MCF7: Number ICso (μΜ) ICso (μΜ) ICso (μΜ)

1-201 A F NA

1-202 B E NA

1-203 A F B

1-204 A F NA

1-205 A F NA

1-206 B F NA

1-207 B F NA

1-208 A F NA

1-209 A F NA

1-210 A F NA

1-211 A F NA

1-212 A F NA

1-213 A F NA

1-214 A F NA

1-215 A F A

1-216 B F NA

1-217 C F NA

1-218 C F NA

1-219 B F NA

1-220 B F NA

1-221 A F NA

1-222 B F NA

1-223 A F NA

1-224 B F NA

1-225 A E NA

1-226 A F NA

1-227 A F NA

1-228 A F NA

1-229 B F F

1-230 B F NA

1-231 B F A

1-232 C F NA

1-233 B F C

1-234 A F NA

1-235 B F NA

1-236 A F NA

1-237 C F NA Compound pS6Kl in MCF7 pAKT in MCF7 Glucose uptake in MCF7: Number ICso (μΜ) ICso (μΜ) ICso (μΜ)

1-238 B F NA

1-239 C F NA

1-240 B F NA

1-241 B F NA

1-242 A F NA

1-243 A F NA

1-244 C F NA

1-245 B F NA

1-246 A F NA

1-247 A F NA

1-248 B F NA

1-249 B F NA

1-250 B F NA

1-251 A F NA

1-252 A F A

1-253 C F NA

1-254 B F NA

1-255 A E NA

1-256 B F NA

1-257 B E NA

1-258 B F NA

1-259 A F NA

1-260 B F NA

1-261 A E NA

1-262 A F A

1-263 A E NA

1-264 A E NA

1-265 C F NA

1-266 C F NA

1-267 B F NA

1-268 B F NA

1-269 A F F

1-270 A F NA

1-271 B F NA

1-272 B F NA

1-273 B F NA

1-274 A F NA Compound pS6Kl in MCF7 pAKT in MCF7 Glucose uptake in MCF7: Number ICso (μΜ) ICso (μΜ) ICso (μΜ)

1-275 A F NA

1-276 B F NA

1-277 B F NA

1-278 B F NA

1-279 B F NA

1-280 B F B

1-281 B E NA

1-282 B F NA

1-283 B F NA

1-284 C F NA

1-285 C F NA

1-286 C F NA

1-287 B F NA

1-288 A F NA

1-289 A F NA

1-290 A F NA

1-291 B F NA

1-292 C F NA

1-293 B F NA

1-294 A F A

1-295 C F NA

1-296 A F NA

1-297 A F NA

1-298 A E NA

1-299 A E NA

1-300 B F NA

1-301 A F NA

1-302 A E NA

1-303 C F NA

1-304 C F NA

1-305 C F NA

1-306 C F NA

1-307 A F NA

1-308 A F NA

1-309 B F NA

1-310 B F NA

1-311 B F NA Compound pS6Kl in MCF7 pAKT in MCF7 Glucose uptake in MCF7: Number ICso (μΜ) ICso (μΜ) ICso (μΜ)

1-312 A E NA

1-313 C F NA

1-314 B F NA

1-315 A F NA

1-316 B F NA

1-317 B F NA

1-318 B F NA

1-319 B F NA

1-320 A E NA

1-321 A E NA

1-322 B F NA

1-323 B F NA

1-324 B F NA

1-325 A E NA

1-326 A E A

1-327 A F NA

1-328 B F NA

1-329 A F NA

1-330 F F NA

1-331 F F NA

1-332 F F F

1-333 F F NA

1-334 F F F

1-335 F F NA

1-337 F F NA

1-341 F F NA

1-343 F F NA

1-344 C F NA

1-345 F F NA

1-346 F F NA

1-347 F F NA

1-348 F F NA

1-349 F F NA

1-350 F F NA

1-351 F F F

1-352 F F F

1-353 F F NA Compound pS6Kl in MCF7 pAKT in MCF7 Glucose uptake in MCF7: Number ICso (μΜ) ICso (μΜ) ICso (μΜ)

1-354 F F NA

1-355 F F NA

1-356 F F F

1-357 F F NA

1-358 F F NA

1-359 F F NA

1-360 F F NA

1-361 F F NA

1-362 F F NA

1-363 F F NA

1-364 F F NA

1-365 F F F

1-366 F F NA

1-367 F F NA

1-368 F F NA

1-369 F F F