COMPOUNDS FOR THE TREATMENT OF HEPATITIS C

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated

170 million persons worldwide - roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.; Walker, B. D. N. Engl. J. Med. 2001, 345, 41-52).

HCV is a positive-stranded RΝA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5 '-untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RΝA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.

The single strand HCV RΝA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (also referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV. The HCV NS5B protein is described in "Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides

(Bressanelli; S. et al., Journal of Virology 2002, 3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7, 211-242.

Currently, the most effective HCV therapy employs a combination of alpha- interferon and ribavirin, leading to sustained efficacy in 40% of patients (Poynard, T. et al. Lancet 1998, 352, 1426-1432). Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N. Engl. J. Med. 2000, 343, 1666-1672). However, even with experimental therapeutic regimens involving combinations of pegylated alpha- interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. Thus, there is a clear and important need to develop effective therapeutics for treatment of HCV infection.

DESCRIPTION OF THE INVENTION

One aspect of the invention is a compound of formula I

where: R ¹ is CO ₂ R ⁵ or CONR ⁶ R ⁷ ;

R ² is furanyl, pyrrolyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, or tetrazolyl, and is substituted with 0-2 substituents selected from oxo, amino, alkylthio, alkyl, and haloalkyl, and 1 substituent selected from CO ₂ R ⁵ , CON(R ¹² ) ₂ , and COR ¹³ ;

R ³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, or alkoxy;

R ⁴ is cycloalkyl;

R is hydrogen or alkyl;

R ⁶ is hydrogen, alkyl, alkylSO ₂ , cycloalkylSO ₂ , haloalkylSO ₂ , (R ⁹ )(R ¹⁰ )NSO ₂ , or (R ¹ ^SO ₂ ;

R ⁷ is hydrogen or alkyl;

R is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, alkylcarbonyl, cycloalkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkylSO ₂ , cycloalkylSO ₂ , haloalkylSO ₂ , aminocarbonyl, (alkylamino)carbonyl, (dialkylamino)carbonyl, benzyl, benzyloxycarbonyl, or pyridinyl;

R is hydrogen or alkyl;

R , 10 is hydrogen or alkyl;

R ¹¹ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-1 alkyl substituents;

R ¹² is hydrogen, alkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or (R ^u )alkyl; R is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, R . 11 , aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (R )alkyl, or CO ₂ R ;

Ji N _v N.

-N. _P

*^P=^ R ⁸ or R 1 ^lj 3 is N ,M"~>

_R 14 I

or R . 13 is a [4.3.0] or [3.3.0] bicyclic diamine attached to the carbonyl through one nitrogen, and is substituted with 0-2 R ⁸ substituents; or

R ¹⁴ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

R ¹⁵ is is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

or NR ¹⁴ R ¹⁵ taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,

N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, or homomorpholinyl;

R ¹⁶ is hydrogen or alkyl;

R ¹⁷ is hydrogen, alkyl, or cycloalkyl; and

X is methylene, a bond, or absent;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where:

R ¹ is CO ₂ R ⁵ or CONR ⁶ R ⁷ ;

R ² is furanyl, pyrrolyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, or tetrazolyl, and is substituted with 0-2 substituents selected from oxo, amino, alkyl, and haloalkyl, and 1 substituent selected from CO ₂ R ⁵ , CON(R ¹² ) ₂ , and COR ¹³ ;

R ³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, or alkoxy;

R ⁴ is cycloalkyl;

R ⁵ is hydrogen or alkyl;

R ⁶ is hydrogen, alkyl, alkylSO ₂ , cycloalkylSO ₂ , haloalkylSO ₂ ,

(R ⁹ )(R ¹⁰ )NSO ₂ , or (R ¹ ^SO ₂ ;

R ⁷ is hydrogen or alkyl;

R ⁸ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, alkylcarbonyl, cycloalkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkylSO ₂ , cycloalkylSO ₂ , haloalkylSO ₂ , aminocarbonyl, (alkylamino)carbonyl, (dialkylamino)carbonyl, benzyl, benzyloxycarbonyl, or pyridinyl;

R ⁹ is hydrogen or alkyl;

R ¹⁰ is hydrogen or alkyl;

R ¹¹ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-1 alkyl substituents;

R ¹² is hydrogen, alkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or (R ^u )alkyl;

R ¹³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, R , aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (R )alkyl, or

CO ₂ R ⁵

or R . 13 is a [4.3.0] or [3.3.0] bicyclic diamine attached to the carbonyl through one nitrogen, and is substituted with 0-2 R ⁸ substituents;

R » 14 . is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or benzyl; R ¹⁵ is is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

or NR ¹⁴ R ¹⁵ taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, or homomorpholinyl;

R , 16 is hydrogen or alkyl;

R ¹⁷ is hydrogen, alkyl, or cycloalkyl; and

X is methylene, a bond, or absent;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where:

R ¹ is CO ₂ R ⁵ or CONR ⁶ R ⁷ ;

R ² is furanyl, pyrrolyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, or tetrazolyl, and is substituted with 0-2 substituents selected from oxo, amino, and alkyl, and 1 substituent selected from CO ₂ R ⁵ , CON(R ¹² ) ₂ , and COR ¹³ ;

R ³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, or alkoxy;

R ⁴ is cycloalkyl;

R , 5 is hydrogen or alkyl;

R ⁶ is hydrogen, alkyl, alkylSO ₂ , cycloalkylSO ₂ , haloalkylSO ₂ , (R ⁹ )( R ¹ ^NSO ₂₁ Or (R ¹ ^SO ₂ ; R ⁷ is hydrogen or alkyl;

R ⁸ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, alkylcarbonyl, cycloalkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkylSO ₂ , cycloalkylSO ₂ , haloalkylSO ₂ , aminocarbonyl, (alkylamino)carbonyl, (dialkylamino)carbonyl, benzyl, benzyloxycarbonyl, or pyridinyl;

R ⁹ is hydrogen or alkyl;

R , 10 is hydrogen or alkyl;

R ¹¹ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl;

R ¹² is hydrogen, alkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or (R ^u )alkyl;

R ¹³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from alkyl, amino, alkylamino, dialkylamino, R ¹¹ , aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or (R ^π )alkyl;

or R . 1"3 i •s ... N J-ϊb%. "V ^J , . NM--

or R . 13 is a [4.3.0] or [3.3.0] bicyclic diamine attached to the carbonyl through one nitrogen, and is substituted with 0-2 R ⁸ substituents;

R is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

R . 15 is is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl,

(alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

or NR _> 14r R. l5 taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl, or homomorpholinyl; R is hydrogen or alkyl;

R ¹⁷ is hydrogen, alkyl, or cycloalkyl; and

X is methylene, a bond, or absent;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R ¹ is CONR ⁶⁶ RR ⁷⁷ ;; RR ⁶⁶ iiss a allfckylSO ₂ , cycloalkylSO ₂ , haloalkylSO ₂ , (R ⁹ ) ₂ NSO ₂ , or (R ¹⁰ )SO ₂ ; and R ⁷ is hydrogen.

Another aspect of the invention is a compound of formula I where R ³ is hydrogen.

Another aspect of the invention is a compound of formula I where R ³ is methoxy.

Another aspect of the invention is a compound of formula I where R ⁴ is cyclohexyl.

Another aspect of the invention is a compound of formula I where R ⁶ is alkylSO ₂ , cycloalkylSO ₂ , (R ⁹ )(R ¹⁰ )NSO ₂ or (R ^U )SO ₂ .

Another aspect of the invention is a compound of formula I where R ² is pyrazolyl substituted with 2 substituents selected from alkyl and haloalkyl and 1

COR

NH I N-alkyl NH

-N. / -alkyl -NH

-N-

-alkyl / ^N -CO ₂ ET r-Sj. . _R ⁸ _{ig hydrogen or alkyl; R} i ^β _ig hydrogen or alkyl; and R 17 is alkyl.

Another aspect of the invention is a compound of formula I where X is methylene.

Another aspect of the invention is a compound of formula I where X is a bond.

Another aspect of the invention is a compound of formula I where X is absent.

Another aspect of the invention is a compound of formula I according to the following stereochemistry.

Another aspect of the invention is a compound of formula I according to the following stereochemistry.

Another aspect of the invention is a compound of formula I according to the following stereochemistry.

Another aspect of the invention is a compound of formula I according to the following stereochemistry.

Any scope of any variable, including R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ ,

R ¹¹ , R ^{1 l22} ,, RR ¹¹³³ ,, RR ¹¹⁴⁴ ,, RR ¹¹⁵⁵ ,, RR ¹¹⁶⁶ ,, RR ¹¹⁷⁷ ,, and X can be used independently with the scope of any other instance of a variable.

Unless specified otherwise, these terms have the following meanings. "Alkyl" means a straight or branched alkyl group composed of 1 to 6 carbons. "Alkenyl" means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. "Cycloalkyl" means a monocyclic ring system composed of 3 to 7 carbons. "Hydroxy alkyl," "alkoxy" and other terms with a substituted alkyl moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. "Haloalkyl" and "haloalkoxy" include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl. "Aryl" includes carbocyclic and heterocyclic aromatic substituents. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms (see, for example, the compound below). The invention includes all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as racemates. Some stereoisomers can be made using methods known in the art. Stereoisomeric mixtures of the compounds and related intermediates can be separated into individual isomers according to methods commonly known in the art.

Synthetic Methods

The compounds may be made by methods known in the art including those described below. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using available materials. The variables (e.g. numbered "R" substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. Abbreviations used within the schemes generally follow conventions used in the art.

The scheme shown below illustrates methods that can be used for making intermediates and compounds.

DMAP

/THF

Alternatively, the reaction sequence can be modified as shown below.

7H-Indolo[2, 1-aJ [2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3- methoxy-6-(phenyllsulfonyl)-, tert-butyl ester.

To a solution of 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-lH-indole-6- carboxylate (6.00 g, 13.8 mmol) in dioxane (28.0 mL) and BEMP (7.97 mL, 27.6 mmol) was added phenyl vinyl sulfone (27.6 g, 2.21 mmol). The resulting mixture was stirred in a sealed tube in a microwave at 120 ⁰ C for 15 min. The resulting solution was concentrated under reduced pressure. Silica gel chromatography (CH ₂ CI ₂ ) of the concentrate afforded the title compound 6.36g (79%) as a yellow oil. MS m/z 584 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-d) δ ppm 1.18-1.33 (1 H, m), 1.34-1.45 (2 H, m), 1.49-57 (1 H, m), 1.64 (9 H, s.), 1.74-1.82 (2 H, m), 1.90- 2.09 (4 H, m), 2.73 (1 H, m,), 3.93 (3 H, s), 4.38 (1 H, broad d), 5.08 (1 H, br. d), 7.09 (1 H, d, J=2.75 Hz), 7.12-7.18 (3 H, m), 7.22 (1 H, d, J=7.45 Hz), 7.30 (1 H, s), 7.48 (1 H, d, J=8.85 Hz), 7.54 (1 H, dd, J=8.55, 1.22 Hz), 7.61 (2 H, m), 7.67 (1 H, d, J=8.55), 8.01 (1 H, s).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxylic acid, 13-cyclohexyl-3- methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester. 1 , 1 -dimethylethyl 13- cyclohexyl-3-(methyloxy)-6-(tributylstannanyl)-7H-indolo[2,l -a] [2] benzazepine-10- carboxylate. 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3- methoxy-6-(phenylsulfonyl)-, 1,1-dimethylethyl ester (1.00g, 1.71 mMol) was dissolved in 26mL of benzene along with bis(tributyltin) (2.8mL, 5.54 mMol), tributyltin hydride (136uL, 0.513 mMol ) and triethylamine (1.05mL, 7.5 mMol). The solution was sparged for approximately for 10 minutes with nitrogen then 2,2'- bisazoisobutyronitrile (AIBN) (96mg, 0.58mMol) added to the reaction. The reaction was heated to reflux under nitrogen for 2hr. The reaction was followed by LC-MS using the following ΗPLC conditions: Shimadzu Analytical ΗPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, lOmmol Ammonium Acetate %B= 95% acetonitrile, 5% water, lOmmol Ammonium Acetate; Initial %B= 0; Final % B=IOO; Gradient= 3 min; Runtime= 10 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Waters Xterra, 3mm x 50mm, S7. To the reaction was added tributyltin hydride (0.45mL, 1.7mMol) and AIBN(95mg, 0.58mMol), the reaction heated to reflux for 2hrs, and analyzed for progress. AIBN (99mg, 0.6OmMoI) added to the reaction and the reaction heated to reflux under for an additional 6hrs using a timer. The reaction was analyzed by LC-MS for progress then tributyltin hydride( 1.0ml, 3.8mMol) and AIBN (97mg, 0.59mMol) was added and the reaction heated to reflux for 2hrs 20min. The reaction was analyzed by LC-MS and AIBN (97mg, 0.59mMol) added to the reaction. The reaction was heated for lhr under nitrogen at reflux and the cooled and analyzed by LC-MS. Volatiles were removed in vacuuo from the reaction and the reaction was purified by column chromatography using a Cispacking of 190g of YMC GEL ODS-A, 120A spherical 75 uM. The reaction residue (6.67g of yellow oil) was dissolved in a minimum of dichloromethane and the solution applied onto the reverse phase column packed in 10% dichloromethane in acetonitrile. Initial elution was done using 10% dichloromethane in acetonitrile followed by elution with 15% dichloromethane in acetonitrile. The chromatography was monitored by TLC using Whatman MKC 18F reverse phase I"x3" 20OuM thickness TLC plates eluting using 15% dichloromethane in acetonitrile. Compound observation was accomplished by UV lamp at 254nm and iodine staining of TLC plates. Product fractions were collected and volatiles removed in vacuuo to yield 647mg (52%) as a pale yellow foam. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.71 - 0.83 (m, 9 H) 0.85 - 0.96 (m, 3 H) 0.95 - 1.08 (m, 6 H) 1.15 - 1.27 (m, 7 H) 1.27 - 1.49 (m, H H) 1.53 (s, 5 H) 1.60 - 1.67 (m, 9 H) 1.68 - 1.82 (m, 2 H) 1.84 - 1.96 (m, 1 H) 1.96 - 2.16 (m, 3 H) 2.74 - 2.91 (m, 1 H) 3.90 (s, 3 H) 4.16 - 4.40 (m, 1 H) 4.82 - 5.03 (m, 1 H) 6.72 - 6.90 (m, 2 H) 6.96 (dd, J=8.55, 2.44 Hz, 1 H) 7.43 (d, J=8.55 Hz, 1 H) 7.66 (dd, J=8.39, 1.37 Hz, 1 H) 7.81 (d, J=8.55 Hz, 1 H) 8.04 (s, 1 H) LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, lOmmol Ammonium Acetate %B= 95% acetonitrile, 5% water, lOmmol Ammonium Acetate; Initial %B= 0; Final % B=IOO; Gradient= 3 min; Runtime= 10 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Waters Xterra, 3mm x 50mm, S7. Retention Time= 4.2min, MS m/z 734(MH ⁺ ).

7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxylic acid, 13-cyclohexyl-3- methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester. 1,1-dimethylethyl 13- cyclohexyl-3-(methyloxy)-6-(tributylstannanyl)-7H-indolo[2,l -a][2]benzazepine-10- carboxvlate. An assembly of a three necked flask fitted with an argon bubbler, reflux condenser and dropping funnel was flame dried and then cooled under a stream of argon. The flask was then charged with benzene (5 mL) and 7H-indolo[2,l- a] [2]benzazepine- 10-carboxylic acid, 13 -cyclohexyl-3 -methoxy-6-(phenylsulfonyl)-, 1,1-dimethylethyl ester 1 (500 mg, 0.857 mmol). The resultant mixture was sonnicated under argon for 5 min (to remove oxygen) and then heated under reflux. A solution of tri-N-butyltin hydride (0.459 ml, 1.713 mmol) and 2,2'-azobis(2- methylpropionitrile (52.0 mg, 0.317 mmol) in degassed benzene (5 mL) was then added to the dropping funnel. Approximately 2.5 mL of this solution was added dropwise over a period of approximately 30 min, and the resultant solution was left to stir under reflux for 1.5 h. The remaining solution was added dropwise, slowly over a period of approximately 30 min, and heating was continued for a further 1.5 h. The mixture was then evaporated under reduced pressure to remove volatiles. The residue was slurried in hexane and applied to a silica gel biotage cartridge and then loaded onto a silica gel column equilibrated in 100% hexanes. The product was then eluted using a step gradient of ethyl acetate-hexane: 0 -100%, then 2-98%, then 5- 95%. Homogeneous fractions were combined and evaporated to give yellow oil. This was placed under high vacuum overnight to give the title compound as a viscous yellow colored oil. [373 mg, 57%]. The product was stored under nitrogen in a refrigerator.

tert-butyl 13-cyclohexyl-6-(4-(ethoxycarbonyl)-l,3-oxazol-2-yl)-3-metho xy- 7H-indolo[2,l-a][2]benzazepine-10-carboxylate.

1 , 1 -dimethylethyl 13 -cyclohexyl-3 -(methyloxy)-6-(tributylstannanyl)-7H- indolo[2,l-α][2]benzazepine-10-carboxylate (266mg, 0.36mMol) was dissolved in 3.4mL of 1,4-dioxane in a 2 dram vial. Ethyl 2-chlorooxazole-4-carboxylate (83.4mg, 0.47mMol) was dissolved in the reaction followed by the addition of bis(triphenylphosphine)palladium(II) chloride (17.7mg, 0.025mMol). The reaction was capped under nitrogen and heated in an oil bath at 100 C for 17hrs, after which the reaction was cooled and the reaction progress was measured by LC-MS. To the reaction mixture was added bis(triphenylphosphine)palladium(II) chloride (lOmg, 0.014mMol). The reaction was capped under nitrogen and heated for an additional 5hrs at lOOC. The reaction was concentrated in vacuuo and the residue adsorbed onto silica gel purified by silica gel chromatography eluting with a gradient of dichloromethane to 2% ethyl acetate in dichloromethane to yield 233mg of a yellow solid product. 1 Η NMR (500 MHz, CHLOROFORM-D) δ ppm 1.13 - 1.37 (m, 4 H) 1.37 - 1.44 (m, 4 H) 1.46 - 1.55 (m, 1 H) 1.64 (s, 9 H) 1.68 - 1.81 (m, 2 H) 1.83 - 1.98 (m, 3 H) 1.98 - 2.13 (m, 3 H) 2.74 - 2.88 (m, 1 H) 3.91 (s, 3 H) 4.34 - 4.48 (m, 3 H) 5.84 - 6.00 (m, 1 H) 7.00 (d, J=2.44 Hz, 1 H) 7.08 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 (d, J=8.85 Hz, 1 H) 7.69 (dd, J=8.55, 1.22 Hz, 1 H) 7.74 (s, 1 H) 7.82 (d, J=8.24 Hz, 1 H) 8.21 (s, 1 H) 8.30 (s, 1 H); LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 0; Final % B=IOO; Gradient= 3 min; Runtime= 5 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SlO; Retention Time= 3.4 min, MS m/z 583(MH ⁺ ).

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-2-oxazolyl]-3-methoxy-. tert-butyl 13-cyclohexyl-6-(4-(ethoxycarbonyl)-l,3-oxazol-2-yl)-3-metho xy-

7H-indolo[2,l-α][2]benzazepine-10-carboxylate (109mg, 0.19mMol) was dissolved in 2mL of 1,2-dichloroethane and 2mL of trifluoroacetic acid added to the reaction. The reaction was stirred at room temperature for 1.5hrs. Volatiles were removed and the product dried in vacuuo to yield 102mg of a yellow solid. 1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 1.11 - 1.37 (m, 4 H) 1.42 (t, J=7.02 Hz, 4 H) 1.48 - 1.62 (m, 1 H) 1.77 (d, J=10.07 Hz, 2 H) 1.86 - 2.13 (m, 4 H) 2.73 - 2.90 (m, 1 H) 2.98 - 3.39 (m, 6 H) 3.92 (s, 3 H) 4.30 - 4.53 (m, 3 H) 5.87 - 6.03 (m, 1 H) 7.02 (d, J=2.44 Hz, 1 H) 7.09 (dd, J=8.70, 2.59 Hz, 1 H) 7.75 (s, 1 H) 7.79 (dd, J=8.39, 1.37 Hz, 1 H) 7.88 (d, J=8.55 Hz, 1 H) 8.24 (s, 1 H) 8.50 (s, 1 H); LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, lOmmol

Ammonium Acetate %B= 95% acetonitrile, 5% water, lOmmol Ammonium Acetate; Initial %B= 0; Final % B=IOO; Gradient= 2 min; Runtime= 3 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SlO; Retention Time= 1.7min, MS m/z 525(MH ^" ).

Ethyl 2-(l 3-cyclohexyl-l 0-(((dimethylamino)sulfonyl)carbamoyl)-3-methoxy- 7H-indolo[2,l-a][2]benzazepin-6-yl)-l,3-oxazole-4-carboxylat e. Ethyl 2-(l 3-cyclohexyl- 10-(((dimethylamino)sulfonyl)carbamoyl)-3- methoxy-7H-indolo [2, 1 -a] [2]benzazepin-6-yl)- 1 ,3 -oxazole-4-carboxylate. 7H- indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-2-oxazolyl]-3-methoxy- (115mg, 0.22mMol) was dissolved in 3ml of anhydrous TΗF and l,l'-carbonyldiimidazole (61mg, 0.38mMol) added to the reaction. The reaction was stirred under nitrogen for lhr 20min at room temperature then heated to reflux under nitrogen for 45 minutes. The reaction was cooled and dimethylsulfamide (186mg, 1.49mMol) was added to the reaction followed by 1,8- diazabicyclo[5.4.0]undec-7-ene (39uL,0.26mMol) (DBU). The reaction was heated at 55C for 16hrs under nitrogen. The reaction was partitioned between dichloromethane and 0. IM monosodium phosphate. The dichloromethane extract was washed with 0. IM monosodium phosphate then dried over sodium sulfate. Volatiles were removed in vacuuo to yield 167mg of crude yellow product. One-half of the crude sample was dissolved in a mixture of acetonitrile and methanol and purified by reverse phase prep ΗPLC under the following conditions: Shimadzu preparative ΗPLC using Discovery VP software: %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 50; Final % B=IOO; Gradient= 12 min; Runtime= 17 min; Flow rate= 25 ml/min; Wavelength= 220nm; Column= Waters Sunfire 19mm x 100mm. Product retention time= 12.25min to 17min (tailing due to solubility). Obtained 25.2mg of amorphous yellow solid. 1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 1.18 - 1.30 (m, 2 H) 1.34 - 1.46 (m, 5 H) 1.47 - 1.62 (m, 1 H) 1.70 - 1.85 (m, 2 H) 1.86 - 2.21 (m, 4 H) 2.72 - 2.92 (m, 1 H) 3.07 (s, 6 H) 3.92 (s, 3 H) 4.08 - 4.34 (m, 2 H) 4.41 (q, J=7.22 Hz, 3 H) 5.75 - 5.99 (m, 1 H) 7.02 (d, J=2.75 Hz, 1 H) 7.10 (dd, J=8.70, 2.59 Hz, 1 H) 7.45 - 7.65 (m, 2 H) 7.71 (s, 1 H) 7.89 (d, J=8.55 Hz, 1 H) 8.20 (s, 1 H) 8.29 (s, 1 H) 9.36 (s, 1 H); LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, lOmmol Ammonium Acetate %B= 95% acetonitrile, 5% water, lOmmol Ammonium Acetate; Initial %B= 0; Final % B=IOO; Gradient= 2 min; Runtime= 4 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SlO; Retention Time= 1.9 min, MS m/z 631 (MH ^" ), m/z 633(MH ⁺ ).

13-cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(4- ((3-methyl-3,8- diazabicyclo[3.2.1]oct-8-yl)carbonyl)-l,3-oxazol-2-yl)-7H-in dolo[2,l- a][2]benzazepine-10-carboxamide.

Ethyl 2-(l 3-cyclohexyl- 10-(((dimethylamino)sulfonyl)carbamoyl)-3- methoxy-7H-indolo[2,l-α][2]benzazepin-6-yl)-l,3-oxazole-4-c arboxylate (35.7mg, 0.056mMol) was dissolved in 0.6ml of TΗF in a 2 dram vial. Tetrabutylammonium hydroxide (17OuL, 0.17mMol) as a IM solution in methanol was added to the reaction. The reaction was capped and stirred for 3hrs at room temperature. The reaction was partitioned between IN hydrochloric acid and dichloromethane. The organic phase was washed with IN hydrochloric acid and dried over sodium sulfate. The material was concentrated to dryness, dried in vacuuo and used without further purification. The hydrolysis product (0.056mMol) was dissolved in ImL of DMF and TBTU(39mg, 0.12mMol)added. The reaction was stirred at room temperature under nitrogen for approximately 50 minutes then add DMAP(37.9mg, 0.31mMol)was added followed by 3-methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (23mg, 0.1 ImMoI). The reaction was stirred for 4hrs at room temperature under nitrogen atmosphere until complete, then added to 2OmL of water and extracted with dichloromethane, washed organic layer with water and dry over sodium sulfate to yield 50mg of crude product. The product was purified by Prep HPLC under the following conditions: Shimadzu preparative HPLC using Discovery VP software: %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 30; Final % B=IOO; Gradient= 12 min; Runtime= 20 min; Flow rate= 25 ml/min; Wavelength= 220nm; Column= Waters Sunfire 19mm x 100mm. Product retention time= 6. lmin. Product fractions were concentrated in vacuuo to yield 30.5mg of the title compound as a trifluoroacetic acid salt. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.09 - 1.30 (m, 1 H) 1.31 - 1.61 (m, 3 H) 1.68 - 1.85 (m, 2 H) 1.87 - 2.20 (m, 5 H) 2.26 - 2.44 (m, 2 H) 2.51 - 2.66 (m, 1 H) 2.77 - 2.90 (m, 1 H) 2.91 - 3.01 (m, 3 H) 3.04 (s, 6 H) 3.12 (d, J=11.90 Hz, 1 H) 3.23 (d, J=I 1.60 Hz, 1 H) 3.78 (d, J=12.21 Hz, 1 H) 3.94 (s, 3 H) 4.24 (d, ./=13.12 Hz, 1 H) 4.43 (d, J=14.34 Hz, 1 H) 5.01 (d, J=5.80 Hz, 1 H) 5.13 - 5.47 (m, 1 H) 5.85 (d, J=14.04 Hz, 1 H) 6.02 (s, 1 H) 7.03 (d, J=2.75 Hz, 1 H) 7.12 (dd, J=8.70, 2.59 Hz, 1 H) 7.25 - 7.32 (m, 1 H) 7.56 (d, J=8.55 Hz, 1 H) 7.69 (s, 1 H) 7.88 (d, J=8.24 Hz, 1 H) 8.18 (s, 1 H) 8.28 (s, 1 H) 8.52 (s, 1 H) 11.72 (s, 1 H); LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, lOmmol Ammonium Acetate %B= 95% acetonitrile, 5% water, lOmmol Ammonium Acetate; Initial %B= 0; Final % B=IOO; Gradient= 2 min; Runtime= 3 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SlO Retention Time= 1.7 min, MS m/z 711 (MH ^" ), m/z 713(MH ⁺ ).

13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(4- ((3-methyl-3,8- diazabicyclo[3.2. l]oct-8-yl)carbonyl)-l, 3-oxazol-2-yl)-6, 7-dihydro-5H-indolo[2, 1- a] [2]benzazepine-10-carboxamide.

13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(4- ((3-methyl-3,8- diazabicyclo[3.2.1]oct-8-yl)carbonyl)-l,3-oxazol-2-yl)-7H-in dolo[2,l- α][2]benzazepine-10-carboxamide (26.5mg, 0.037mMol) was dissolved in ImL of TΗF and 0.3mL of methanol added followed by lOmg of 10% palladium on carbon. The reaction was placed under hydrogen at 1 atmosphere (balloon) and stirred for

18hrs at room temperature. The reaction was filtered through a celite plug and rinsed with acetonitrile. Volatiles were removed from the filtrate in vacuuo and the residue was dissolved in acetonitrile and purified by Prep ΗPLC under the following conditions: Shimadzu preparative ΗPLC using Discovery VP software: %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 30; Final % B=IOO; Gradient= 12 min; Runtime= 17 min; Flow rate= 25 ml/min; Wavelength= 220nm; Column= Waters Sunfire 19mm x 100mm. Product retention time= 5.3 minutes. The title compound was isolated as a TFA salt, 17.6mg obtained. 1Η ΝMR (500 MHz, CHLOROFORM-D) δ ppm 1.20 - 1.33 (m, 1.1H) 1.33 - 1.54 (m, 2.1 H) 1.65 (t, J=10.99 Hz, 1.1 H) 1.74 - 1.86 (m, 1.9 H) 1.89 - 2.11 (m, 5.6 H) 2.11 - 2.44 (m, 3.0H) 2.71 - 2.86 (m, 3.2 H) 2.87 - 2.98 (m, 2.9 H) 2.98 - 3.10 (m, 7.7 H) 3.08 - 3.45 (m, 6.1 H) 3.72 - 3.83 (m, 0.9 H) 3.82 - 3.93 (m, 3.1 H) 3.92 - 4.00 (m, 0.8 H) 4.05 (dd, J=14.80, 5.65 Hz, 0.8 H) 4.55 - 5.12 (m, 2.6 H) 5.60 (d, J=12.82 Hz, 0.3 H) 6.64 - 7.12 (m, 2.0 H) 7.29 - 7.62 (m, 1.8 H) 7.77 - 7.97 (m, 1.2 H) 7.97 - 8.43 (m, 1.2 H) 8.55 - 9.33 (m, 0.7 H) 11.70 (s, 0.5 H). LC-MS:

Shimadzu Analytical HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, lOmmol Ammonium Acetate %B= 95% acetonitrile, 5% water, lOmmol Ammonium Acetate; Initial %B= O; Final % B=IOO; Gradient= 3 min; Runtime= 5 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Gemini 4.6mm x 50mm S5; Retention Time= 2.2 min, MS m/z 715(MH ⁺ ), m/z 713(MH ^" ).

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-3- methoxy-6- [2-(methoxycarbonyl)-3-thienyl] -, 1,1-dimethylethyl ester. 7H-indolo[2,l- α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester (140mg, 0.19mMol) was dissolved in 2mL of 1,4-dioxane along with methyl 3-bromothiophene-2-carboxylate (79mg, 0.36mMol) in a 2 dram vial. To the reaction was added bis(triphenylphosphine)palladium dichloride (9.2mg, 0.013mMol). The reaction was capped under a nitrogen atmosphere and heated to IOOC for 4.5hrs. The reaction was cooled and filtered through a 0.45uM nylon syringe filter and the volatiles removed in vacuuo to yield 226mg of a yellow oil. The title compound was purified by silica gel chromatography eluting with 30% hexanes in dichloromethane to yield 73mg (66%) of product. 1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 0.92 (t, J=7.32 Hz, 2 H) 1.24 - 1.44 (m, 6 H) 1.57 (s, 9 H) 1.58 - 1.71 (m, 2 H) 1.77 (d, J=8.85 Hz, 2 H) 1.85 - 1.99 (m, 1 H) 2.00 - 2.17 (m, 3 H) 2.83 - 2.93 (m, 1 H) 3.82 (s, 3 H) 3.88 (s, 3 H) 4.71 (s, 1 H) 5.10 (s, 1 H) 6.80 (s, 1 H) 6.83 (d, J=4.88 Hz, 1 H) 6.90 (d, J=2.75 Hz, 1 H) 7.01 (dd, J=8.55, 2.75 Hz, 1 H) 7.40 (d, J=5.19 Hz, 1 H) 7.51 (d, J=8.85 Hz, 1 H) 7.63 (dd, J=8.55, 1.22 Hz, 1 H) 7.82 (d, J=8.55 Hz, 1 H) 7.88 (s, 1 H); LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 0; Final % B=IOO; Gradient= 2 min; Runtime= 5 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SlO; Retention Time= 2.95 min, MS m/z 584(MH ⁺ ).

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxylic acid, 6-(2-carboxy-3-thienyl)- 13-cyclohexyl-3-methoxy-, 10-(l,l-dimethylethyl) ester.

7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3- methoxy-6-[2-(methoxycarbonyl)-3-thienyl]-, 1,1-dimethylethyl ester (65mg, 0.1 ImMoI) was dissolved in ImL of THF in a 2 dram vial. To this solution was added 1.0M tetrabutylammonium hydroxide (O.33mL, 0.33mMol) in methanol. The reaction was capped and stirred at room temperature for 3hrs then monitored by HPLC. Additional 1.0M tetrabutylammonium hydroxide (0.1OmL, 0. ImMoI) in methanol was added to the reaction and the reaction stirred capped at room temperature for an additional 2 lhrs. The reaction was partitioned between dichloromethane and 0. IM citric acid. The aqueous phase was extracted with dichloromethane and the organic extracts were combined and dried over sodium sulfate. Volatiles were removed in vacuuo to yield 72mg of crude product. LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, lOmmol Ammonium Acetate %B= 95% acetonitrile, 5% water, lOmmol Ammonium Acetate; Initial %B= 0; Final % B=IOO; Gradient= 3 min; Runtime= 5 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SlO; Retention Time= 2.50min, MS m/z 570(MH ⁺ ).

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-6-[2- [(diethylamino)carbonyl] -3-thienyl] -3-methoxy-, 1, 1-dimethylethyl ester. 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 6-(2-carboxy-3-thienyl)-

13-cyclohexyl-3-methoxy-, 10-(l, 1-dimethylethyl) ester (36mg, 0.063mMol) was dissolved in 0.7mL of anhydrous DMF and TBTU (36.5mg, 0.114mMol) added to the reaction. The reaction was capped under nitrogen and stirred at room temperature for 1.5hrs. DMAP (29mg, 0.24mMol) was then dissolved in the reaction then diethyl amine (26uL, 0.25mMol) added. The reaction was capped under a nitrogen atmosphere and stirred for 21hrs at room temperature. The reaction was added to 15mL of water and the aqueous suspension extracted with dichloromethane. The organic phase was washed sequentially with 0. IM citric acid, water and dried over sodium sulfate, filtered and volatiles removed in vacuuo to yield a amber oil. LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=IOO; Gradient= 5 min; Runtime= 6 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SlO; Retention Time= 4.64 min, MS m/z 625(MH ⁺ ), 647(M+Na) ⁺ .

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-6-[2- [(diethylamino)carbonyl] -3-thienyl] -3-methoxy-. 7H-indolo[2, 1 -a] [2]benzazepine- 10-carboxylic acid, 13-cyclohexyl-6-[2-[(diethylamino)carbonyl]-3-thienyl]-3- methoxy-, 1 , 1 -dimethylethyl ester (39mg, O.OόmMol) was dissolved in ImL of 1,2- dichloroethane and ImL of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2hrs then volatiles were removed in vacuuo. The reaction product was repeatedly dissolved in benzene and volatiles removed in vacuuo to aid in the removal of residual TFA. Weight of product was 39mg as an amorphous solid. LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, lOmmol Ammonium Acetate %B= 95% acetonitrile, 5% water, lOmmol Ammonium Acetate; Initial %B= 0; Final % B=IOO; Gradient= 3 min; Runtime= 5 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SlO; Retention Time= 2.31, MS m/z 569(MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[2- [(diethylamino)carbonyl] -3-thienyl] -N-[(dimethylamino)sulfonyl] -3-methoxy-. 7H- indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[2- [(diethylamino)carbonyl]-3-thienyl]-3-methoxy- (36.7mg, 0.064mmol) was dissolved in THF (ImI) and carbonyldiimidazole (19mg, 0.117mmol) added to the reaction. The reaction was stirred under a nitrogen atmosphere at room temperature for 1.5 hours. The reaction was then heated to 6OC for 1.5 hours, then cooled and dimethylsulfamide (55mg, 0.444mmol) was added to the reaction followed by DBU (13.3uL, 0.089mmol). The reaction was capped under a nitrogen atmosphere and heated at 65 C to 7OC overnight. The reaction was cooled then partitioned between dichloromethane and IN aqueous hydrochloric acid. The aqueous phase was back extracted with dichloromethane and the organic layers combined and washed sequentially with IN aqueous hydrochloric acid, aqueous 0.1M NaH2PO4. The dichloromethane phase was dried over sodium sulfate, filtered and volatiles removed in vacuuo to yield 47mg of brown film. The sample was dissolved in acetonitrile / DMF (1: 1) and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 50 solvent A / 50% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Solvent was removed from the product fraction in vacuuo to yield 18.1 mg of an amorphous yellow solid. 1 H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.53 (br.s, 3 H) 0.96 (br.s, 3 H) 1.04 - 1.44 (m, 4 H) 1.51 (d, J=10.07 Hz, 1 H) 1.78 (d, J=9.46 Hz, 2 H) 1.88 - 2.13 (m, 4 H) 2.40 - 2.52 (m, 1 H) 2.80 - 2.97 (m, 3 H) 3.05 (s, 6 H) 3.57 (br.s, 1 H) 3.89 (s, 3 H) 4.49 (d, J=14.65 Hz, 1 H) 5.20 (d, J=14.04 Hz, 1 H) 6.93 (d, J=2.75 Hz, 1 H) 6.98 (s, 1 H) 7.02 (dd, J=8.70, 2.59 Hz, 1 H) 7.11 (d, J=5.19 Hz, 1 H) 7.38 (d, J=4.88 Hz, 1 H) 7.41 - 7.52 (m, 2 H) 7.86 (d,

J=8.55 Hz, 1 H) 8.01 (s, 1 H) 9.18 (s, 1 H); LC-MS retention time 2.19 min; 673 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

tert-Butyl 13-cyclohexyl-3-methoxy-6-(2-(4-morphoHnylcarbonyl)-3-thieny l)- 7H-indolo[2,l-a][2]benzazepine-10-carboxylate. In a 2 dram vial, 7H-indolo[2,l- a][2]benzazepine-10-carboxylic acid, 6-(2-carboxy-3-thienyl)-13-cyclohexyl-3- methoxy-, 10-(l,l-dimethylethyl) ester (33.7mg, 0.059 mmol) and 0-(1H- Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (34.2 mg, 0.106 mmol) was dissolved in DMF (0.7 ml) to give a clear yellow solution. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for lhr 20min. DMAP (28.9 mg, 0.237 mmol) was dissolved in the reaction then morpholine (10.5 μl, 0.121 mmol) was added. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 2 days. Pour reaction into 15mL of water. A pale yellow precipitate forms. Extract into dichloromethane. Wash dichloromethane solution with 0. IM aqueous citric acid, back extract aqueous using dichloromethane. Combine dichloromethane phases wash Ix with water and dry over sodium sulfate. Remove volatiles in vacuuo to yield 45mg of the title product as a yellow oil. LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=IOO; Gradient= 6 min; Runtime= 6 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SlO; Retention Time= 4.38 min, MS m/z 639(MH ⁺ ).

13-Cyclohexyl-3-methoxy-6-(2-(4-morpholinylcarbonyl)-3-th ienyl)-7H- indolo[2, 1 -a] [2] benzazepine-1 O-carboxylic acid. In a 2 dram vial, dissolve tert- Butyl 13-cyclohexyl-3-methoxy-6-(2-(4-morpholinylcarbonyl)-3-thien yl)-7H- indolo[2,l-a][2]benzazepine-10-carboxylate (37.7 mg, 0.059 mmol) in 1,2- Dichloroethane (1 mL) add TFA (1 mL, 12.98 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 1.5hrs. Transfer reaction contents to a 25mL pear flask using benzene to rinse. Remove volatiles in vacuuo. Dissolve product in benzene and rotovap to aid in trace TFA removal.

Obtained 41mg of title compound as a yellow brown film. A LC-MS was obtained to confirm product and the product used in the next step without further purification. LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, lOmmol Ammonium Acetate %B= 95% acetonitrile, 5% water, lOmmol Ammonium Acetate; Initial %B= 0; Final % B=IOO; Gradient= 3 min; Runtime= 5 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Waters Xterra, 3mm x 50mm, S7. Retention Time= 1.73 min, MS m/z 583(MH ⁺ ), m/z

581(M-H)-.

13-Cyclohexyl-N-(dimethylsulfamoyl)-3-methoxy-6-(2-(4- morpholinylcarbonyl)-3-thienyl)-7H-indolo[2,l-a][2]benzazepi ne-10-carboxamide.

In a 2 dram vial, dissolve 13-Cyclohexyl-3-methoxy-6-(2-(4- morpholinylcarbonyl)-3-thienyl)-7H-indolo[2, 1 -a] [2]benzazepine- 10-carboxylic acid (38 mg, 0.065 mmol) in ImL of anhydrous THF, add CDI (19.03 mg, 0.117 mmol) to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for approximately 1 hour. The reaction was heated capped under nitrogen at 65 C for 1 hour, then cooled to room temperature and N,N- Dimethylsulfamide (44.3 mg, 0.357 mmol) then DBU (13.8 μL, 0.092 mmol) added to the reaction. The reaction was capped and heated under nitrogen over night at 65°C. Analysis of an aliquot by LC-MS indicated that the reaction was incomplete. To the reaction was added more dimethylsulfamide(19mg, 0.153mmol) and DBU (13.8uL, 0.092mmol). The reaction was capped under a nitrogen atmosphere and heated at 69C for 3.25hrs. Analysis of the reaction by LC-MS indicated that the reaction was complete. The reaction was partitioned between dichloromethane and IN aqueous hydrochloric acid. The aqueous layer was extracted with dichloromethane. The organic layers were combined and washed sequentially with IN aqueous hydrochloric acid then 0.1M sodium dihydrogen phosphate (NaH^PO ₄ ) and dried over sodium sulfate. Volatiles were removed in vacuuo to give a yellow oil/film. The crude title compound was dried in vacuuo overnight at room temperature. Weight of crude product is 43mg as a yellow/brown solid. Dissolve in a mixture of acetonitrile and DMF and purify by reverse phase HPLC under the following conditions: Shimadzu Preparative HPLC running Discovery VP software, %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 50; Final % B=IOO; Gradient= 15 min; Runtime= 25 min; Flow rate= 25 ml/min; Wavelength= 220nm; Column= Waters Sunfire 19mm x 100mm. Product collection time= 9.72min. to 10.49min. Volatiles were removed in vacuuo from the product fraction to yield 14.2mg of the title compound as a yellow solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.17 - 1.30 (m, 1 H) 1.32 - 1.50 (m, 2 H) 1.55 (d, J=I 1.29 Hz, 1 H) 1.78 (d, J=10.99 Hz, 2 H) 1.90 - 2.16 (m, 4 H) 2.42 - 2.58 (m, 1 H) 2.60 - 2.86 (m, 4 H) 2.85 - 2.94 (m, 2 H) 2.95 - 3.04 (m, 2 H) 3.06 (s, 6 H) 3.10 - 3.30 (m, 1 H) 3.91 (s, 3 H) 4.56 (d, J=14.65 Hz, 1 H) 5.09 (d, J=14.65 Hz, 1 H) 6.87 (s, 1 H) 6.93 (d, J=2.75 Hz, 1 H) 7.05 (dd, J=8.70, 2.59 Hz, 1 H) 7.08 (d, J=4.88 Hz, 1 H) 7.45 (d, J=4.88 Hz, 1 H) 7.47 - 7.54 (m, 2 H) 7.83 (s, 1 H) 7.91 (d, J=8.55 Hz, 1 H) 9.59 (s, 1 H). LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, lOmmol Ammonium Acetate %B= 95% acetonitrile, 5% water, lOmmol Ammonium Acetate; Initial %B= O; Final % B=IOO; Gradient= 3 min; Runtime= 4 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Waters Xterra, 3mm x 50mm, S7. Retention

Time= 2.05min min, MS m/z 689 (MH ⁺ ), m/z 687 (M-H) ^" .

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-2-(methylthio)-5-thiazolyl]-3-methoxy-, 1,1-dimethylethyl ester

7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6- (tributylstannyl)-, 1,1-dimethylethyl ester (203 mg, 0.277 mmol) was dissolved in 1,4-dioxane (2.7 ml) ) in a 2-5mL tapered microwave vessel with magnetic stir bar. To the reaction was added ethyl 5-bromo-2-(methylthio)thiazole-4-carboxylate (171 mg, 0.606 mmol), and bis(triphenylphosphine)palladium(II) chloride (14.9 mg, 0.021 mmol). The reaction was capped under a nitrogen atmosphere and heated to IOOC for 17.5hrs. HP LC analysis of the reaction indicated only approximately 45% conversion of starting material. Additional catalyst bis(triphenylphosphine)palladium(II) chloride (5.7mg) was added to the reaction and the reaction was heated under a nitrogen atmosphere at 11OC for 23hrs. Volatiles were removed from the reaction mixture in vacuuo and the crude reaction mixture was dissolved in a 8ml of a DMF/acetonitrile mixture and purified as four 2mL injections using reverse phase HPLC. The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile and DMF purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 40% solvent A / 60% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product = 26.6min. Volatiles from the product fractions were removed in vacuuo using a speed vac at a medium heating setting. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.16 - 1.26 (m, 1 H) 1.30 (t, J=7.02 Hz, 3 H) 1.33 - 1.56 (m, 3 H) 1.60 (s, 10 H) 1.63 - 1.83 (m, 5 H) 1.94 (br.s, 1 H) 1.98 - 2.16 (m, 3 H) 2.71 (s, 3 H) 2.82 - 2.92 (m, 1 H) 3.90 (s, 3 H) 4.28 (q, J=7.02 Hz, 2 H) 4.53 (d, J=14.95 Hz, 1 H) 5.52 (d, J=14.65 Hz, 1 H) 6.98 (d, J=2.75 Hz, 1 H) 7.03 (dd, J=8.85, 2.75 Hz, 1 H) 7.49 - 7.54 (m, 2 H) 7.65 (dd, J=8.55, 1.53 Hz, 1 H) 7.81 (d, J=8.55 Hz, 1 H) 8.13 (d, J=I.22 Hz, 1 H).

LC-MS retention time 3.08 min; 645m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

The scheme shown below is illustrative of methods that can be used to make intermediates and compounds.

1,2-DCE, RT

lθ-(tert-butoxycarbonyl)- 13-cyclohexyl-3-methoxy-7H-indolo[2, 1 - a] [2]benzazepine-6-carboxylic acid. Dissolve 10-(l,l-dimethylethyl) 6-methyl 13- cyclohexyl-3-(methyloxy)-7H-indolo[2,l-α][2]benzazepine-6,1 0-dicarboxylate (5.53 g, 11.02 mmol) in TΗF (70ml) with heating, add DMF (20 ml) to maintain solubility, allow to cool to room temperature then add tetrabutylammonium hydroxide (33.1 ml, 33.1 mmol) 1.0M in methanol. Stir reaction at room temperature for 2hrs then add 0. IN aqueous 0. IN hydrochloric acid to the reaction followed by 01M aqueous NaH2PO4. Separate phases, wash organic layer sequentially with 1.0N aqueous hydrochloric acid, 0. IM aqueous NaH2PO4. Back extract aqueous Ix using ethyl acetate. Combine ethyl acetate fractions and wash sequentially with 0.1M aqueous NaH2PO4 and brine. Dry over magnesium sulfate, filter and remove solvents in vacuuo to yield a bright yellow solid. Dry product in vacuuo at room temperature to give 5.2 Ig (97%). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.12 - 1.28 (m, 2 H) 1.28 - 1.45 (m, 2 H) 1.46 - 1.60 (m, 2 H) 1.63 (s, 9 H) 1.66 - 1.96 (m, 4 H) 1.96 - 2.16 (m, 3 H) 2.76 - 2.84 (m, 1 H) 3.91 (s, 3 H) 4.18 (br.s., 1 H) 5.66 (br.s, 1 H) 7.00 (d, J=2.44 Hz, 1 H) 7.10 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 (d, J=8.54 Hz, 1 H) 7.65 - 7.71 (m, 1 H) 7.82 (d, J=8.24 Hz, 1 H) 7.93 (s, 1 H) 8.22 (s, 1 H). LC-MS retention time 1.47 min; 486 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode

tert-Butyl 13-cyclohexyl-3-methoxy-6-(4-(methoxycarbonyl)-l,3-oxazol-5- yl)-7H-indolo[2, 1 -a] [2]benzazepine- 10-carboxylate. lθ-(tert-butoxycarbonyl)- 13- cyclohexyl-3-methoxy-7H-indolo[2,l-α][2]benzazepine-6-carbo xylic acid (1.00 g, 2.051 mmol) was dissolve in DMF (10 ml) and potassium carbonate (0.624 g, 4.51 mmol)was added to the reaction followed by methyl isocyanoacetate (0.24 ml, 2.64 mmol). The reaction was stirred under a nitrogen atmosphere at room temperature for approximately 5 minutes then cooled to OC. Diphenylphosphoryl azide (0.5 ml, 2.320 mmol) was slowly added to the reaction over 10 minutes. The reaction was stirred at OC under a nitrogen atmosphere and allowed to slowly warm to room temperature overnight. Dilute reaction, with 100ml of benzene/ethyl acetate (1 : 1) and wash with water. Back extract aqueous layer using ethyl acetate. Combine organic extracts and wash successively with 0.1M aqueous citric acid, saturated aqueous sodium bicarbonate and then brine and dry over magnesium sulfate. Filter and remove volatiles in vacuuo. Chromatograph on 43.4g of silica gel slurry packed in 5% ethyl acetate /dichloromethane. Elute with 5% ethyl acetate / dichloromethane. Combination of pure product fractions and removal of volatiles in vacuuo yeilded 215mg of an amorphous yellow solid. Combination of less pure fractions yielded an additional 189mg of product with purity greater than 92%. 1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 1.11 - 1.29 (m, 2 H) 1.30 - 1.48 (m, 3 H) 1.57 (s, 2 H) 1.61 (s, 10 H) 1.69 - 1.80 (m, 2 H) 1.86 - 1.98 (m, 1 H) 1.99 - 2.13 (m, 4 H) 2.76 - 2.90 (m, 1 H) 3.92 (s, 3 H) 3.98 (s, 3 H) 4.47 (d, J=12.82 Hz, 1 H) 5.84 (d, J=14.65 Hz, 1 H) 7.02 (d, J=2.44 Hz, 1 H) 7.07 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 (d, J=8.55 Hz, 1 H) 7.65 - 7.71 (m, 1 H) 7.82 (d, J=8.24 Hz, 1 H) 7.87 (s, 1 H) 8.08 (s, 1 H) 8.16 (s, 1 H). LC-MS retention time 2.75 min; m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 0 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

5-(l O-(tert-Butoxycarbonyl)- 1 i-cyclohexyl-i-methoxy- 7H-indolo[2, 1- a] [2] benzazepin-6-yl)-l ,3-oxazole-4-carboxylic acid. tert-Butyl 13-cyclohexyl-3- methoxy-6-(4-(methoxycarbonyl)- 1 ,3 -oxazol-5-yl)-7H-indolo [2, 1 -a] [2]benzazepine- 10-carboxylate (205 mg, 0.360 mmol) was dissolved in TΗF (3.0ml) and tetrabutylammonium hydroxide (1.1 mL, 1.100 mmol) (1.0M in methanol) was added to the reaction. The reaction was capped and stirred at room temperature for 2hrs. A 0. IM aqueous solution of NaΗ2PO4 was added to the reaction followed by 0. IN aqueous hydrochloric acid. The product was extracted into ethyl acetate and the organic phase washed sequentially with 0.1N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4, brine and dried over magnesium sulfate. The product solution was filtered, solvent removed and product dried in vacuuo to yield 191mg of a yellow solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.77 - 0.94 (m, 1 H) 1.12 - 1.31 (m, 3 H) 1.30 - 1.59 (m, 5 H) 1.62 (s, 9 H) 1.76 (d, J=I 1.29 Hz, 2 H) 1.87 - 2.18 (m, 4 H) 2.76 - 2.90 (m, 1 H) 3.91 (s, 3 H) 4.45 (d, J=14.04 Hz, 1 H) 6.03 (d, J=12.21 Hz, 1 H) 7.03 (d, J=2.44 Hz, 1 H) 7.08 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 (d, J=8.85 Hz, 1 H) 7.68 (d, J=8.24 Hz, 1 H) 7.82 (d, J=8.55 Hz, 1 H) 7.91 (s, 1 H) 8.21 (d, J=5.80 Hz, 2 H). LC-MS retention time 1.86 min; m/z 553 (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

tert-Butyl 13-cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-l, 3-oxazol-

5-yl)-7H-indolo[2,l-a] [2]benzazepine-10-carboxylate.

5-(10-(tert-Butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-in dolo[2,l- α][2]benzazepin-6-yl)-l,3-oxazole-4-carboxylic acid (185mg, 0.334 mmol) was dissolved in DMF (3.2 ml), and O-benzotriazol-l-yl-N,N,N',N'-tetra-methyluronium tetrafluoroborate (193 mg, 0.600 mmol) was added. The reaction was stirred capped at room temperature for 25 minutes and DMAP (163 mg, 1.334 mmol) was dissolved in the reaction then morpholine (0.058 ml, 0.667 mmol) was added. The reaction was capped and stirred at room temperature overnight. The reaction was poured into 30ml of water and extracted with dichloromethane. The organic layer was washed sequentially with 0. IM aqueous citric acid, 0. IM aqueous NaΗ2PO4, then dried over anhydrous sodium sulfate. The sample was filtered, volatiles removed and the sample dried in vacuuo to obtain 227mg of an amorphous orange solid . IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.16 - 1.50 (m, 7 H) 1.53 - 1.61 (m, 6 H) 1.62 (s, 10 H) 1.76 (d, J=10.38 Hz, 2 H) 1.83 - 2.15 (m, 5 H) 3.40 - 3.84 (m, 7 H) 3.83 - 3.95 (m, 5 H) 4.40 (d, J=I 1.60 Hz, 1 H) 5.64 (d, J=12.21 Hz, 1 H) 6.97 (d, J=2.75 Hz, 1 H) 7.05 (dd, J=8.39, 2.59 Hz, 1 H) 7.50 (d, J=8.55 Hz, 1 H) 7.53 (s, 1 H) 7.65 (d, J=8.24 Hz, 1 H) 7.77 - 7.86 (m, 2 H) 7.97 - 8.04 (m, 1 H) 8.10 (s, 1 H). LC-MS retention time 2.64 min m/z 624 (MH+). LC data was recorded on a Shimadzu LC- 10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-l,3- oxazol-5-yl)-7H- indolo[2,l-a][2]benzazepine-10-carboxylic acid.

Dissolve tert-Butyl 13-cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)- l,3-oxazol-5-yl)-7H-indolo[2,l-α][2]benzazepine-10-carboxyl ate (203mg, 0.325 mmol) in 1,2-dichloroethane (3 ml) add TFA (3 ml, 38.9 mmol). The reaction was capped under a nitrogen atmosphere at 25 ⁰ C for 2 hrs. Reaction volatiles were removed in vacuuo and the residue dissolved in 8OmL of ethyl acetate with heating. The solution was washed with IN aqueous hydrochloric acid (2x40mL), brine and dried over magnesium sulfate. The product solution was filtered, volatiles removed and the sample dried in vacuuo at room temperature overnight to give 179mg (97%) of a yellow solid. 1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 0.74 - 1.03 (m, 4 H) 1.06 - 1.31 (m, 6 H) 1.32 - 1.50 (m, 3 H) 1.56 (d, J=9.16 Hz, 2 H) 1.77 (d, J=8.85 Hz, 2 H) 1.86 - 2.18 (m, 5 H) 2.83 - 2.91 (m, 1 H) 3.60 (s, 3 H) 3.64 - 3.89 (m, 4 H) 3.88 - 3.93 (m, 4 H) 3.95 - 4.08 (m, 1 H) 4.43 (d, J=15.56 Hz, 1 H) 5.64 (d, J=14.95 Hz, 1 H) 6.99 (d, J=2.75 Hz, 1 H) 7.07 (dd, J=8.70, 2.59 Hz, 1 H) 7.48 - 7.56 (m, 2 H) 7.85 - 7.94 (m, 2 H) 8.15 (s, 1 H). LC-MS retention timel.65 min; 568 m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u Cl 8 3.0x50mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

13-Cyclohexyl-N-(dimethylsulfamoyl)-3-methoxy-6-(4-(4- morpholinylcarbonyl)-l, 3-oxazol-5-yl)- 7H-indolo[2, 1-a] [2]benzazepine-10- carboxamide. In a 2 dram vial, 13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)- l,3-oxazol-5-yl)-7H-indolo[2,l-α][2]benzazepine-10-carboxyl ic acid (40 mg, 0.070 mmol) in TΗF (1 ml) and CDI (23.8mg, 0.147 mmol) was added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for lhr. The reaction was then heated at 6OC for lhr, cooled and N,N- Dimethylsulfamide (46.5 mg, 0.375 mmol) was added to the reaction followed by

DBU (0.014 ml, 0.092 mmol). The reaction was capped under a nitrogen atmosphere and heated overnight(16hrs) at 6OC. The reaction was monitored by ΗPLC and additional N,N-Dimethylsulfamide (22.9 mg, 0.184 mmol) and DBU (0.015 ml, 0.099 mmol) was added and the reaction heated to 7OC under a nitrogen atmosphere for 5hrs. The reaction mixture was partitioned between IN aqueous hydrochloric acid and dichloromethane. The organic phase was washed sequentially with IN aqueous hydrochloric acid and 0.1M aqueous NaH2PO4 and dried over sodium sulfate. Solvent was removed in vacuuo to yield 46mg of crude product. The title compound was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software and interfaced with a SCL-IOA controller, SIL- 1OA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 12 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.05 - 1.28 (m, 1.2 H) 1.29 - 1.62 (m, 3.7 H) 1.64 - 1.84 (m, 4.0 H) 1.84 - 2.20 (m, 4.6 H) 2.47 (d, J=14.04 Hz, 0.1 H) 2.78 - 2.88 (m, 1.1 H) 3.04 (s, 5.9 H) 3.10 (s, 0.9 H) 3.35 - 3.89 (m, 9.0 H) 3.91 (s, 3.0 H) 4.09 (s, 0.4 H) 4.18 (d, J=I.83 Hz, 0.9 H) 4.41 (d, J=15.56 Hz, 0.9 H) 4.55 (d, J=16.48 Hz, 0.1 H) 5.59 (d, J=14.95 Hz, 0.9 H) 6.62 (d, J=14.34 Hz, 0.1 H) 6.97 (d, J=2.44 Hz, 1.0 H) 7.07 (dd, J=8.70, 2.59 Hz, 1.0 H) 7.27 - 7.36 (m, 0.3 H) 7.46 - 7.54 (m, 1.9 H) 7.59 (d, J=8.55 Hz, 0.9 H) 7.75 (d, J=7.93 Hz, 0.1 H) 7.82 (s, 1.0 H) 7.87 (d, J=8.54 Hz, 0.9 H) 8.15 (s, 0.1 H) 8.28 - 8.35 (m, 0.2 H) 8.44 (s, 0.9 H) 8.94 (d, J=9.16 Hz, 0.1 H) 9.43 (s, 0.9 H) 9.88 (s, 0.1 H) 12.11 (s, 0.1 H). LC-MS retention time 1.40min; 672 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

13-cyclohexyl-N-(isopropylsulfonyl)-3-methoxy-6-(4-(4- morpholinylcarbonyl)-l, 3-oxazol-5-yl)- 7H-indolo[2, l-a][2]benzazepine-10- carboxamide.

13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-l,3- oxazol-5-yl)- 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid (40.8mg, 0.072 mmol) was dissolved in TΗF(lml) and CDI (26 mg, 0.160 mmol) added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 50min then heated in an oil bath at 6OC for 1.5hrs. The reaction was cooled and propane-2-sulfonamide (46 mg, 0.373 mmol) was added to the reaction followed by DBU (0.022 ml, 0.144 mmol). The reaction was capped under a nitrogen atmosphere and heated at 65C overnight (16hr). The reaction was partitioned between dichloromethane and 1.0N aqueous hydrochloric acid. The organic layer was washed sequentially with IN aqueous hydrochloric acid, 0.1M aqueous NaH2PO4. The organic layer was dried over sodium sulfate and solvent removed in vacuuo to yield 50mg of an amorphous yellow solid. The title was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1: 1) purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 12 minutes with a run time of 15 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Removal of solvents and drying in vacuuo yielded 28.3mg of a yellow solid. IH NMR (500 MHz, CHLOROFORM- D) δ ppm l. l5 - 1.28 (m, 1.2 H) 1.29 - 1.60 (m, 10.9 H) 1.59 - 1.85 (m, 6.7 H) 1.86 - 2.15 (m, 4.7 H) 2.78 - 2.87 (m, 1.0 H) 3.37 - 3.50 (m, 1.4 H) 3.51 - 3.89 (m, 7.3 H) 3.91 (s, 3.3 H) 4.02 - 4.12 (m, 1.5 H) 4.15 - 4.26 (m, 0.9 H) 4.42 (d, J=13.73 Hz, 0.9 H) 4.54 (d, J=15.26 Hz, 0.1 H) 5.54 (d, J=14.65 Hz, 0.9 H) 6.57(d, J=14.04Hz, 0.1H) 6.97 (d, J=2.44 Hz, 0.9 H) 7.07 (dd, J=8.55, 2.44 Hz, 1.0 H) 7.28 - 7.35 (m, 0.3 H) 7.48 - 7.54 (m, 2.0 H) 7.62 - 7.67 (m, 1.0 H) 7.75 (d, J=7.93 Hz, 0.1 H) 7.82 (s, 1.0 H) 7.87 (d, J=8.55 Hz, 1.0 H) 8.21 (s, 0.9 H) 8.31 (s, 0.2 H) 8.48 (s, 1.0 H) 8.94 (d, J=9.15 Hz, 0.1 H) 9.46 (s, 0.9 H) 9.86 (s, 0.1 H). LC-MS retention time 1.26 min; 671 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

13-cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-l,3- oxazol-5-yl)-N- (4-morpholinylsulfonyl)-7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxamide.

13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-l,3- oxazol-5-yl)- 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid (40.8mg, 0.072 mmol) was dissolved in THF(ImI) and CDI (26 mg, 0.160 mmol) added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 50min then heated in an oil bath at 6OC for 1.5hrs. The reaction was cooled and propane-2-sulfonamide (46 mg, 0.373 mmol) was added to the reaction followed by DBU (0.022 ml, 0.144 mmol). The reaction was capped under a nitrogen atmosphere and heated at 65 C overnight (16hr). The reaction was partitioned between dichloromethane and 1.0N aqueous hydrochloric acid. The organic layer was washed sequentially with IN aqueous hydrochloric acid, 0.1M aqueous NaH2PO4. The organic layer was dried over sodium sulfate and solvent removed in vacuuo to yield 50mg of an amorphous yellow solid. The title was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1: 1) purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 12 minutes with a run time of 15 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Removal of solvents and drying in vacuuo yielded 28.3mg of a yellow solid. IH NMR (500 MHz, CHLOROFORM- D) δ ppm l. l5 - 1.28 (m, 1.3 H) 1.30 - 1.46 (m, 2.4 H) 1.48 - 1.61 (m, J=16.48 Hz, 1.2 H) 1.77 (d, J=9.77 Hz, 2.3 H) 1.87 - 2.15 (m, 4.8 H) 2.22 - 2.52 (m, 4.6 H) 2.78 - 2.90 (m, 1.1 H) 3.37 - 3.72 (m, 8.9 H) 3.76 (s, 6.2 H) 3.80 - 3.89 (m, 3.2 H) 3.91 (s, 3.6 H) 4.08 (s, 0.3 H) 4.13 - 4.23 (m, 1.0 H) 4.42 (d, J=13.73 Hz, 0.9 H) 4.65 (d, J=14.95 Hz, 0.1 H) 5.55 (d, J=14.04 Hz, 1.0 H) 6.97 (d, J=2.44 Hz, 1.0 H) 7.07 (dd, J=8.70, 2.59 Hz, 1.0 H) 7.27 - 7.33 (m, 0.2 H) 7.38 (s, 0.1 H) 7.46 - 7.55 (m, 2.0 H) 7.60 (d, J=9.77 Hz, 1.0 H) 7.78 (d, J=8.24 Hz, 0.1 H) 7.83 (s, 1.0 H) 7.87 (d, J=8.55 Hz, 1 H) 8.07 (s, 0.1 H) 8.10 (d, J=4.27 Hz, 0.1 H) 8.31 (d, J=8.54 Hz, 0.1 H) 8.42 (s, 0.9 H) 8.94 (d, J=9.16 Hz, 0.1 H) 9.55 (s, 0.9 H) 9.60 (s, 0.1 H). LC-MS retention time 1.63 min;714 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-(4-(4- morpholinylcarbonyl)-l, 3-oxazol-5-yl)- 7H-indolo[2, 1-a] [2]benzazepine-10- carboxamide.

13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-l,3- oxazol-5-yl)-

7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid (40mg, 0.070 mmol) was dissolved in THF(I ml) and CDI (26 mg, 0.160 mmol) added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for lhr 50min then heated in an oil bath at 65C for lhr lOmin. The reaction was cooled and cyclopropanesulfonamide (48 mg, 0.396 mmol) then DBU (0.022 ml, 0.146 mmol) was added to the reaction. The reaction was capped under a nitrogen atmosphere and heated at 68C overnight (18hr). The reaction was partitioned between dichloromethane and 1.0N aqueous hydrochloric acid. The organic layer was washed sequentially with IN aqueous hydrochloric acid, 0.1M aqueous NaH2PO4. The organic layer was dried over sodium sulfate and solvent removed in vacuuo to yield 62mg of an amorphous yellow solid. The title was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 :1) purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Removal of solvents and drying in vacuuo yielded 30.8mg of the title compound as a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.99 - 1.28 (m, 4.0 H) 1.29 - 1.45 (m, 3.9 H) 1.47 - 1.68 (m, 7.9 H) 1.75 (m, 2.3 H) 1.84 - 2.17 (m, 4.5 H) 2.77 - 2.88 (m, 1.0 H) 3.14 - 3.23 (m, 1.2 H) 3.33 - 3.89 (m, 8.3 H) 3.91 (s, 3.3 H) 4.09 (s, 0.5 H) 4.17 (s, 0.9 H) 4.42 (d, J=14.34 Hz, 0.9 H) 5.54 (d, J=15.56 Hz, 0.9 H) 6.60 (d, 0.1 H) 6.97 (d, J=2.44 Hz, 1.0 H) 7.07 (dd, J=8.55, 2.75 Hz, 1.0 H) 7.27 - 7.35 (m, 0.3 H) 7.49 (s, 1.0 H) 7.52 (d, J=8.85 Hz, 1.0 H) 7.64 (dd, J=8.55, 1.53 Hz, 1.0 H) 7.75 (d, J=7.94 Hz, 0.2 H) 7.82 (s, 1.0 H) 7.87 (d, J=8.55 Hz, 1.0 H) 8.21 (s, 0.1 H) 8.31 - 8.36 (m, 0.3 H) 8.43 (d, J=I.53 Hz, 1.0 H) 8.95 (d, J=9.16 Hz, 0.2 H) 9.61 (s, 1.0 H) 9.82 (s, 0.1 H). LC-MS retention time 1.59 min; 669 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

The scheme depiced below is illustrative of methods that can be used to make intermediates and compounds.

An additional variation in the methodology that can be employed for the synthesis of intermediates and compounds is shown in the following scheme.

A further variation of the methodology that can be used for the synthesis of further intermediates and compouns is depicted the the scheme shown below.

tert-Butyl 6-acetyl-13-cyclohexyl-3-methoxy-7H-indolo[2, 1- a][2]benzazepine-10-carboxylate.

To a suspension of tert-butyl 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)- lH-indole-6-carboxylate (2 g, 4.61 mmol) in dioxane (9.2 mL) add 2-tert-butylimino- 2-diethylamino-l,3-di- methylperhydrodiazaphosphorine (2.00 mL, 6.92 mmol) then but-3-en-2-one (0.756 mL, 9.23 mmol) in a 20ml microwave vessel. Cap the heterogenous reaction under nitrogen and heat in the microwave at 120C for 40 minutes. This reaction was repeated two more times on the above scale and one last time with tert-butyl 3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-lH-indole-6- carboxylate (2.5 Ig, 5.79mmol) dissolved in dioxane (11.5ml), add BEMP (2.5ml, 8.64 mmol) followed by but-3-en-2-one (0.95ml, 11.46 mmol). Each reaction segment was worked up while the next sequence was running in the microwave.

Work up consisted of partitioning the reaction between ethyl acetate and IN aqueous hydrochloric acid in a 250ml separatory funnel. The aqueous phase was back extracted once with ethyl acetate and the organic phases combined and washed sequentially with IN aqueous hydrochloric acid, 0. IM NaH2PO4, and brine. The solution was then combined with a previous workup in a IL erlenmeyer flask containing magnesium sulfate. Filter and remove volatiles, dry in vacuuo at room temperature overnight to obtain 10.67g of a yellow-orange foam. Adsorb the crude product onto 25g of silica gel using dichloromethane, removing volatiles in vacuuo. Chromatograph on 299g of silica gel slurry packed in 20% ethyl acetate in hexanes and eluting with 20% ethyl acetate in hexanes. Pure product fractions from the chromatography were combined and solvents removed in vacuuo. The residue was dissolved in benzene and removed in vacuuo to aid in the removal of trace ethyl acetate. The title compound as a yellow foam/amorphous solid was dried in vacuuo overnight at room temperature to yield 6.83g (71.7%). IH NMR (500 MHz,

CHLOROFORM-D) δ ppm 1.12 - 1.29 (m, 1 H) 1.30 - 1.61 (m, 4 H) 1.64 (s, 10 H) 1.67 - 2.00 (m, 4 H) 1.98 - 2.19 (m, 3 H) 2.43 (s, 3 H) 2.75 - 2.87 (m, 1 H) 3.85 - 4.01 (m, 4 H) 5.86 (s, 1 H) 7.00 (d, J=2.75 Hz, 1 H) 7.11 (dd, J=8.55, 2.75 Hz, 1 H) 7.35 (s, 1.8 H, benzene) 7.69 (dd, J=8.55, 1.53 Hz, 1 H) 7.82 (d, J=8.24 Hz, 1 H) 8.24 (s, 1 H). LC-MS retention time 3.28 min; m/z (MH+). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 30% solvent A / 70% solvent B to 0% solvent A / 100% solvent B, a gradient time of 5min, a hold time of 1 min, and an analysis time of 6 min where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% MeOH / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-Indolo[2, 1-a] [2] benzazepine-6-propanoic acid, 13-cyclohexyl-10-[(l, 1- dimethylethoxy)carbonyl]-3-methoxy-beta-oxo-, ethyl ester.

To a solution of 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 6-acetyl- 13-cyclohexyl-3-methoxy-, 1,1-dimethylethyl ester (2.50 g, 5.15 mmol) in THF (15.0 mL) was added a IM solution of LHMDS (5.41 mL, 5.41 mmol) in THF at -78 ⁰ C and stirred for 15 min. Ethyl cyanoformate (0.510 mL, 5.15 mmol) was added at -78 ⁰ C to the resulting solution and stirring continued for 30 min. Saturated aqueous NH ₄ Cl (50 mL) was added and the aqueous layer was extracted with CHCI3 (2 x 50 mL). The organic phase was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. Silica gel chromatography (2: 1 methylene chloride:hexanes) of the concentrate afforded the title compound (1.75 g, 61%) as a yellow oil. MS m/z 558 (MH ⁺ ). A previous reaction which was run in an analogous fashion to the above reaction and in which starting material 7H-indolo[2,l-a][2]benzazepine-10- carboxylic acid, ό-acetyl-lS-cyclohexyl-S-methoxy-, 1,1-dimethylethyl ester was still present was separated under the following conditions: This procedure describes the separation of tert-butyl 13-cyclohexyl-6-(3-ethoxy-3-oxopropanoyl)-3-methoxy-7H- indolo[2,l-a][2]benzazepine-10-carboxylate (desired product) from the starting material ketone, tert-butyl 6-acetyl-13-cyclohexyl-3-methoxy-7H-indolo[2,l- a][2]benzazepine-10-carboxylate. Total weight of materials was estimated to be 2.6g. 3.9g of an the sample mixture as an orange oil was dissolved in dichloromethane and adsorbed on 1Og of silica gel. The volatiles were removed in vacuuo using a rotoary evaporator. The sample adsorbed onto silica gel was applied to a column of 294g of silica gel which was slurry packed in 30% diethyl ether in hexanes. A bed of sand was placed on top of the adsorbed sample to aid in solvent addition. The approximate size of the silica gel column packing was 75mm diameter x 175mm in height. The product was eluted using a gradient of 30% diethyl ether in hexanes to 35% diethyl ether in hexanes to 40% diethyl ether in hexanes. Elute with approximately IL of 30%Et2O/hexanes, then IL of 35%Et2O/hexanes, and finally using 40%Et2O/hexanes. The volumes of fractions collected were approximately 125ml to 150ml. The product fractions were combined and volatiles removed and the title keto-ester dried in vacuuo to yield 1.63g of a yellow-orange amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.12 (t, J=7.02 Hz, 2.5 H) 1.15 - 1.28 (m, 1.6 H) 1.32 (q, J=I .12 Hz, 1.0 H) 1.35 - 1.43 (m, 1.5 H) 1.59 (s, 1.5 H) 1.61 - 1.69 (m, 9.4 H) 1.72 - 1.82 (m, 2.0 H) 1.94 (s, 1.2 H) 2.04 (s, 2.9 H) 2.76 - 2.85 (m, 1.0 H) 3.64 - 3.79 (m, 0.8 H) 3.88 (s, 0.7 H) 3.90 (s, 0.7 H) 3.92 (s, 2.6 H) 3.94 - 4.06 (m, 0.7 H) 4.12 (q, J=7.22 Hz, 1.9 H) 4.21 - 4.33 (m, 0.7 H) 4.39 (q, J=I .12 Hz, 0.2 H) 5.67 (s, 0.2 H) 5.71 - 5.90 (m, 0.7 H) 6.95 - 7.02 (m, 1.0 H) 7.06 (dd, J=8.55, 2.75 Hz, 0.2 H) 7.12 (dd, J=8.70, 2.59 Hz, 0.82 H) 7.46 - 7.57 (m, 1.2 H) 7.64 (s, 0.8 H) 7.69 (d, J=8.55 Hz, 0.9 H) 7.76 - 7.85 (m, 0.9 H) 8.14 (s, 0.2 H) 8.22 (s, 0.8 H) 12.40 (s, 0.1 H). LC-MS retention time 2.78 min; 556 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

tert-Butyl 13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl) -2- propenoyl)-3-methoxy-7H-indolo[2, 1 -a] [2] benzazepine-10-carboxylate. tert-Butyl 13 -cyclohexyl-6-(3 -ethoxy-3 -oxopropanoyl)-3 -methoxy-7H- indolo[2,l-a][2]benzazepine-10-carboxylate (1.63 g, 2.92 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (7.0 mL, 52.7 mmol) in a 50ml round bottom flask. The reaction was maintained under a nitrogen atmosphere and heated in oil bath under refluxing conditions (110 ⁰ C) for 2.75hrs. The reaction was then cooled reaction under a nitrogen atmosphere and the volatiles were evaporated in vacuuo to give an orange colored foam. TLC analysis (SiO2 plate, elution- 50% diethyl ether in hexanes) confirmed that the reaction had gone to completion. This material was dried in vacuuo at room temperature overnight to yield 1.87g of the enamine intermediate as an orange amber foam which was used in the next step without any further purification. LC-MS of intermediate enamine: LC-MS retention time 2.81 min; 613 m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH / 90% H2O / 0.1% trifluoroacetic acid and solvent B was 10% H2O / 90% MeOH / 0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l -methyl- lH-pyrazol-5-yl] -3-methoxy-, 1,1-dimethylethyl ester and 7H-indolo [2, 1-a] [2] benzazepine-1 O-carboxylic acid, 13-cyclohexyl-6-[4-

(ethoxycarbonyl)-l -methyl- lH-pyrazol-3-yl] -3-methoxy-, 1, 1-dimethylethyl ester.

The intermediate enamine, tert-butyl 13-cyclohexyl-6-((2E,Z)-3- (dimethylamino)-2-(ethoxycarbonyl)-2-propenoyl)-3-methoxy-7H -indolo[2,l- a][2]benzazepine-10-carboxylate, (1.83 g, 2.99 mmol) was dissolved in absolute ethanol (10 mL). Within a few minutes of dissolution in ethanol the reaction became heterogeneous with a fine yellow/orange precipitate forming. Methylhydrazine (0.173 mL, 3.29 mmol) was added to the reaction and the reaction was placed under a nitrogen atmosphere with a condenser. The reaction was heated to 8OC and remained heterogeneous at 80C. An additional 5ml of absolute ethanol was added and the reaction stirred at 80C for 15minutes. The reaction was still heterogeneous and 1,4- dioxane (5ml) was added and the reaction slowly became homogeneous. The reaction was heated for 2 hours then cooled and the volatiles removed in vacuuo to obtain an orange amber foam. The residue was dissolved in benzene and then volatiles removed in vacuuo and the sample was dried at room temperature overnight in vacuuo to yield 1.79g of a yellow amorphous solid/foam. LC-MS analysis indicated two possible isomeric products. 102mg of the crude product was purified by reverse phase prep HPLC. The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) (4ml) purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD- IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 25% solvent A / 75% solvent B to 0% solvent A / 100% solvent B, a gradient time of 10 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. First eluting product is 7H- indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4-

(ethoxycarbonyl)- 1 -methyl- 1 H-pyrazol-5 -yl] -3 -methoxy-, 1 , 1 -dimethylethyl ester with retention time of 11.7minutes with the minor component product being 7H- indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l -methyl- lH-pyrazol-3-yl] -3 -methoxy-, 1, 1 -dimethylethyl ester with a retention of 14.5 minutes.

7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-methyl-lH-pyrazol-5-yl]-3-methoxy-, 1,1 -dimethylethyl ester. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.13 - 1.27 (m, 1 H) 1.30 (t, J=7.02 Hz, 3 H) 1.34 - 1.55 (m, 3 H) 1.58 (s, 9 H) 1.61 - 1.84 (m, 3 H) 1.85 - 2.00 (m, 1 H) 1.99 - 2.18 (m, 3 H) 2.86 (t, J=I 1.75 Hz, 1 H) 3.28 (s, 3 H) 3.90 (s, 3 H) 4.27 (d, J=4.27 Hz, 2 H) 4.71 (s, 1 H) 4.97 (s, 1 H) 6.77 (s, 1 H) 6.93 (d, J=2.44 Hz, 1 H) 7.07 (dd, J=8.55, 2.44 Hz, 1 H) 7.65 (d, J=8.55 Hz, 1 H) 7.79 - 7.88 (m, 2 H) 7.97 (s, 1 H). LC-MS retention time 3.92min; 596 m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 70% solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 5min, a hold time of 1 min, and an analysis time of 6 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-methyl-lH-pyrazol-3-yl]-3-methoxy-, 1,1-dimethylethyl ester. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.13 - 1.26 (m, 1 H) 1.30 (t, J=IAl Hz, 3 H) 1.33 - 1.60 (m, 3 H) 1.61 (s, 9 H) 1.64 - 1.83 (m, 3 H) 1.91 (s, 2 H) 1.98 - 2.16 (m, 3 H) 2.82 - 2.91 (m, 1 H) 3.90 (s, 3 H) 3.94 (s, 3 H) 4.20 - 4.30 (m, 2 H) 4.41 (d, J=14.04 Hz, 1 H) 5.76 (d, J=14.04 Hz, 1 H) 6.96 - 7.03 (m, 2 H) 7.49 - 7.54 (m, 1 H) 7.64 (dd, J=8.39, 1.37 Hz, 1 H) 7.79 (d, J=8.55 Hz, 1 H) 7.84 (s, 1 H) 7.90 (s, 1 H) 8.26 (s, 1 H). LC-MS retention time 4.26min; 596 m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 70% solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 5min, a hold time of 1 min, and an analysis time of 6 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H ₂ O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. The remainder of the sample (1.615g) was adsorbed onto 4g of silica gel using dichloromethane and chromatographed on 50g of silica gel slurry packed using 2% ethyl acetate in dichloromethane and eluting with 2% ethyl acetate in dichloromethane. The first component to elute is the minor product, 7H-indolo[2,l- a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4-(ethoxycarbonyl)-l- methyl-lH-pyrazol-3-yl]-3-methoxy-, 1 , 1 -dimethylethyl ester, 179mg isolated. The second component, 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-6-[4-(ethoxycarbonyl)- 1 -methyl- lH-pyrazol-5-yl]-3-methoxy-, 1,1- dimethylethyl ester was the major component to elute and yielded 966mg.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-methyl-lH-pyrazol-5-yl]-3-methoxy-.

7H-indolo [2, 1 -a] [2]benzazepine- 10-carboxylic acid, 13 -cyclohexyl-6- [4- (ethoxycarbonyl)-l -methyl- lH-pyrazol-5-yl] -3 -methoxy-, 1,1-dimethylethyl ester (53 mg, 0.089 mmol) was dissolved in 1 ,2-dichloroethane (2 mL), under a nitrogen atmosphere. Tifluoroacetic acid was then added (2 ml, 26.0 mmol), and the reaction was stirred at room temperature for 2.5 hours. The volatiles were then removed in vacuuo and the residue dissolved in benzene and the resultant solution was evaporated under reduced pressure to remove residual TFA. This process was repeated once. This gave the title compound as a yellow solid, (46.2mg).

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.12 - 1.26 (m, 1 H) 1.31 (t, J=7.02 Hz, 3 H) 1.40 (s, 2 H) 1.51 - 1.89 (m, 3 H) 1.87 - 2.23 (m, 4 H) 2.87 (t, J=I 1.29 Hz, 1 H) 3.29 (s, 3 H) 3.91 (s, 3 H) 4.27 (br.s, 2 H) 4.73 (br.s, 1 H) 4.97 (br.s, 1 H) 6.78 (s, 1 H) 6.94 (d, J=2.14 Hz, 1 H) 7.08 (dd, J=8.55, 2.44 Hz, 1 H) 7.54 (d, J=8.85 Hz, 1 H) 7.77 (d, J=8.24 Hz, 1 H) 7.86 - 7.95 (m, 2 H) 7.98 (s, 1 H) 8.36 (br.s, 2 H). LC- MS retention time 1.84 min; 538 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV -Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 70% solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 5min, a hold time of 0 min, and an analysis time of 5 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H?O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl] amino] carbonyl] -7H-indolo[2,l-a] ' [2]benzazepin-6-yl]-l- methyl-, ethyl ester.

7H-indolo [2, 1 -a] [2]benzazepine- 10-carboxylic acid, 13 -cyclohexyl-6- [4- (ethoxycarbonyl)-l -methyl- lH-pyrazol-5-yl] -3 -methoxy- (981mg, 1.818 mmol) was dissolved in THF (18 mL). Carbonyldiimidazole (649 mg, 4.00 mmol) was added to the reaction. The reaction was placed under a nitrogen atmosphere and stirred at room temperature for 45minutes then heated to reflux for 1 hour. The reaction was cooled under a nitrogen atmosphere and propane-2-sulfonamide (1164 mg, 9.45 mmol) was added to the reaction followed by DBU (0.548 mL, 3.64 mmol). The reaction was then immersed in oil bath at 80 ⁰ C under nitrogen atmosphere and heated overnight at 70-80 ⁰ C. The reaction was then diluted with ethyl acetate and the organic layer washed sequentially with 1.0 N aqueous hydrochloric acid, 0. IM aqueous NaH ₂ PO ₄ and brine. The organic layer was dried over MgSO ₄ , filtered and volatiles removed in vacuuo to yield a yellow foam which was dried in vacuuo at room temperature overnight to yield 1.17Og of a yellow amorphous solid. Proton NMR analysis revealed the presence of propane-2-sulfonamide (1.41ppm, d, 500MHz, CDC13) in the sample. The crude sample was dissolved in approximately 200ml of dichloromethane and washed 2 x with 125ml of water, then sequentially with IN aqueous hydrochloric acid, 2 x with 0.1M NaH2PO4 then again with IN aqueous hydrochloric acid. The dichloromethane solution was dried over sodium sulfate, filtered and volatiles removed and the product dried in vacuuo at room temperature overnight to yield 1.046g (89%) of the title compound as a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.80 - 0.90 (m, 1 H) 1.20 - 1.27 (m, 4 H) 1.30 (t, J=7.02 Hz, 4 H) 1.32 - 1.43 (m, 3 H) 1.46 (d, J=7.02 Hz, 6 H) 1.53 - 1.64 (m, 3 H) 1.79 (d, J=9.77 Hz, 3 H) 1.85 - 2.13 (m, 5 H) 2.81 - 2.91 (m, 1 H) 3.90 (s, 3 H) 4.00 - 4.10 (m, 1 H) 4.24 (s, 2 H) 4.71 (d, ./=12.21 Hz, 1 H) 4.99 (d, J=I 6.48 Hz, 1 H) 6.77 (s, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.08 (dd, J=8.55, 2.75 Hz, 1 H) 7.38 (dd, J=8.55, 1.22 Hz, 1 H) 7.52 (d, J=8.85 Hz, 1 H) 7.76 (d, ./=1.22 Hz, 1 H) 7.86 - 7.92 (m, 2 H) 8.26 (br.s, 1 H). LC-MS retention time 1.79 min; 643 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a] [2]benzazepin-6-yl]-l- methyl-.

1 H-pyrazole-4-carboxylic acid, 5 -[ 13 -cyclohexyl-3 -methoxy- 10- [[ [( 1 - methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][2]benz azepin-6-yl]-l- methyl-, ethyl ester (1.044 g, 1.619 mmol) was dissolved in THF (11 ml) with heating. DMF was then added (5 mL) and the mixture was gently heated to ensure dissolution. The mixture was then cooled to room temperature and tetrabutylammonium hydroxide (6.5 ml, 6.50 mmol) (1.0M in methanol) was added. The resultant mixture was then stirred at room temperature under nitrogen for 2.5hrs and progress was monidered by LC-MS. Results showed predominately methyl and ethyl esters. The mixture was then stirred for an additional 3hrs, after which a further 2.OmL (2mmol) of tetrabutylammonium hydroxide(1.0M in methanol) was added and the reaction was stirred at room temperature under nitrogen for a further 2 days. Subsequent analysis shows reaction had proceeded to approximately 22% conversion to the desired acid product. Volatiles (methanol, ethanol, THF) were removed from the reaction in vacuuo (30 ⁰ C) using a rotary evaporator. To the reaction was added 20OuL of ION aqueous sodium hydroxide and 4 ml of THF. The reaction was mixed by placing on rotary evaporator, gently heated (25°C, 3hrs) then add approximately 6ml of DMF and heat at 35C for3hrs and using house vacuum to remove volatiles generated from hydrolysis. Analysis of the reaction by LC-MS indicated approximately 83% conversion to acid product. The reaction was stirred overnight at room temperature and subsequent analysis showed no additional conversion to product. An additional 4.0ml of 1.0M tetrabutylammonium hydroxide in methanol was added to the reaction. The reaction was placed on a rotary evaporator and volatiles removed in vacuuo and the reaction continued to heat at 40- 45 C for approximately 6 hours. The reaction was then worked up by adding IN aqueous hydrochloric acid (100ml) into the reaction and then the mixture was rinsed into a 500ml sepratory funnel using ethyl acetate bring the organic volume to approx. 200ml. Partition the reaction between ethyl acetate and 1.0N aqueous hydrochloric acid. The organic layer was wash 3x (~300ml each) with 1.0N aqueous hydrochloric acid, then brine and dried over MgSO4, filtered and the volatiles removed in vacuuo to yield 1.03g of a yellow film foam. The sample was dried in vacuuo at room temperature to 0.92g (92%) of the title compound. LC-MS retention time 1.48 min; 615 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

An alterantive procedure for the preparation of the title compound is described below.

Dissolve lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][2]benz azepin-6-yl]-l- methyl-, ethyl ester (1.044 g, 1.619 mmol) in a pre-mixed solution of THF (20 mL), MeOH (20 mL) and sodium hydroxide (20 mL, 20.00 mmol). The reaction was homogenous and was stirred at room temperature under a nitrogen atmosphere for 26hrs then concentrated in vacuuo using a rotary evaporator with a bath temperature at 2OC. The reaction was poured into IN aqueous hydrochloric acid and extract using ethyl acetate. The combined organic layers were washed sequentially with IN aqueous hydrochloric acid and brine, then dried over magnesium sulfate, filtered and solvent removed in vacuuo. The crude product dried in vacuuo at room temperature to yield 1.68g of an orange amorphous solid. The crude product was dissolved in chloroform (approximately 5OmL) with heating and hexanes were added until some material starts to precipitate but re-dissolves on swirling (approximately 10- 12ml of hexanes). The mixture was allowed to slowly cool to room temperature and then allowed to stand at room temperature for a few hours. The very fine particulate yellow precipitate was filtered using a Buchner funnel and dried in vacuuo at room temperature to yield 819mg (45%) of purified product as a bright yellow amorphous solid. The title compound 4.6mg was dissolved in CDC13 (2ml) with the addition of approximately 5 drops of CD3OD to aid in dissolution for IH NMR acquisition.

IH NMR (500 MHz, CHLOROFORM-D / CD3OD) δ ppm 1.11 - 1.39 (m, 3 H) 1.41 (d, J=7.02 Hz, 6 H) 1.47 - 1.65 (m, 1 H) 1.75 (d, J=8.85 Hz, 2 H) 1.82 - 2.27 (m, 13 H) 2.77 - 2.90 (m, 1 H) 3.28 (s, 3 H) 3.88 (s, 3 H) 3.97 - 4.06 (m, 1 H) 4.66 (s, 1 H) 5.01 (s, 1 H) 6.76 (s, 1 H) 6.92 (d, J=2.75 Hz, 1 H) 7.04 (dd, J=8.70, 2.59 Hz, 1 H) 7.47 - 7.54 (m, 2 H) 7.81 (d, J=1.22 Hz, 1 H) 7.86 (d, J=8.54 Hz, 1 H) 7.91 (s, 1 H). LC-MS retention time 1.39 min; 615 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4-

(ethoxycarbonyl)-l-methyl-lH-pyrazol-3-yl]-3-methoxy-.

Dissolve 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl- 6-[4-(ethoxycarbonyl)-l-methyl-lH-pyrazol-3-yl]-3-methoxy-, 1,1-dimethylethyl ester (176 mg, 0.295 mmol) in 1,2-dichloroethane (3 mL), place reaction under a nitrogen atmosphere, then add trifluoroacetic acid (3 ml, 38.9 mmol). Stir the reaction at room temperature under a nitrogen atmosphere for 2hr 20min then remove volatiles in vacuuo. Dissolve product in a mixture of benzene and dichloromethane then remove volatiles in vacuuo. Repeat dissolution in benzene and dichloromethane and remove volatiles to aid in removal of trace trifluoroacetic acid. The title compound was dried in vacuuo at room temperature to yield 164mg of a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.01 - 1.29 (m, 3 H) 1.32 (t, J=7.17 Hz, 3 H) 1.35 - 1.53 (m, 2 H) 1.52 - 1.85 (m, 3 H) 1.86 - 2.20 (m, 4 H) 2.79 - 2.95 (m, 1 H) 3.91 (s, 3 H) 3.97 (s, 3 H) 4.27 (q, J=7.22 Hz, 2 H) 4.41 (d, J=14.34 Hz, 1 H) 5.84 (d, J=14.34 Hz, 1 H) 6.97 - 7.08 (m, 2 H) 7.54 (d, J=8.24 Hz, 1 H) 7.76 (d, J=8.55 Hz, 1 H) 7.85 (d, J=8.54 Hz, 1 H) 7.91 (s, 1 H) 7.95 (s, 1 H) 8.50 (s, 1 H). LC-MS retention time 2.08 min; 538 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 70% solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 5min, a hold time of 1 min, and an analysis time of 6 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 3-[13-cyclohexyl-10- [[[(dimethylamino)sulfonyl] amino] carbonyl]-3-methoxy-7H-indolo[2,l- a] [2] benzazepin-6-yl] -1 -methyl-, ethyl ester. Dissolve 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-

6-[4-(ethoxycarbonyl)-l-methyl-lH-pyrazol-3-yl]-3-methoxy - (60mg, 0.111 mmol) in THF (1.0 mL), then add carbonyl diimidazole (42 mg, 0.259 mmol) to the reaction. The reaction was stirred under a nitrogen atmosphere for 1 hour at room temperature. The reaction was then heated at 7OC for 1 hour then cooled and N,N- dimethylsulfamide (70 mg, 0.564 mmol) was added to the reaction followed by DBU (0.034 mL, 0.222 mmol). The reaction was again capped under a nitrogen atmosphere and heated at 7OC for 16.5 hours. The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4 and again with 1.0N aqueous hydrochloric acid, and finally with brine. The organic phase was dried over magnesium sulfate, filtered, solvent removed and the product dried in vacuuo at room temperature to yield 70mg of an amorphous yellow solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.76 - 0.95 (m, 2 H) 1.12 - 1.26 (m, 5 H) 1.32 (t, J=IAl Hz, 3 H) 1.38 (s, 2 H) 1.51 - 1.61 (m, 4 H) 1.67 - 1.81 (m, 3 H) 1.87 - 2.01 (m, 2 H) 2.01 - 2.11 (m, 3 H) 2.82 - 2.92 (m, 1 H) 3.06 (s, 6 H) 3.91 (s, 3 H) 3.96 (s, 3 H) 4.26 (d, J=7.02 Hz, 2 H) 4.42 (d, J=14.34 Hz, 1 H) 5.75 (d, J=14.04 Hz, 1 H) 6.99 - 7.05 (m, 2 H) 7.38 (d, J=8.24 Hz, 1 H) 7.52 (d, J=8.24 Hz, 1 H) 7.85 (d, J=8.55 Hz, 1 H) 7.89 - 7.96 (m, 2 H) 8.18 (s, 1 H) 8.36 (br.s, 1 H). LC-MS retention time 2.34 min; 644 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 3-[13-cyclohexyl-10- [ [ [(dimethylamino)sulfonyl] amino] carbonyl] -3-methoxy-7H-indolo [2, 1 - a] [2] benzazepin-6-yl] -1 -methyl-. lH-pyrazole-4-carboxylic acid, 3-[13-cyclohexyl-10- [[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indo lo[2,l- α][2]benzazepin-6-yl]-l-methyl-, ethyl ester (66mg, 0.102 mmol) was dissolved in TΗF (1 mL) and a 1.0M solution of tetrabutylammonium hydroxide (0.41 mL, 0.410 mmol) in methanol was added to the reaction. The reaction was stirred at room temperature under a nitrogen atmosphere for 4hrs then analyzed by LC-MS. The reaction was concentrated in vacuuo on a rotary evaporator then ImI of TΗF was added to the reaction and the reaction once again capped under a nitrogen atmosphere. The reaction was placed in a water bath at 4OC and allowed to stir overnight. Sometime overnight the heating element on the water bath failed and the reaction was observed to at room temperature the next morning. LC-MS analysis of the reaction indicated the reaction was complete. The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid, then again with 1.0N aqueous hydrochloric acid and finally with brine. The organic layer was dried over magnesium sulfate, filtered and solvent removed in vacuuo. The title compound was dried in vacuuo to yield 63mg of an amorphous yellow solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.81 - 0.97 (m, 3 H) 1.18 - 1.30 (m, 4 H) 1.30 - 1.65 (m, 6 H) 1.66 - 1.83 (m, 3 H) 1.84 - 2.10 (m, 6 H) 2.84 - 2.92 (m, 3 H) 3.04 (s, 6 H) 3.88 (s, 3 H) 3.97 (s, 3 H) 4.43 (d, J=14.34 Hz, 1 H) 5.68 (d, J=13.73 Hz, 1 H) 6.99 (d, J=2.75 Hz, 1 H) 7.02 (dd, J=8.55, 2.44 Hz, 1 H) 7.35 (d, J=8.24 Hz, 1 H) 7.52 (d, J=8.55 Hz, 1 H) 7.77 (s, 1 H) 7.83 (d, J=8.24 Hz, 1 H) 7.98 (s, 1 H) 8.15 (s, 1 H) 8.71 (s, 1 H). LC-MS retention time 1.58 min; 616 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- [(dimethylamino)sulfonyl]-3-methoxy-6-[l-methyl-4-(4-morphol inylcarbonyl)-lH- pyrazol-3-ylJ-. lH-pyrazole-4-carboxylic acid, 3-[13-cyclohexyl-10- [[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indo lo[2,l- α][2]benzazepin-6-yl]-l-methyl- (57mg, 0.092 mmol) was dissolved in DMF (1.0ml) and TBTU (55.8 mg, 0.174 mmol) added to the reaction. The reaction was capped under a nitrogen atmosphere and stir at room temperature for 1 hour then DMAP (47 mg, 0.385 mmol) was added to the reaction followed by morpholine (16 μL, 0.184 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid, 0.1M aqueous NaΗ2PO4 and brine. The organic phase was dried over magnesium sulfate, filtered and solvent removed in vacuuo. The title compound was dried overnight in vacuuo at room temperature to yield 63 mg of a yellow amorphous solid. The title compound was further purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) (total volume 2ml) purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 60% solvent A / 40% solvent B to 0% solvent A / 100% solvent B, a gradient time of 12 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The sample was run as two ImI injections. The run time of the second Prep HPLC run was truncated to 15 minutes base on data from the first run. The product fractions (retention time= 8.75min.) were combined and solvent removed in vacuuo. The compound was dried at room temperature in vacuuo to yield 38mg of the title compound as a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.23 (q, ./=12.21 Hz, 1 H) 1.30 - 1.56 (m, 3 H)

1.77 (d, J=10.38 Hz, 2 H) 1.90 - 2.14 (m, 4 H) 2.54 - 2.81 (m, 4 H) 2.82 - 2.95 (m, 2 H) 2.95 - 3.05 (m, 2 H) 3.07 (s, 6 H) 3.09 - 3.39 (m, 5 H) 3.90 (s, 3 H) 3.97 (s, 3 H) 4.45 (d, J=14.65 Hz, 1 H) 5.45 (d, J=14.65 Hz, 1 H) 6.95 (d, J=2.75 Hz, 1 H) 6.97 (s, 1 H) 7.04 (dd, J=SJO, 2.59 Hz, 1 H) 7.46 (dd, J=8.55, 1.53 Hz, 1 H) 7.52 (d, J=8.55 Hz, 1 H) 7.55 (s, 1 H) 7.89 (d, J=8.55 Hz, 1 H) 7.94 (d, J=1.22 Hz, 1 H) 9.13 (br.s, 1 H). LC-MS retention time 1.82 min; 685 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, H-cyclohexylS-methoxy-

N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[[4-(l-methylet hyl)-l- piperazinyl]carbonyl]-lH-pyrazol-5-yl]-. lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l- methyl- (0.92g, 1.5mmol) was dissolved in DMF (25ml) and ΗATU (1141mg, 3.0mmol) was added followed by diisopropylethylamine (1306uL, 7.5mmol). A ImL solution of the reaction solution containing lH-pyrazole-4-carboxylic acid, 5- [13-cyclohexyl-3-methoxy-10-[[[(l-methylethyl)sulfonyl]amino ]carbonyl]-7H- indolo[2,l-α][2]benzazepin-6-yl]-l-methyl- / ΗATU / DIEA was transferred a 16xl00mm wheaton vial containing 1-isopropylpiperazine (36.9mg, 0.288mmol). The reaction was capped and shaken at room temperature overnight. The reaction was transferred into a 96well plate and the reaction vial rinsed with DMF (80OuL) to bring the final reaction volume to 1.80OmL. The reaction mixture was purified by reverse phase HPLC under the following conditions. The Prep HPLC was controlled by Dionex Chromeleon 6.70 spl LC software using Varian a prostar binary pump with 50 mL/min pump head and detection using a Sedex 75 ELS detector for fraction collection. A Dionex UVD340U UV spectrometer was used to observe the UV trace of the HPLC run. A Waters Sunfire C18 19mm x 25mm 1Ou was employed for the isolation using a solvent system of A= water and 2OmM ammonium acetate, B= acetonitrile. The following gradient was used: 80%A and 20%B hold for 3 minutes followed by a 19 minute gradient to 5%A and 95%B with a final hold at 5%A and 95%B of 5 minutes. The flow rate for purification was 20ml/ min. The fractions of interest were collected and concentrated to dryness using a Zymark Turbo Vap Evaporator. NMR analysis was performed on the peaks of interest (analytical retention time 5.69 minutes and 6.30minutes). The title compound was determined to be the peak with analytical retention time of 6.30 minutes by NMR analysis

(rotomers). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.17 (s, 0.5 H) 0.91 (t, J=6.87 Hz, 3.3 H) 1.10 (t, J=14.95 Hz, 1.2 H) 1.17 - 1.32 (m, 2.6 H) 1.33 - 1.59 (m, 13.1 H) 1.68 - 1.83 (m, 3.5 H) 1.88 - 2.18 (m, 8.7H) 2.20 - 2.67 (m, 7.8 H) 2.76 - 3.05 (m, 3.3 H) 3.23 (d, J=10.99 Hz, 1.3 H) 3.29 - 3.53 (m, 1.6 H) 3.63 - 3.86 (m, 2.7 H) 3.88 - 3.98 (m, 6.0 H) 4.02 - 4.10 (m, 1.0 H) 4.61 (d, J=14.65 Hz, 1.3 H) 4.89 (d, J=14.95 Hz, 0.9 H) 6.76 - 6.86 (m, 0.8 H) 6.91 - 7.00 (m, 1.9 H) 7.06 - 7.13 (m, 1.3 H) 7.51 - 7.57 (m, 1.4 H) 7.57 - 7.66 (m, 1.6 H) 7.66 - 7.75 (m, 1.9 H) 7.89 (d, J=8.55 Hz, 1.5 H). LCMS analysis using MassLynx 4.0 SP4 LC-MS software, a CTC-Leap HTS-PAL autosampler, with an Agilent 1100 binary pump, Agilent 1100 photodiode array UV detector, Polymer Lab 2100 ELS detector (Temp=45C, nebulizer temp 35C) and a Waters ZQ With ESCi mass spectrometer. The analysis was performed using a Phenomenex Gemini 4.6x 150mm C18 3u column with a mobile phase solvent system of A= water and 2OmM ammonium acetate, B= acetonitrile with a flow rate of l.Oml/min and a gradient starting at 70%A and 30%B and a final composition 5%A and 95%B, gradient time of 11 minutes and a hold time of 2 minutes to give an analysis runtime of 13 minutes. Retention time = 6.63 minutes, m/z= 725 (MH+). The following compounds were synthesized by an analogous method as described above for 7H-indolo[2,l-α][2]benzazepine-10-carboxamide, 13-cyclohexyl-N- [(dimethylamino)sulfonyl]-3-methoxy-6-[ 1 -methyl-4-(4-morpholinylcarbonyl)- IH- pyrazol-3-yl]- and 7H-indolo[2,l-α][2]benzazepine-10-carboxamide, 13-cyclohexyl- 3 -methoxy-N- [( 1 -methylethyl)sulfonyl] -6- [ 1 -methyl-4- [[4-(I -methylethyl)- 1 - piperazinyl]carbonyl]-lH-pyrazol-5-yl]-. Analytical LCMS data on the following examples were acquired using the following columns and conditions. Method 1 : Gradient: 3 minutes; Flow rate: 5 mL/min; Stop time: Gradient time + 1 minute; Eluent A: 5% CH ₃ CN / 95% H ₂ O with 10 mM NH ₄ OAc; Eluent B: 95% CH ₃ CN / 5% H ₂ O with 10 mM NH ₄ OAc; Initial %B= 30; Final % B=IOO; Column: Waters

Xterra, 3mm x 50mm, S7. Method 2: Gradient: 3 minutes; Flow rate: 5 mL/min; Stop time: Gradient time + 1 minute; Eluent A= 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 40; Final % B=IOO; Column: Phenomenex Luna 3.0mm x 50mm SlO.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[[methyl(l-methyl-3-pyrrolidinyl)amino] carbonyl] -lH-pyrazol-5-yl] - N-(4-morpholinylsulfonyl)-. LCMS: m/e 756 (M+H), ret time 2.30 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [(hexahydro-4-methyl-lH-l ,4-diazepin-l-yl)carbonyl] -l-methyl-lH-pyrazol-5-yl] -3- methoxy-N-(4-morpholinylsulfonyl)-. LCMS: m/e 756 (M+H), ret time 2.10 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[3- (dimethylamino)-l-pyrrolidinyl] carbonyl] -l-methyl-lH-pyrazol-5-yl] -3-methoxy-N- (4-morpholinylsulfonyl)-. LCMS: m/e 756 (M+H), ret time 2.40 min.

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-6- fl-methyl-4-(4-morpholinylcarbonyl)-lH-pyrazol-5-ylJ-N-(4-mo rpholinylsulfonyl)-. LCMS: m/e 729 (M+H), ret time 2.60 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[2- [(dimethylamino)methyl] -4-morpholinyl] carbonyl] -l-methyl-lH-pyrazol-5-yl] -3- methoxy-N-(4-morpholinylsulfonyl)-. LCMS: m/e 787 (M+H), ret time 2.40 min.

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [[(2R,6S)-2,6-dimethyl-4-morphotinyl] carbonyl] -1 -methyl- lH-pyrazol-5-yl] -3- methoxy-N-(4-morpholinylsulfonyl)-. LCMS: m/e 757 (M+H), ret time 2.80 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [(hexahydropyrrolo[l ,2-a]pyrazin-2(lH)-yl)carbonyl] -l-methyl-lH-pyrazol-5-yl] -3- methoxy-N-(4-morpholinylsulfonyl)-. LCMS: m/e 768 (M+H), ret time 2.40 min.

1 H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-(l,4- diazabicyclo[3.2.2]non-4-ylcarbonyl)-l-methyl-lH-pyrazol-5-y l]-3-methoxy-N-(4- morpholinylsulfonyl)-. LCMS: m/e 768 (M+H), ret time 2.10 min.

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [[(1R, 4R)-5-ethyl-2, 5-diazabicyclo[2.2. l]hept-2-yl]carbonyl]-l -methyl- lH-pyrazol- 5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-. LCMS: m/e 768 (M+H), ret time 2.30 min.

7H-indolo[2, 1-a] [2]benzazepine-10-carboxamide, 6-[4-(7- azabicyclo[2.2.1] hept-7-ylcarbonyl)-l-methyl-lH-pyrazol-5-yl] -13-cyclohexyl-3- methoxy-N-(4-morpholinylsulfonyl)-. LCMS: m/e 739 (M+H), ret time 3.10 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, li-cyclohexyl-i-methoxy- 6-[l-methyl-4-[(4-methyl-l-piperazinyl)carbonyl]-lH-pyrazol- 5-yl]-N-(4- morpholinylsulfonyl)-. LCMS: m/e 742 (M+H), ret time 2.30 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[[4-(l-methylethyl)-l-piperazinyl] carbonyl] -lH-pyrazol-5-yl] -N-(4- morpholinylsulfonyl)-. LCMS: m/e 771 (M+H), ret time 2.40 min.

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[3- (dimethylamino)-l-piperidinyl] carbonyl] -l-methyl-lH-pyrazol-5-yl]-3-methoxy-N- (4-morpholinylsulfonyl)-. LCMS: m/e 771 (M+H), ret time 2.20 min.

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[[(lR, 5S)-3-methyl-3, 8-diazabicyclo[3.2.1] oct-8-yl] carbonyl] -IH- pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-. LCMS: m/e 768 (M+H), ret time 2.60 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[[(lR, 5S)-8-methyl-3, 8-diazabicycϊo[3.2. lJoct-3-ylJcarbonylJ-lH- pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-. LCMS: m/e 768 (M+H), ret time 2.60 min.

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[(l-oxo-2, 7-diazaspiro[4.5] dec-7-yl)carbonyl] -lH-pyrazol-5-yl] -N-(4- morpholinylsulfonyl)-. LCMS: m/e 797 (M+H), ret time 2.40 min.

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[[2-(l-piperidinylmethyl)-l-pyrrolidinyl] carbonyl] -lH-pyrazol-5-yl] - N-(4-morpholinylsulfonyl)-. LCMS: m/e 811 (M+H), ret time 2.50 min.

1 -piper azinecarboxylic acid, 4-[[5-[13-cyclohexyl-3-methoxy-10-[[(4- morpholinylsulfonyl)amino] carbonyl] -7H-indolo[2,l-a] [2] benzazepin-6-yl]-l- methyl-lH-pyrazol-4-yl] carbonyl] -, ethyl ester. LCMS: m/e 800 (M+H), ret time 2.60 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[[(2-methoxyethyl)(l-methylethyl)amino] carbonyl] -l-methyl-lH-pyrazol-5-yl] - N-(4-morpholinylsulfonyl)-. LCMS: m/e 759 (M+H), ret time 2.80 min.

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[[2- (dimethylamino)ethyl] methylamino] carbonyl] -l-methyl-lH-pyrazol-5-yl] -3-methoxy- N-(4-morpholinylsulfonyl)-. LCMS: m/e 744 (M+H), ret time 2.20 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[[4-(l-pyrrolidinyl)-l-piperidinyl] carbonyl] -lH-pyrazol-5-yl] -N-(4- morpholinylsulfonyl)-. LCMS: m/e 797 (M+H), ret time 2.30 min.

-—o

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6- [4- [ [(2S)-2-(methoxymethyl)-4-morpholinyl] carbonyl] - 1-methyl- lH-pyrazol-5-yl] - N-(4-morpholinylsulfonyl)-. LCMS: m/e 773 (M+H), ret time 2.60 min.

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[(3- endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1] oct-8-yl] carbonyl] -1-methyl-lH- pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-. LCMS: m/e 784 (M+H), ret time 2.70 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[[(3R, 5S)-3, 4, 5-trimethyl-l-piperazinyl] carbonyl] -lH-pyrazol-5-yl] - N-(4-morpholinylsulfonyl)-. LCMS: m/e 771 (M+H), ret time 2.30 min.

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-(3, 7- dioxa-9-azabicyclo[3.3.l]non-9-ylcarbonyl)-l-methyl-lH-pyraz ol-5-yl] ' -3-methoxy- N-(4-morpholinylsulfonyl)-. LCMS: m/e 771 (M+H), ret time 2.60 min.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-(4-morpholinylcarb onyl)-lH-pyrazol-5- yl]-\ LCMS: m/e 686 (M+H), ret time 3.49 min (method T).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [(hexahydropyrrolo[l ,2-a]pyrazin-2(lH)-yl)carbonyl] -l-methyl-lH-pyrazol-5-yl] -3- methoxy-N-[(l-methylethyl)sulfonyl]-\ LCMS: m/e 725 (M+H), ret time 2.99 min (method 2).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [[(1S, 4S)-5-ethyl-2, 5-diazabicyclo[2.2. IJ hept-2-ylJcarbonylJ-l -methyl- lH-pyrazol- 5-yl]-3-methoxy-N-[(l-methylethyl)sulfonyl]-: LCMS: m/e 725 (M+H), ret time 3.11 min (method T).

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxamide, 6-[4-(7- azabicyclo[2.2.1] 'hept-7-ylcarbonyl)-l -methyl- lH-pyrazol-5-ylj '-13-cyclohexyl-3- methoxy-N-[(l-methylethyl)sulfonyl]-\ LCMS: m/e 696 (M+H), ret time 3.32 min (method 2).

7H-indolo [2,1 -a] [2] benzazepine-1 O-carboxamide, li-cyclohexyl-i-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[(4-methyl-l-piper azinyl)carbonyl]-lH- pyrazol-5-yl]-: LCMS: m/e 699 (M+H), ret time 3.05 min (method 2).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[[4-(l-methylethyl )-l- piperazinyl]carbonyl]-lH-pyrazol-5-yl]-\ LCMS: m/e 727 (M+H), ret time 3.19 min (method T).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[[(2-methoxyethyl)(l-methylethyl)amino] carbonyl] -l-methyl-lH-pyrazol-5-yl] - N-[(l-methylethyl)sulfonyl]-: LCMS: m/e 716 (M+H), ret time 3.37 min (method T).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[[4-(l-pyrrolidiny l)-l- piperidinyl] carbonyl] -lH-pyrazol-5-yl]-: LCMS: m/e 753 (M+H), ret time 3.22 min (method T).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-

6- [4- [ [(2S)-2-(methoxymethyl)-4-morpholinyl] carbonyl] - 1-methyl- lH-pyrazol-5-yl] - N-[(l-methylethyl)sulfonyl]-: LCMS: m/e 730 (M+H), ret time 3.51 min (method 2).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[(3- endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1] oct-8-yl] carbonyl] -1-methyl-lH- pyrazol-5-yl]-3-methoxy-N-[(l-methylethyl)sulfonyl]-: LCMS: m/e 740 (M+H), ret time 2.53 min (method 2).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[[(3R, 5S)-3, 4, 5-trimethyl-l- piperazinylJcarbonylJ-lH-pyrazol-5-ylJ-: LCMS: m/e 727 (M+H), ret time 2.26 min (method T).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-(3, 7- dioxa-9-azabicyclo[3.3.l]non-9-ylcarbonyl)-l-methyl-lH-pyraz ol-5-yl] ' -3-methoxy- N-[(l-methylethyl)sulfonyl]-: LCMS: m/e 727 (M+H), ret time 3.50 min (method T).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopentylsulfonyl)-3-methoxy-6-[l-methyl-4-(4-morpholinyl carbonyl)-lH-pyrazol- 5-yl]-: LCMS: m/e 712 (M+H), ret time 2.65 min (method 1).

7H-indolo[2, 1-aJ [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopentylsulfonyl)-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholi nyl]carbonyl]-l- methyl-lH-pyrazol-5-yl]-3-methoxy-: LCMS: m/e 740 (M+H), ret time 2.84 min (method 1).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopen tylsulfonyl)-3-methoxy- 6-[4-[[(2S)-2- (methoxymethyl) -4- morpholinyl] carbonyl] - 1 -methyl- lH-pyrazol- 5 -ylj-: LCMS: m/e 756 (M+H), ret time 2.79 min (method 1).

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopentylsulfonyl)-6-[4-[[3-(dimethylamino)-l-piperidinyl ]carbonyl]-l-methyl- lH-pyrazol-5-yl] -3-methoxy-: LCMS: m/e 753 (M+H), ret time 2.41 min (method 1).

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopentylsulfonyl)-6-[4-[[(lS,4S)-5-ethyl-2,5-diazabicycl o[2.2.1]hept-2- yl] carbonyl] -l-methyl-lH-pyrazol-5-yl] -3-methoxy-: LCMS: m/e 751 (M+H), ret time 2.51 min (method 1).

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopentylsulfonyl)-6-[4-[(hexahydropyrrolo[l, 2-a]pyrazin-2(lH)-yl)carbonyl]-l- methyl-lH-pyrazol-5-yl] -3-methoxy-: LCMS: m/e 751 (M+H), ret time 2.29 min (method 1).

7H-indolo[2, 1-aJ [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopentylsulfonylj-ό-^-ffethylfl-methylethyljaminoJcarbo nylJ-l-methyl-lH- pyrazol-5-yl]-3-methoxy-: LCMS: m/e 712 (M+H), ret time 2.45 min (method 1).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopentylsulfonyl)-3-methoxy-6-[l-methyl-4-[(3-methyl-3,8 - diazabicyclo[3.2.1]oct-8-yl)carbonyl]-lH-pyrazol-5-yl]-: LCMS: m/e 751 (M+H), ret time 2.36 min (method 1).

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopentylsulfonyl)-3-methoxy-6-[l-methyl-4-[[(3R, 5S)-3, 4, 5-trimethyl-l- piperazinylJcarbonylJ-lH-pyrazol-5-ylJ-: LCMS: m/e 753 (M+H), ret time 2.39 min (method 1).

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopentylsulfonyl)-6-[4-(3, 7-dioxa-9-azabicyclo[3.3. l]non-9-ylcarbonyl)-l- methyl-lH-pyrazol-5-yl]-3-methoxy-: LCMS: m/e 754 (M+H), ret time 2.87 min (method 1).

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N-

(cyclopentylsulfonyl)-3-methoxy-6-[l-methyl-4-(3-oxa-9-az abicyclo[3.3.1]non-9- ylcarbonyl)-lH-pyrazol-5-yl]-: LCMS: m/e 752 (M+H), ret time 2.92 min (method

I)-

The following compounds were synthesized by an analogous method as described above for 7H-indolo[2,l-α][2]benzazepine-10-carboxamide, 13-cyclohexyl-N- [(dimethylamino)sulfonyl]-3-methoxy-6-[ 1 -methyl-4-(4-morpholinylcarbonyl)- IH- pyrazol-3-yl]- and 7H-indolo[2,l-α][2]benzazepine-10-carboxamide, 13-cyclohexyl- 3 -methoxy-N- [( 1 -methylethyl)sulfonyl] -6- [ 1 -methyl-4- [[4-(I -methylethyl)- 1 - piperazinyl]carbonyl]-lH-pyrazol-5-yl]-. Analytical LCMS data on the following examples were acquired using the following column and conditions: Gradient: 6 minutes; Flow rate: 4 mL/min; Stop time: 6 minutes; Eluent A: 5% CΗ3CΝ / 95% H ₂ O with 10 mM NH ₄ OAc; Eluent B: 95% CH ₃ CN / 5% H ₂ O with 10 mM NH ₄ OAc; Initial %B= 0; Final % B=IOO; Column: Phenomenex Luna 4.6mm x 50mm S5.

13-cyclohexyl-6-(l-ethyl-4-(((2R)-2-(methoxymethyl)-4-mor pholinyl)carbonyl)-lH- pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy-7H-indolo[2,l- a][2]benzazepine-10- carboxamide:

LCMS: m/e 745 (M+H), ret time 4.90 min.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-4-(3- oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-lH-pyrazol-5-yl]-3- methoxy-N-[(l- methylethyl)sulfonyl]-:

LCMS: m/e 741 (M+H), ret time 5.80 min.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-ό- [ 1 -ethyl-4-(2- oxa-5-azabicyclo[2.2.1]hept-5-ylcarbonyl)-lH-pyrazol-5-yl]-3 -methoxy-N-[(l- methylethyl)sulfonyl]-:

LCMS: m/e 713 (M+H), ret time 4.81 min.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-ό- [ 1 -ethyl-4- [[(3R, 5S)-3, 4, 5-trimethyl-l-piperazinyl] carbonyl] -lH-pyrazol-5-yl] -3-methoxy-N- [(l-methylethyl)sulfonyl]-: LCMS: m/e 742 (M+H), ret time 4.64 min.

7H-indolo[2, 1-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-4-[(3- methyl-3, 8-diazabicyclo[3.2.1] oct-8-yl)carbonyl] -lH-pyrazol-5-yl] -3-methoxy-N-[(l- methylethyl)sulfonyl]-:

LCMS: m/e 740 (M+H), ret time 5.25 min.

7H-indolo[2, 1-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-4-[(5- ethyl-2, 5-diazabicyclo[2.2.1] hept-2-yl)carbonyl] -lH-pyrazol-5-yl] -3-methoxy-N-[(l- methylethyl)sulfonyl]-: LCMS: m/e 740 (M+H), ret time 4.44 min.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-N-[(l- methylethyl)sulfonyl]-6-[4-(8-oxa-3-azabicyclo[3.2.1] oct-3-ylcarbonyl)-l-(2, 2, 2- trifluoroethyl)-lH-pyrazol-5-yl]-: LCMS: m/e 780 (M+H), ret time 5.49 min.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-N-[(l - methylethyl)sulfonyl] -6-[l-methyl-4-[[4-(l-pyrrolidinyl)-l-piperidinyl] carbonyl] - lH-pyrazol-5-yl]-:

LCMS: m/e 796 (M+H), ret time 5.12 min.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-N-[(l - methylethyl)sulfonyl] -6-[l-methyl-4-[[4-(l-pyrrolidinyl)-l-piperidinyl] carbonyl] - lH-pyrazol-5-yl]-: LCMS: m/e 766 (M+H), ret time 5.40 min.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-N-[(l- methylethyl)sulfonyl] -6-[l-methyl-4-[[4-(l-pyrrolidinyl)-l-piperidinyl] carbonyl] - lH-pyrazol-5-yl]-:

LCMS: m/e 767 (M+H), ret time 4.86 min.

13-cyclohexyl-6-(l-isopropyl-4-(8-oxa-3-azabicyclo[3.2.1] oct-3-ylcarbonyl)-lH- pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy-7H-indolo[2,l- a][2]benzazepine-10- carboxamide: LCMS : m/e 740 (M+H), ret time 5.17 min.

13-cyclohexyl-6-(l-isopropyl-4-(3-oxa-9-azabicyclo[3.3.1] non-9-ylcarbonyl)-lH- pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy-7H-indolo[2,l- a] [2]benzazepine-10- carboxamide:

LCMS: m/e 754 (M+H), ret time 5.94 min.

13-cyclohexyl-6-(l-isopropyl-4-(2-oxa-5-azabicyclo[2.2.1] hept-5-ylcarbonyl)-lH- pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy-7H-indolo[2,l- a][2]benzazepine-10- carboxamide:

LCMS: m/e 726 (M+H), ret time 4.96 min.

13-cyclohexyl-6-(l-isopropyl-4-((4-methyl-l-piperazinyl)c arbonyl)-lH-pyrazol-5-yl)- N-(isopropylsulfonyl)-3-methoxy-7H-indolo[2,l-a][2]benzazepi ne-10-carboxamide: LCMS: m/e 727 (M+H), ret time 4.61 min.

13-cyclohexyl-6-(l-isopropyl-3-methyl-4-(8-oxa-3-azabicyclo[ 3.2.1]oct-3- ylcarbonyl)-lH-pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy -7H-indolo[2,l- a] [2]benzazepine-10-carboxamide: LCMS: m/e 754 (M+H), ret time 5.20 min.

13-cyclohexyl-6-(l-isopropyl-3-methyl-4-(2-oxa-5-azabicyc lo [2.2.1] hept-5- ylcarbonyl)-lH-pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy -7H-indolo[2,l- a][2]benzazepine-10-carboxamide: LCMS: m/e 740 (M+H), ret time 5.10 min.

13-cyclohexyl-6-(l-isopropyl-3-methyl-4-(2-oxa-5-azabicyc lo [2.2.1] hept-5- ylcarbonyl)-lH-pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy -7H-indolo[2,l- a][2]benzazepine-10-carboxamide:

LCMS: m/e 767 (M+H), ret time 5.70 min. IH NMR (500 MHz, DMSO/CHLOROFORM-D) δ ppm 1.10-1.57 (m, 17 H) 1.75 - 2.16 (m, 9 H) 2.35 (s, 3 H) 2.65 (m, 2 H) 2.91 (m, 1 H) 2.96 (s, 3 H) 3.24 (m, 4 H) 3.92-3.95 (m, 5 H) 4.67 (br d, 1 H) 5.02 (br d, 1 H) 7.10 (br m, 1 H) 7.16 (s, 1 H) 7.25 (m, 1 H) 7.59 (d, J=8.24 Hz, 1 H) 7.67 (d, J=8.55 Hz, 1 H) 7.94 (d, J=8.24 Hz, 1 H) 8.00 (s, 1 H) 8.17 (s, 1 H).

13-cyclohexyl-6-(4-((5-ethyl-2, 5-diazabicyclo[2.2. l]hept-2-yl)carbonyl)-l-isopropyl- 3-methyl-lH-pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy-7H -indolo[2,l- a] [2]benzazepine-10-carboxamide:

LCMS: m/e 767 (M+H), ret time 4.44 min. IH NMR (500 MHz, DMSO/CHLOROFORM-D) δ ppm 1.10-1.57 (m, 18 H) 1.75 - 2.16 (m, 9 H) 2.29 (m, 4 H) 2.91 (m, 1 H) 2.96 (s, 3 H) 3.24 (m, 4 H) 3.92-3.96 (m, 5 H) 4.66 (br d, 1 H) 5.05 (br d, 1 H) 7.10 (br m, 1 H) 7.30 (m, 2 H) 7.58 (d, J=8.24 Hz, 1 H) 7.67 (br m, 1 H) 7.95 (br d,l H) 8.00 (s, 1 H) 8.14 (br s, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[(3-methyl-3, 8-diazabicyclo[3.2.1] oct-8-yl)carbonyl] -lH-pyrazol-5- yl]-N-[(2-methylpropyl)sulfonyl]-

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 -a] [2]benzazepin-6- yl]-l -methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. 3-methyl-3,8-diazabicyclo[3.2.1] octane, 2ΗC1 (14.21 mg, 0.071 mmol) was then added and the solution was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC using CH3 CN-H^O-TFA as solvent system. Homogeneous fractions were combined and concentrated to afford the title compound as a brown colored solid, (36.3 mg, 0.043 mmol, 89 % yield). MS m/z 739(MH ⁺ ), Retention time: 2.070 min.(basic).

IH NMR (500 MHz, MeOD) δ ppm 1.12 (d, J=6.71 Hz, 6 H) 1.18 - 2.19 (m, 14 H) 2.24 - 2.37 (m, 1 H) 2.75 (s, 3 H) 2.81 - 3.28 (m, 7 H) 3.45 - 3.52 (m, 2 H) 3.63 - 3.83 (s, br, 3 H) 3.91 (s, 3 H) 4.61 (d, J=14.65 Hz, 1 H) 4.90 - 4.94 (m, 1 H) 7.07 - 7.19 (m, 3 H) 7.54 - 7.60 (m, 2 H) 7.81 (s, br, 2 H) 7.93 (d, J=8.54 Hz, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-lH -pyrazol-5-yl]-N-[(2- methylpropyl)sulfonyl] -

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 -a] [2]benzazepin-6- yl]-l -methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. 3-oxa-9-azabicyclo[3.3.1]nonane, HCl (11.67 mg, 0.071 mmol) was then added and the solution was stirred at RT overnight. The reaction mixture was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as solvent system. Homogeneous fractions were combined and concentrated under vacuum. The title compound was obtained as a brownish solid, (29.5 mg, 0.040 mmol, 84 % yield).

MS m/z 738(M-H ^" ), Retention time: 1.928 min.(basic). IH NMR (500 MHz, MeOD) δ ppm 1.04 - 2.40 (m, 23 H) 2.72 - 3.05 (m, 3 H) 3.41 - 4.02 (m, 12 H) 4.61 - 4.69 (m, br, 1 H) 4.99 - 5.08 (m, br, 1 H) 7.09 - 7.25 (m, 3 H) 7.55 - 7.66 (m, 2 H) 7.66 - 7.73 (m, 1 H) 7.85 - 8.03 (m, 2 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [(hexahydropyrrolo[l ,2-a]pyrazin-2(lH)-yl)carbonyl] -l-methyl-lH-pyrazol-5-yl] -3- methoxy-N-[(2-methylpropyl)sulfonyl]-

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 -a] [2]benzazepin-6- yl]-l -methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. Octahydropyrrolo[l,2-a]pyrazine (9.00 mg, 0.071 mmol) was then added and the solution was stirred at RT overnight. The reaction mixture was then purified by preparative ΗPLC column using CΗ3CN-Η2O-TFA as solvent system. Homogeneous fractions were combined and concentrated under speed vacuum. The TFA salt of the title compound was obtained as a brownish solid, (35.5 mg, 0.042 mmol, 88 % yield).

MS m/z 737 (M-H ^" ), Retention time: 1.722 min.(basic). IH NMR (500 MHz, MeOD) δ ppm 1.15 (d, J=6.71 Hz, 6 H) 1.19 - 2.23 (m, 14 H) 2.26 - 2.40 (m, 1 H) 2.88 - 3.05 (m, 1 H) 3.11 - 3.58 (m, 11 H) 3.72 (s, 3 H) 3.95 (s, 3 H) 4.60-4.70 (m, br, 1 H) 5.00 - 5.16 (m, br, 1 H) 7.11 (s, 1 H) 7.16 (d, J=2.44 Hz, 1 H) 7.20 (dd, J=8.54, 2.75 Hz, 1 H) 7.58 - 7.64 (m, 2 H) 7.76 (s, 1 H) 7.91 (s, 1 H) 7.99 (d, J=8.55 Hz, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(2-methylpropyl)sulfonyl]-6-[l-methyl-4-[[cis-3,4,5-trime thyl-l- piperazinyl] carbonyl] -lH-pyrazol-5-yl] -

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 -a] [2]benzazepin-6- yl]-l -methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. Cis-l,2,6-trimethylpiperazine (9.15 mg, 0.071 mmol) was then added and the solution was stirred at RT overnight. The reaction mixture was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as solvent system.

Homogeneous fractions were combined and concentrated under vacuum. The TFA salt of the title compound was obtained as a brownish solid, (39.1 mg, 0.046 mmol, 96 % yield).

MS m/z 739 (M-H ^" ), Retention time: 1.723 min.(basic). IH NMR (500 MHz, MeOD) δ ppm 1.15 (d, J=7.02 Hz, 6 H) 1.21 - 1.65 (m, 10 H) 1.77 - 2.22 (m, 6 H) 2.28 - 2.40 (m, 1 H) 2.54 - 3.05 (m, 8 H) 3.51 (d, J=6.41 Hz, 2 H) 3.74 (s, 3 H) 3.95 (s, 3 H) 4.03 - 4.42 (m, br, 2 H) 4.59 - 4.70 (m, br, 1 H) 5.01 - 5.12 (m, br, 1 H) 7.13 (s, 1 H) 7.16 (d, J=2.75 Hz, 1 H) 7.21 (dd, J=8.85, 2.75 Hz, 1 H) 7.59 - 7.66 (m, 2 H) 7.74 (s, 1 H) 7.93 (s, 1 H) 8.00 (d, J=8.55 Hz, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[(lS, 4S)-5-ethyl-2, 5-diazabicyclo[2.2. l]hept-2-yl] carbonyl] -l-methyl-lH-pyrazol-5-yl] -3- methoxy-N-[(2-methylpropyl)sulfonyl]-

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 -a] [2]benzazepin-6- yl]-l -methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. (IS, 4S)-2-ethyl-2,5-diazabicyclo[2.2.1]heptane, 2TFA (25.3 mg, 0.071 mmol) was then added and the resultant solution was stirred at RT for 3 hours. LC/MS analysis showed that the reaction had progressed to completion. The reaction mixture was then purified by preparative ΗPLC using CΗ3CN-Η2O-

TFA as solvent system. Homogeneous fractions were collected and concentrated under vacuum. The TFA of the title compound was obtained as a brown colored solid, (35.30 mg, 0.041 mmol, 87 % yield).

MS m/z 737(M-H ^" ), Retention time: 1.850 min.(basic). IH NMR (500 MHz, MeOD) δ ppm 1.15 (d, J=6.71 Hz, 6 H) 1.21 - 2.22 (m, 15 H) 2.25 - 2.39 (m, 1 H) 2.89 - 3.02 (m, 1 H) 3.05 - 3.80 (m, 12 H) 3.95 (s, 3 H) 4.09 - 4.48 (m, 1 H) 4.57 - 4.70 (m, 1 H) 4.99 - 5.12 (m, 1 H) 6.97 - 7.08 (s, br, 1 H) 7.14 (s, 1 H) 7.20 (dd, J=8.55, 2.44 Hz, 1 H) 7.61 (d, J=8.85 Hz, 2 H) 7.82 (s, 1 H) 7.88 (s, 1 H) 7.97 (d, J=8.55 Hz, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-(4-morpholinylcarbonyl)-lH-pyrazol-5-yl]-N-[(2 - methylpropyl)sulfonyl] -

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 -a] [2]benzazepin-6- yl]-l -methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. Morpholine (6.22 mg, 0.071 mmol) was then added and the resultant solution was stirred at RT for 3 hours. LC/MS analysis showed the reaction had progressed to completion. The reaction mixture was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as solvent system. Homogeneous fractions were combined and concentrated under vacuum. The title compound was obtained as a yellow solid,(28.4 mg, 0.041 mmol, 85 % yield).

MS m/z 698(M-H ^" ), Retention time: 1.618 min.(basic). IH NMR (500 MHz, MeOD) δ ppm 1.16 (d, J=6.71 Hz, 6 H) 1.21 - 1.36 (m, 1 H) 1.40 - 1.64 (m, 3 H) 1.75 - 1.87 (m, 2 H) 1.94 - 2.25 (m, 4 H) 2.27 - 2.41 (m, 1 H) 2.70 - 3.12 (m, 9 H) 3.49 - 3.55 (m, 2 H) 3.85 (s, 3 H) 3.95 (s, 3 H) 4.69 (d, J=14.34 Hz, 1 H) 5.10 (d, J=14.95 Hz, 1 H) 7.09 (s, 1 H) 7.16 (d, J=2.44 Hz, 1 H) 7.20 (dd, J=8.55, 2.44 Hz, 1 H) 7.62 (d, J=8.54 Hz, 2 H) 7.66 (s, 1 H) 7.94 (s, 1 H) 7.99 (d, J=8.55 Hz, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[ [cis- 2,6-dimethyl-4-morpholinyl] carbonyl] -l-methyl-lH-pyrazol-5-yl] -3-methoxy-N-[(2- methylpropyl)sulfonyl] -

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 -a] [2]benzazepin-6- yl]-l -methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. Cis-2,6-dimethylmorpholine (8.22 mg, 0.071 mmol) was then added and the resultant solution was stirred at RT for 3 hours. LC/MS then showed that the reaction had progressed to completion. The reaction mixture was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as solvent system.

Homogeneous fractions were collected and concentrated under vacuum. The title compound was obtained as a yellow colored solid, (29.6 mg, 0.041 mmol, 85 % yield).

MS m/z 726(M-H ^" ), Retention time: 1.753 min.(basic). IH NMR (500 MHz, MeOD) δ ppm 0.50 - 2.56 (m, 23 H) 2.68 - 3.06 (m, 2 H) 3.21 - 3.63 (m, 7 H) 3.83 - 4.02 (m, 6 H) 4.67 (d, J=14.34 Hz, 1 H) 5.04 (d, J=14.65 Hz, 1 H) 7.11 - 7.25 (m, 3 H) 7.56 - 7.69 (m, 3 H) 7.93 (s, 1 H) 7.99 (d, J=8.24 Hz, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- 6- [4- [ [(2S)-2-(methoxymethyl)-4-morphoHnyl] carbonyl] - 1-methyl- lH-pyrazol-5-yl] - N-[(2-methylpropyl)sulfonyl]- To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-

10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[ 2, 1 -a] [2]benzazepin-6- yl]- 1-methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. (S)-2-(methoxymethyl)morpholine, HCl (11.96 mg, 0.071 mmol) was then added and the resultant solution was stirred at RT for 3 hours. LC/MS analysis then showed the reaction had progressed to completion. The reaction mixture was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as solvent system. Homogeneous fractions were combined and concentrated under vacuum. The title compound was obtained as a yellow colored solid, (28.6 mg, 0.038 mmol, 81 % yield).

MS m/z 742(M-H ^" ), Retention time: 1.598 min.(basic). IH NMR (500 MHz, MeOD) δ ppm 1.16 (d, J=6.71 Hz, 6 H) 1.22 - 1.65 (m, 4 H) 1.75 - 2.24 (m, 6 H) 2.28 - 2.42 (m, 1 H) 2.88 - 3.63 (m, 15 H) 3.81 (s, 3 H) 3.95 (s, 3 H) 4.61 - 4.72 (m, 1 H) 5.02 - 5.14 (m, 1 H) 7.11 (s, 1 H) 7.17 (d, J=2.44 Hz, 1 H) 7.20 (dd, J=8.55, 2.44 Hz, 1 H) 7.56 - 7.65 (m, 2 H) 7.66 (s, 1 H) 7.93 (s, 1 H) 7.96 - 8.03 (m, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[3- (dimethylamino)-l-piperidinyl] carbonyl] -l-methyl-lH-pyrazol-5-yl] -3-methoxy-N- f(2-methylpropyl)sulfonylj- To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-

10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[ 2, 1 -a] [2]benzazepin-6- yl]-l -methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. N,N-dimethylpiperidin-3 -amine, 2ΗC1 (14.35 mg, 0.071 mmol) was then added and the resultant solution was stirred at RT for 3 hours. LC/MS then showed the reaction had progressed to completion. The reaction mixture was then purified by preparative HPLC using CH3CN-H2O-TFA as solvent system. Homogeneous fractions were collected and concentrated under vacuum.

The TFA salt of the title compound was obtained as a yellow colored solid, (36.3 mg, 0.042 mmol, 89 % yield).

MS m/z 739(M-H ^" ), Retention time: 1.810 min.(basic).

IH NMR (500 MHz, MeOD) δ ppm 1.16 (d, J=6.71 Hz, 6 H) 1.22 - 1.64 (m,

6 H) 1.75 - 2.24 (m, 8 H) 2.29 - 2.39 (m, 1 H) 2.46 - 3.13 (m, 11 H) 3.51 (d, J=6.41

Hz, 2 H) 3.83 (s, 3 H) 3.95 (s, 3 H) 4.16 (s, br, 1 H) 4.61 - 4.73 (m, br, 1 H) 5.00 - 5.12 (m, br, 1 H) 7.09 (s, 1 H) 7.16 (d, J=2.44 Hz, 1 H) 7.20 (dd, J=8.70, 2.59 Hz, 1

H) 7.60 (d, J=8.85 Hz, 1 H) 7.64 (dd, J=8.55, 1.22 Hz, 1 H) 7.69 (s, 1 H) 7.94 (s, 1

H) 8.01 (d, J=8.24 Hz, I H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-(3, 7- dioxa-9-azabicyclo[3.3.l]non-9-ylcarbonyl)-l-methyl-lH-pyraz ol-5-yl] '-3-methoxy- N-[(2-methylpropyl)sulfonyl]-

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 -a] [2]benzazepin-6- yl]-l -methyl- (30 mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA (0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred at RT for 15 min. 3,7-dioxa-9-azabicyclo[3.3.1]nonane (9.21 mg, 0.071 mmol) was then added and the solution was stirred at RT overnight. LC/MS then showed that only 40% SM had reacted. Two more equivalents of TBTU were then added and the reaction mixture was stirred at RT overnight. LC/MS then showed that the reaction had progressed to completion. The reaction mixture was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as solvent system. Homogeneous fractions were combined and evaporated under vacuum to give the title compound as a light-yellow colored solid, (26.7 mg, 0.036 mmol, 76 % yield). MS m/z 740(M-H ^" ), Retention time: 1.887 min.(basic). IH NMR (500 MHz, MeOD) δ ppm 1.16 (d, J=6.71 Hz, 6 H) 1.21 - 1.64 (m, 4 H) 1.71 - 3.15 (m, 10 H) 3.43 - 3.88 (m, 13 H) 3.96 (s, 3 H) 4.63 - 4.72 (m, 1 H) 5.01 - 5.11 (m, 1 H) 7.13 - 7.18 (m, 2 H) 7.22 (dd, J=8.70, 2.59 Hz, 1 H) 7.61 (d, J=8.55 Hz, 1 H) 7.64 (d, J=8.85 Hz, 1 H) 7.74 (s, 1 H) 7.91 (s, 1 H) 7.98 (d, J=8.55 Hz, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl] amino] carbonyl] -7H-indolo[2,l-a] ' [2]benzazepin-6-yl]-l- methyl)-, ethyl ester

CDI (451 mg, 2.78 mmol) was added to a THF (10 mL) solution of 7H- indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-methyl-lH-pyrazol-5-yl]-3-methoxy-(750 mg, 1.39 mmol) and the resultant mixture was stirred at 60 ⁰ C for 1 h. The reaction was then cooled to r.t. and butane-2 -sulfonamide (572 mg, 4.17 mmol) and DBU (0.419 mL, 2.78 mmol) were added. The mixture was then heated at 60 ⁰ C overnight, after which the solvent was removed and the residue dissolved in EtOAc. The organic layer was washed with sequentially with IN HCl solution (3 x 20 mL), and Brine (3 x 20 mL) and then dried over Na ₂ SO ₄ . The mixture was then filtered and the filtrate was evaporated in vacuo. The residue was purified using a Shimadzu preparative HPLC employing

ACN/water and 0.1 % TFA buffter with a Xterra column,30 mm x 100 mm,Gradient over 15 min; Starting cone: 10 %B;Ending cone: 100 %B. Homogeneous fractions were combined and evaporated under reduced pressure to afford the title compound as light yellow solid, (450 mg, 49 %). ESI-MS m/e 659 (MH ⁺ ).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a] [2]benzazepin-6-yl]-l- methyl-

NaOH (IN, 5 mL) was added to a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l-methylethyl)sulfonyl]ami no]carbonyl]-7H- indolo[2,l-a][2]benzazepin-6-yl]-l-methyl-, ethyl ester (250 mg, 0. 379 mmol) in a 1: 1 mixture of THF:MeOH (10 mL) and the resultant solution was agitated at r.t. for 48 h. HCl (IN, 5 mL) was then added and the resultant mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with brine (3 x 20 mL) and then dried over Na ₂ SO ₄ . The mixture was then filtered and the filtrate was evaporated in vacuo to afford the title product as yellow solid, (235 mg, 98%). ESI-MS m/e 631 (MH ⁺ ).

Using the standard amide coupling conditions described for related examples, the following examples can be prepared.

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[(3-methyl-3, 8-diazabicyclo[3.2.1] oct-8-yl)carbonyl] -lH-pyrazol-5- yl]-N-[(l-methylpropyl)sulfonyl]-

ESI-MS m/e 739 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.08 (t, J=7.32 Hz, 3 H) 1.16 - 1.56 (m, 9 H) 1.58 - 1.85 (m, 4 H) 1.90 - 2.24 (m, 6 H) 2.48 - 2.62 (m, 3 H) 2.81 - 2.99 (m, 3 H) 3.15 - 3.45 (m, 3 H) 3.73 - 4.05 (m, 5 H) 3.94 (s, 3 H) 4.58 - 4.69 (m, 1 H) 4.80 - 5.02 (m, 1 H) 6.92 - 7.01 (m, 2 H) 7.13 (dd, J=8.70, 2.29 Hz, 1 H) 7.53 - 7.82 (m, 4 H) 7.92 (d, J=8.24 Hz, 1 H) 10.14 (s, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-lH -pyrazol-5-yl]-N-[(l- methylpropyl)sulfonyl] -

ESI-MS m/e 740 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.00 - 1.57 (m, 12 H) 1.68 - 1.84 (m, 3 H) 1.91 - 2.48 (m, 9 H) 2.81 - 2.94 (m, 1 H) 3.03 - 3.16 (m, 1 H) 3.18 - 3.72 (m, 5 H) 3.76 - 4.02 (m, 7 H) 4.53 - 4.68 (m, 1 H) 4.94 (d, J=15.87 Hz, 1 H) 6.81 - 6.91 (m, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.13 (d, J=8.54 Hz, 1 H) 7.54 - 7.62 (m, 1 H) 7.62 - 7.85 (m, 3 H) 7.87 - 7.96 (m, 1 H).

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-(3, 7- dioxa-9-azabicyclo[3.3.l]non-9-ylcarbonyl)-l-methyl-lH-pyraz ol-5-yl] ' -3-methoxy- N-[(l-methylpropyl)sulfonyl]-

ESI-MS m/e 742 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.02 - 1.13 (m, 3 H) 1.15 - 1.27 (m, I H) 1.31 - 1.56 (m, 6 H) 1.69 - 1.84 (m, 2 H) 1.92 - 2.39 (m, 6 H) 2.62 - 2.70 (m, 1 H) 2.83 - 2.93 (m, 1 H) 3.25 (s, 1 H) 3.30 - 3.49 (m, 3 H) 3.52 - 3.59 (m, 1 H) 3.66 - 3.76 (m, 3 H) 3.80 - 3.86 (m, 2 H) 3.89 (s, 3 H) 3.94 (s, 3 H) 4.63 (d, J=15.26 Hz, 1 H) 4.93 (d, J=15.56 Hz, 1 H) 6.86 (s, 1 H) 6.95 (d, J=2.44 Hz, 1 H) 7.13 (dd, J=SJO, 2.59 Hz, 1 H) 7.59 (d, J=8.55 Hz, 1 H) 7.63 (d, J=8.54 Hz, 1 H) 7.72 (d, J=5.49 Hz, 2 H) 7.94 (d, J=8.55 Hz, 1 H) 10.08 - 10.26 (m, I H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-6-[4- [[(1S, 4S)-5-ethyl-2, 5-diazabicyclo[2.2. IJ hept-2-ylJcarbonylJ-l -methyl- 1 H-pyrazol- 5-yl] -3-methoxy-N-[(l-methylpropyl)sulfonyl] -

ESI-MS m/e 739 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.85 - 1.56 (m, 15 H) 1.58 - 2.39 (m, 8 H) 2.68 - 2.96 (m, 4 H) 3.03 - 3.38 (m, 3 H) 3.55 (d, J=5.19 Hz, 1 H) 3.72 - 4.03 (m, 5 H) 4.05 - 4.43 (m, 2 H) 4.51 - 5.04 (m, 3 H) 6.68 - 6.86 (m, 1 H) 6.88 - 7.18 (m, 2 H) 7.49 - 7.97 (m, 5 H) 8.17 - 8.28 (m, 1 H).

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [(hexahydropyrrolofl , 2-a]pyrazin-2(lH)-yl)carbonyl] -l-methyl-lH-pyrazol-5-yl] -3- methoxy-N-[(l-methylpropyl)sulfonyl]-

ESI-MS m/e 739 (MH ⁺ )IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.00 - 1.13 (m, 3 H) 1.21 - 1.58 (m, 7 H) 1.59 - 1.85 (m, 4 H) 1.90 - 2.49 (m, 11 H) 2.80 - 2.99 (m, 2 H) 3.34 - 3.88 (m, 9 H) 3.92 (s, 3 H) 4.54 - 4.69 (m, 1 H) 4.76 - 5.00 (m, 1 H) 6.83 - 6.94 (m, 1 H) 6.97 (s, 1 H) 7.06 - 7.15 (m, 1 H) 7.48 - 7.68 (m, J=35.71 Hz, 3 H) 7.75 (s, 1 H) 7.89 (s, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-(4-morphotinylcarbonyl)-lH-pyrazol-5-yl]-N-[(l - methylpropyl)sulfonyl] -

ESI-MS m/e 700 (MH ⁺ )IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.02 - 1.14 (m, 3 H) 1.16 - 1.30 (m, I H) 1.49 (dd, J=20.91, 6.87 Hz, 6 H) 1.34 - 1.45 (m, 1 H) 1.93 - 2.40 (m, 7 H) 2.58 - 2.71 (m, 1 H) 2.77 - 2.97 (m, 4 H) 3.04 - 3.25 (m, 2 H) 3.35 - 3.65 (m, 2 H) 3.79 - 3.88 (m, 1 H) 3.90 (s, 3 H) 3.94 (s, 3 H) 4.61 (d, J=15.87 Hz, 1 H) 4.90 (d, J=15.56 Hz, 1 H) 6.86 (s, 1 H) 6.96 (d, J=2.44 Hz, 1 H) 7.13 (dd, J=8.55, 2.44 Hz, 1 H) 7.58 (d, J=8.55 Hz, 1 H) 7.61 (d, J=7.93 Hz, 1 H) 7.65 - 7.74 (m, 2 H) 7.94 (d, J=8.54 Hz, 1 H) 10.20 - 10.44 (m, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-6-[4- [[(2R,6S)-2,6-dimethyl-4-morphotinyl]carbonyl]-l -methyl- lH-pyrazol-5-yl] -3- methoxy-N-[(l-methylpropyl)sulfonyl]-

ESI-MS m/e 728 (MH ⁺ )IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.98 - 1.13 (m, 3 H) 1.14 - 1.31 (m, 2 H) 1.34 - 1.59 (m, 6 H) 1.70 - 1.86 (m, 3 H) 1.88 - 2.32 (m, 12 H) 2.81 - 2.98 (m, 1 H) 2.95 - 3.14 (m, 1 H) 3.13 - 3.34 (m, 2 H) 3.36 - 3.67 (m, 1 H) 3.83 - 3.93 (m, 1 H) 3.92 (s, 3 H) 3.95 (s, 3 H) 4.61 (d, J=14.34 Hz, 1 H) 4.91 (d, J=15.56 Hz, 1 H) 6.83 (s, 1 H) 6.96 (s, 1 H) 7.13 (d, J=8.55 Hz, 1 H) 7.51 - 7.81 (m, 4 H) 7.92 (d, J=7.32 Hz, 1 H) 10.33 - 10.59 (m, 1 H).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylpropyl)sulfonyl]-6-[l-methyl-4-[(3,4,5-trimethyl -l- piperazinyl)carbonyl] -lH-pyrazol-5-yl] -

ESI-MS m/e 741 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.85 - 2.25 (m, 25 H) 2.27 - 2.64 (m, 3 H) 2.93 (s, 1 H) 3.28 - 3.69 (m, 4 H) 3.71 - 3.87 (m, 5 H) 3.94 (s, 3 H) 4.53 - 4.69 (m, 1 H) 4.83 - 5.01 (m, 1 H) 6.90 (s, 1 H) 6.97 (d, J=2.44 Hz, 1 H) 7.08 - 7.15 (m, 1 H) 7.50 - 7.66 (m, 3 H) 7.79 (d, J=I.53 Hz, 1 H) 7.93 (d, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-6-[4-[[3- (dimethylamino)-l-piperidinyl] carbonyl] -l-methyl-lH-pyrazol-5-yl] -3-methoxy-N- [(l-methylpropyl)sulfonyl]-

ESI-MS m/e 741 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.01 - 1.15 (m, 3 H) 1.19 - 1.61 (m, 7 H) 1.64 - 2.28 (m, 15 H) 2.41 - 2.76 (m, 5 H) 2.82 - 2.96 (m, 1 H) 3.35 - 3.83 (m, 3 H) 3.78 - 3.91 (m, 3 H) 3.90 - 3.98 (m, 3 H) 4.19 - 4.40 (m, 1 H) 4.54 - 4.71 (m, 1 H) 4.78 - 4.98 (m, 1 H) 6.84 - 6.96 (m, 1 H) 6.95 - 7.01 (m, 1 H) 7.07 - 7.15 (m, 1 H) 7.50 - 7.58 (m, 1 H) 7.59 - 7.87 (m, 3 H) 7.90 - 7.99 (m, 1 H) 10.02 - 10.36 (m, 1 H).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-

6- [4- [ [2-(methoxymethyl)-4-morpholinyl] carbonyl] - 1-methyl- lH-pyrazol-5-yl] -N- [(l-methylpropyl)sulfonyl] -

ESI-MS m/e IAA (MH ⁺ ) IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.01 - 1.15 (m, 2 H) 1.23 (d, J=15.26 Hz, I H) 1.33 - 1.59 (m, 5 H) 1.70 - 2.31 (m, 13 H) 2.36 - 2.53 (m, 1 H) 2.83 - 3.49 (m, 10 H) 3.81 - 3.93 (m, 3 H) 3.94 (s, 3 H) 4.60 (d, J=15.26 Hz, 1 H) 4.79 - 5.00 (m, 1 H) 6.85 (s, 1 H) 6.95 (s, 1 H) 7.12 (dd, J=8.55, 2.75 Hz, 1 H) 7.50 - 7.81 (m, 4 H) 7.86 - 7.99 (m, 1 H) 10.29 - 10.54 (m, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)- 1 -ethyl- lH-pyrazol-5-yl] -3-methoxy-, 1,1-dimethylethyl ester, tert- butyl 13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl) -2-propenoyl)- 3-methoxy-7H-indolo[2,l-a][2]benzazepine-10-carboxylate (370mg, 0.604mmol) was dissolved in ethanol (1.7ml) and the oxylate salt of ethyl hydrazine (100 mg, 0.664 mg) was added to the reaction at room temperature. The reaction was heated to 80 deg C for 3hrs. The reaction was diluted with chloroform and washed with water. The organic phase was concentrated under reduced pressure and purified by prep HPLC under the following conditions: Shimadzu preparative HPLC using Discovery VP software: %A= 10% acetonitrile, 90% water, 0.1% TFA; %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 30; Final % B=IOO; Gradient= 12min; Runtime=20min; Flow rate= 40ml/min; Column= Waters Sunfire 30 x 100mm S5. This afforded the title compound (265 mg, 72%) as a yellow paste.. MS m/z 610 (MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-(l-methylethyl)-lH-pyrazol-5-yl]-3-methox y-, 1,1-dimethylethyl ester. tert-Butyl 13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl) -2- propenoyl)-3-methoxy-7H-indolo[2,l-a][2]benzazepine-10-carbo xylate ( 180mg, 0.294mmol) was dissolved in a solution of ethanol (ImI), triethyl amine (82.0 uL, 0.588mmol) and the hydrochloride salt of 2-propyl hydrazine (36 mg, 0.323 mmol). The reaction was heated in a microwave at 160 ⁰ C for 2 hours and then concentrated. The resulting solid was purified by preparative HPLC under the following conditions: Shimadzu preparative HPLC using Discovery VP software: %A= 10% acetonitrile, 90% water, 0.1% TFA; %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 30; Final % B=IOO; Gradient= 12min; Runtime=20min; Flow rate= 40ml/min; Column= Waters Sunfire 30 x 100mm S5. Homogeneous fractions were combined and evaporated in vacuo to afford the title compound (127 mg, 69%) as a yellow paste. MS m/z 624 (MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxylic acid, 6-(4-carboxy-l-ethyl- lH-pyrazol-5-yl)-13-cyclohexyl-3-methoxy-, 10-(l ,1-dimethylethyl) ester.

7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)- 1 -ethyl- lH-pyrazol-5-yl]-3 -methoxy-, 1 , 1 -dimethylethyl ester (250mg, 0.410mmol) was dissolved in 12 mL of methanol/TΗF (1: 1, v/v) and IM aqueous sodium hydroxide (6ml, 6mmol) was added to the reaction. The resulting mixture was stirred at room temperature for 18 hr, and then diluted with IM aqueous hydrochloric acid and the product was extracted with chloroform. The organic phase was dried over Na ₂ SO ₄ , filtered and the filtrate concentrated in vacuuo to give the title compound (251mg, 100%) that was used in subsequent steps without further purification. MS m/z 612 (MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxylic acid, 13-cyclohexyl-6-[l- ethyl-4-(4-morpholinylcarbonyl)-lH-pyrazol-5-yl]-3-methoxy-, 1,1-dimethylethyl ester.

To a solution of 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 6-(4- carboxy-l-ethyl-lH-pyrazol-S-y^-lS-cyclohexyl-S-methoxy-, 10-( 1,1-dimethylethyl) ester (120mg, 0.206mmol) in TΗF (1 mL) at 60 ⁰ C was added carbonyldiimidazole (47mg, 0.288mmol) and the solution stirred for lhour. Morpholine (36mg, 0.412mmol) and DBU (33mg, 0.268mmol) were then added and the reaction was heated for a further lhr and was then allowed to stir to room temperature overnight. The reaction was then diluted with IM aqueous hydrochloric acid and the resultant mixture was extracted with chloroform. The extracts were dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo to provide the title compound in quantitative yield. MS m/z 651 (MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxylic acid, 13-cyclohexyl-6-[l- ethyl-4-(4-morpholinylcarbonyl)- lH-pyrazol-5-yl] -3-methoxy-.

7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[l- ethyl-4-(4-morpholinylcarbonyl)-lH-pyrazol-5-yl] -3-methoxy-, 1,1-dimethylethyl ester (61mg, 0.094 mmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at room temperature for 3 hours and the mixture was then concentrated in vacuuo. Residual trifluoroacetic acid was removed by azeotroping with benzene and the final product was dried in vacuuo to provide the title compound, (56 mg, 100%) that was used without further purification. MS m/z 595 (MH ⁺ ).

Morpholine, 4-[[13-cyclohexyl-6-[l-ethyl-4-(4-morpholinylcarbonyl)-lH- pyrazol-5-yl] -3-methoxy- 7H-indolo[2, 1-a] [2]benzazepin-l 0-yl]carbonyl]-. 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[l- ethyl-4-(4-morpholinylcarbonyl)- lH-pyrazol-5-yl]-3-methoxy-, (60mg, 0.092mmol) was dissolved in TΗF (0.9 mL) and carbonyldiimidazole (21mg, 0.130mmol) was added. The resultant mixture was then stirred at 60 ⁰ C for lhr. Upon cooling to room temperature under a nitrogen atmosphere, morpholine (40 mg, 0.460 mmol) and DBU (0.012 mL, 0.120 mmol) were added. The reaction was heated for lhr then allowed to stir to room temperature overnight. The resulting mixture was filtered and the resultant filtrate was purified by preparative ΗPLC under the following conditions: Shimadzu preparative ΗPLC using Discovery VP software: %A= 10% acetonitrile, 90% water, 0.1% TFA; %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 30; Final % B=IOO; Gradient= 12min; Runtime=20min; Flow rate= 40 mL/min; Column= Waters Sunfire 30 x 100mm S5. This afforded the title compound (31 mg, 51%) as a yellow paste. MS m/z 664 (MH ⁺ ). The following compounds were synthesized by an analogous sequence as described above for 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-6-[l-ethyl-4-(4-morpholinylcarbonyl)-lH-pyrazol-5 -yl]-3-methoxy-:

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-3- methoxy-6-[l-methyl-4-(4-morpholinylcarbonyl)-lH-pyrazol-5-y l]-. MS m/z 581 (MH ⁺ ).

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-3- methoxy-6-[l-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct- 8-yl)carbonyl]-lH- pyrazol-5-yl]-. MS m/z 620 (MH ⁺ ).

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-3- methoxy-6-[l-(l-methylethyl)-4-(4-morpholinylcarbonyl)-lH-py razol-5-yl]-. MS m/z 609 (MH ⁺ ).

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-4-(4- morpholinylcarbonyl)-lH-pyrazol-5-yl]-3-methoxy-N-[(l-methyl ethyl)sulfonyl]-.

7H-indolo [2, 1 -a] [2]benzazepine- 1 O-carboxylic acid, 13 -cyclohexyl-6-[ 1 - ethyl-4-(4-morpholinylcarbonyl)- lH-pyrazol-5-yl]-3-methoxy-, (56mg, 0.094mmol) was dissolved in TΗF (0.9 mL) and carbonyldiimidazole (21mg, 0.129mmol) added to the reaction at 60 ⁰ C and the resultant mixture was stirred for lhr. Propane-2- sulfonamide (57mg,0.246mmol) and DBU (15mg, 0.120mmol) were then added to the reaction and the mixture was heated for a further 1 hour, then allowed to stir to room temperature for 18 hours. The resulting mixture was filtered and the filtrate purified by prep ΗPLC under the following conditions: Shimadzu preparative ΗPLC using Discovery VP software: %A= 10% acetonitrile, 90% water, 0.1% TFA; %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 30; Final % B=IOO; Gradient= 12min; Runtime=20min; Flow rate= 40 mL/min; Column= Waters Sunfire 30 x 100mm S5. This afforded the title compound (40 mg, 61%) as a yellow paste. MS m/z 700 (MH ⁺ ).

The following compounds were synthesized by an analogous method as described above for 7H-indolo[2,l-a][2]benzazepine-10-carboxamide, 13- cyclohexyl-6-[l-ethyl-4-(4-morpholinylcarbonyl)-lH-pyrazol-5 -yl]-3-methoxy-N- [( 1 -methylethyl)sulfonyl]- :

7H-indolo[2, 1-aJ [2]benzazepine-l 0-carboxamide, 13-cyclohexyl-6-[l-ethyl- 4-[(4-methyl-l-piperazinyl)carbonyl]-lH-pyrazol-5-yl]-3-meth oxy-N-(l- pyrrolidinylsulfonyl)-. MS m/z 740 (MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl- 4-[(4-methyl-l-piperazinyl)carbonyl]-lH-pyrazol-5-yl]-3-meth oxy-N-[(l- methylethyl)sulfonyl]-. MS m/z 713 (MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl- 4-(4-morpholinylcarbonyl)-lH-pyrazol-5-yl]-3-methoxy-N-(l-py rrolidinylsulfonyl)-. MS m/z 727 (MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- [(dimethylamino)sulfonyl]-6-[l-ethyl-4-(4-morpholinylcarbony l)-lH-pyrazol-5-yl]-3- methoxy-. MS m/z 701 (MH ⁺ ).

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- f(dimethylamino)sulfonyl]-3-methoxy-6-fl-methyl-4-(4-morphol inylcarbonyl)-lH- pyrazol-5-yl]-. MS m/z 687 (MH ⁺ ).

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- [(dimethylamino)sulfonyl] -3-methoxy-6-[ 1 -methyl-4- [(3-methyl-3 ,8- diazabicyclo[3.2.1]oct-8-yl)carbonyl]-lH-pyrazol-5-yl]-. MS m/z 726 (MH ⁺ ).

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- (cyclopropylsulfonyl)-3-methoxy-6-[l-methyl-4-[(3-methyl-3,8 - diazabicyclo[3.2. l]oct-8-yl)carbonyl]-lH-pyrazol-5-yl]-. MS m/z 723 (MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-methyl-4-[(3-methyl-3, 8-diazabicyclo[3.2.1] oct-8-yl)carbonyl] -lH-pyrazol-5- ylJ-N-(l-pyrrolidinylsulfonyl)-. MS m/z 752 (MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- [(dimethylamino)sulfonyl]-3-methoxy-6-[l-(l-methylethyl)-4-( 4- morpholinylcarbonyl)- lH-pyrazol-5-yl] '-. MS m/z 715 (MH ⁺ ).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-l-(l-methylethyl)-lH-pyrazol-5-yl]-3-meth oxy-. Dissolve 7H- indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)- 1 -( 1 -methylethyl)- 1 H-pyrazol-5-yl] -3 -methoxy-, 1 , 1 -dimethylethyl ester (2.00 g, 3.21 mmol) in 1 ,2-dichloroethane (6.41 mL), place reaction under a nitrogen atmosphere, then add trifluoroacetic acid (6.41 ml). Stir reaction at room temperature under a nitrogen atmosphere for 2 hours. Remove volatiles in vacuuo and dissolve the reaction product in benzene and remove in vacuuo to aid in removal of trace TFA. Repeat dissolution in benzene and removal in vacuuo. Dry sample at room temperature in vacuuo to obtain the title compound (1.92 g, 100% yield) as a yellow solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.48 (br s, 3H) 1.12 - 1.65 (m, 9 H) 1.72 - 2.19 (m, 7 H) 2.87 (t, J=I 1.29 Hz, 1 H) 3.91 (s, 3 H) 4.22 (m, 1 H) 4.32 (br.s, 2 H) 4.73 (br.s, 1 H) 4.97 (br.s, 1 H) 6.70 (s, 1 H) 6.94 (d, J=2.14 Hz, 1 H) 7.08 (dd, J=8.55, 2.44 Hz, 1 H) 7.52 (m, 2 H) 7.64 (d, J=8.24 Hz, 1 H) 7.82 (d, J=8.24 Hz, 1 H) 7.96 (s, 1 H). LCMS 566 m/z (MH-).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony I] amino] carbonyl] - 7H-indolo[2, 1-a] [2]benzazepin-6-yl]-l-l-(l- methylethyl)-, ethyl ester. Dissolve 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4-(ethoxycarbonyl)- l-(l-methylethyl)-lH-pyrazol-5-yl]-3- methoxy- (1.00 g, 1.76 mmol) in THF (5.87 mL). Carbonyldiimidazole (857 mg, 5.28 mmol) was added to the reaction. The reaction was placed under a nitrogen atmosphere and stirred at room temperature for 45 minutes then heated to reflux for 1 hour. The reaction was cooled under a nitrogen atmosphere and propane-2- sulfonamide (868 mg, 7.05 mmol) was added to the reaction followed by DBU (0.797 mL, 5.28 mmol). The reaction was immerse in oil bath at 80 deg C under nitrogen atmosphere and heated overnight at 70-80 deg C. The reaction was diluted with ethyl acetate (50 mL) and the organic layer washed sequentially with 1.0N aqueous hydrochloric acid (50 mL), 0.1M aqueous NaH2PO4 (50 mL) and brine (25 mL). The organic layer was dried over MgS 04, filtered and volatiles removed in vacuuo to yield a yellow foam which was dried in vacuuo at room temperature overnight to yield 1.03g (1.57mmol, 87%) of the title compound as a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.40 (br s, 3H) 1.12 - 1.70 (m, 15 H) 1.72 - 2.18 (m, 7 H) 2.84 (t, J=U 29 Hz, 1 H) 3.90 (s, 3 H) 4.11 (m, 1 H) 4.26 (m, 3 H) 4.66 (br.s, 1 H) 4.97 (br.s, 1 H) 6.68 (s, 1 H) 6.94 (d, J=2.14 Hz, 1 H) 7.08 (m, 2 H) 7.52 (d, J=8.24 Hz, 1 H) 7.67 (d, J=8.24 Hz, 1 H) 7.80 (d, J=8.24 Hz, 1 H) 7.89 (s, 1 H). LCMS 671 m/z (MH-).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony I] 'amino] carbony I]- 7H-indolo[2, 1-a] ' [2] benzazepin-6-yl] - 1-(1- methylethyl)-. Dissolve lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3- methoxy-10-[[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-ind olo[2,l- a][2]benzazepin-6-yl]- l-(l-methylethyl)-, ethyl ester (1.20 g, 1.78 mmol) was dissolved in THF (15.0 mL) and methanol (15.0 mL) was added to the reaction followed by IN aqueous sodium hydroxide (15.0 mL). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 18 hrs. The reaction was diluted with ethyl acetate (25.0 mL) and washed with 1.0N aqueous hydrochloric acid (2 x 2OmL). The organic layer was concentrated in vacuuo using a rotary evaporator to yield the title compound as a yellow solid (1.15 g, 100%). MS m/z 645 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.46 (br s, 3H) 1.12 - 1.70 (m, 12 H) 1.72 - 2.15 (m, 7 H) 2.85 (t, J=11.29 Hz, 1 H) 3.90 (s, 3 H) 4.26 (m, 1 H) 4.62 (br.s, 1 H) 4.99 (br.s, 1 H) 6.69 (s, 1 H) 6.96 (d, ./=2.14 Hz, 1 H) 7.06 (dd, J=8.55, 2.44 Hz, 1 H) 7.50 (m, 2 H) 7.80 (m, 2 H) 7.85 (s, 1 H) 9.09 (br s , 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[l-(l-methylethyl)-4-(4-morpholinylcarbonyl)-lH-pyrazol-5- yl]-N-[(l- methylethyl)sulfonyl]-:

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]- 1-(1- methylethyl)- (125 mg, 0.194 mmol) in DMSO (1.94 mL), TBTU (124 mg, 0.388 mmol) and DIPEA (0.100 mg, 0.775 mmol) were added. The reaction mixture was stirred at RT for 15 min. Then morpholine (68 mg, 0.775 mmol) was added. The solution was stirred at RT for overnight. The reaction mixture was purified by prep ΗPLC column using CΗ3CN/Η2O/TFA as solvent system. Fractions were collected and concentrated under speedvac overnight to yield the title compound as a yellow solid (82 mg, 0.114 mmol, 59 % yield). MS m/z 714 (M-H ⁺ ). IH NMR (500 MHz, CDC13) δ ppm 1.20 (m, 1 H) 1.32 - 1.65 (m, 15 H) 1.73 - 2.20 (m, 6 H) 2.63 - 3.24 (m, 7 H) 3.50 (br m, 2 H) 3.93 (s, 3 H) 4.07 (m, 1 H) 4.58 (m, 2 H) 4.90 (m, br, 1 H) 6.78 (s, 1 H) 6.93 (d, J=2.44 Hz, 1 H) 7.13 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 - 7.64 (m, 2 H) 7.71 (m, 2 H) 7.93 (d, J=8.55 Hz, 1 H) 10.15 (s, br, IH). The following compounds were synthesized by an analogous method as described above for 7H-indolo[2,l-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-3- methoxy-6-[l-(l-methylethyl)-4-(4-morpholinylcarbonyl)-lH-py razol-5-yl]-N-[(l- methylethyl)sulfonyl]-:

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[(2,6- dimethyl-4-morpholinyl)carbonyl] -1 -(I -methylethyl)-l H-pyrazol-5-yl] -3-methoxy-N- [(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CDC13) δ ppm 0.61-0.92 (m, 6 H) 1.23 (m, 1 H) 1.35 - 1.70 (m, 15 H) 1.73 - 2.20 (m, 6 H) 2.88 (m, 1 H) 3.12-3.70 (m, 6 H) 3.92 (s, 3 H) 4.09 (m, 1 H) 4.58 (m, 2 H) 4.91 (m, br, 1 H) 6.75 (s, 1 H) 6.92 (d, J=2.44 Hz, 1 H) 7.12 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 - 7.68 (m, 2 H) 7.75 (m, 2 H) 7.92 (d, J=8.55 Hz, 1 H) 10.10 (s, br, IH). LCMS: m/e 742 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[(3-methyϊ-3, 8-diazabicyclo[3.2. l]oct-8-yl)carbonyl]-l-(l-methylethyl)-lH- pyrazol-5-yl]-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CDC13) δ ppm 0.02 (m, 2 H) 0.82 (m, 2 H) 1.20-1.82 (m, 16 H) 1.91 - 2.18 (m, 6 H) 2.39-2.70 (m, 4H) 2.88 (m, 1 H) 2.96-3.59 (m, 5 H) 3.94 (s, 3 H) 4.06 (m, 1 H) 4.62 (m, 2 H) 4.85 (m, br, 1 H) 6.92 (m, 2 H) 7.12 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 - 7.69 (m, 3 H) 7.86 (br s, 1 H) 7.92 (d, J=8.55 Hz, 1 H) 10.10 (s, br, IH). LCMS: m/e 753 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[(lS)- 5-ethyl-2, 5-diazabicyclo[2.2.1] hept-2-yl] carbonyl] -l-(l-methylethyl)-lH-pyrazol-5- yl]-3-methoxy-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CDC13) δ ppm 0.02 (m, 1 H) 1.10-1.59 (m, 19 H) 1.91 - 2.49 (m, 8 H) 2.80-3.69 (m, 4H) 2.88 (m, 1 H) 3.81-4.41 (s, 7 H) 4.62 (m, 2 H) 4.90 (m, br, 1 H) 6.97 (m, 2 H) 7.10 (m, 1 H) 7.53 - 7.67 (m, 2 H) 7.71-7.95 (m, 3 H) 10.20 (s, br, IH). LCMS: m/e 753 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[(3-methyl-3, 6-diazabicyclo[3.1. l]hept-6-yl)carbonyl]-l-(l-methylethyl)-lH- pyrazol-5-yl]-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CDC13) δ ppm 1.17-1.85 (m, 15 H) 1.90 - 2.18 (m, 9 H) 2.59-2.99 (m, 6 H) 3.35-4.10 (m, 8 H) 4.66- 5.00 (m, 3 H) 6.92 (m, 2 H) 7.12 (dd, J=8.55, 2.75 Hz, 1 H) 7.50 - 7.69 (m, 3 H) 7.75-8.01 (m, 2 H) 10.00 (s, br, IH). LCMS: m/e 739 (M+H).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-

6-[4-[(8-methyl-3, 8-diazabicyclo[3.2. l]oct-3-yl)carbonyl]-l-(l-methylethyl)-lH- pyrazol-5-yl]-N-[(l-methylethyl)sulfonyl]-: m NMR (500 MHz, CDC13) δ ppm 0.021 (m, 2 H) 0.81 (m, 2 H) 1.20-1.86 (m, 16 H) 1.91 - 2.17 (m, 6 H) 2.41-2.71 (m, 4 H) 2.88 (m, 1 H) 2.97-3.70 (m, 5 H) 3.94 (s, 3 H) 4.08 (m, 1 H) 4.62 (m, 2 H) 4.85 (m, br, 1 H) 6.94 (m, 2 H) 7.12 (dd, J=8.55, 2.75 Hz, 1 H) 7.52 - 7.69 (m, 3 H) 7.80- 7.95 (m, 2 H) 10.10 (s, br, IH). LCMS: m/e 753 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-(l-methylethyl)-4-[(3,4,5-t rimethyl-l- piperazinyl)carbonyl]-lH-pyrazol-5-yl]-: IH NMR (500 MHz, CDC13) δ ppm 1.20- 1.82 (m, 22 H) 1.91 - 2.18 (m, 6 H) 2.50 (br s, 3H) 2.90 (m, 1 H) 3.35-3.69 (m, 7 H) 3.92 (s, 3 H) 4.02 (m, 1 H) 4.61 (br m, 1 H) 4.93 (br m, 1 H) 6.80 (br s , 1 H) 6.95 (s, 1 H) 7.11 (dd, J=8.55, 2.75 Hz, 1 H) 7.51 - 7.65 (m, 3 H) 7.80 (br s, 1 H) 7.90 (d, J=8.55 Hz, 1 H) 10.20 (s, br, IH). LCMS: m/e 755 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-(3, 7- dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-l-(l-methylethyl) -lH-pyrazol-5-yl]-3- methoxy-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CDC13) δ ppm 1.15-1.82 (m, 19 H) 1.91 - 2.18 (m, 3 H) 2.88 (m, 1 H) 3.12-3.80 (m, 9 H) 3.92 (s, 3 H) 4.05 (m, 1 H) 4.40 (m, 2 H) 4.61 (br d, 1 H) 4.92 (br d, 1 H) 6.78 (s, 1 H) 6.91 (d, J=2.44 Hz, 1 H) 7.13 (dd, J=8.55, 2.75 Hz, 1 H) 7.59 - 7.65 (m, 2 H) 7.77 (m, 2 H) 7.93 (d, J=8.55 Hz, 1 H) 10.10 (s, br, IH). LCMS: m/e 756 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-6-[4-[[(3- endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]carbony l]-l-(l-methylethyl)- lH-pyrazol-5-yl]-3-methoxy-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CDC13) δ ppm -0.25 (m, 1 H) 0.52 (m, I H) 1.04 (s, 3 H) 1.15-1.82 (m, 24 H) 1.91 - 2.18 (m, 4 H) 2.89 (m, 1 H) 3.29 (m, 1 H) 3.62 (m, 1 H) 3.92 (s, 3 H) 4.06 (m, 1 H) 4.54-4.71 (m, 2 H) 5.00 (br d, 1 H) 6.82 (br s, 1 H) 6.91 (d, J=2.75 Hz, 1 H) 7.12 (dd, J=8.55, 2.75 Hz, 1 H) 7.50 - 7.60 (m, 2 H) 7.70 (m, 1 H) 7.80-7.95 (m, 2 H) 10.20 (s, br, IH). LCMS: m/e 768 (M+H), ret time 2.75 min (method 1).

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[(3-methyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-l -(l-methylethyl)-lH- pyrazol-5-yl]-N-[(l-methylethyl)sulfonyl]-: m/e 750 (M+H), ret time 2.89 min (method 1).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6- [4- [ [(2S)-2-(methoxymethyl)-4-morpholinyl] carbonyl] - l-(l-methylethyl)-lH- pyrazol-5-yl]-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CDC13) δ ppm 1.21 (m, 1 H) 1.32 - 1.70 (m, 15 H) 1.73 - 2.20 (m, 6 H) 2.72-3.47 (m, 8 H) 3.88-4.17 (m, 10 H) 4.61 (m, 1 H) 4.95 (m, br, 1 H) 6.80 (br d, 1 H) 6.93 (br s, 1 H) 7.12 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 - 7.64 (m, 2 H) 7.71-7.96 (m, 3 H) 10.15 (s, br, IH). LCMS: m/e 758 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6- [ 1-(1 -methylethyl)-4-(4-morphotinylcarbonyl)- lH-pyrazol-5-yl] -N- [(2- methylpropyl)sulfonyl]-: LCMS: m/e 728 (M+H), ret time 3.59 min (method 2).

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[(2,6- dimethyl-4-morpholinyl)carbonyl] -1 -(I -methylethyl)-l H-pyrazol-5-yl] -3-methoxy-N- f(2-methylpropyl)sulfonylj-: LCMS: m/e 756 (M+H), ret time 3.71 min (method 2).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[(3-methyϊ-3, 8-diazabicyclo[3.2. l]oct-8-yl)carbonyl]-l-(l-methylethyl)-lH- pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-: LCMS: m/e 767 (M+H), ret time 3.35 min (method T).

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[(lS)- 5-ethyl-2, 5-diazabicyclo[2.2.1] hept-2-yl] carbonyl] -l-(l-methylethyl)-lH-pyrazol-5- yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-: LCMS: m/e 767 (M+H), ret time 3.31 min (method 2).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[(8-methyl-3, 8-diazabicyclo[3.2. l]oct-3-yl)carbonyl]-l-(l-methylethyl)-lH- pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-: LCMS: m/e 767 (M+H), ret time 3.38 min (method T).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(2-methylpropyl)sulfonyl]-6-[l-(l-methylethyl)-4-[(3,4,5- trimethyl-l- piperazinyl)carbonyl] -lH-pyrazol-5-yl] -: LCMS: m/e 769 (M+H), ret time 3.32 min (method 2).

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-(3, 7- dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-l-(l-methylethyl) -lH-pyrazol-5-yl]-3- methoxy-N-[(2-methylpropy I) sulfony I] ^' -:LCMS: m/e 770 (M+H), ret time 3.65 min (method 2).

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-6-[4- [[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-l-(l-methyl ethyl)-lH-pyrazol-5- yl]-N-[(2-methylpropyl)sulfonyl]-: LCMS: m/e 772 (M+H), ret time 3.61 min (method T).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, li-cyclohexyl-i-methoxy- 6-[4-[(3-methyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-l -(l-methylethyl)-lH- pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-: LCMS: m/e 764 (M+H), ret time 3.69 min (method T).

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-(2, 2, 2-trifluoroethyl)-l H-pyrazol-5-yl] -3-methoxy-, 1, 1- dimethylethyl ester, tert-butyl 13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2- (ethoxycarbonyl)-2-propenoyl)-3-methoxy-7H-indolo[2,l-a][2]b enzazepine-10- carboxylate (1.20 g, 1.96 mmol) was dissolved in a solution of ethanol (6.53 niL), triethyl amine (0.396 g, 3.92 mmol), and (2,2,2-trifluoroethyl)hydrazine (0.246 g, 2.15 mmol). The reaction was heated in a microwave at 160 deg C for 2 hours and concentrated. The resulting solid was purified by prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software: %A= 10% acetonitrile, 90% water, 0.1% TFA; %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 30; Final % B=IOO; Gradient= 12min; Runtime=20min; Flow rate= 40ml/min; Column= Waters Sunfire 30 x 100mm S5. This afforded the title compound (1.09 g, 84%) as a yellow paste. MS m/z 664 (MH ⁺ ).

7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-l-(2, 2, 2-trifluoroethyl)- lH-pyrazol-5-yl] -3-methoxy-. Dissolve 7H-indolo [2, 1 -a] [2]benzazepine- 10-carboxylic acid, 13 -cyclohexyl-6-[4- (ethoxycarbonyl)- l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]-3-methoxy-, 1,1- dimethylethyl ester (1.20 g, 1.81 mmol) in 1,2-dichloroethane (3.62 mL), place reaction under a nitrogen atmosphere, then add trifluoroacetic acid (3.62 mL). Stir reaction at room temperature under a nitrogen atmosphere for 2 hours. Remove volatiles in vacuuo and dissolve the reaction product in benzene and remove in vacuuo to aid in removal of trace TFA. Repeat dissolution in benzene and removal in vacuuo. Dried sample at room temperature in vacuuo to obtain the title compound (0.923 g, 100% yield) as a yellow solid. 1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 1.20 - 1.62 (m, 7 H) 1.70 - 2.19 (m, 6 H) 2.87 (m, 1 H) 3.91 (s, 3 H) 4.12-4.45 (m, 4 H) 4.76 (br.s, 1 H) 4.97 (br.s, 1 H) 6.82 (s, 1 H) 6.96 (d, J=2.14 Hz, 1 H) 7.10 (dd, J=8.55, 2.44 Hz, 1 H) 7.56 (d, J=8.85 Hz, 1 H) 7.78 (d, J=8.24 Hz, 1 H) 7.90 (m, 2 H) 8.11 (s, 1 H). LCMS 608 m/z (MH+).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a] [2]benzazepin-6-yl]-l- (2,2,2-trifluoroethyl), ethyl ester. Dissolve 7H-indolo[2,l-a][2]benzazepine-10- carboxylic acid, 13 -cyclohexyl-6-[4-(ethoxycarbonyl)- 1-1 -(2,2,2 -trifluoroethyl)- IH- pyrazol-5-yl]-3-methoxy- (800 mg, 1.32 mmol) in THF (4.39 mL).

Carbonyldiimidazole (640 mg, 3.95 mmol) was added to the reaction. The reaction was placed under a nitrogen atmosphere and stirred at room temperature for 45minutes then heated to reflux for 1 hour. The reaction was cooled under a nitrogen atmosphere and propane-2-sulfonamide (649 mg, 5.27 mmol) was added to the reaction followed by DBU (0.595 mL, 3.95 mmol). The reaction was immerse in oil bath at 80 deg C under nitrogen atmosphere and heated overnight at 70-80 deg C. The reaction was diluted with ethyl acetate (50 mL) and the organic layer washed sequentially with 1.0N aqueous hydrochloric acid (50 mL), 0.1M aqueous NaH2PO4 (50 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered and volatiles removed in vacuuo to yield a yellow foam which was dried in vacuuo at room temperature overnight to yield the title compound (949 mg, 100%) as a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.20 - 1.62 (m, 13 H) 1.70 - 2.18 (m, 6 H) 2.87 (m, 1 H) 3.90 (s, 3 H) 4.05 (m, 1 H) 4.10-4.40 (m, 4 H) 4.73 (br.s, 1 H) 4.99 (br.s, 1 H) 6.82 (s, 1 H) 6.93 (d, J=IAA Hz, 1 H) 7.10 (dd, J=8.55, 2.44 Hz, 1 H) 7.45 (br d, 1 H) 7.52 (d, J=8.85 Hz, 1 H) 7.80 (br s , 1 H) 7.88 (d, J=8.85 Hz, 1 H) 8.02 (s, 1 H) 8.60 (br s, 1 H). LCMS 713 m/z (MH+).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony IJ amino] carbonylj- 7H-indolo[2, 1-a] [2]benzazepin-6-yl]- 1- (2,2,2-trifluoroethyl). Dissolve lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3- methoxy-10-[[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-ind olo[2,l- a][2]benzazepin-6-yl]-l -(2,2,2-trifluoroethyl), ethyl ester (0.816 g, 1.15 mmol) in THF (2.86 mL) and methanol (2.86 mL) was added to the reaction followed by IN aqueous sodium hydroxide (2.29 mL). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 18 hrs. The reaction was diluted with ethyl acetate (25.0 mL) and washed with 1.0N aqueous hydrochloric acid (2 x 2OmL). The organic layer was concentrated in vacuuo using a rotary evaporator to yield the title compound as a yellow solid (0.784 g, 100%). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.20 - 1.62 (m, 10 H) 1.70 - 2.18 (m, 6 H) 2.87 (m, 1 H) 3.90 (s, 3 H) 4.05 (m, 1 H) 4.27 (br m, 2 H) 4.73 (br.s, 1 H) 4.99 (br.s, 1 H) 6.82 (s, 1 H) 6.93 (d, J=IAA Hz, 1 H) 7.10 (dd, J=8.55, 2.44 Hz, 1 H) 7.45 (br d, 1 H) 7.52 (d, J=8.85 Hz, 1 H) 7.80 (br s , 1 H) 7.88 (d, J=8.85 Hz, 1 H) 8.02 (s, 1 H) 8.60 (br s, 1 H). LCMS 685 m/z (MH+).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[4-(4-morpholinylcarbonyl)-l-( 2,2,2-trifluoroethyl)- lH-pyrazol-5-yl] -: lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10- [[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α] [2]benzazepin-6-yl]- 1- (2,2,2-trifluoroethyl) (90 mg, 0.131 mmol) in DMSO (1.31 mL), TBTU (84 mg, 0.263 mmol) and DIPEA (68 mg, 0.526 mmol) were added. The reaction mixture was stirred at RT for 15 min. Then morpholine (46 mg, 0.526 mmol) was added. The solution was stirred at RT for overnight. The reaction mixture was purified by prep ΗPLC column using CΗ3CN/Η2O/TFA as solvent system. Fractions were collected and concentrated under speedvac overnight to yield the title compound as a yellow solid (53 mg, 0.070 mmol, 53 % yield). MS m/z 754 (M-H ⁺ ); IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.22 (m, 1 H)1.33 - 1.57 (m, 9 H) 1.70 - 2.18 (m, 6 H) 2.59 (br m, 1 H) 2.70-2.95 (m, 6 H) 3.05-3.21 (m, 2 H) 3.92 (s, 3 H) 4.07 (m, 1 H) 4.73 (br.d, 1 H) 4.76 (br m, 2 H) 4.86 (br.d, 1 H) 6.90 (s, 1 H) 6.94 (d, J=2.14 Hz, 1 H) 7.15 (dd, J=8.55, 2.44 Hz, 1 H) 7.60 (d, J=8.85 Hz, 1 H) 7.63 (d, J=8.24 Hz, 1 H) 7.67 (s, 1 H) 7.80 (s, 1 H) 7.93 (d, J=8.85 Hz, 1 H).

The following compounds were synthesized by an analogous method as described above for 7H-indolo[2,l-a][2]benzazepine-10-carboxamide, 13- cyclohexyl-3-methoxy-N-[(l-methylethyl)sulfonyl]-6-[4-(4-mor pholinylcarbonyl)-l- (2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]-:

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-l-(2,2,2-trif luoroethyl)-lH-pyrazol- 5-yl]-3-methoxy-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.64-0.90 (m, 5 H) 1.16-1.28 (m, 2 H) 1.33 - 1.57 (m, 9 H) 1.73 - 2.18 (m, 8 H) 2.30 (br m, 1 H) 2.87 (m, 2 H) 3.05-3.29 (m, 3 H) 3.94 (s, 3 H) 4.07 (m, 1 H) 4.58 (br.d, 1 H) 4.72 (br m, 2 H) 4.93 (br.d, 1 H) 6.87-6.96 (m, 1 H) 7.15 (dd, J=8.55, 2.44 Hz, 1 H) 7.52-7.68 (m, 2 H) 7.72-7.85 (m, 2 H) 7.93 (m, 1 H) 8.48 (br s , 1 H). LCMS: m/e 782 (M+H).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[(3-methyϊ-3, 8-diazabicyclo[3.2. l]oct-8-yl)carbonyl]-l-(2, 2,2-trifluoroethyl)- lH-pyrazol-5-yl]-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.19 (br s, 1 H) 0.80 (br s, 1 H) 1.25-1.62 (m, 11 H) 1.76 - 2.18 (m, 7 H) 2.48 (br m, 1 H) 2.62 (br s, 3 H) 2.88 (m, 2 H) 2.95-3.50 (m, 4 H) 3.92 (s, 3 H) 4.06 (m, 1 H) 4.59 (br.d, 1 H) 4.86 (br m, 3 H) 6.93 (s, 1 H) 7.05 (br s, 1 H) 7.17 (dd, J=8.55, 2.44 Hz, 1 H) 7.60 (d, J=8.85 Hz, 1 H) 7.65 (d, J=8.24 Hz, 1 H) 7.86 (br s, 1 H) 7.96 (m, 2 H) 10.0 (br s, 1 H). LCMS: m/e 793 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [[(1S, 4S)-5-ethyl-2, 5-diazabicyclo[2.2. l]hept-2-yl]carbonyl]-l-(2, 2, 2-trifluoroethyl)- lH-pyrazol-5-yl]-3-methoxy-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.10-1.59 (m, 14 H) 1.70 - 2.18 (m, 7 H) 2.38 (m, 1 H) 2.80-3.85 (m, 8 H) 3.95 (s, 3 H) 4.03 (m, 1 H) 4.58 (br.d, 1 H) 4.98 (br.m, 3 H) 6.87- 6.96 (m, 1 H) 7.15 (dd, J=8.55, 2.44 Hz, 1 H) 7.52-7.68 (m, 2 H) 7.72-7.85 (m, 2 H) 7.93 (m, 1 H) 8.48 (br s , 1 H). LCMS: m/e 793 (M+H).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-l- (2,2,2-trifluoroethyl)- lH-pyrazol-5-yl]-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.18 (br s, 1 H) 0.81 (br s, 1 H) 1.26-1.62 (m, 11 H) 1.80 (m, 2 H) 1.94 - 2.18 (m, 5 H) 2.44 (br m, 1 H) 2.62 (br s, 3 H) 2.90 (m, 2 H) 2.95- 3.55 (m, 4 H) 3.92 (s, 3 H) 4.06 (m, 1 H) 4.59 (br.d, 1 H) 4.86 (br m, 3 H) 6.92 (s, 1 H) 7.03 (br s, 1 H) 7.17 (dd, J=8.55, 2.44 Hz, 1 H) 7.58-7.65 (m, 1 H) 7.86 (br s, 1 H) 7.96 (m, 2 H) 10.0 (br s, 1 H). LCMS: m/e 793 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-(2, 2, 2-trifluoroethyl)-4-[[(3R, 5S)-3, 4, 5-trimethyl-l- piperazinyl]carbonyl]-lH-pyrazol-5-yl]-: IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.05 - 1.57 (m, 15 H) 1.70 - 2.12 (m, 7 H) 2.30-2.99 (m, 6 H) 3.20-3.65 (m, 4 H) 3.92 (s, 3 H) 4.03 (m, 1 H) 4.60 (br.d, 1 H) 4.65-4.98 (br.m, 3 H) 6.95 (m, 2 H) 7.15 (dd, J=8.55, 2.44 Hz, 1 H) 7.57 (m, 2 H) 7.71 (s, 1 H) 7.82 (br s, 1 H) 7.93 (d, J=8.85 Hz, 1 H). LCMS: m/e 795 (M+H).

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[4-(3-oxa-9-azabicyclo[3.3.1]n on-9-ylcarbonyl)-l- (2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]-: IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.12-1.53 (m, 13 H) 1.70 - 2.40 (m, 9 H) 2.87 (m, 1 H) 3.03-3.62 (m, 6 H) 3.92 (s, 3 H) 4.07 (m, 1 H) 4.73 (br.d, 1 H) 4.76 (br m, 2 H) 4.86 (br.d, 1 H) 6.90 (s, 1 H) 6.94 (d, J=2.14 Hz, 1 H) 7.15 (dd, J=8.55, 2.44 Hz, 1 H) 7.60 (d, J=8.85 Hz, 1 H) 7.63 (d, J=8.24 Hz, 1 H) 7.67 (s, 1 H) 7.80 (s, 1 H) 7.93 (d, J=8.85 Hz, 1 H). LCMS: m/e 794 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-6-[4-[(3- hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-l-(2, 2,2-trifluoroethyl)-lH- pyrazol-5-yl]-3-methoxy-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CDC13) δ ppm -0.25 (m, 1 H) 0.52 (m, I H) 1.06 (s, 3 H) 1.15-1.82 (m, 18 H) 1.91 - 2.18 (m, 4 H) 2.88 (m, 1 H) 3.32 (m, 1 H) 3.60 (m, 1 H) 3.93 (s, 3 H) 4.07 (m, 1 H) 4.56 (br d, 1 H) 4.82 (m, 2 H) 4.97 (br d, 1 H) 6.82 (br s, 2 H) 7.16 (dd, J=8.55, 2.75 Hz, 1 H) 7.60 (d, J=8.55 Hz , 1 H) 7.70 (d, J=8.24 Hz, 1 H) 7.84-7.92 (m, 3 H). LCMS: m/e 808 (M+H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- 6-[4-[[(2S)-2-(methoxymethyl)-4-morphotinyl]carbonyl]-l-(2,2 ,2-trifluoroethyl)-lH- pyrazol-5-yl]-N-[(l-methylethyl)sulfonyl]-: IH NMR (500 MHz, CDC13) δ ppm 1.21 (m, 1 H) 1.32 - 1.70 (m, 9 H) 1.73 - 2.20 (m, 6 H) 2.72-3.40 (m, 13 H) 3.92 (m, 3 H) 4.10 (m, 1 H) 4.60 (m, 1 H) 4.82 (m, br, 3 H) 6.85-6.96 (m, 2 H) 7.17 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 - 7.72 (m, 3 H) 7.80-7.96 (m, 2 H)XCMS: m/e 798 (M+H).

Methyl 5-chloro-l-methyl-3-(trifluoromethyl)-lH-pyrazole-4-carboxyl ate . To a solution of S-chloro-l-methyl-S-^rifluoromethy^-lH-pyrazole^-carboxyllic acid (1.0Og, 4.38 mmol) in benzene (5.83 mL) and methanol (2.92 mL) at room temperature was added 2M trimethylsilyldiazomethane (8.75 mL). The resulting solution was stirred at room temperature for 3 hours. Solvent was removed at reduced pressure on a rotory evaporator to yield the title compound (1.06 g, 4.38 mmol, 100 % yield) as a white solid. MS m/z 243(MH ⁺ ) IH NMR (500 MHz, CHLOROFORM-D) δ ppm 3.82 (s, 3 H) 3.89 (s, 3 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxylic acid, 13-cyclohexyl-3- methoxy-6-[4-(methoxycarbonyl)-l-methyl-3-(trifluoromethyl)- lH-pyrazol-5-yl]-, 1, 1-dimethylethyl ester. In a microwave tube, 7H-indolo[2, 1 -a] [2]benzazepine- 10- carboxylic acid, 13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1, 1-dimethylethyl ester (1.00 g, 1.37 mmol), methyl 5 -chloro-l-methyl-3-(trifluoromethy I)-IH- pyrazole-4-carboxylate (497 mg, 2.05 mmol) and bis(dibenzylideneacetone) palladium (78 mg, 0.136 mmol) were added. It was then sealed, degassed and flushed with nitrogen. 1,4-dioxane (6.83 mL) was added. The reaction mixture was heated at 16O ⁰ C under microwave condition for 3 hours. It was then filtered and the filtrate was concentrated. The residue was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) (8 mL) purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD- IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 25% solvent A / 75% solvent B to 0% solvent A / 100% solvent B, a gradient time of 10 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product-containing fractions were collected and concentrated to give title compound as a yellow solid (547 mg, 0.842 mmol, 61% yield). MS m/z 650 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.06 - 2.29 (m, 19 H) 2.85 (m, 1 H) 3.30 (s, br, 3 H) 3.78 (s, br, 3H) 3.91 (s, 3 H) 4.76 (m, br, 1 H) 4.97 (m, br, 1 H) 6.80 (s, 1 H) 6.93 (d, J=2.44 Hz, 1 H) 7.11 (dd, J=8.55, 2.75 Hz, 1 H) 7.56 (d, J=8.54 Hz, 1 H) 7.82 (dd, J=8.24, 1.22 Hz, 1 H) 7.91 (dd, J=8.24, 1.22 Hz, 1 H) 7.98 (s, 1 H).

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-3- methoxy-6-[4-(methoxycarbonyl)- l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl]-. To a solution of 7H-indolo [2,1 -α][2]benzazepine-l 0-carboxylic acid, 13-cyclohexyl-3- methoxy-6-[4-(methoxycarbonyl)- 1 -methyl-3-(trifluoromethyl)- lH-pyrazol-5-yl]-, 1,1-dimethylethyl ester (547 mg, 0.842 mmol) in 1,2-dichloroethane (5 mL), TFA (5 mL) was added. The reaction mixture was stirred at RT for 4 hours. Volatiles were removed on a rotary evaporator to give the title compound as a brownish thick oil as crude product (500 mg, 0.842 mmol, 100 % yield). MS m/z 594(MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.06 - 2.28 (m, 10 H) 2.86 (m, 1 H) 3.30 (s, br, 3 H) 3.78 (s, br, 3H) 3.91 (s, 3 H) 4.75 (m, br, 1 H) 4.96 (m, br, 1 H) 6.80 (s, 1 H) 6.93 (d, J=2.44 Hz, 1 H) 7.10 (dd, J=8.55, 2.75 Hz, 1 H) 7.54 (d, J=8.54 Hz, 1 H) 7.81 (dd, J=8.24, 1.22 Hz, 1 H) 7.91 (dd, J=8.24, 1.22 Hz, 1 H) 7.97 (s, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony I] amino] 'carbonylj- 7H-indolo[2, 1-a] ' [2] benzazepin-6-yl] - 1- methyl-3-(trifluoromethyl)-, methyl ester. To a solution of 7H-indolo[2,l- α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[4- (methoxycarbonyl)- l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl]- (480 mg, 0.809 mmol) in tetrahydrofuran (2.70 mL) was added carbonyldiimidazole (393 mg, 2.43 mmol). The reaction mixture was heated at 6O ⁰ C for one hour and then allowed to cool. Propane-2-sulfonamide (398 mg, 3.23 mmol) and DBU (0.366 mL, 2.43 mmol) were added at room temperature, and the reaction mixture was then heated at 6O ⁰ C for 4 hours. The resultant mixture was then diluted with IN HCl (50 mL) solution and extracted with ethyl acetate (2 X 4OmL). The organic layers were combined and concentrated on a rotory evaporator to give the product as an orange colored oil. This material was then purified by preparative ΗPLC column using CΗ3CN/Η2O/TFA as solvent system. Homogeneous fractions were collected and concentrated under reduced pressure. The title compound was obtained as a yellow solid, (492 mg, 0.704 mmol, 87 % yield). MS m/z 699 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.16 - 1.61 (m, 10 H) 1.69 - 2.21 (m, 6 H) 2.86 (m, 1 H) 3.34 (s, br, 3H) 3.67 (s, br, 3 H) 3.91 (s, 3 H) 4.01 - 4.19 (m, 1 H) 4.70 (m, br, 1 H) 4.97 (m, br, 1 H) 6.70 (s, 1 H) 6.94 (d, J=2.75 Hz, 1 H) 7.09 (dd, J=8.55, 2.75 Hz, 1 H) 7.51 (dd, J=8.55, 1.22 Hz, 1 H) 7.81 (d, J=1.22 Hz, 1 H) 7.88 (d, J=8.55 Hz, 1 H) 7.92 (d, J=8.55 Hz, 1 H) 8.68 (s, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony I] 'amino] carbony I]- 7H-indolo[2, 1-a] ' [2] benzazepin-6-yl] - 1- methyl-3-(trifluoromethyl)-. lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3- methoxy- 10-[[[(l -methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 - α][2]benzazepin-6-yl]- l-methyl-3-(trifluoromethyl)-, methyl ester (0.300 g, 0.429 mmol) was dissolved in TΗF (1.07 mL) and methanol (1.07 mL) was added followed by IN aqueous sodium hydroxide (0.900 mL). The reaction was then placed under a nitrogen atmosphere and stirred at room temperature for 18 hrs. The mixture was then diluted with ethyl acetate (50.0 mL) and washed with 1.0 N aqueous hydrochloric acid (2 x 50ml). The organic layer was concentrated in vacuuo using a rotary evaporator to yield the title compound as a yellow solid (282 mg, 0.412 mmol, 96%). MS m/z 685(MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.16 - 1.61 (m, 10 H) 1.69 - 2.21 (m, 6 H) 2.86 (m, 1 H) 3.34 (s, br, 3 H) 3.91 (s, 3 H) 4.01 - 4.19 (m, 1 H) 4.70 (m, br, 1 H) 4.99 (m, br, 1 H) 6.70 (s, 1 H) 6.94 (d, J=2.75 Hz, 1 H) 7.10 (dd, J=8.55, 2.75 Hz, 1 H) 7.51 (dd, J=8.55, 1.22 Hz, 1 H) 7.81 (d, J=I.22 Hz, 1 H) 7.88 (d, J=8.55 Hz, 1 H) 7.92 (d, J=8.55 Hz, 1 H) 9.00 (s, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-(4-morpholinylcarb onyl)-3- (trifluoromethyl)-lH-pyrazol-5-yl]-. To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l-methylethyl)sulfonyl]ami no]carbonyl]-7H- indolo[2,l-α][2]benzazepin-6-yl]- l-methyl-3-(trifluoromethyl)- (75 mg, 0.11 mmol) in DMSO (1.1 mL), TBTU (70 mg, 0.22 mmol) and DIPEA (0.057 mL, 0.4444 mmol) were added. The reaction mixture was stirred at RT for 15 min. Then morpholine (38 mg, 0.44 mmol) was added. The solution was stirred at RT overnight. The reaction mixture was then purified by preparative ΗPLC using CΗ3CN/Η2O/TFA as solvent system. Homogeneous fractions were collected and concentrated under under reduced pressure to yield the title compound as a yellow solid, (67 mg, 0.089 mmol, 81 % yield). MS m/z 754 (M-H ⁺ ). IH NMR (500 MHz, MeOD) δ ppm 1.18 - 1.52 (m, 10 H) 1.75 - 2.25 (m, 6 H) 2.63 - 3.26 (m, 9 H) 3.50 (s, br, 3 H) 3.95 (s, 3 H) 3.96 - 4.03 (m, 1 H) 4.64 (d, br, 1 H) 4.98 (m, br, 1 H) 6,88 (s, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.15 (dd, J=8.55, 2.75 Hz, 1 H) 7.55 - 7.65 (m, 2 H) 7.80 (s, br, 1 H) 7.93 (d, J=8.55 Hz, 1 H) 10.30 (s, br, IH).

The following compounds were synthesized by an analogous method as described above for 7H-indolo[2,l-a][2]benzazepine-10-carboxamide, 13- cyclohexyl-3-methoxy-N-[(l-methylethyl)sulfonyl]-6-[l-methyl -4-(4- morpholinylcarbonyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl]-:

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-6-[4- [[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-l-methyl-3-(t rifluoromethyl)-lH- pyrazol-5-yl]-3-methoxy-N-[(l-methylethyl)sulfonyl]-. MS m/z 782 (M-H ⁺ ). IH NMR (500 MHz, MeOD) δ ppm 0.71 (s, br, 3H), 0.75 (s, br, 3H) 1.18 - 1.52 (m, 10 H) 1.75 - 2.21 (m, 9 H) 2.35 (m, 1 H) 2.83 - 3.21 (m, 3 H) 3.50 (s, br, 3 H) 3.95 (s, 3 H) 3.96 - 4.03 (m, 1 H) 4.64 (d, br, 1 H) 5.02 (d, br, 1 H) 6.81 (s, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.13 (dd, J=8.55, 2.75 Hz, 1 H) 7.55 - 7.65 (m, 2 H) 7.80 (s, br, 1 H) 7.93 (d, J=8.55 Hz, 1 H) 10.50 (s, br, 1 H).

7H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, li-cyclohexyl-i-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[(3-methyl-3, 8-diazabicyclo[3.2. lJoct-8- yl)carbonyl]-3-(trifluoromethyl)-lH-pyrazol-5-yl]-. MS m/z 793 (M-H ⁺ ). IH NMR (500 MHz, MeOD) δ ppm 1.16 - 2.20 (m, 20 H) 2.40-2.99 (m, 7 H) 3.22-3.71 (m, 3H) 3.90-4.11 (m, 7 H) 4.63 (m, br, 1 H) 4.98 (m, br, 1 H) 6.98 (m, 1 H) 7.03 (m, 1 H) 7.23 (m, IH) 7.52 - 7.73 (m, 3 H) 7.82 (s, br, 1 H) 10.10 (s, br, IH).

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-3-(trifluoromethyl)- 4-[[(3R, 5S)-3, 4, 5- trimethyl-l-piperazinyl]carbonyl]-lH-pyrazol-5-yl]-. MS m/z 795 (M-H ⁺ ). IH NMR (500 MHz, MeOD) δ ppm 1.10 - 1.51 (m, 16 H) 1.71 - 2.50 (m, 11 H) 2.59-2.94 (m, 5 H) 3.50 (s, br, 3 H) 3.96 (s, 3 H) 4.63 (m, br, 2 H) 4.95 (m, br, 1 H) 6.93 (m, 2 H) 7.13 (m, 1 H) 7.49 - 7.65 (m, 2 H) 7.82 (s, br, 1 H) 7.93 (m, 1 H) 10.10 (s, br, IH).

7H-indolo [2, 1-a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-(8-oxa-3-azabicycl o[3.2.1]oct-3- ylcarbonyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl]-

MS m/z 780 (M-H ⁺ )

IH NMR (500 MHz, CDC13) δ ppm 0.70 (m, IH) 1.21 - 1.52 (m, 13 H) 1.75 - 2.20 (m, 8 H) 2.30 (m, IH) 2.79 - 2.98 (m, 3 H) 3.11 (m, IH) 3.87 (m, IH) 3.98 (s, br, 3 H) 4.05 (s, 3 H) 4.61 (d, br, 1 H) 4.89 (m, br, 1 H) 6.85-6.98 (m, 2 H) 7.17 (dd, J=8.55, 2.75 Hz, 1 H) 7.55 - 7.70 (m, 2 H) 7.84-8.03 (m, 1 H) 7.93 (d, J=8.55 Hz, 1 H) 10.45 (s, br, IH). 7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- 6- [4- [ [(2S)-2-(methoxymethyl)-4-morpholinyl] carbonyl] -1 -methyl-3- (trifluoromethyl)-lH-pyrazol-5-yl]-N-[(l-methylethyl)sulfony l]-

MS m/z 798 (M-H ⁺ )

IH NMR (500 MHz, CDC13) δ ppm 1.11 - 1.61 (m, 10 H) 1.75 - 2.52 (m, 10 H) 2.81 - 3.60 (m, 9 H) 3.95 (s, br, 3 H) 4.03 (s, 3 H) 3.95 - 4.03 (m, 1 H) 4.65 (d, br, 1 H) 5.01 (m, br, 1 H) 6.85 (br s, 1 H) 6.97 (s, 1 H) 7.15 (dd, J=8.55, 2.75 Hz, 1 H) 7.50 - 7.71 (m, 2 H) 7.79-7.93 (m,2 H) 10.40 (s, br, IH).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[(4-methyl-l-piper azinyl)carbonyl]-3- (trifluoromethyl)-lH-pyrazol-5-yl]-

MS m/z 767 (M-H ⁺ ) IH NMR (500 MHz, CDC13) δ ppm 1.13 - 1.58 (m, 10 H) 1.75 - 2.12 (m, 6 H) 2.20 2.97 (m, 5 H) 3.19-3.79 (m, 7H) 3.95 (s, 3 H) 3.99 (br s, 3 H) 3.95 - 4.03 (m, 1 H) 4.50 (m, br, 1 H) 4.92 (m, br, 1 H) 6.87-7.01 (m, 2 H) 7.11 (dd, J=8.55, 2.75 Hz, 1 H) 7.50 (dd, J=8.55, 2.75 Hz, 1 H) 7.59-7.80 (m, 2 H) 7.91 (br s, 1 H) 10.50 (s, br, IH).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, H-cyclohexylS-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[(8-methyl-3, 8-diazabicyclo[3.2. lJoct-3- yl) carbonylJ-3- (trifluoromethyl) - lH-pyrazol-5-yl]-

NES m/z 793 (M-H ⁺ )

IH NMR (500 MHz, CDC13) δ ppm 0.37 (br m, IH) 0.83 (br m, IH) 1.14 - 1.70 (m, 11 H) 1.75-2.16 (m, 7H) 2.35-2.70 (m, 4 H) 2.86 (m, 2 H) 3.20-3.79 (m, 4H) 3.90- 4.11 (m, 7 H) 4.63 (d, br, 1 H) 4.94 (m, br, 1 H) 6.95-7.10 (m, 2 H) 7.15 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 - 7.70 (m, 3 H) 7.81 (s, br, 1 H) 10.10 (s, br, IH).

7 H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- ff(lS, 4S)-5-ethyl-2, 5-diazabicyclo[2.2. l]hept-2-yl]carbonyl]-l-methyl-3- (trifluoromethyl)-lH-pyrazol-5-yl]-3-methoxy-N-[(l-methyleth yl)sulfonyl]-

MS m/z 793 (M-H ⁺ )

IH NMR (500 MHz, CDC13) δ ppm 0.55 (br m, IH) 1.14 - 1.70 (m, 13 H) 1.75-2.16 (m, 7H) 2.52-3.70 (m, 9 H) 3.89-4.11 (m, 7 H) 4.69 (d, br, 1 H) 5.00 (m, br, 1 H) 6.95-7.15 (m, 3 H) 7.50-7.81 (m, 4 H) 10.20 (s, br, IH).

Methyl 5-iodo-l, 3 -dimethyl- lH-pyrazole-4-car boxy late.

To a solution of methyl 1, 3 -dimethyl- lH-pyrazole-4-carboxylate (154 mg, 1 mmol) in dry tetrahydrofuran (10 mL) at -78 ⁰ C, 2 M solution of BuLi (0.550 mL,

1.100 mmol) in pentane was added dropwise. The reaction mixture was then warmed to -45 ⁰ C and stirred for 1 h. It was then cooled to -78 ⁰ C and a solution of IODINE (279 mg, 1.100 mmol) in THF (2 mL) was added. The reaction mixture was warmed to RT and stirred for Ih. It was then quenched with saturated NH4CI solution and extracted with ethyl acetate (2X25 mL). The organic layers were combined, washed with brine, dried over MgSOφ and then concentrated in vacuo. The crude product was obtained as a brown thick oil. This material was then purified by preparative HPLC using CH3CN/H2O/TFA as solvent system. Homogeneous fractions were combined and concentrated in vacuo. The concentrate was then extracted with ethyl acetate and the extracts combined and dried over MgSOφ The suspension was then filtered and the filtrand evaporated under reduced pressure to give the title compound as a white solid, (137 mg, 0.460 mmol, 46.0 % yield). MS m/z 281(MH ⁺ ), Retention time: 1.107 min.(basic). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 2.45 (s, 3 H) 3.84 (s, 3 H) 3.91 (s, 3 H).

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-3- methoxy-6-[4-(methoxycarbonyl)-l, 3-dimethyl-lH-pyrazol-5-yl]-, 1, 1-dimethylethyl ester.

7H-indolo [2, 1 -a] [2]benzazepine- 1 O-carboxylic acid, 13 -cyclohexyl-3 - methoxy-6-(tributylstannyl)-, 1 , 1 -dimethylethyl ester (50 mg, 0.068 mmol), methyl 5-iodo- 1,3 -dimethyl- lΗ-pyrazole-4-carboxylate (38.2 mg, 0.136 mmol) and Bis(triphenylphosphine)-palladium(II) chloride (4.79 mg, 6.82 μmol) were added to a Standard microwave tube. The vessel was then sealed, degassed and flushed with nitrogen. 1,4-Dioxane (2.0 mL) was added and the resultant mixtue was heated at

12O ⁰ C under microwave conditions for 2h. It was then filtered and the filtrate concentrated. The residue was purified by preparative.HPLC using CH3 CN-H^O-

TFA as solvent system. Homogeneous fractions were collected and concentrated in vacuo to give the title compound as an orange colored solid, (9.1 mg, 0.015 mmol, 21.26 % yield). MS m/z 596 (MH ⁺ ), Retention time: 2.893 min.(basic). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.06 - 2.28 (m, 19 H) 2.47 (s, 3 H) 2.77 - 2.93 (m, 1 H) 3.19 (s, 3 H) 3.53 - 3.83 (s, br, 3 H) 3.90 (s, 3 H) 4.58 - 4.73 (m, br, 1 H) 4.86 - 5.03 (m, br, 1 H) 6.71 (s, 1 H) 6.92 (d, J=2.44 Hz, 1 H) 7.06 (dd, J=8.55, 2.75 Hz, 1 H) 7.52 (d, J=8.54 Hz, 1 H) 7.65 (dd, J=8.24, 1.22 Hz, 1 H) 7.80 - 7.85 (m, 2 H).

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-3- methoxy-6-[4-(methoxycarbonyl)-l,3-dimethyl-lH-pyrazol-5-yl] -. To a solution of 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-S-methoxy-ό-^-^ethoxycarbony^-l^-dimethyl-lH-pyr azol-S-yl]-, 1,1- dimethylethyl ester (601 mg, 1.009 mmol) in 1 ,2-Dichloroethane (10 mL), TFA (5 mL, 64.9 mmol) was added. The reaction mixture was stirred at RT for 4 hours. Solvent and TFA were then evaporated to give a brownish thick oil,(650 mg, 1.144 mmol, 113 % yield). 10 mg of this crude product was purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as solvent system. Homogeneous fractions were combined and concentrated under reduced pressure to give the title compound as a yellow solid, (3.5 mg, 35% recovery). MS m/z 540(MH ⁺ ), Retention time: 1.925 min. (basic). IH NMR (500 MHz, MeOD) δ ppm 1.15 - 1.59 (m, 4 H) 1.68 - 2.24 (m, 6 H) 2.41 (s, 3 H) 2.84 - 2.97 (m, 1 H) 3.11 - 3.50 (m, br, 6 H) 3.90 (s, 3 H) 4.55 - 4.69 (m, br, 1 H) 4.94 - 5.06 (m, br, 1 H) 6.88 (s, 1 H) 7.07 (d, J=2.44 Hz, 1 H) 7.14 (dd, J=8.70, 2.59 Hz, 1 H) 7.57 (d, J=8.55 Hz, 1 H) 7.67 (dd, J=8.55, 1.22 Hz, 1 H) 7.87 (d, J=8.54 Hz, 1 H) 7.89 (s, 1 H).

Note: The remaining crude product was used in the subsequent steps without further purification.

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(2- methylpropyl) sulfony I] amino] 'carbonylj- 7H-indolo[2, l-a][2]benzazepin-6-yl]-l, 3- dimethyl-, methyl ester.

To a solution of 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-S-methoxy-o-^-^ethoxycarbony^-l^-dimethyl-lH-pyra zol-S-yl]- (225 mg, 0.417 mmol) in tetrahydrofuran (10 niL), CDI (101 mg, 0.625 mmol) was added.

The reaction mixture was heated at 6O ⁰ C for one hour and then allowed to cool to RT. 2-Methylpropane-l -sulfonamide (172 mg, 1.251 mmol) and DBU (0.126 mL,

0.834 mmol) were then added and the resultant mixture was heated at 6O ⁰ C for 4 hours. The reaction was then quenched with IN HCl solution and the product extracted with ethyl acetate (2 x 4OmL). The organic layers were combined, washed with IN HCl solution, brine, dried (MgSC^) and then filtered. Evaporation of the filtrate gave the product as an orange colored oil. This material was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as solvent system. Homogeneous fractions were combined and concentrated in vacuo, to provide the title compound as a yellow colored solid, (46.6 mg, 0.067 mmol, 16.12 % yield). MS m/z 659(MH ⁺ ), Retention time: 2.197 min. (basic). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.14 (d, J=6.7 I Hz, 6 H) 1.19 - 1.60 (m, 4 H) 1.70 - 2.15 (m, 6 H) 2.34 - 2.43 (m, 1 H) 2.49 (s, 3 H) 2.80 - 2.92 (m, 1 H) 3.12 - 3.75 (m, 8 H) 3.91 (s, 3 H) 4.63 - 4.74 (m, br, 1 H) 4.85 - 4.99 (m, br, 1 H) 6.75 (s, 1 H) 6.94 (d, J=2.75 Hz, 1 H) 7.09 (dd, J=8.55, 2.75 Hz, 1 H) 7.39 (dd, J=8.55, 1.53 Hz, 1 H) 7.53 (d, J=8.55 Hz, 1 H) 7.75 (d, J=1.22 Hz, 1 H) 7.90 (d, J=8.55 Hz, 1 H) 8.52 (s, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony I] amino] 'carbonylj- 7H-indolo[2, 1-a] [2]benzazepin-6-yl]-l, 3- dimethyl-, methyl ester.

To a solution of 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-S-methoxy-ό-^-^ethoxycarbony^-l^-dimethyl-lH-pyr azol-S-yl]- (225 mg, 0.417 mmol) in tetrahydrofuran (10 mL), CDI (101 mg, 0.625 mmol) was added.

The reaction mixture was heated at 6O ⁰ C for one hour and was then allowed to cool to room temperature. Propane-2-sulfonamide (154 mg, 1.251 mmol) and DBU (0.126 mL, 0.834 mmol) were then added and the resultant mixture was heated at

6O ⁰ C for 4 hours. The reaction was then quenched with IN HCl solution and the product extracted with ethyl acetate (2 x 4OmL). The organic layers were combined, washed with IN HCl solution, brine, then dried (MgSC^) and filtered. Evaporation of solvents gave the product as an orange colored thick oil. This material was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as solvent system.

Homogeneous fractions were combined and concentrated in vacuoto provide the title compound as a yellow colored solid, (42.5 mg, 0.066 mmol, 15.81 % yield). MS m/z 645(MH ⁺ ), Retention time: 2.105 min. (basic). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.16 - 1.61 (m, 10 H) 1.69 - 2.21 (m, 6 H) 2.48 (s, 3 H) 2.81 - 2.92 (m, 1 H) 3.24 (s, 3 H) 3.66 (s, br, 3 H) 3.91 (s, 3 H) 4.01 - 4.10 (m, 1 H) 4.63 - 4.75 (m, br, 1 H) 4.84 - 4.98 (m, br, 1 H) 6.74 (s, 1 H) 6.94 (d, J=2.75 Hz, 1 H) 7.08 (dd, J=8.55, 2.75 Hz, 1 H) 7.39 (dd, J=8.55, 1.22 Hz, 1 H) 7.53 (d, J=8.55 Hz, 1 H) 7.74 (d, J=I.22 Hz, 1 H) 7.90 (d, J=8.55 Hz, 1 H) 8.28 (s, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-10- [[[(dimethylamino)sulfonyl] amino] carbonyl]-3-methoxy-7H-indolo[2,l- a][2]benzazepin-6-yl]-l,3-dimethyl-, methyl ester.

To a solution of 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-S-methoxy-ό-^-^ethoxycarbony^-l^-dimethyl-lH-pyr azol-S-yl]- (120 mg, 0.222 mmol) in TΗF (5 mL), CDI (54.1 mg, 0.334 mmol) was added. The reaction mixture was heated at 6O ⁰ C for one hour, and then allowed to cool to room temperature. N,N-dimethylsulfamide (83 mg, 0.667 mmol) and DBU (0.067 mL,

0.445 mmol) were then added and the resultant mixture was heated at 6O ⁰ C overnight. The reaction was then quenched with IN HCl solution and the product extracted with ethyl acetate (2 x 3OmL). The organic layers were combined, washed with IN HCl solution, brine, dried (MgSC^) and then filtered. Evaporation of solvents gave the curde product as an orange colored thick oil. This material was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as a solvent system.

Homogeneous fractions were combined and concentrated under vacuum to provide the title compound as an orange colored solid, (31.4 mg, 0.049 mmol, 21.87 % yield). MS m/z 646(MH ⁺ ), Retention time: 2.245min. (basic). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.18 - 1.60 (m, 4 H) 1.70 - 2.14 (m, 6 H) 2.49 (s, 3 H) 2.80 - 2.91 (m, 1 H) 3.05 (s, 6 H) 3.24 (s, 3 H) 3.68 (s, br, 3 H) 3.91 (s, 3 H) 4.64 -

4.74 (m, br, 1 H) 4.86 - 5.00 (m, br, 1 H) 6.74 (s, 1 H) 6.94 (d, J=2.75 Hz, 1 H) 7.08 (dd, J=8.85, 2.75 Hz, 1 H) 7.35 (dd, J=8.55, 1.53 Hz, 1 H) 7.53 (d, J=8.55 Hz, 1 H)

7.75 (d, J=1.22 Hz, 1 H) 7.89 (d, J=8.54 Hz, 1 H) 8.44 (s, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(2- methylpropyl) sulfony I] amino] 'carbonylj- 7H-indolo[2, l-a][2]benzazepin-6-yl]-l, 3- dimethyl-.

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 -a] [2]benzazepin-6- yl]-l,3-dimethyl-, methyl ester (44.2 mg, 0.067 mmol) in tetrahydrofuran (2.0 mL) and MeOH (2.000 mL), IN NaOH (0.537 mL, 0.537 mmol) solution was added. The reaction mixture was stirred at RT for 4 days. LC/MS showed that only ~ 25% of the starting ester was hydrolyzed. 0.5 mL of more IN NaOH solution was added. The reaction mixture was then stirred at RT for three more days. The reaction mixture was concentrated, and the residue was acidified using IN HCl solution. The resultant mixture was then extracted with ethyl acetate (2 x 20 mL) and the organic layers were combined, washed with brine, dried (MgSC^) and then filtered. Evaporation of filtrate gave the crude product as a viscous orange-colored oil. This material was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as a solvent system.

Homogeneous fractions were collected concentrated under reduced pressure to give the title compound as a light yellow colored solid, (12.2 mg, 0.019 mmol, 28.2 % yield). MS m/z 645(MH ⁺ ), Retention time: 1.847 min.(basic). IH NMR (500 MHz, DMSO-D6) δ ppm 1.02 (d, J=6.71 Hz, 6 H) 1.08 - 1.53 (m, 4 H) 1.64 - 2.09 (m, 6 H) 2.08 - 2.20 (m, 1 H) 2.36 (s, 3 H) 2.71 - 2.85 (m, 1 H) 3.09 (s, 3 H) 3.45 (d, J=6.71 Hz, 2 H) 3.88 (s, 3 H) 4.42 - 4.62 (m, br, 1 H) 4.96 - 5.18 (m, br, 1 H) 6.97 (s, 1 H) 7.15 (d, J=2.75 Hz, 1 H) 7.21 (dd, J=8.85, 2.75 Hz, 1 H) 7.54 (d, J=8.85 Hz, 1 H) 7.60 (dd, J=8.39, 1.37 Hz, 1 H) 7.90 (d, J=8.54 Hz, 1 H) 8.14 (s, 1 H) 11.76 (s, 1 H) 12.37 (s, br, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-10- [[[(dimethylamino)sulfonyl] amino] carbonyl]-3-methoxy-7H-indolo[2,l- a][2]benzazepin-6-yl]-l, 3-dimethyl-.

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-10- [[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indo lo[2,l- α][2]benzazepin-6-yl]-l, 3-dimethyl-, methyl ester (29.4 mg, 0.046 mmol) in TΗF (1.5 mL) and MeOH (1.500 mL), IN NaOH (0.364 mL, 0.364 mmol) solution was added. The reaction mixture was stirred at RT for 4 days. LC/MS showed that only ~ 40% ester was hydrolyzed. 0.5 mL of more IN NaOH solution was added. The reaction mixture was then stirred at RT for three more days. The reaction mixture was concentrated and the residue acidified using IN HCl solution. The product was then extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, washed with brine, dried (MgSC^) and then filtered. Evaporation of filtrate gave the crude product as an orange colored oil. This material was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as a solvent system. Homogeneous fractions were combined and concentrated in vacuo to give the title compound as a light yellow colored solid, (9.5 mg, 0.015 mmol, 33.0 % yield). MS m/z 632(MH ⁺ ), Retention time: 1.853 min.(basic). IH NMR (500 MHz, DMSO-D6) δ ppm 1.06 - 1.53 (m, 4 H) 1.58 - 2.07 (m, 6 H) 2.35 (s, 3 H) 2.74 - 2.83 (m, 1 H) 2.87 (s, 6 H) 3.02 - 3.16 (s, br, 3 H) 3.88 (s, 3 H) 4.41 - 4.61 (m, br,l H) 4.96 - 5.20 (m, br, 1 H) 6.97 (s, 1 H) 7.15 (d, J=2.75 Hz, 1 H) 7.20 (dd, J=8.55, 2.75 Hz, 1 H) 7.54 (d, J=8.55 Hz, 1 H) 7.60 (dd, J=8.55, 1.53 Hz, 1 H) 7.89 (d, J=8.54 Hz, 1 H) 8.14 (s, 1 H) 11.51 (s, 1 H) 12.35 (s, br, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony I] amino] 'carbonylj- 7H-indolo[2, 1-a] [2]benzazepin-6-yl]-l, 3- dimethyl-.

To a mixture of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l- α][2]benzazepin-6-yl]- 1,3-dimethyl-, methyl ester (80 mg, 0.124 mmol) and potassium trimethylsilanolate (TMSOK) (31.8 mg, 0.248 mmol) in a round-bottomed flask, Tetrahydrofuran (8 mL) was added. The resultant mixture was then stirred at RT overnight. LC/MS showed that only 40% of SM reacted. Two more equivalents of TMSOK were added and stirring was contined for 48 hrs. The reaction mixture was then concentrated and IN HCl solution was added. A yellow solid separated (85 mg). and 10 mg of the matieral was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as solvent system. Homogeneous fractions were combined and evaporated under vacuum to give the title compound as a yellow colored solid, (7.6 mg, 76% recovery). MS m/z 631(MH ⁺ ), Retention time: 1.648 min. (basic). IH NMR (500 MHz, Acetone) δ ppm 1.11 - 1.61 (m, 10 H) 1.63 - 2.21 (m, 6 H) 2.38 (s, 3 H) 2.85 - 3.00 (m, 1 H) 3.17 (s, 3 H) 3.83 - 3.97 (m, 4 H) 4.54 - 4.72 (m, br, 1 H) 5.09 - 5.29 (m, br, 1 H) 6.93 (s, 1 H) 7.11 (d, J=2.75 Hz, 1 H) 7.17 (dd, J=8.55, 2.75 Hz, 1 H) 7.61 (d, J=8.55 Hz, 1 H) 7.68 (dd, J=8.55, 1.53 Hz, 1 H) 7.96 (d, J=8.55 Hz, 1 H) 8.21 (s, 1 H) 9.96 (s, 1 H). Note: The crude product describe above can be used without further purification for the preparation of carboxamide examples of the current invention.

7H-indolo[2, 1-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-N- [(dimethylamino)sulfonyl]-6-[l,3-dimethyl-4-(4-morphotinylca rbonyl)-lH-pyrazol-. To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-10-

[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-i ndolo[2,l- α][2]benzazepin-6-yl]-l,3-dimethyl- (9.5 mg, 0.015 mmol) in DMSO (1 mL), TBTU (9.66 mg, 0.030 mmol) and DIPEA (0.013 mL, 0.075 mmol) were added. The reaction mixture was stirred at RT for 15 min. Morpholine (1.965 mg, 0.023 mmol) was then added and the resultant solution was stirred at RT for 48 hours. The reaction mixture was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as a solvent system. Homogeneous fractions were combined and concentrated under vacuum. The title compound was obtained as a yellow colored solid, (8.0 mg, 0.011 mmol, 74.4 % yield). MS m/z 699 (M-H ^" ), Retention time: 1.990 min.(basic). IH NMR (500 MHz, MeOD) δ ppm 1.18 - 1.64 (m, 4 H) 1.73 - 2.26 (m, 9 H) 2.59 - 3.09 (m, 15 H) 3.85 (s, 3 H) 3.95 (s, 3 H) 4.67 (d, J=14.96 Hz, 1 H) 5.02 - 5.15 (m, 1 H) 7.07 (s, 1 H) 7.15 (d, J=2.44 Hz, 1 H) 7.20 (dd, J=8.55, 2.75 Hz, 1 H) 7.56 - 7.64 (m, 2 H) 7.92 (s, 1 H) 7.98 (d, J=8.55 Hz, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-6-[l ,3- dimethyl-4-(4-morpholinylcarbonyl)- lH-pyrazol-5-yl] -3-methoxy-N- [(2- methylpropyl)sulfonyl] -.

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l -α][2]benzazepin-6- yl]-l,3-dimethyl- (10 mg, 0.016 mmol) in DMSO (1 mL), TBTU (9.96 mg, 0.031 mmol) and DIPEA (0.014 mL, 0.078 mmol) were added. The reaction mixture was stirred at RT for 15 min. Morpholine (1.351 mg, 0.016 mmol) was then added and the resultant solution was stirred at RT overnight. The reaction mixture was then purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as a solvent system.

Homogeneous fractions were collected and concentrated under vacuum, to provide the title compound as a yellow colored solid, (10.7 mg, 0.015 mmol, 95 % yield). MS m/z 712(M-H ^" ), Retention time: 1.895 min.(basic). IH NMR (500 MHz, MeOD) δ ppm 1.16 (d, ./=6.71 Hz, 6 H) 1.20 - 1.64 (m, 4 H) 1.73 - 2.27 (m, 9 H) 2.29 - 2.43 (m, 1 H) 2.56 - 3.14 (m, 9 H) 3.49 - 3.55 (m, 2 H) 3.85 (s, 3 H) 3.95 (s, 3 H) 4.67 (d, J=14.96 Hz, 1 H) 4.98 - 5.16 (m, br, 1 H) 7.07 (s, 1 H) 7.15 (d, J=2.44 Hz, 1 H) 7.20 (dd, J=8.70, 2.59 Hz, 1 H) 7.55 - 7.66 (m, 2 H) 7.95 (s, 1 H) 7.98 (d, J=8.55 Hz, 1 H).

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[l ,3- dimethyl-4-(4-morpholinylcarbonyl)-lH-pyrazol-5-yl] -3-methoxy-N- [(1- methylethyl)sulfonyl]-. To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-

10-[[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2 ,l-α][2]benzazepin-6-yl]- 1,3-dimethyl- (20 mg, 0.032 mmol) in DMSO (1 mL), TBTU (20.36 mg, 0.063 mmol) and DIPEA (0.028 mL, 0.159 mmol) were added. The reaction mixture was stirred at RT for 15 min. Morpholine (4.14 mg, 0.048 mmol) was then added and the resultant solution was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC using CH3CN-H2O-TFA as a solvent system. Homogeneous fractions were combined and concentrated under vacuum. The title compound was obtained as a yellow colored solid, (16.8 mg, 0.024 mmol, 74.2 % yield). MS m/z 698(M-H ^" ), Retention time: 1.798 min. (basic). IH NMR (500 MHz, MeOD) δ ppm 1.18 - 1.62 (m, 10 H) 1.72 - 2.25 (m, 9 H) 2.53 - 3.23 (m, 9 H) 3.84 (s, 3 H) 3.95 (s, 3 H) 3.96 - 4.03 (m, 1 H) 4.64 (d, J=14.95 Hz, 1 H) 5.00 - 5.15 (m, br, 1 H) 7.06 (s, 1 H) 7.14 (d, J=2.44 Hz, 1 H) 7.19 (dd, J=8.55, 2.75 Hz, 1 H) 7.55 - 7.65 (m, 2 H) 7.94 (s, 1 H) 7.98 (d, J=8.55 Hz, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[l,3- dimethyl-4-[(3-methyl-3, 8-diazabicyclo[3.2.1] oct-8-yl)carbonyl] -lH-pyrazol-5-yl] -3- methoxy-N-[(l-methylethyl)sulfonyl.

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy- 10-[[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l- α][2]benzazepin-6-yl]- 1,3-dimethyl- (20 mg, 0.032 mmol) in DMSO (1 mL), TBTU (20.36 mg, 0.063 mmol) and DIPEA (0.028 mL, 0.159 mmol) were added. The reaction mixture was stirred at RT for 15 min. Then 3-methyl-3,8-diazabicyclo[3.2.1]octane.2 HCl (9.47 mg, 0.048 mmol) was added. The solution was then stirred at RT overnight. The crude reaction mixture was then purified by preparative ΗPLCusing CΗ3CN-Η2O- TFA as solvent system. Homogeneous fractions were combined and concentrated under vacuum to afford the title compound as a yellow solid, (19.7 mg, 0.023 mmol, 71.4 % yield) as TFA salt. MS m/z 737(M-H ^" ), Retention time: 2.040 min. (basic). IH NMR (500 MHz, MeOD) δ ppm 1.16 - 1.67 (m, 14 H) 1.74 - 2.25 (m, 6 H) 2.38 (s, 3 H) 2.51 - 2.66 (m, 1 H) 2.72 (s, 3 H) 2.94 - 3.05 (m, 1 H) 3.16 - 3.39 (m, 5 H) 3.84 (s, 3 H) 3.96 (s, 3 H) 3.98 - 4.05 (m, 1 H) 4.59 - 4.71 (m, br, 1 H) 4.94 - 5.05 (m, br, 1 H) 7.14 - 7.28 (m, 3 H) 7.62 - 7.66 (m, 2 H) 7.91 (s, 1 H) 8.00 (d, J=8.54 Hz, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-6-[l,3- dimethyl-4-l [cis-2,6-dimethyl- 4-morpholinyl] carbonyl] -lH-pyrazol-5-yl] -3- methoxy-N-[(l-methylethyl)sulfonyl]-. To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l-methylethyl)sulfonyl]ami no]carbonyl]- 7H-indolo[2,l-α][2]benzazepin-6-yl]-l,3-dimethyl- (13 mg, 0.021 mmol) in DMSO (1 mL), TBTU (13.24 mg, 0.041 mmol) and DIPEA (0.018 mL, 0.103 mmol) were added. The reaction mixture was stirred at RT for 15 min. Then cis-2,6- dimethylmorpholine (3.56 mg, 0.048 mmol) was added and the resultant mixture was stirred at RT overnight. The crude reaction mixture was purified by preparative ΗPLC using CΗ3CN-Η2O-TFA as a solvent system. Homogeneous fractions were combined and concentrated under vacuum to afford the title compound as a yellow colored solid, (10.1 mg, 0.014 mmol, 67.3 % yield). MS m/z 326(M-H ^" ), Retention time: 1.958 min. (basic). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.57 - 2.33 (m, 25 H) 2.81 - 3.60 (m, 5 H) 3.77 - 3.99 (m, 8 H) 4.03 - 4.12 (m, 1 H) 4.57 (d, J=15.26 Hz, 1 H) 4.76 - 4.94 (m, 1 H) 6.75 - 6.88 (m, 1 H) 6.95 (s, 1 H) 7.12 (dd, J=8.55, 2.14 Hz, 1 H) 7.50 - 7.67 (m, 2 H) 7.71 (s, 1 H) 7.91 (d, J=8.24 Hz, 1 H). The following compounds were synthesized by an analogous method as described above for 7H-indolo[2,l-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l,3- dimethyl-4-[[cis-2,6-dimethyl- 4-morpholinyl]carbonyl]-lH-pyrazol-5-yl]-3- methoxy-N-[(l-methylethyl)sulfonyl]-:

7H-indolo[2,l-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l,3-dimethyl-4-

(8-oxa-3-azabicyclo[3.2.1]oct-3-ylcarbonyl)-lH-pyrazol-5- yl]-3-methoxy-N-[(l- methylethyl)sulfonyl]-.

MS m/z 726(M+H). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.70 - 2.32 (m,

23 H) 2.75 - 3.69 (m, 5 H) 3.81 - 3.99 (m, 8 H) 4.03 (m, 1 H) 4.55 (br d, 1 H) 4.90

(br d, 1 H) 6.75 (s, 1 H) 6.96 (s, 1 H) 7.14 (m, 1 H) 7.51 - 7.65 (m, 2 H) 7.72 (s, 1 H)

7.87 (d, J=8.24 Hz, 1 H) 10.12 (br s, 1 H).

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-6-[4- [[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-l,3-dimethy l-lH-pyrazol-5-yl]- N-[(l-methylethyl)sulfonyl]-. MS m/z 744 (M+H). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.19 - 2.52 (m, 21 H) 2.85 - 3.59 (m, 11 H) 3.85 - 3.95 (m, 6 H) 4.07 (m, 1 H) 4.60 (br d, 1 H) 4.93 (br d, 1 H) 6.86 (br s, 1 H) 6.97 (s, 1 H) 7.16 (m, 1 H) 7.53 - 7.69 (br m, 2 H) 7.22 (br m, 1 H) 7.94 (br m, 1 H) 10.20 (br s, 1 H).

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l,3-dimethyl-4- [(4-methyl-l-piperazinyl)carbonyl]-lH-pyrazol-5-yl]-3-methox y-N-[(l- methylethyl)sulfonyl]-.

MS m/z 713 (M+H). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.13 - 2.26 (m, 19 H) 2.39 - 3.71 (m, 12 H) 3.75 - 3.86 (m, 6 H) 4.03 (m, 1 H) 4.61 (br d, 1 H) 4.83 (br d, 1 H) 6.96 (m, 2 H) 7.13 (m, 1 H) 7.53 (d, J=8.24 Hz, 1 H) 7.61 - 7.82 (m, 2 H) 7.92 (d, J=8.24 Hz, 1 H) 10.20 (br s, 1 H).

Methyl l-(l-methylethyl)-3-methyl-lH-pyrazole-4-carboxylate

To a solution of l-(l-methylethyl)-3 -methyl- lH-pyrazole-4-carboxyllic acid

(2.0Og, 11.9 mmol) in benzene (15.9 mL) and methanol (7.93 mL) at room temperature was added 2M trimethylsilyldiazomethane (23.8 mL). The resulting solution was stirred at room temperature for 3 hours. Solvent was removed at reduced pressure on a rotory evaporator to yield the title compound (2.17 g, 11.89 mmol, 100 % yield) as a white solid. MS m/z 183(MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.49 (d, 6H) 2.48 (s, 3 H) 3.81 (s, 3 H) 4.42 (m, IH) 7.86 (s, IH).

Methyl 5-iodo-l-(l-methylethyl)-3-methyl-lH-pyrazole-4-carboxylate

To a solution of methyl l-(l-methylethyl)-3 -methyl- lH-pyrazole-4- carboxylate (2.0Og, 11.0 mmol) in dry tetrahydrofuran (22.0 mL) at -78 ⁰ C, 2 M solution of butyllithium (6.04 mL, 12.1 mmol) in pentane was added dropwise. The reaction mixture was then warmed to -45 ⁰ C and stirred for 1 h. It was then cooled to

-78 ⁰ C and a solution of iodine (3.06 g, 12.1 mmol) in THF (11.0 mL) was added. The reaction mixture was warmed to RT and stirred for Ih. Then it was quenched with saturated NH4CI solution and extracted with ethyl acetate (2X25 mL). The organic layers were combined, washed with brine and dried (MgSC^). Evaporation of solvent gave a tan solid as title compound (3.38 g, 11.0 mmol, 100 % crude yield). MS m/z 309 (MH ⁺ ); IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.41 (d, 6H)

2.47 (s, 3 H) 3.82 (s, 3 H) 4.77 (m, IH).

7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxylic acid, 13-cyclohexyl-3- methoxy-6- [4-(methoxycarbonyl)- 1-(1 -methylethyl) -3 -methyl- lH-pyrazol-5-yl) '-, 1,1- dimethylethyl ester

In a microwave tube, 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester (611 mg, 0.834 mmol), methyl 5-iodo-l-(l-methylethyl)-3-methyl-lΗ-pyrazole-4-carboxylate (360 mg, 1.17 mmol) and bis(triphenylphosphine)palladium II chloride (58.5 mg, 0.083 mmol) were added. It was then sealed, degassed and flushed with nitrogen. 1,4-

Dioxane (4.17 mL) was added. The reaction mixture was heated at 16O ⁰ C under microwave condition for 1 hour. It was then filtered and the filtrate was concentrated. The residue was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL- 1OA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 :1) (8ml) purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 25% solvent A / 75% solvent B to 0% solvent A / 100% solvent B, a gradient time of 10 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system.

The product-containing fractions were collected and concentrated to give title compound as a yellow solid (156 mg, 0.250 mmol, 30% yield). MS m/z 624 (MH ⁺ ); IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.41 (br s, 3H) 1.18 - 1.59 (m, 16 H) 1.72 - 2.20 (m, 6 H) 2.49 (s, 3 H) 2.86 (m, 1 H) 3.68 (m, 1 H) 3.85 (br s, 3 H) 3.92 (s, 3 H) 4.69 (br.d, 1 H) 4.97 (br.d, 1 H) 6.68 (s, 1 H) 6.92 (d, J=2.14 Hz, 1 H) 7.06 (dd, J=8.55, 2.44 Hz, 1 H) 7.51 (d, J=8.55 Hz 1 H) 7.73 (d, J=8.24 Hz, 1 H) 7.81 (d, J=8.24 Hz, 1 H) 7.87 (s, 1 H).

7H-indolo[2, 1-a] [2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[4- (methoxycarbonyl)- l(l-methylethyl)-3-trifluoromethyl-lH-pyrazol-5-yl]-

To a solution of 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-3 -methoxy-6- [4-(methoxycarbonyl)- 1 -( 1 -methylethyl)-3 -methyl- 1 H- pyrazol-5-yl]-, 1 , 1 -dimethylethyl ester (156 mg, 0.250 mmol) in 1 ,2-dichloroethane (4 mL), TFA (4 mL) was added. The reaction mixture was stirred at RT for 2 hours. Volatiles were removed on a rotary evaporator to give the title compound as a brownish thick oil as crude product (142 mg, 0.8250 mmol, 100 % yield). MS m/z 568(MH ⁺ ).

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.41 (br s, 3H) 1.18 - 1.59 (m, 7 H) 1.72 - 2.20 (m, 6 H) 2.52 (s, 3 H) 2.87 (m, 1 H) 3.63 (m, 1 H) 3.85 (br s, 3 H) 3.91 (s, 3 H) 4.71 (br.d, 1 H) 4.96 (br.d, 1 H) 6.68 (s, 1 H) 6.96 (d, J=2.14 Hz, 1 H) 7.08 (dd, J=8.55, 2.44 Hz, 1 H) 7.52 (d, J=8.55 Hz 1 H) 7.77 (d, J=8.24 Hz, 1 H) 7.87 (d, J=8.24 Hz, 1 H) 7.97 (s, 1 H).

7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxylic acid, 13-cyclohexyl-3- methoxy-6- [4-(methoxycarbonyl)- 1 (l-methylethyl)-3-trifluoromethyl-lH-pyrazol-5- yil-

To a solution of 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)- l(l-methylethyl)-3-trifluoromethyl- lH-pyrazol-5-yl]- (110 mg, 0.194 mmol) in tetrahydrofuran (0.646 mL) was added carbonyldiimidazole (94.0 mg, 0.581 mmol). The reaction mixture was heated at 6O ⁰ C for one hour. Propane-2-sulfonamide (95 mg, 0.775 mmol) and DBU (0.088 mL, 0.581 mmol) were added at room temperature. The reaction mixture was then heated at 6O ⁰ C for 4 hours. The reaction mixture was diluted with IN HCl (50 mL) solution and extracted with ethyl acetate (2 X 4OmL). The organic layers were combined and concentrated on a rotory evaporator to give an orange oil as crude product. It was then purified by prep ΗPLC column using CΗ3CN/Η2O/TFA as solvent system. Fractions were collected and concentrated under speedvac for 16h. A yellow solid was obtained as title compound (114 mg, 0.169 mmol, 87 % yield). MS m/z 673 (MH ⁺ ).

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.41 (br s, 3H) 1.18 - 1.52 (m, 13 H) 1.70 - 2.20 (m, 6 H) 2.51 (s, 3 H) 2.85 (m, 1 H) 3.59 (m, 1 H) 3.87 (s, 3 H) 3.92 (s, 3 H) 4.02 (m, 1 H) 4.73 (br.d, 1 H) 4.97 (br.d, 1 H) 6.67 (s, 1 H) 6.96 (d, J=2.14 Hz, 1 H) 7.08 (dd, J=8.55, 2.44 Hz, 1 H) 7.40-7.62 (m, 2 H) 7.78-7.84 (m, 2 H), 9.00 (br s, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony I] 'amino] carbony I]- 7H-indolo[2, 1-a] ' [2] benzazepin-6-yl] - 1-(1- methylethyl)-3-methyl-

To a mixture of 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)- l(l-methylethyl)-3-trifluoromethyl- lH-pyrazol-5-yl]- (110 mg, 0.163 mmol) was dissolved in TΗF (0.272 mL) and methanol (0.272 mL) was added to the reaction followed by IN aqueous sodium hydroxide (0.600 mL). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 18 hrs. The reaction was diluted with ethyl acetate (25.0 mL) and washed with 1.0N aqueous hydrochloric acid (2 x 20ml). The organic layer was concentrated in vacuuo using a rotary evaporator to yield the title compound as a yellow solid (107 mg, 0.163 mmol, 100%). MS m/z 659(MH ⁺ )

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.39 (br s, 3H) 1.18 - 1.52 (m, 13 H) 1.70 - 2.20 (m, 6 H) 2.48 (s, 3 H) 2.83 (m, 1 H) 3.51 (m, 1 H) 3.87 (s, 3 H) 4.02 (m, 1 H) 4.72 (br.d, 1 H) 4.98 (br.d, 1 H) 6.65 (s, 1 H) 6.95 (d, J=2.14 Hz, 1 H) 7.08 (dd, J=8.55, 2.44 Hz, 1 H) 7.41-7.60 (m, 2 H) 7.79-7.83 (m, 2 H), 8.96 (br s, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[3-methyl-l-(l-methylethyl)-4- (4- morpholinylcarbonyl)-lH-pyrazol-5-yl]-

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-

10-[[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2 ,l-α][2]benzazepin-6-yl]- l-(l-methylethyl)-3 -methyl- (25 mg, 0.038 mmol) in DMSO (0.38 mL), TBTU (24 mg, 0.076 mmol) and DIPEA (0.020 mg, 0.44 mmol) were added. The reaction mixture was stirred at RT for 15 min. Then morpholine (38 mg, 0.15 mmol) was added. The solution was stirred at RT for overnight. The reaction mixture was purified by prep ΗPLC column using CΗ3CN/Η2O/TFA as solvent system. Fractions were collected and concentrated under speedvac overnight to yield the title compound as a yellow solid (24 mg, 0.031 mmol, 81 % yield). MS m/z 728 (M-H ⁺ )

IH NMR (SOO MHz ₁ CHLOROFORM-D) O PPm L lS - 1.70 (m, 16 H) 1.75 - 2.16 (m, 6 H) 2.30 (s, 3 H) 2.60-3.31 (m, 9 H) 3.94 (m, 3 H) 4.04 (m, 1 H) 4.56 (br.m, 2 H) 4.93 (br.d, 1 H) 6.79 (br s, 1 H) 6.94 (s, 1 H) 7.12 (dd, J=8.55, 2.44 Hz, 1 H) 7.57 (d, J=8.55 Hz 1 H) 7.66 (br s, 1 H) 7.82 (s, 1 H) 7.97 (d, J=8.55 Hz, 1 H), 10.20 (br s, I H).

The following compounds were synthesized by an analogous method as described above for 7H-indolo[2,l-a][2]benzazepine-10-carboxamide, 13- cyclohexyl-3 -methoxy-N-[( 1 -methylethyl)sulfonyl]-6- [3 -methyl- L(I -methylethyl)-4- (4-morpholinylcarbonyl)- 1 H-pyrazol-5 -yl]- :

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-

[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-3-methyl-l -(l-methylethyl)-lH- pyrazol-5-yl] -3-methoxy-N-[(l-methylethyl)sulfonyl] -

MS m/z 756 (M-H ⁺ )

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.70-0.91 (br m, 6 H)1.02 - 1.81 (m, 16 H) 1.86 - 2.16 (m, 6 H) 2.28 (s, 3 H) 2.85-3.29 (m, 5 H) 3.96 (s, 3 H) 4.12 (br m, 3 H) 4.55 (br.m, 2 H) 4.92 (br.d, 1 H) 6.73 (br s, 1 H) 6.94 (br s, 1 H) 7.16 (dd, J=8.55, 2.44 Hz, 1 H) 7.51-7.72 (m, 2 H) 7.76-7.98 (m, 2 H), 10.50 (br s, 1 H). 7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[3-methyl-l-(l-methylethyl)-4- [(4-methyl-l- piperazinyl)carbonyl] - lH-pyrazol-5-yl] -

MS m/z 741 (M-H ⁺ )

IH NMR (SOO MHz ₁ CHLOROFORM-D) O PPm L lS - 1.81 (m, 18 H) 1.86 - 2.12 (m, 4 H) 2.21-2.45 (m, 5 H) 2.61-3.05 (m, 6 H) 3.10-3.75 (m, 4 H) 3.93 (s, 3 H) 4.04 (m, 1 H) 4.61 (br.m, 2 H) 4.90 (br.d, 1 H) 6.86 (br s, 1 H) 6.96 (s, 1 H) 7.14 (br m, 1 H) 7.59-7.83 (m, 3 H) 7.93 (br s, 1 H), 10.10 (br s, 1 H).

7 H-indolo [2,1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[3-methyl-l-(l-methylethyl)-4- [[(3R, 5S)-3, 4, 5- trimethyl-l-piperazinyl]carbonyl]-lH-pyrazol-5-yl]-

MS m/z 769 (M-H ⁺ ) IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.21 (br s, 1 H) 1.02 (br s, 3 H) 1.15-1.60 (m, 17 H) 1.69 - 2.12 (m, 8 H) 2.28 (m, 4 H) 2.69-3.60 (m, 6 H) 3.96 (s, 3 H) 4.08 (br m, 3 H) 4.60 (br.m, 2 H) 4.88 (br.m, 1 H) 6.82 (br s, 1 H) 6.95 (s, 1 H) 7.15 (br m, 1 H) 7.55-7.74 (m, 2 H) 7.78-7.99 (m, 2 H), 10.12 (br s, 1 H).

lH-pyrazole-4-carboxylic acid, l-methyl-3-(l-methylethyl)-, ethyl ester

To ethyl 4-methyl-3-oxopentanoate (5.0Og, 31.6 mmol) was added N,N- dimethylformamide dimethyl acetal (37.7 g, 316 mmol). The resulting solution was stirred at 100 ⁰ C for 3 hours. Solvent was removed at reduced pressure on a rotory evaporator to yield an orange oil. 3.00 grams of this oil was redissolved in ethanol (46.9 mL). Triethylamine (2.85 g, 28.1 mmol) and methylhydrazine (0.713 g, 15.5 mmol) was added added at room temperature, the resulting solution was stirred for 2 hours, diluted with IM HCl (100 mL) and extracted with chloroform (100 mL). The resulting oil was purified through a column of silica gel using 5: 1 hexanes/ethyl acetate as the eluent to yield a yellow oil (2.40 g, 12.1 mmol). MS m/z 197 (MH ⁺ ).

lH-pyrazole-4-carboxylic acid, 5-iodo-l-methyl-3-(l-methylethyl)-, ethyl ester

To a solution of lH-pyrazole-4-carboxylic acid, l-methyl-3-(l-methylethyl)-, ethyl ester (2.14 g, 10.9 mmol) in dry tetrahydrofuran (21.8 mL) at -78 ⁰ C, 1.4 M solution of seobutyllithium (8.57 mL, 12.0 mmol) in pentane was added dropwise. The reaction mixture was then warmed to -45 ⁰ C and stirred for 1 h. It was then cooled to -78 ⁰ C and iodine (3.04 g, 12.0 mmol) was added. The reaction mixture was warmed to RT and stirred for Ih. Then it was quenched with saturated NH4CI solution and extracted with ethyl acetate (2X25 mL). The organic layers were combined, washed with brine and dried (MgSC^). Evaporation of solvent gave a solid that was purified by prep HPLC column using CH3CN/H2O/TFA as solvent system. Fractions were collected and concentrated under speedvac overnight to yield a title compound (0.843 g, 2.62 mmol, 24 % crude yield) as a beige solid. MS m/z 323 (MH ⁺ )

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.25 (d, 6 H) 1.37 (t, 3H) 3.52 (m, 1 H) 3.91 (s, 3 H) 4.31 (q, 2H).

7H-indolo[2, l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-methyl-3-(l-methylethyl)-lH-pyrazol-5-yl] -3-methoxy-, 1,1- dimethvlethvl ester

In a microwave tube, 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester (800 mg, 1.09 mmol), lΗ-pyrazole-4-carboxylic acid, 5-iodo-l-methyl-3-(l-methylethyl)-, ethyl ester (422 mg, 1.31 mmol), LiCl (231 mg, 5.46 mmol), CuCl (454 mg, 4.59 mmol) and bis(triphenylphosphine)palladium II chloride (77.0 mg, 0.109 mmol) were added. It was then sealed, degassed and flushed with nitrogen. 1,4-Dioxane (5.46 mL) was added. The reaction mixture was heated at 16O ⁰ C under microwave condition for 1 hour. It was then filtered and the filtrate was concentrated. The residue was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC- 1OA fraction collector. The sample was dissolved in acetonitrile / DMF (1: 1) (8ml) purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 25% solvent A / 75% solvent B to 0% solvent A / 100% solvent B, a gradient time of 10 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product-containing fractions were collected and concentrated to give title compound as a yellow solid (286 mg, 0.448 mmol, 41% yield). MS m/z 638 (MH ⁺ )

7H-indolo[2, l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-methyl-3-(l-methylethyl)-lH-pyrazol-5-yl] -3-methoxy-

To a solution of 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl- 6-[4-(ethoxycarbonyl)-l-methyl-3-(l-methylethyl)-lH-pyrazol- 5-yl]-3-methoxy-, 1,1-dimethylethyl ester (286 mg, 0.448 mmol) in 1,2-dichloroethane (4 mL), TFA (4 mL) was added. The reaction mixture was stirred at RT for 2 hours. Volatiles were removed on a rotary evaporator to give the title compound as a brownish thick oil as crude product (260 mg, 0.448 mmol, 100 % yield). MS m/z 582(MH ⁺ ) lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a] [2]benzazepin-6-yl]-l- methyl-3-(l-methylethyl)-, ethyl ester

To a solution of 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl- 6- [4-(ethoxycarbonyl)- 1 -methyl-3 -( 1 -methylethyl)- 1 H-pyrazol-5-yl] -3 -methoxy- (140 mg, 0.241 mmol) in tetrahydrofuran (0.802 mL) was added carbonyldiimidazole (117 mg, 0.722 mmol). The reaction mixture was heated at 6O ⁰ C for one hour. Propane-2-sulfonamide 119 mg, 0.963 mmol) and DBU (0.109 mL, 0.722 mmol) were added at room temperature. The reaction mixture was then heated at 6O ⁰ C for 2 hours. The reaction mixture was diluted with IN HCl (50 mL) solution and extracted with chloroform (5OmL). The organic layers were combined and concentrated on a rotory evaporator to give an orange oil as crude product. It was purified through silica gel using 90/9/1 methylene chloride/MeOH/AcOH as the eluent to give the title compound (160 mg, 0.233 mmol, 97 % yield) as a yellow oil. MS m/z 687 (MH ⁺ )

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony I] amino] carbonyl] - 7H-indolo[2, 1-a] [2]benzazepin-6-yl]-l- methyl-3-(l -methylethyl) -

To a mixture of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10- [[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][ 2]benzazepin-6-yl]-l- methyl-3-(l-methylethyl)-, ethyl ester (160 mg, 0.233 mmol) was dissolved in THF (0.582 mL) and methanol (0.582 mL) was added to the reaction followed by IN aqueous sodium hydroxide (2.32 mL). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 120 hrs. The reaction was diluted with chloroform (50 mL) and washed with 1.0N aqueous hydrochloric acid (50 mL). The organic layer was concentrated in vacuuo using a rotary evaporator to yield the title compound as a yellow solid (153 mg, 0.233 mmol, 100%). MS m/z 659(MH ⁺ )

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-N-[(l- methylethyl)sulfonyl] -6- [ 1 -methyl-3-(l -methylethyl)-4-(4-morpholinylcarbonyl)- IH- pyrazol-5-ylJ-

To a solution of lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10- [[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][ 2]benzazepin-6-yl]-l- methyl-3-(l-methylethyl)- (50 mg, 0.076 mmol) in DMSO (0.760 mL), TBTU (49 mg, 0.152 mmol) and DIPEA (0.039 mg, 0.30 mmol) were added. The reaction mixture was stirred at RT for 15 min. Then morpholine (26 mg, 0.304 mmol) was added. The solution was stirred at RT for overnight. The reaction mixture was purified by prep HPLC column using CH3CN/H2O/TFA as solvent system.

Fractions were collected and concentrated under speedvac overnight to yield the title compound as a yellow solid (26 mg, 0.035 mmol, 47 % yield). MS m/z 728 (M-H ⁺ )

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.15 - 1.62 (m, 16 H) 1.72 - 2.25 (m, 7 H) 2.53 - 3.36 (m, 9 H) 3.90 (s, 3 H) 3.94 (s, 3 H) 4.07 (m, 1 H) 4.60 (br d, 1 H) 4.94 (br d, 1 H) 6.82 (d, J=2.44 Hz, 1 H) 6.96 (s, 1 H) 7.14 (dd, J=8.55, 2.75 Hz, 1 H) 7.57 (d, J=8.55 Hz, 1 H) 7.64 (m, 1 H) 7.76 (s, 1 H) 7.96 (d, J=8.55 Hz, 1 H) 10.56 (br s, 1 H).

The following compounds were synthesized by an analogous method as described above for 7H-indolo[2,l-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-3- methoxy-N-[(l-methylethyl)sulfonyl]-6-[l-methyl-3-(l-methyle thyl)-4-(4- morpholinylcarbonyl)-lH-pyrazol-5-yl]-:

7H-indolo[2,l-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[(2R,6S)-2,6- dimethyl-4-morpholinyl]carbonyl]-l-methyl-i-(l-methylethyl)- lH-pyrazol-5-yl]-i- methoxy-N-f(l-methylethyl)sulfonylJ-

MS m/z 756 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.70 (m, 6 H) 1.05 - 1.62 (m, 16 H) 1.72 - 2.28 (m, 7 H) 2.83 - 3.21 (m, 5 H) 3.90-3.94 (m, 8 H) 4.08 (m, 1 H) 4.59 (br d, 1 H) 4.96 (br d, 1 H) 6.79 (d, J=2.44 Hz, 1 H) 6.96 (s, 1 H) 7.14 (dd, J=8.55, 2.75 Hz, 1 H) 7.58 (d, J=8.55 Hz, 1 H) 7.69 (m, 1 H) 7.81 (s, 1 H) 7.96 (d, J=8.55 Hz, 1 H) 10.70 (br s, 1 H).

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-N-[(l - methylethyl)sulfonyl]-6-[l-methyl-3-(l-methylethyl)-4-[(4-me thyl-l- piperazinyl)carbonyl] -lH-pyrazol-5-yl] -

MS m/z 741 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.12- 1.70 (m, 16 H) 1.70 - 2.12 (m, 7 H) 2.33 (br s, 3 H) 2.70 - 3.32 (m, 7 H) 3.45-4.07 (m, 9 H) 4.61 (br s, 1 H) 4.97 (br s, 1 H) 6.89 (br s, 1 H) 7.96 (s, 1 H) 7.13 (br m, 1 H) 7.50- 7.86 (br m, 3 H) 7.94 (d, J=8.55 Hz, 1 H) 10.30 (br s, 1 H).

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-N-[(l- methylethyl)sulfonyl]-6-[l-methyl-3-(l-methylethyl)-4-[[(3R, 5S)-3, 4, 5-trimethyl-l- piperazinyl] carbonyl] -lH-pyrazol-5-yl] -

MS m/z 769 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.05 (m, 6 H) 1.05 - 1.62 (m, 16 H) 1.72 - 2.13 (m, 7 H) 2.28 (br s, 3 H) 2.83 - 3.48 (m, 5 H) 3.79- 4.11 (m, 9 H) 4.62 (br d, 1 H) 4.99 (br d, 1 H) 6.86 (br s, 1 H) 6.97 (s, 1 H) 7.18 (br s, 1 H) 7.60-7.81 (br m, 3 H) 7.95 (d, J=8.55 Hz, 1 H) 10.32 (br s, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][2]benz azepin-6-yl]-l- methyl-

Dissolve lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10- [[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][ 2]benzazepin-6-yl]-l- methyl-, ethyl ester (1.044 g, 1.619 mmol) in a pre-mixed solution of THF (20 mL), MeOH (20 mL) and sodium hydroxide (20 mL, 20.00 mmol). The reaction was homogenous and was stirred at room temperature under a nitrogen atmosphere for 26hrs then concentrated in vacuuo using a rotary evaporator with a bath temperature at 2OC. The reaction was poured into IN aqueous hydrochloric acid and extract using ethyl acetate. The combined organic layers were washed sequentially with IN aqueous hydrochloric acid and brine, then dried over magnesium sulfate, filtered and solvent removed in vacuuo. The crude product dried in vacuuo at room temperature to yield 1.68g of an orange amorphous solid. The crude product was dissolved in chloroform (approximately 5OmL) with heating and hexanes were added until some material starts to precipitate but re-dissolves on swirling (approximately 10- 12ml of hexanes). The mixture was allowed to slowly cool to room temperature and then allowed to stand at room temperature for a few hours. The very fine particulate yellow precipitate was filtered using a Buchner funnel and dried in vacuuo at room temperature to yield 819mg (45%) of purified product as a bright yellow amorphous solid. The title compound 4.6mg was dissolved in CDC13 (2ml) with the addition of approximately 5 drops of CD3OD to aid in dissolution for IH NMR acquisition.

IH NMR (500 MHz, CHLOROFORM-D / CD3OD) δ ppm 1.11 - 1.39 (m, 3 H) 1.41 (d, J=7.02 Hz, 6 H) 1.47 - 1.65 (m, 1 H) 1.75 (d, J=8.85 Hz, 2 H) 1.82 - 2.27 (m, 13 H) 2.77 - 2.90 (m, 1 H) 3.28 (s, 3 H) 3.88 (s, 3 H) 3.97 - 4.06 (m, 1 H) 4.66 (s, 1 H) 5.01 (s, 1 H) 6.76 (s, 1 H) 6.92 (d, J=2.75 Hz, 1 H) 7.04 (dd, J=8.70, 2.59 Hz, 1 H) 7.47 - 7.54 (m, 2 H) 7.81 (d, ./=1.22 Hz, 1 H) 7.86 (d, J=8.54 Hz, 1 H) 7.91 (s, 1 H).

LC-MS retention time 1.39 min; 615 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[(3-rnethyl-3, 8-diazabicyclo[3.2. lJoct-8- yl)carbonyl] -lH-pyrazol-5-yl] -

In a 2 dram vial, 900 uL of a stock solution containing lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l- methyl- (0.09M, 0.081mmol) and TBTU (0.19M, 0.171mmol) in DMF was stirred under a nitrogen atmosphere for 1 hour at room temperature. DMAP (40 mg, 0.327 mmol) was added to the reaction and stirred until dissolved then the amine reagent, 3- methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (35 mg, 0.176 mmol), was added and the reaction capped under nitrogen and stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid and brine. The organic phase was dried over

MgSO4, filtered and solvent removed in vacuuo. The crude product was dried in vacuuo at room temperature to yield 63mg of an amorphous yellow film/ foam. The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) (2mL) purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Sample was purified in two HPLC injections, and the product fractions combined (retention time=5.5min) and volatiles removed in vacuuo. The sample was dried in vacuuo at room temperature to yield 44.4mg of the title compound as a TFA salt. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.10 - 1.31 (m, 1 H) 1.33 -

1.57 (m, 10 H) 1.80 (s, 2 H) 1.89 - 2.16 (m, 5 H) 2.57 (s, 4 H) 2.74 (s, 9 H) 2.84 - 3.12 (m, 4 H) 3.27 (s, 2 H) 3.32 - 3.72 (m, 4 H) 3.88 (s, 3 H) 3.94 (s, 4 H) 4.00 - 4.14 (m, 1 H) 4.63 (d, J=15.56 Hz, 1 H) 4.89 (d, ./=12.21 Hz, 1 H) 6.96 (d, J=2.14 Hz, 2 H) 7.13 (dd, J=8.55, 2.44 Hz, 1 H) 7.57 (d, J=8.85 Hz, 1 H) 7.63 (d, J=7.63 Hz, 2 H) 7.76 (s, 1 H) 7.93 (d, J=8.55 Hz, 1 H).

LC-MS retention time 1.81 min; 723 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide, 13-cyclohexyl-6-[4-[[3- (dimethylamino)-l-piperidinyl] carbonyl] -l-methyl-lH-pyrazol-5-yl] -3-methoxy-N- [(l-methylethyl)sulfonyl]-

In a 2 dram vial, 900 uL of a stock solution containing lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l- methyl- (0.09M, 0.081mmol) and TBTU (0.19M, 0.171mmol) in DMF was stirred under a nitrogen atmosphere for 1 hour at room temperature. DMAP (42 mg, 0.344 mmol) was added to the reaction and stirred until dissolved then the amine reagent, N,N-dimethylpiperidin-3 -amine dihydrochloride (34 mg, 0.169 mmol) was added and the reaction capped under nitrogen and stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuuo. The crude product was dried in vacuuo at room temperature to yield 67mg as a yellow film. The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1: 1) (2mL) purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA.

Combine product fractions, retention time =5.03min, remove volatiles in vacuuo and dry at room temperature in vacuuo to yield 26.2mg of the title compound as an amorphous yellow solid.

1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 1.04 - 1.18 (m, 1 H) 1.18 - 1.45 (m, 6 H) 1.48 (d, J=6.71 Hz, 7 H) 1.80 (d, J=8.55 Hz, 3 H) 1.86 - 2.26 (m, 5 H) 2.37 - 2.99 (m, 20 H) 3.12 - 3.72 (m, 4 H) 3.85 (s, 4 H) 3.93 (s, 3 H) 3.98 - 4.08 (m, 1 H) 4.23 (s, 0.4 H) 4.60 (d, J=14.34 Hz, 1 H) 4.86 (d, J=I 1.90 Hz, 1 H) 6.82 - 7.02 (m, 2 H) 7.11 (d, J=I .02 Hz, 1 H) 7.53 (d, J=8.55 Hz, 1 H) 7.58 - 7.88 (m, 3 H) 7.94 (d, J=8.24 Hz, 1 H) 10.05 (s, 0.6H).

LC-MS retention timel.54 min; 725 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

13-cyclohexyl-6-(4-(((2R, 6S)-2, 6-dimethyl-4-morpholinyl)carbonyl)-l-methyl- lH-pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy-7H-indolo[2 ,l-a] ' [2] benzazepine- 10-carboxamide.

In a 2 dram vial, 932 uL of a stock solution containing lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l- methyl- (0.087M, 0.081mmol) and TBTU (0.18M, 0.168 mmol), in DMF was stirred under a nitrogen atmosphere for 1.75 hours at room temperature. DMAP (40 mg, 0.327 mmol) was added to the reaction and stirred until dissolved then the amine reagent, (2R,6S)-2,6-dimethylmorpholine (0.030 mL, 0.243 mmol), was added and the reaction capped under nitrogen and stirred at room temperature overnight (19hrs). The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuuo. The crude product was dried in vacuuo at room temperature to yield 65mg of a yellow film. The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) (2mL) purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min, a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA Retention time of product = 12.83 minutes. The sample was purified in two ImI injections, the second run was cut to a runtime of 20 minutes with the same 15min gradient. Combine product fractions and remove volatiles in vacuuo using a rotary evaporator then dry sample in vacuuo at room temperature to yield 26. lmg of the title compound as an opaque yellow solid / amorphous film.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.60 - 0.93 (m, 6 H) 1.16 - 1.29 (m, 2 H) 1.30 - 1.58 (m, 9 H) 1.79 (d, J=10.68 Hz, 2 H) 1.92 (s, 14 H) 2.05 - 2.27 (m, 3 H) 2.88 (t, J=UM Hz, 1 H) 3.13 - 3.31 (m, 2 H) 3.46 (br.s, 1 H) 3.91 (s, 3 H) 3.94 (s, 3 H) 4.02 - 4.13 (m, 1 H) 4.60 (d, J=15.56 Hz, 1 H) 4.90 (d, J=15.56 Hz, 1 H) 6.83 (br. s, 1 H) 6.95 (d, J=2.14 Hz, 1 H) 7.06 - 7.17 (m, 1 H) 7.49 - 7.80 (m, 4 H) 7.93 (s, 1 H) 10.12 (br.s, 0.2 H) 10.47 (br.s, 0.6 H).

LC-MS retention time 1.90 min; 712 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

13-cyclohexyl-6-(4-(dimethylcarbamoyl)-l -methyl- lH-pyrazol-5-yl)-N- (isopropylsulfonyl)-3-methoxy- 7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide In a 2 dram vial, 932 uL of a stock solution containing lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l- methyl- (0.087M, 0.081mmol) and TBTU (0.18M, 0.168 mmol), in DMF was stirred under a nitrogen atmosphere for 1.75 hours at room temperature. DMAP (41.8 mg, 0.342 mmol) was added to the reaction and stirred until dissolved then the amine reagent, dimethylamine hydrochloride (17.5 mg, 0.215 mmol), was added and the reaction capped under nitrogen and stirred at room temperature overnight (19hrs). The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuuo. The crude product was dried in vacuuo at room temperature to yield 57mg as a yellow foam/amorphous solid/film.

The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) (2mL) purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min, a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA Retention time of product = 12.05 minutes. The sample was purified in two ImI injections. Combine product fractions and remove volatiles in vacuuo using a rotary evaporator then dry sample in vacuuo at room temperature to yield 37.6mg (68%) as an amorphous yellow solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.15 - 1.30 (m, 1 H) 1.33 - 1.45 (m, 2 H) 1.49 (br.s, 7 H) 1.79 (d, J=8.55 Hz, 2 H) 1.91 - 2.17 (m, 7 H) 2.32 (br.s, 9 H) 2.45 (br.s, 3 H) 2.78 - 2.91 (m, 1 H) 3.50 (br.s, 1 H) 3.82 (s, 3 H) 3.93 (s, 3 H) 4.01 - 4.10 (m, 1 H) 4.60 (d, J=14.34 Hz, 1 H) 4.93 (d, J=14.65 Hz, 1 H) 6.86 (s, 1 H) 6.96 (d, J=2.75 Hz, 1 H) 7.10 (dd, J=8.70, 2.59 Hz, 1 H) 7.53 (d, J=8.55 Hz, 1 H) 7.58 (d, J=8.55 Hz, 1 H) 7.66 (s, 1 H) 7.75 (s, 1 H) 7.91 (d, J=8.55 Hz, 1 H) 9.99 (br.s,l H). LC-MS retention time 1.74 min;642 m/z (MH-). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-

N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[[(lR,5S)-8-met hyl-3,8- diazabicyclo[3.2.1]oct-3-yl]carbonyl]-lH-pyrazol-5-yl]-

In a 2 dram vial, 900 uL of a stock solution containing lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l- methyl- (0.09M, 0.081mmol) and TBTU (0.19M, 0.171mmol) in DMF was stirred under a nitrogen atmosphere for 1 hour at room temperature. DMAP (41mg, 0.336 mmol) was added to the reaction and stirred until dissolved then the amine reagent, (lR,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (30mg, 0.151 mmol), was added and the reaction capped under nitrogen and stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuuo. The crude product was dried in vacuuo at room temperature to yield 70mg. The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) (2mL) purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA.

Retention time of product was 5.56minutes and remove volatiles/solvent in vacuuo. HPLC analysis of the first Prep HPLC purification using %A= 1OmM Ammonium Acetate, pH=6.8 in Water / Acetonitrile (95%/ 5%) %B= 1OmM

Ammonium Acetate, pH=6.8 in Water / Acetonitrile (5%/ 95%) solvent system show impurities in the sample. The sample was further purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in 0.5ml DMF/ 1.5ml acetonitrle and purified using a Phenonemex Gemini 30mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4OmL/ min, a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 1OmM Ammonium Acetate, pH=6.8 in Water / Acetonitrile (95%/ 5%) %B= 1OmM Ammonium Acetate, pH=6.8 in Water / Acetonitrile (5%/ 95%) solvent system. Product elution time is from 9.7minutes to 11.7minutes. Combine product fractions and remove volatiles and dry in vacuuo. The trifluoroacetic acid salt of the title compound was made by dissolving the purified product in dichloromethane and adding lOuL of trifluoroacetic acid then removing volatiles in vacuuo. Drying in vacuuo at room temperature yielded 23.6mg (35%) of the trifluoroacetic acid salt of the title compound as a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.11 - 1.29 (m, 1 H) 1.32 -

1.45 (m, 3 H) 1.49 (dd, J=I l.14, 6.87 Hz, 6 H) 1.79 (d, J=10.68 Hz, 2 H) 1.89 - 2.13 (m, 4 H) 2.28 - 2.73 (m, 15 H) 2.84 - 2.95 (m, 1 H) 3.25 (s, 2 H) 3.39 (s, 2 H) 3.76 - 3.92 (m, 3 H) 3.94 (s, 3 H) 4.01 - 4.12 (m, 1 H) 4.63 (d, J=15.87 Hz, 1 H) 4.87 (s, 1 H) 6.96 (d, J=2.14 Hz, 2 H) 7.13 (dd, J=8.85, 2.44 Hz, 1 H) 7.57 (d, J=8.55 Hz, 1 H) 7.63 (s, 1 H) 7.77 (s, 1 H) 7.92 (d, J=8.55 Hz, 1 H) 10.06 (s, 1 H).

LC-MS retention time 1.73 min; 723 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxamide, 6-[4-[[[2-[Ms(I- methylethyl) amino] ethyl] (1-methylethyl) amino] carbonyl] -1 -methyl- lH-pyrazol-5- yl] -13-cyclohexyl-3-methoxy-N-[(l-methylethyl)sulfonyl] - In a 2 dram vial, lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3- methoxy- 10-[[[(l -methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 - α][2]benzazepin-6-yl]-l-methyl- (52.1 mg, 0.084 mmol) was dissolved in DMF(0.9ml) and TBTU (56.2 mg, 0.175 mmol) was added and the reaction stirred under a nitrogen atmosphere for 1 hour at room temperature. DMAP (46mg, 0.377 mmol) was added to the reaction and stirred until dissolved then the amine reagent, N,N,N'-triisopropylethylenediamine (55mg, 0.295 mmol), was added and the reaction capped under nitrogen and stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuuo. The crude product was dried in vacuuo at room temperature to yield 84mg as a yellow glass/film.

The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) (2mL) purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA. The retention time of product =6 minutes. Combine product fractions and remove volatiles in vacuuo using a rotary evaporator then dry sample in vacuuo at room temperature to yield 36.0mg (47%) as a yellow amorphous solid. 1 Η NMR (500 MHz, CHLOROFORM-D) δ ppm 1.05 (s, 6 H) 1.18 - 1.43 (m,

15 H) 1.46 (d, J=7.02 Hz, 8 H) 1.78 (d, J=8.55 Hz, 2 H) 1.87 - 2.12 (m, 4 H) 2.62 (s, 14 H) 2.80 - 2.90 (m, 1 H) 3.12 (s, 2 H) 3.24 - 3.70 (m, 9 H) 3.92 (s, 3 H) 3.97 - 4.06 (m, 1 H) 4.19 (s, 1 H) 4.55 (s, 1 H) 4.99 (s, 1 H) 6.86 (s, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.09 (dd, J=8.55, 2.75 Hz, 1 H) 7.48 - 7.57 (m, 3 H) 7.85 (s, 1 H) 7.90 (d, J=8.54 Hz, 1 H) 9.33 (s, 1 H) 10.12 (s, 1 H).

LC-MS retention time 1.80 min;783 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-

6-[4-[[[(2-methoxyphenyl)methyl] (l-methylethyl)amino] carbonyl] -1-methyl-lH- pyrazol-5-yl]-N-[(l-methylethyl)sulfonyl]-

In a 2 dram vial, lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3- methoxy- 10-[[[(l -methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 - α][2]benzazepin-6-yl]-l-methyl- (50 mg, 0.081 mmol) was dissolved in DMF (811 μL) and TBTU (51.5 mg, 0.160 mmol) was added and the reaction stirred under a nitrogen atmosphere for 1.3 hour at room temperature. DMAP (52 mg, 0.426 mmol) was added to the reaction and stirred until dissolved then the amine reagent, N-(2- methoxybenzyl)propan-2-amine hydrochloride (36 mg, 0.167 mmol), was added and the reaction capped under nitrogen and stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuuo. The crude product was dried in vacuuo at room temperature to yield 75mg as a yellow film. The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) (2mL) purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min, a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA Retention time of product = 14.7 minutes. Remove volatiles from product fraction in vacuuo using a rotary evaporator then dry sample in vacuuo at room temperature to yield 45.4mg (72%) as a amorphous yellow solid. Proton NMR exhibits rotomeric characteristics.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.34 - 1.03 (m, 6.3 H) 1.04 - 1.32 (m, 3.4 H) 1.29 - 1.66 (m, 7.6 H) 1.78 (d, 2.2 H) 1.90 - 2.24 (m, 4.3 H) 2.52 (s, 3.6 H) 2.87 (s, 1.1 H) 3.36 - 3.71 (m, 2.1 H) 3.71 - 3.88 (m, 5.5 H) 3.92 (s, 3.4 H) 4.00-4.06 (m, 0.8 H) 4.13 - 4.39 (m, 1.1 H) 4.63 (d, J=12.21 Hz, 1.0 H) 5.08 (d, J=14.04 Hz, 0.9 H) 6.54 - 6.83 (m, 2.5 H) 6.86 - 6.99 (m, 2.6 H) 7.02 - 7.20 (m, 2.1 H) 7.34 - 7.71 (m, 3.1 H) 7.74 - 7.99 (m, 2.0 H) 9.39 (br.s, 0.4 H) 9.85 (br.s, 0.5 H). LC-MS retention time 1.99 min;776 m/z (MH-). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[[(5- ethyl-l,3,4-oxadiazol-2-yl)methyl](l-methylethyl)amino]carbo nyl]-l-methyl-lH- pyrazol-5-yl] -3-methoxy-N-[(l-methylethyl)sulfonyl] -

In a 2 dram vial, lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3- methoxy- 10-[[[(l -methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 - α][2]benzazepin-6-yl]-l-methyl- (50 mg, 0.081 mmol) was dissolved in DMF(811 μL) and TBTU (51.5 mg, 0.160 mmol) was added and the reaction stirred under a nitrogen atmosphere for 1 hour at room temperature. DMAP (43.2 mg, 0.354 mmol) was added to the reaction and stirred until dissolved then the amine reagent, N-((5- ethyl-l,3,4-oxadiazol-2-yl)methyl)propan-2-amine (47.3 mg, 0.280 mmol) dissolved in 0.2ml of DMF, was added to the reaction. The reaction was capped under nitrogen and stirred at room temperature overnight. The reaction was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL- 1OA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml volume with acetonitrile and the reaction was purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product is 11.45minutes. Combine product fractions and remove volatiles in vacuuo using a rotary evaporator then dry sample in vacuuo at room temperature to yield 47.8mg as a yellow amorphous solid/ film.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.07 - 1.24 (m, 5 H) 1.27 (t, J=7.48 Hz, 4 H) 1.38 (d, J=5.49 Hz, 8 H) 1.56 (d, J=9.46 Hz, 1 H) 1.78 (d, J=9.46 Hz, 2 H) 1.88 - 1.99 (m, 1 H) 2.00 - 2.17 (m, 3 H) 2.55 - 2.82 (m, 4 H) 2.83 - 2.94 (m, 1 H) 3.73 (s, 3 H) 3.89 (s, 3 H) 3.97 - 4.08 (m, 1 H) 4.15 - 4.80 (m, 4 H) 5.22 (d, J=16.79 Hz, 1 H) 6.88 (s, 1 H) 6.94 (d, J=2.75 Hz, 1 H) 7.04 (dd, J=8.55, 2.44 Hz, 1 H) 7.46 (d, J=8.85 Hz, 1 H) 7.59 - 7.67 (m, 2 H) 7.91 (d, J=8.55 Hz, 1 H) 8.31 (br.s, 1 H) 9.62 (br.s, 1 H). LC-MS retention time 1.75 min;766 m/z (MH-). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]- 13-cyclohexyl-3-methoxy-7H-indolo[2, 1-aJ [2] benzazepin-6-ylJ-l -methyl-, ethyl ester

Dissolve 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl- 6-[4-(ethoxycarbonyl)-l-methyl-lH-pyrazol-5-yl]-3-methoxy-(6 53mg, 1.210 mmol) in THF (12ml) in a 50ml RB flask. Carbonyldiimidazole (1.308 g, 8.07 mmol) was added to the reaction. The flask fitted with a condenser was placed under a nitrogen atmosphere and the reaction allowed to stir at room temperature for lhr then refluxed for 50 minutes. The reaction was cooled under a nitrogen atmosphere and cyclobutanesulfonamide (825 mg, 6.10 mmol) was added to the reaction followed by DBU (0.383 ml, 2.54 mmol). The reaction was heated overnight at 7OC under a nitrogen atmosphere. LC-MS analysis indicated primarily imidazolide but an insignificant amount of product, therefore cyclobutylsulfonamide (700mg,

5.17mmol) was added to the reaction followed by DBU (0.383 ml, 2.54 mmol). The reacton was heated to reflux under a nitrogen atmosphere for 3.5 hours and progress rechecked by LCMS. Additional cyclobutylsulfonamide (357mg, 2.64mmol) and DBU (0.383 ml, 2.54 mmol) was added to the reaction and the reaction heated to reflux for 3.25hrs. The reaction was cooled and ethyl acetate and washed two times with 1.0N aqueous hydrochloric acid. The aqueous layer was back extracted with ethyl acetate. The organic layers were combined and wash sequentially with 1.0N aqueous hydrochloric acid, 0.1M NaH2PO4, and again with 1.0N aqueous hydrochloric acid and finally brine. The organic phase was dried over magnesium sulfate, filtered and solvent removed in vacuuo to yield 949mg of a crude product as a yellow solid. The crude product was adsorbed onto 2.6g of silica gel and chromatographed on 28.7g of silica gel slurry packed using 2% methanol in dichloromethane and eluted using 2% methanol in dichloromethane. Pure product fractions were combined and the volatiles removed in vacuuo using a rotary evaporator to yield 465mg (59%) of the title compound as an amorphous yellow solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.20 (m, 1 H) 1.30 (t, J=7.17 Hz, 3 H) 1.33 - 1.48 (m, 2 H) 1.55 (br.s, 4 H) 1.78 (d, J=9.46 Hz, 2 H) 1.87 - 2.14 (m, 6 H) 2.32 - 2.42 (m, 2 H) 2.55 - 2.69 (m, 2 H) 2.79 - 2.92 (m, 1 H) 3.28 (s, 3 H) 3.90 (s, 3 H) 4.25 (br.s, 2 H) 4.53 - 4.63 (m, 1 H) 4.71 (d, J=10.68 Hz, 1 H) 4.97 (d, J=14.34 Hz, 1 H) 6.77 (s, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.07 (dd, J=8.55, 2.75 Hz, 1 H) 7.35 (dd, J=8.39, 1.37 Hz, 1 H) 7.52 (d, J=8.85 Hz, 1 H) 7.73 (d, J=1.22 Hz, 1 H) 7.88 (d, J=8.55 Hz, 1 H) 7.91 (s, 1 H) 8.24 (s, 1 H).

LC-MS retention time 1.78 min; 655 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]- 13-cyclohexyl-3-methoxy-7H-indolo[2,l-a][2]benzazepin-6-yl]- l-methyl- lH-pyrazole-4-carboxylic acid, 5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]- 13-cyclohexyl-3-methoxy-7H-indolo[2,l-a][2]benzazepin-6-yl]- l-methyl-, ethyl ester (463mg, 0.705mmol) was dissolved in THF (6.8mL), then diluted using methanol (6.8mL) with heating and the mixture cooled to room temperature. To the reaction suspension in THF/methanol was added 1.0N aqueous sodium hydroxide (6.8mL, 6.8mmol). Upon addition of the sodium hydroxide solution the reaction became a clear homogeneous solution. The reaction was stirred at room temperature under a nitrogen atmosphere for 20hrs. Concentrate reaction in vacuuo using a rotary evaporator with room temperature bath (20C). Partition the reaction between 200ml of ethyl acetate and 1.0N aqueous hydrochloric acid. Extract aqueous phase using ethyl acetate. Combine organic phases and wash sequentially with 1.0N aqueous hydrochloric acid and brine. Dry the organic layer over magnesium sulfate, filter and remove volatiles from the filtrate in vacuuo to yield 457mg of the title compound as a light yellow colored solid.

IH NMR (500 MHz, MeOD) δ ppm 0.83 (br.s, 1 H) 1.11 - 1.29 (m, 3 H) 1.30 - 1.60 (m, 4 H) 1.74 (d, J=7.93 Hz, 2 H) 1.87 (br.s, 1 H) 1.94 - 2.07 (m, 5 H) 2.25 - 2.35 (m, 2 H) 2.50 - 2.60 (m, 2 H) 2.78 - 2.87 (m, 1 H) 3.24 (s, 3 H) 3.87 (s, 3 H)

4.46 - 4.55 (m, 1 H) 4.67 (br.s, 1 H) 4.99 (br.s, 1 H) 6.78 (s, 1 H) 6.93 (d, J=2.44 Hz, 1 H) 7.05 (dd, J=8.55, 2.75 Hz, 1 H) 7.49 (d, J=8.55 Hz, 1 H) 7.52 (dd, J=8.55, 1.53 Hz, 1 H) 7.81 (d, J=1.53 Hz, 1 H) 7.84 (d, J=8.55 Hz, 1 H) 7.89 (s, 1 H).

LC-MS retention time 1.42 min; 627m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

General Procedure for amide couplings on: lH-pyrazole-4-carboxylic acid, 5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]-

13-cyclohexyl-3-methoxy-7H-indolo[2,l-a] [2]benzazepin-6-yl]-l-methyl-

Into a 2 dram vial place 639ul of a stock solution containing lH-pyrazole-4- carboxylic acid, 5-[ 10-[[(cyclobutylsulfonyl)amino]carbonyl]- 13-cyclohexyl-3- methoxy-7H-indolo[2,l-a][2]benzazepin-6-yl]-l-methyl- (0.639 mL, 0.072 mmol) and TBTU (0.639 mL, 0.138 mmol) which was pre-mixed for 1.25hr at room temperature. To the reaction mixture add 239ul of a stock solution containing DMAP (0.239 mL, 0.358 mmol), then add the amine reagent (0.159 mmol). Cap the reaction under a nitrogen atmosphere and stir at room temperature overnight. The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was diluted to 2ml (or 4ml) using acetonitrile and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes (or 25minutes) using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Volatiles from the product fraction(s) are removed in vacuuo using a speed vac overnight with heating.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-3-methoxy-6-[l-methyl-4-[(3-methyl-3, 8-diazabicyclo[3.2. lJoct-8- yl)carbonyl] -lH-pyrazol-5-yl] -

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.13 - 1.30 (m, 1 H) 1.31 - 1.56 (m, 4 H) 1.79 (d, J=10.68 Hz, 2 H) 1.88 - 2.15 (m, 7 H) 2.37 (s, 4 H) 2.54 (s, 4 H) 2.67 (d, J=9.16 Hz, 4 H) 2.83 - 2.96 (m, 2 H) 3.05 - 3.64 (m, 5 H) 3.89 (s, 3 H) 3.93 (s, 3 H) 4.54 - 4.69 (m, 2 H) 4.88 (s, 1 H) 6.95 (t, J=2.14 Hz, 1 H) 7.13 (dd, J=8.70, 2.59 Hz, 1 H) 7.57 (d, J=8.55 Hz, 1 H) 7.60 (d, J=6.71 Hz, 1 H) 7.77 (s, 1 H) 7.91 (d, J=8.24 Hz, 1 H) 10.17 (s, 1 H). LC-MS retention time 1.55 min; 735m/z (MH-). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-3-methoxy-6-[l-methyl-4-[[(3R, 5S)-3, 4, 5-trimethyl-l- piperaziny I] 'car bony I]-I H-pyrazol-5-y I]-

See procedure for general amide coupling. The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was solubilized by diluting to 2ml using acetonitrile and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV -Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 90% solvent A / 10% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product = 8.3 minutes. IH NMR (500 MHz, CHLOROFORM-D) d ppm 0.99 - 1.32 (m, 7 H) 1.32 -

1.66 (m, 3 H) 1.80 (d, J=8.55 Hz, 2 H) 1.88 - 2.13 (m, 6 H) 2.35 (s, 2 H) 2.54 (s, 2 H) 2.66 (s, 2 H) 2.92 (s, 2 H) 3.02 - 3.71 (m, 10 H) 3.80 (s, 3 H) 3.93 (s, 3 H) 4.08 (s, 1 H) 4.49 - 4.67 (m, 2 H) 4.92 (d, J=12.21 Hz, 1 H) 6.91 (s, 1 H) 6.97 (d, J=2.44 Hz, 1 H) 7.11 (dd, J=8.39, 2.29 Hz, 1 H) 7.54 (d, J=8.54 Hz, 1 H) 7.56 - 7.65 (m, 2 H) 7.78 (s, 1 H) 7.92 (d, J=8.55 Hz, 1 H) 9.71 (s, 1 H). LC-MS retention timel.49 min;737 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-3-methoxy-6-[l-methyl-4-(3-oxa-9-azabicyclo[3.3.1 ]non-9-ylcarbonyl)- lH-pyrazol-5-yl]- See procedure for general amide coupling.

Sample was diluted to 4ml using acetonitrile. The sample needed more than 2ml volume to completely solubilize in acetonitrile indicating lower solubility than previous run samples.

The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was diluted to 4ml using acetonitrile and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The purification was performed as two 2ml injections. Retention time of product was 13.9 minutes.

Volatiles from the product fractions were removed in vacuuo using a speed vac overnight with heating. Weight of isolated title compound was 38.6mg.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.85 (m, 1 H) 1.21 (m, 2 H) 1.31 - 1.57 (m, 6 H) 1.77 (d, J=8.24 Hz, 3 H) 1.89 - 2.14 (m, 6 H) 2.15 - 2.24 (m, 1 H) 2.30 (d, J=I 1.29 Hz, 1 H) 2.34 - 2.43 (m, 2 H) 2.57 - 2.79 (m, 2 H) 2.86 (t, J=10.53 Hz, 1 H) 2.94 - 3.41 (m, 9 H) 3.51 (d, J=14.65 Hz, 1 H) 3.62 (d, J=10.68 Hz, 1 H) 3.86 (s, 1 H) 3.93 (s, 5 H) 4.51 - 4.68 (m, 2 H) 4.83 - 5.06 (m, 1 H) 6.78 - 6.89 (m, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.08 - 7.17 (m, 1 H) 7.58 (d, J=8.54 Hz, 1 H) 7.63 (d, J=7.93 Hz, 1 H) 7.66 - 7.81 (m, 2 H) 7.90 (t, J=9.16 Hz, 1 H) 10.19 (s, 0.2 H) 10.44 (s, 0.7 H).

LC-MS retention time 1.62min; 736m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-6- [4- [ [(2R,6S)-2,6-dimethyl-4-morpholinyl] carbonyl] - 1-methyl- IH- pyrazol-5-yl] -3-methoxy-

See procedure for general amide coupling. The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was diluted to 2ml using acetonitrile and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product = 13.5minutes. Volatiles from the product fractions were removed in vacuuo using a speed vac overnight with heating.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.68 (br.s, 3 H) 0.78 (m, 1 H) 0.81 - 0.91 (m, I H) 1.12 - 1.32 (m, 2 H) 1.32 - 1.50 (m, 3 H) 1.79 (d, J=I 1.29 Hz, 2 H) 1.90 - 2.01 (m, 3 H) 2.01 - 2.16 (m, 5 H) 2.18 - 2.27 (m, 1 H) 2.28 - 2.36 (m, 1 H) 2.35 - 2.46 (m, 1 H) 2.60 - 2.82 (m, 3 H) 2.83 - 3.11 (m, 5 H) 3.12 - 3.31 (m, 2 H) 3.42 (s, 1 H) 3.81 - 3.94 (m, 3 H) 3.94 (s, 3 H) 4.51 - 4.70 (m, 2 H) 4.90 (d, J=14.34 Hz, 1 H) 6.79 - 6.90 (m, 1 H) 6.95 (d, J=I.83 Hz, 1 H) 7.13 (dd, J=8.55, 2.14 Hz, 1 H) 7.60 (dd, J=24.57, 8.39 Hz, 2 H) 7.69 (d, J=16.48 Hz, 1 H) 7.91 (d, J=8.24 Hz, 1 H) 10.03 (s, 0.3 H) 10.42 (s, 0.7 H). LC-MS retention time 1.85 min; 724m/z (MH-). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-6-[4-(3, 7-dioxa-9-azabicyclo[3.3.1 ] non-9 -ylcarbonyl)-l -methyl- IH- pyrazol-5-yl] -3-methoxy-

Into a 2 dram vial place 639ul of a stock solution containing lH-pyrazole-4- carboxylic acid, 5-[ 10-[[(cyclobutylsulfonyl)amino]carbonyl]- 13-cyclohexyl-3- methoxy-7H-indolo[2,l-a][2]benzazepin-6-yl]-l-methyl- (0.639 mL, 0.072 mmol) and TBTU (0.639 mL, 0.138 mmol) which was pre-mixed for 1.25 hr at room temperature. To the reaction mixture add 239ul of a stock solution containing DMAP (0.239 mL, 0.358 mmol), then add the amine reagent 3,7-dioxa-9- azabicyclo[3.3. l]nonane hydrochloride (38.0 mg, 0.229 mmol). Cap the reaction under a nitrogen atmosphere and stir at room temperature. Analysis of the reaction mixture by LCMS indicated only a trace of product present. The reaction was allowed to sit capped at room temperature for 3 days then HATU (92 mg, 0.242 mmol). The reaction was capped and stirred at room temperature overnight. LCMS indicated a complete reaction. The reaction was allowed to stir at room temperature for 2 more days (weekend).

The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml using acetonitrile and purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The retention time of product was observed as split peaks at 10.72min and 11.03 minutes. Volatiles from the product fractions were removed in vacuuo using a speed vac overnight with heating. IH NMR analysis of each product fraction provided identical NMR spectrums. The product fraction were combined and into a vial and dried in vacuuo at room temperature to yield 34.5mg (65%) of the title compound as a yellow amorphous solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.11 - 1.27 (m, 1 H) 1.31 - 1.52 (m, 3 H) 1.71 - 1.83 (m, J=8.85 Hz, 2 H) 1.92 - 2.15 (m, 6 H) 2.31 (s, 1 H) 2.38 (s, 1 H) 2.55 - 2.77 (m, 3 H) 2.81 - 2.91 (m, 1 H) 3.25 (s, 1 H) 3.33 (d, J=9.46 Hz, 1 H) 3.42 (s, 2 H) 3.55 (d, J=10.07 Hz, 1 H) 3.62 - 3.80 (m, 3 H) 3.89 (s, 3 H) 3.93 (s, 3 H) 4.23 (s, 3 H) 4.53 - 4.66 (m, 2 H) 4.93 (d, J=15.26 Hz, 1 H) 6.87 (s, 1 H) 6.95 (d, J=2.44 Hz, 1 H) 7.13 (dd, J=8.54, 2.75 Hz, 1 H) 7.58 (d, J=8.55 Hz, 1 H) 7.61 (d, J=8.55 Hz, 1 H) 7.70 (s, 1 H) 7.74 (s, 1 H) 7.93 (d, J=8.54 Hz, 1 H) 10.09 (s, 1 H).

LC-MS retention time 1.50 min; 738 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morphol inyl]carbonyl]-l- methyl-lH-pyrazol-5-yl]- Into a 2 dram vial place 787ul of a stock solution containing lH-pyrazole-4- carboxylic acid, 5-[ 10-[[(cyclobutylsulfonyl)amino]carbonyl]- 13-cyclohexyl-3- methoxy-7H-indolo[2,l-a][2]benzazepin-6-yl]-l-methyl- (0.091M) (0.787 mL, 0.072 mmol) and TBTU (0.213M) (0.787 mL, 0.168 mmol) which was pre-mixed for 1.25hr at room temperature. To the reaction mixture add DMAP (48.0 mg, 0.393 mmol), then add the amine reagent then add the amine reagent, in this case, (S)-2-

(methoxymethyl)morpholine hydrochloride (30.4 mg, 0.181 mmol). Cap the reaction under a nitrogen atmosphere and stir at room temperature overnight. The reaction is diluted with acetonitrile and purified by reverse phase Prep HPLC.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.19 (m, 1 H) 1.31 - 1.54 (m, 3 H) 1.79 (d, J=10.38 Hz, 2 H) 1.90 - 2.20 (m, 7 H) 2.23 - 2.55 (m, 3 H) 2.58 - 2.82 (m, 4 H) 2.82 - 3.13 (m, 6 H) 3.11 - 3.49 (m, 5 H) 3.90 (s, 3 H) 3.94 (s, 3 H) 4.51 - 4.67 (m, 2 H) 4.78 - 4.96 (m, 1 H) 6.85 (s, 1 H) 6.95 (s, 1 H) 7.12 (dd, J=8.55, 2.44 Hz, 1 H) 7.56 (d, J=8.55 Hz, 1 H) 7.59 (d, J=7.63 Hz, 1 H) 7.63 - 7.74 (m, 2 H) 7.90 (t, J=9.00 Hz, 1 H) 10.09 (s, 0.3 H) 10.41 (s, 0.6 H). LC-MS retention timel.62 min; 740 m/z (MH-). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

The following examples can be prepared in an analogous fashion.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-6-[4-[[(lS,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hep t-2-yl]carbonyl]-l- methyl-lH-pyrazol-5-yl]-3-methoxy-

HPLC Method: The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL- 1OA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction mixture was diluted to 2ml using acetonitrile and purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product retention time is 5.71 minutes. Volatiles from the product fractions were removed in vacuuo using a speed vac with a medium heat setting.

The proton NMR of this sample exhibited characteristics of rotomers. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.49 (s, 0.3 H) 0.96 - 1.29

(m, 2.2 H) 1.30 - 1.59 (m, 3.3 H) 1.79 (d, J=I 1.60 Hz, 1.8 H) 1.86 - 2.17 (m, 3.8 H) 2.19 - 2.46 (m, 2.1 H) 2.49 - 3.74 (m, 6.4 H) 3.76 - 4.21 (m, 5.1 H) 4.24 - 4.39 (m, 0.8 H) 4.43 - 4.70 (m, 1.4 H) 4.73 - 5.07 (m, 1.0 H) 5.23 (s, 0.1 H) 6.73 (d, J=29.30 Hz, 0.4 H) 6.88 - 7.00 (m, 0.8 H) 7.04-7.13 (m, 0.7 H) 7.44 - 7.60 (m, 0.9 H) 7.58 - 7.96 (m, 2.0 H) 8.19 (s, 0.1 H) 10.43 (d, J=81.79 Hz, 0.4 H) 11.20 (d, J=87.28 Hz, 0.5 H) 12.46 (s, 0.6 H).

LC-MS retention timel.60 min;737 m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-6-[4-[[3-(dimethylamino)-l-piperidinyl]carbonyl]- l-methyl-lH-pyrazol- 5-yl] -3-methoxy- HPLC Method: The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL- 1OA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 4ml using acetonitrile with a very small amount of methanol and purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The retention time of product was 5.37minutes. The compound was purified as two 2ml injections.

Peaks in proton NMR spectra are generally broad, characteristic of restricted rotation in molecule.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.13 - 1.32 (m, 2 H) 1.32 - 1.59 (m, 5 H) 1.79 (s, 3 H) 1.89 - 2.18 (m, 7 H) 2.36 (s, 2 H) 2.48 - 2.76 (m, 8 H) 2.88 (s, 1 H) 3.51 (s, 1 H) 3.60 - 3.91 (m, 7 H) 3.93 (s, 3 H) 4.24 (s, 0.6 H) 4.47 - 4.68 (m, 2 H) 4.84 (d, J=13.43 Hz, 1 H) 6.86 - 6.98 (m, 1 H) 7.07 - 7.17 (m, 1 H) 7.53 (d, J=8.55 Hz, 1 H) 7.58 - 7.84 (m, 2 H) 7.93 (d, J=7.93 Hz, 1 H) 10.07 (s, 1 H). LC-MS retention time 1.56 min; 739m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-3-methoxy-6-[l-methyl-4-(4-morpholinylcarbonyl)-l H-pyrazol-5-yl]-

HPLC Method: The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL- 1OA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction mixture was diluted to 4 ml using acetonitrile and purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 50% solvent A / 50% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The compound was purified as two 2ml injections.

Volatiles from the product fractions were removed in vacuuo using a speed vac overnight with heating. The product fractions were combined using dichoromethane and solvent removed in vacuuo to give 35.4mg (71%) of the title compound as a yellow amorphous solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.22 (m, 1 H) 1.33 - 1.55 (m, 3 H) 1.79 (d, J=10.68 Hz, 2 H) 1.91 - 2.21 (m, 7 H) 2.37 (d, J=29.60 Hz, 3 H) 2.56 - 2.79 (m, 4 H) 2.78 - 2.96 (m, 4 H) 3.12 (s, 3 H) 3.90 (s, 3 H) 3.94 (s, 3 H) 4.53 - 4.65 (m, 2 H) 4.89 (d, J=14.95 Hz, 1 H) 6.86 (s, 1 H) 6.95 (d, J=2.44 Hz, 1 H) 7.12 (dd, J=8.70, 2.59 Hz, 1 H) 7.57 (d, J=8.85 Hz, 1 H) 7.59 (d, J=8.55 Hz, 1 H) 7.67 (s, 1 H) 7.69 (s, 1 H) 7.93 (d, J=8.54 Hz, 1 H) 10.24 (s, 1 H).

LCMS for 74814-024-a: LC-MS retention time 1.61min;696 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide, N-(cyclobutylsulfonyl)-13- cyclohexyl-6-[4-[(hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)ca rbonyl]-l-methyl-lH- pyrazol-5-yl] -3-methoxy- HPLC Method: The sample was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL- 1OA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 4ml using acetonitrile and a trace of methanol and in purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product = 5.72minutes.

The compound was purified as two 2ml injections. Volatiles were removed from the product fractions in vacuuo overnight using a speed-vac set at medium heating.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.24 (s, 1 H) 1.30 - 1.45 (m, 2 H) 1.31 - 1.45 (m, 2 H) 1.58 (none, 2 H) 1.78 (s, 4 H) 1.88 - 2.24 (m, 9 H) 2.34 (s, 2 H) 2.65 (s, 3 H) 2.74 - 3.18 (m, 3 H) 3.18 - 3.87 (m, 9 H) 3.89 - 3.96 (m, 3 H) 3.96 - 4.35 (m, 3 H) 4.45 - 4.68 (m, 2 H) 4.76 - 5.00 (m, 1 H) 6.80 - 6.95 (m, 1 H) 6.96 (s, 1 H) 7.05 - 7.15 (m, J=8.24 Hz, 1 H) 7.47 - 7.68 (m, 3 H) 7.68 - 7.81 (m, 1 H) 7.88 (s, 1 H) 9.94 (s, 1 H) 12.54 (s, 1 H). LC-MS retention time 1.61 min;735 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-[[(l-methylethyl)[ (tetrahydro-2- furanyl)methyl] amino] carbonyl] -lH-pyrazol-5-yl] - In a 2 dram vial, lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3- methoxy- 10-[[[(l -methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 - α][2]benzazepin-6-yl]-l-methyl- (51.1mg, 0.083 mmol) was dissolved in DMF (829 μl) and ΗATU (66.3 mg, 0.174 mmol) was added to the reaction. The reaction was stirred under a nitrogen atmosphere for 1.2 hours at room temperature. DMAP (41.5 mg, 0.340 mmol) was added to the reaction and stirred until dissolved then the amine reagent, Isopropyl-(tetrahydro-furan-2-ylmethyl)-amine (36μl, 0.251 mmol), was added and the reaction capped under nitrogen and stirred at room temperature for 17 hours. Note-assume density of amine reagent is lg/cc, important aspect is not exact stoichometry but excess amine present. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 : 1) (2ml) and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product is 13.3minutes. Take product fraction and remove volatiles in vacuuo using a rotary evaporator. The title compound was isolated (47.4mg, 77%) as an amorphous yellow solid. Proton NMR spectra exhibits characteristics of restricted rotation (broad and rotomeric peaks).

IH NMR (500 MHz, CHLOROFORM-D) d ppm θ.61 (s, 1.6 H) 0.80 - 1.11 (m, 5.1 H) 1.23 (s, 2.7 H) 1.31 - 1.57 (m, 10.7 H) 1.76 (s, 4.0 H) 1.87 - 2.13 (m, 5.9 H) 2.20 (s, 2.4 H) 2.38 - 2.75 (m, 0.7 H) 2.78 - 2.92 (m, 1.2 H) 3.06-3.25 (m, 1.3 H) 3.37 - 3.82 (m, 6.9 H) 3.91 (s, 3.9 H) 3.97 - 4.27 (m, 2.0 H) 4.56 (d, J=12.82 Hz, 0.9 H) 4.93 - 5.23 (m, 0.9 H) 6.87 (s, 1.0 H) 6.94 (d, J=2.44 Hz, 1.0 H) 7.07 (d, J=7.93 Hz, 1.0 H) 7.51 (d, J=7.93 Hz, 1.1 H) 7.57 (s, 2.2 H) 7.81 - 8.01 (m, 2.1 H) 9.48 - 9.81 (m, 0.6 H) 9.98 (s, 0.5 H).

LC-MS retention time 1.76 min;740 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-3-methoxy- N-[(l-methylethyl)sulfonyl]-6-[l-methyl-4-(8-oxa-3-azabicycl o[3.2.1]oct-3- ylcarbonyl)-lH-pyrazol-5-yl] -

In a 2 dram vial, lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3- methoxy- 10-[[[(l -methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1 - α][2]benzazepin-6-yl]-l-methyl- (50.8 mg, 0.082 mmol) was dissolved in DMF(824 μL) and ΗATU (72.2mg, 0.190 mmol) was added and the reaction stirred under a nitrogen atmosphere for 1 hour at room temperature. DMAP (41.8mg, 0.342 mmol) was added to the reaction and stirred until dissolved then the amine reagent, 8-oxa-3- azabicyclo[3.2.1]octane hydrochloride (30.6 mg, 0.205 mmol). The reaction capped under nitrogen and stirred at room temperature overnight. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC- 1OA fraction collector. The reaction was acidified with aqueous acetic acid then diluted to 2ml with acetonitrile and filtered using a 0.45uM syringe filter. The filtrate was purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV -Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product was collected as a single fraction from 13.99 to 14.70minutes. Volatiles from the product fraction were removed in vacuuo using a speed vac at medium heat setting. The title compound was isolated (46.0mg, 78% yield) as a yellow amorphous solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.26 - 1.05 (m, 1.2 H) 1.14 - 1.32 (m, 1.9 H) 1.33 - 1.45 (m, 2.3 H) 1.49 (dd, J=14.04, 6.71 Hz, 7.1 H) 1.53 - 1.72 (m, 3.4 H) 1.79 (d, J=9.77 Hz, 2.2 H) 1.97 (d, J=10.99 Hz, 1.2 H) 2.02 - 2.15 (m, 3.1 H) 2.27 (d, J=I 1.29 Hz, 0.7 H) 2.86 (t, J=I 1.60 Hz, 1.6 H) 3.02 (d, J=8.85 Hz, 1.5 H) 3.16 (s, 3.9 H) 3.32 (d, J=I 1.60 Hz, 1.1 H) 3.73 - 3.87 (m, 2.1 H) 3.90 (s, 2.8 H) 3.92 - 3.97 (m, 3.4 H) 4.00 - 4.11 (m, 1.4 H) 4.59 (d, J=15.26 Hz, 1.0 H) 4.86 (d, J=14.34 Hz, 0.8 H) 5.04 (s, 0.3 H) 6.86 (s, 1.0 H) 6.95 (s, 1.0 H) 7.11 (dd, J=8.55, 2.44 Hz, 1.0 H) 7.54 (d, J=8.85 Hz, 1.2 H) 7.57 - 7.77 (m, 2.7 H) 7.80 - 8.02 (m, 1.3 H) 9.74 (s, 0.2 H) 10.11 (s, 0.7 H).

LC-MS retention time 1.61min;710 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl) -2-propenoyl)- 3-methoxy-7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid

In a 50ml round bottom flask dissolve tert-butyl 13-cyclohexyl-6-((2E,Z)-3- (dimethylamino)-2-(ethoxycarbonyl)-2-propenoyl)-3-methoxy-7H -indolo[2,l- a][2]benzazepine-10-carboxylate (538mg, 0.879 mmol) in 1,2-dichloroethane (5mL) then add TFA (5 mL). The reaction mixture turned a darker reddish color upon addition of TFA. Place the reaction under a nitrogen atmosphere and stir at room temperature for 2.25hrs. Remove volatiles in vacuuo using a rotary evaporator, dissolve oily red residue in dichloromethane/benzene and remove volatiles in vacuuo on rotary evaporator. Take resulting red oil dissolve in ethyl acetate wash with 1.0N aqueous hydrochloric acid. The aqueous layer was back extracted with ethyl acetate. The organic layers were combined and sequentially washed with 1.0N aqueous hydrochloric acid and brine. The organic layer was dried over MgSO4, filtered and the solvents removed in vacuuo to give a reddish-orange oil which was dissolved in benzene and volatiles removed in vacuuo to yield 519mg of the title compound a red- orange foam. The compound was used without further purification.

LC-MS retention time 1.86 min; 555 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxylic acid, 13-cyclohexyl-6-[l-(l, 1- dimethylethyl)-4-(ethoxycarbonyl)-lH-pyrazol-5-yl]-3-methoxy -

7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6- [(2£',Z)-3-(dimethylamino)-2-[[(2R,65 ^r )-2,6-dimethyl-4-morpholinyl]carbonyl]-l- oxo-2-propenyl]-3-methoxy- (101 mg, 0.181 mmol) was dissolved in ethanol (726 μL) and dioxane (181 μL). Triethyl amine(59 μL, 0.423 mmol) was added to the reaction followed by the hydrazine reagent, tert-butylhydrazine hydrochloride (23.6 mg, 0.189 mmol). The reaction was capped under a nitrogen atmosphere and heated in a microwave to 160C for 45minutes. The reaction was concentrated in vacuuo using a rotary evaporator and the residue was dissolved in ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid then brine. The organic layer was dried over magnesium sulfate, filtered and volatiles removed in vacuuo to give 91mg of a yellow amorphous solid. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF mixture purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system.

The above isomeric major product retention time was 18.54minutes. The minor region-is omeric alkylated pyrazole was collected with retention time of 20.54minutes.

The volatiles were removed from product fractions in vacuuo to obtain 29.8mg of the title compound as a yellow amorphous solid.

1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 1.09 (s, 9 H) 1.18 - 1.56 (m, 8 H) 1.63 (d, 1 H) 1.78 (d, J=8.55 Hz, 2 H) 1.88 - 2.22 (m, 5 H) 2.89 (t, J=I 1.75 Hz, 1 H) 3.89 (s, 3 H) 4.27 (s, 2 H) 4.84 (d, J=14.65 Hz, 1 H) 4.96 (d, J=14.95 Hz, 1 H) 6.81 (s, 1 H) 6.90 (d, J=2.14 Hz, 1 H) 7.05 (dd, J=8.70, 2.59 Hz, 1 H) 7.52 (d, J=8.54 Hz, 1 H) 7.76 (dd, J=8.55, 1.22 Hz, 1 H) 7.88 (d, J=8.55 Hz, 1 H) 7.92 (s, 1 H) 8.01 (s, 1 H).

LC-MS retention time 2.20 min; 580 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony I] amino] carbony IJ- 7H-indolo[2, 1-a] [2]benzazepin-6-yl]-l-(l, 1- dimethylethyl)-, ethyl ester

In a 2 dram vial, 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-6-[ 1 -( 1 , 1 -dimethylethyl)-4-(ethoxycarbonyl)- 1 H-pyrazol-5 -yl] -3 - methoxy- (139mg, 0.239 mmol) was dissolved in dichloromethane (2.4ml) and propane-2-sulfonamide (98 mg, 0.796 mmol) and DMAP (90 mg, 0.737 mmol) were added to the reaction followed by EDC (70.3 mg, 0.367 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 18hrs. The reaction was monitored by HPLC then allowed to continue stirring under a nitrogen atmosphere at room temperature for 24hrs.

Subsequent HPLC analysis revealed no discernable change in reaction composition over the last 24hrs. Volatiles were removed from the reaction in vacuuo using a rotary evaporator and the reaction residue was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid, 0. IM aqueous NaH2PO4 and 1.0N aqueous hydrochloric acid then brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuuo. The product was dried in vacuuo at room temperature to give 165mg of product as an amorphous yellow solid. The product was used without any further purification.

LC-MS retention time 2.03min; 685m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony I] amino] carbony IJ- 7H-indolo[2, 1-a] [2]benzazepin-6-yl]-l-(l, 1- dimethylethyl) - lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l-(l,l- dimethylethyl)-, ethyl ester (164 mg, 0.239 mmol) was dissolved in TΗF (3 mL) and methanol (3.00 mL) then 1.0 N aqueous sodium hydroxide (3.00 mL) was added to the reaction and the reaction was placed under a nitrogen atmosphere and stirred at room temperature for 25hrs. The reaction was concentrated in vacuuo using a rotary evaporator without heating then partitioned between ethyl acetate and 1.0N aqueous hydrochloric acid. Wash ethyl acetate with IN aqueous hydrochloric acid, combine aqueous layers and back extract with ethyl acetate. The organic layers were combined and wash with brine, dry over magnesium sulfate and solvent removed in vacuuo using a rotary evaporator. The product was dried in vacuuo at room temperature to give 158.4mg as a yellow amorphous solid. The product was carried on without any further purification.

LC-MS retention time 1.54min; 657 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-(l,l- dimethylethyl)-4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbon yl]-lH-pyrazol-5-yl]- 3-methoxy-N- [(I -methylethyl)sulfonyl] - lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l-(l,l- dimethylethyl)- (60mg, 0.091 mmol) was dissolved in DMF (911 μL). ΗATU (81.5 mg, 0.214 mmol) was added to the reaction and the reaction was capped under a nitrogen atmosphere and stir at room temperature for 1.25hrs. DMAP (45.9 mg, 0.376 mmol) was added to reaction followed by amine reagent, (2R,6S)-2,6- dimethylmorpholine (34 μL, 0.275 mmol). The reaction was capped under a nitrogen atmosphere and stir at room temperature for 18hr. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile and a couple of drops of aqueous acetic acid then purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product was 18.5 minutes. Product fractions were combined and volatiles removed in vacuuo using a rotary evaporator. The sample was dried in vacuuo at room temperature to give 32.5mg as a yellow amorphous film. IH NMR results are characteristic of restricted rotation with broadening and splitting of peaks.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.66 (d, J=6.10 Hz, 2.4 H) 0.71 (d, J=6.10 Hz, 2.3 H) 0.78 (dd, J=I 1.29, 6.10 Hz, 1.8 H) 1.10 (s, 1.2 H) 1.25 (dd, J=13.73, 6.71 Hz, 3.0 H) 1.35 - 1.44 (m, 2.5 H) 1.46 (t, J=7.02 Hz, 4.7 H) 1.54 (d, J=6.71 Hz, 3.7 H) 1.67 (s, 0.6 H) 1.71 (s, 6.8 H) 1.72 - 1.75 (m, 2.7 H) 1.79 (d, J=I 1.90 Hz, 2.5 H) 1.83 - 1.92 (m, 1.0 H) 1.98 (d, J=12.51 Hz, 2.2 H) 2.02 - 2.21 (m, 7.9 H) 2.21 - 2.30 (m, 1.4 H) 2.80 - 2.95 (m, 2.3 H) 3.04 (d, J=42.42 Hz, 0.6 H) 3.23 (d, J=13.73 Hz, 0.3 H) 3.34 (d, J=12.82 Hz, 0.8 H) 3.92 (d, J=4.88 Hz, 0.5 H) 3.95 (s, 3.0 H) 4.04 - 4.13 (m, 1.1 H) 4.49 - 4.58 (m, 1.0 H) 4.79 (d, J=14.65 Hz, 0.3 H) 4.86 (d, J=15.26 Hz, 0.7 H) 6.78 (s, 0.8 H) 6.85 (s, 0.3 H) 6.87 (d, J=2.75 Hz, 0.8 H) 6.91 (s, 0.3 H) 7.14 (dd, J=8.55, 2.44 Hz, 1.0 H) 7.55 - 7.60 (m, 0.9 H) 7.60 - 7.64 (m, 2.3 H) 7.64 - 7.68 (m, 1.0 H) 7.83 - 7.95 (m, 1.3 H) 10.32 (s, 0.3 H) 10.60 (s, 0.7 H).

LC-MS retention time 2.10 min; 754m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-aJ [2]benzazepine-l O-carboxamide, 13-cyclohexyl-6-[l-(l, 1- dimethylethyl)-4-[[(3R, 5S)-3, 4, 5-trimethyl-l-piperazinyl] carbonyl] -lH-pyrazol-5- yl] -3-methoxy-N-[(l-methylethyl)sulfonyl] - lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l-(l,l- dimethylethyl)- (48.8 mg, 0.074 mmol) was dissolved in DMF (741 μL). ΗATU (65.3 mg, 0.172 mmol) was added to the reaction and the reaction was capped under a nitrogen atmosphere and stir at room temperature for lhrs. DMAP (53.8 mg, 0.440 mmol) was added to reaction followed by amine reagent, (2R,6S)- 1,2,6- trimethylpiperazine dihydrochloride (34.5 mg, 0.172 mmol). The reaction was capped under a nitrogen atmosphere and stir at room temperature for 18hr. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was acidified with a few drops of aqueous acetic acid and diluted to 2ml with acetonitrile then purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 25 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Product was collected from 8.14 minutes to 9.45minutes. Volatiles were removed in vacuuo from the combined product fractions to ultimately yield 11. lmg of the title compound as a yellow amorphous film.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.93 - 1.34 (m, 9.7 H) 1.37 - 1.52 (m, 9.5 H) 1.56 - 1.68 (m, 1.6 H) 1.68 - 1.83 (m, 9.2 H) 1.87 - 2.20 (m, 5.4 H) 2.28 - 2.52 (m, 2.0 H) 2.55 - 3.01 (m, 9.4 H) 3.19 (d, J=40.59 Hz, 0.8 H) 3.63 (d, J=134.28 Hz, 2.4 H) 3.83 - 4.04 (m, 4.0 H) 4.54 (d, J=14.65 Hz, 0.8 H) 4.76 (d, J=14.34 Hz, 0.8 H) 6.72 - 6.97 (m, 2.0 H) 7.08 (d, J=7.32 Hz, 1.0 H) 7.36 - 7.76 (m, 3.4 H) 7.88 (s, 1.2 H) 10.86 (s, 0.5 H) 11.26 (s, 0.4 H). LC-MS retention time 1.81min;767 m/z (MH-). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxylic acid, 13-cyclohexyl-6-[3- f(2R, 6S)-2, 6-dimethyl-4-morpholinyl]-l, 3-dioxopropylJ -3-methoxy-, 1,1- dimethylethyl ester In a 250ml round bottom flask dissolve tert-butyl 13-cyclohexyl-6-(3-ethoxy-

3-oxopropanoyl)-3-methoxy-7H-indolo[2,l-a][2]benzazepine- 10-carboxylate (3.13g, 5.61 mmol) in toluene (56 mL) and add cis-2,6-Dimethylmorpholine (2.6 mL, 20.99 mmol) to the reaction. Place reaction under a nitrogen atmosphere and heat to reflux for 9hours. The reaction was partitioned between ethyl acetate and 1.0M aqueous citric acid. The organic layer was washed sequentially with 1.0M aqueous citric acid, 0. IM NaH2PO4, and brine. Dry organic phase over magnesium sulfate, filter and remove solvent in vacuuo to give 3.01g of crude product as a orange-amber foam. Dissolve the crude product in dichloromethane and adsorb onto 8.2g of silica gel. Chromatograph crude product on 90g of silica gel slurry packed in 5% ethyl acetate in dichloromethane, elute with gradient of 5% ethyl acetate in dichloromethane to 10% ethyl acetate in dichloromethane. Pure product fractions were combined and solvent removed in vacuuo using a rotary evaporator to yield a yellow amorphous solid which was further dried in vacuuo at room temperature to yield 1.28g of the title compound. Less pure fractions yielded another 0.48g of product. LCMS analysis gave two peaks of equivalent mass to that of the desired product. Resolution of the two peaks by Prep HPLC under the following conditions yielded peaks which inter-converted when analyzed after isolation: Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL- 1OA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample 76816-035-a (63mg) was dissolved in acetonitrile / DMF mixture (2: 1, 2ml) purified using a Phenonmenex Luna C18 30 x 100mm 1Ou column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4OmL/ min , a gradient of 60% solvent A / 40% solvent B to 0% solvent A / 100% solvent B, a gradient time of 15 minutes with a run time of 25 minutes using %A= 1OmM Ammonium Acetate in 95:5 Water/Acetonitrile %B= 1OmM Ammonium Acetate in 5:95 Water/Acetonitrile solvent system. Two peaks were isolated from the sample: First peak at RT= 16.3 minutes. Both samples exhibited identical HPLC spectra after isolation indicating inter-conversion.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.89 (s, 2.0 H) 1.01 (s, 3.3 H) 1.19 (d, J=26.25 Hz, 3.5 H) 1.30 - 1.47 (m, 4.5 H) 1.55 (s, 4.2 H) 1.60 (s, 3.6 H) 1.63 (s, 9.0 H) 1.76 (d, J=8.24 Hz, 3.1 H) 1.93 (d, J=9.46 Hz, 1.9 H) 1.98 - 2.15 (m, 4.2 H) 2.23 (s, 1.2 H) 2.39 (s, 0.4 H) 2.56 - 2.72 (m, 1.6 H) 2.74 - 2.86 (m, 1.6 H) 2.91 (s, 0.8 H) 3.47 - 3.65 (m, 2.8 H) 3.74 - 3.85 (m, 1.6 H) 3.90 (s, 1.4 H) 3.91 (s, 3.1 H) 3.93 - 4.04 (m, 1.8 H) 4.19 (d, J=12.82 Hz, 0.5 H) 4.26 (d, J=14.65 Hz,0.5 H) 4.39 (s, 0.5 H) 4.47 (d, J=I 1.29 Hz, 0.4 H) 5.18 (s, 0.3 H) 5.71 - 5.92 (m, 1.1 H) 7.01 (d, J=2.75 Hz, 0.4 H) 7.03 - 7.06 (m, 1.4 H) 7.11 (dd, J=8.70, 2.59 Hz, 1.0 H) 7.47 - 7.51 (m, 0.9 H) 7.52 (s, 0.5 H) 7.57 (s, 0.4 H) 7.65 (d, J=I.53 Hz, 0.2 H) 7.68 (dd, J=8.55, 1.22 Hz, 1.2 H) 7.80 (s, 0.6 H) 7.80 - 7.82 (m, 0.7 H) 7.84 (s, 0.2 H) 7.91 (s, 0.4 H) 8.04 (s, 0.5 H) 8.19 (s, 0.3 H) 8.21 (d, J=1.22 Hz, 1.0 H) 15.15 (d, J=23.80 Hz, 0.4 H).

LC-MS retention time 4.21min (88%); 625m/z (MH-) and 5.23min (12%); 625m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 70% solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 5min, a hold time of 2 min, and an analysis time of 7 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxylic acid, I 3-cyclohexyl-6-

[(2E,Z)-3-(dimethylamino)-2-[[(2R,6S)-2,6-dimethyl-4-morp holinyl]carbonyl]-l- oxo-2-propenyl] -3-methoxy-, 1, 1-dimethylethyl ester

7H-indolo [2, 1 -a] [2]benzazepine- 10-carboxylic acid, 13 -cyclohexyl-6-[3 - [(2R,65)-2,6-dimethyl-4-moφholinyl]-l,3-dioxopropyl]-3-meth oxy-, 1,1- dimethylethyl ester was dissolved in N,N-Dimethylformamide dimethyl acetal (10 mL,). The reaction was fitted with a condenser and placed under a nitrogen atmosphere. The reaction was heated to reflux for 3hrs, cooled then the volatiles were removed in vacuuo using a rotary evaporator, then dry in vacuuo at room temperature to obtain the product as an amorphous orange solid (517mg, 86%).

LC-MS retention time 4.60min;682 m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 5min, a hold time of 2 min, and an analysis time of 7 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. The intermediate was used without further purification.

7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxylic acid, 13-cyclohexyl-6- [(2E,Z)-3-(dimethylamino)-2-[[(2R,6S)-2,6-dimethyl-4-morphol inyl]carbonyl]-l- oxo-2-propenylj '-3-methoxy- 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-

[(2£',Z)-3-(dimethylamino)-2-[[(2R,65 ^r )-2,6-dimethyl-4-morpholinyl]carbonyl]-l- oxo-2-propenyl]-3-methoxy-, 1,1-dimethylethyl ester was dissolved in 1,2- dichloroethane (5mL) and TFA (5mL) was added to the reaction. The reaction was placed under a nitrogen atmosphere and stirred for 2.5hrs. Volatiles were removed in vacuuo from the reaction using a rotary evaporator to give a reddish oil. The product was dissolved in benzene/dichloromethane and the volatiles again removed in vacuuo to give a red foam. The product was dissolved in ethyl acetate and washed with 1.0N aqueous hydrochloric acid. The aqueous layer was back extracted with ethyl acetate. The organic extracts were combined, washed with brine and dried over magnesium sulfate. The organic solution was filtered and the volatiles removed in vacuuo using a rotary evaporator to give a amber-orange foam. The product was dried in vacuuo at room temperature to give 388mg of amorphous amber-orange solid.

LC-MS retention time 2.83 min; 624 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 5min, a hold time of 2 min, and an analysis time of 7 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6- [(2E,Z)- 3-(dimethylamino)-2-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]car bonyl]-l-oxo-2- propenyl] -3-methoxy-N- [(I -methylethyl)sulfonyl] - In a 25ml rb flask, dissolve 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[(2£,Z)-3-(dimethylamino)-2-[[(2R,6S)-2,6-d imethyl-4- morpholinyl]carbonyl]-l-oxo-2-propenyl]-3-methoxy- (385mg, 0.616 mmol) in dichloromethane (6.2 mL), add propane-2-sulfonamide (233 mg, 1.892 mmol) and DMAP (230 mg, 1.880 mmol) to the reaction followed by EDC (177 mg, 0.924 mmol). The reaction was placed under a nitrogen atmosphere and stirred at room temperature for 18.5hrs. The reaction was diluted with ethyl acetate and washed with 1.0N aqueous hydrochloric acid. The aqueous phases were combined and back extracted with ethyl acetate. The organic layers were combined and sequentially washed with 1.0N aqueous hydrochloric acid and brine. The organic solution was dried over magnesium sulfate, filtered and the solvent removed in vacuuo using a rotary evaporator to give an amorphous orange solid/foam which was dried in vacuuo to give 415mg of crude product.

LC-MS retention time 3.00 min; 729m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 5min, a hold time of 2 min, and an analysis time of 7 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

The crude product was used without any further purification in subsequent pyrazole synthesis.

4:1 45min

The following analog can be prepared using the general methodology described below.

7H-indolo[2,l-α][2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[(2£ ^' ,Z)-3- (dimethylamino)-2-[[(2R,6«S')-2,6-dimethyl-4-morpholinyl]ca rbonyl]- l-oxo-2- propenyl]-3-methoxy-N-[(l-methylethyl)sulfonyl]- (100 mg, 0.137 mmol) in ethanol (547 μL) and dioxane (137 μL). Add the hydrazine reagent (0.146 mmol) followed by TEA (58.2 μL, 0.417 mmol) to the reaction in a 0.5-2mL microwave reaction vessel. The vessel was capped under a nitrogen atmosphere and heated at 160C for 45 minutes. The reaction was diluted in DMF/Acetonitrile and product compound purified by reverse phase HPLC.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- [[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-l-(2-methylpr opyl)-lH-pyrazol-5- yl] -3-methoxy-N-[(l-methylethyl)sulfonyl] -

This compound was isolated using reverse phase HPLC with the instrumentation listed below using gradient method Bin# 16. Dionex APS-3000: Chromeleon 6.70 spl LC software; Thermo-Finnigan Xcalibur MS software; Dionex P680 binary pump for analytical; Dionex PP 150 binary pump prep; Dionex UVD340U UV spectrometer; Polymer Labs PL-ELS 1000 ELS detector; Thermo- Finnigen MSQ Surveyor Plus mass spectrometer. LC Conditions: Column; Waters Xbridge 19x200mm 5 urn C 18; Guard Column; Waters Xbridge 19x10mm 5 urn C 18; Mobile Phase; A = Water, 20 mM NH4OH; B = CAN. LC-MS retention time 5.47 min; 756.87m/z (MH+). LC data was recorded using Masslynx 4.0 SP4 with a system equipped with: CTC-Leap HTS-PAL autosampler with Harney 4-port injection module, Waters 1525 binary pump, Waters 2488 UV detector at 220 nm,

Polymer Lab 1000 ELS detector (evap. Temp.=90C, Neb. Temp.= 80C) and a Waters LCT mass spectrometer with 4 way MUX source. The sample was analyzed using an Ascentis 4.6x50mm 5uM Cl 8 column. The elution conditions employed a flow rate of 2 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 8min, a hold time of 1 min, and an analysis time of 9 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS ionization using a Waters LCT mass spectrometer in ESI positive mode.

Methyl l-ethyl-3-methyl-lH-pyrazole-4-carboxylate, and Methyl l-ethyl-5- methyl-lH-pyrazole-4-carboxylate

Methyl 2-((dimethylamino)methylene)-3-oxobutanoate (1.712 g, 10 mmol) in was suspended in diethyl ether (50 mL), under a nitrogen atmosphere to 0 ⁰ C. Ethylhydrazine oxalate (1.651 g, 11 mmol) in diethyl ether (13 mL), triethyl amine (7.0 mL, 50.2 mmol) and ethanol (6 mL) were then added. The resultant mixture slowly became more homogeneous and stirring was continued 0 ⁰ C for 40min, afterwhich the ice bath was removed and the mixture stirred for an additional 1.5 hours. The reaction was then partitioned between ethyl acetate and 1.0N aqueous hydrochloric acid. Extract aqueous phase with ethyl acetate. Combine the organic layers and wash sequentially with 1.0N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine. Dry organic layer over magnesium sulfate, filter and remove volatiles in vacuuo to yield a yellow oil, transfer to a small pear shaped flask in benzene, remove volatiles in vacuuo using rotary evaporator. The sample was briefly dried in vacuuo on a rotary evaporator to yield 1.549g of a yellow liquid/oil. IH NMR analysis indicated an mixture of isomers of 53:46 ratio.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.32 Hz, 3.01 H) 1.46 (t, J=7.32 Hz, 3.56 H) 2.44 (s, 3.45 H) 2.52 (s, 2.99 H) 3.79 (s, 3.49 H) 3.79 (s, 2.79 H) 4.05 - 4.13 (m, 4.44 H) 7.80 (s, 1.09 H) 7.82 (s, 0.86 H).

LC-MS retention time 0.80min; 169m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Methyl l-ethyl-5-iodo-3-methyl-lH-pyrazole-4-carboxylate

In a 100ml RB a mixture of methyl l-ethyl-3 -methyl- lH-pyrazole-4- carboxylate, and methyl l-ethyl-5 -methyl- lH-pyrazole-4-carboxylatemixture (1.539 g, 9.15 mmol) was dissolved in anhydrous THF (44 mL). The reaction was placed under a nitrogen atmosphere and cooled to -78C, then n-butyl lithium (5.49 mL, 10.98 mmol) 2.0M in pentane was added in a dropwise fashion. The orange solution at -78C was then immersed in a acetonitrile/CO2 bath at -44C and stirred for 1 hour. The reaction was cooled to -78C and a solution of iodine (2.55 g, 10.07 mmol) in tetrahydrofuran (10 mL) was added by cannua over approximately lOminutes. The reaction was stirred at -78C for 10 minutes after the addition of iodine then the cold bath removed and the reaction allowed to warm to room temperature over lhr. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted into ethyl acetate. The reaction was partitioned between ethyl acetate and aqueous saturated ammonium chloride, washed with aqueous sodium sulfite and again with saturated aqueous ammonium chloride and brine. The product solution was dried over magnesium sulfate and volatiles removed in vacuuo using rotary evaporator. The crude product was isolated as an amber oil (approx 2. Ig). The title compound (Rf=0.66 in 50% ethyl acetate / hexanes on Analtech Uniplate silica gel GHLF 250 micron TLC plate) was isolated by silica gel chromatography. The crude reaction was adsorbed onto 5.5g of silica gel using dichloromethane and chromatographed on 55.9g of silica gel slurry packed in a column using 10% ethyl acetate in hexanes. Elution with 10% ethyl acetate in hexanes then a step gradient of 15%, 20%, 25%, 30%, 40%, 50% and finally to 70% ethyl acetate in hexanes yielded the purified product and separation of crude reaction components.

The title compound (424mg, 30%) was isolated as a nearly colorless solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.17 Hz, 3 H) 2.45 (s, 3 H) 3.84 (s, 3 H) 4.24 (q, J=7.32 Hz, 2 H).

LC-MS retention time 1.19 min;295 m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a] [2] benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[l- ethyl-4-(methoxycarbonyl)-3-methyl-lH-pyrazol-5-yl]-3-methox y-, 1,1-dimethylethyl ester

Into a 20 ml microwave vessel charge, 7H-indolo[2,l-a][2]benzazepine-10- carboxylic acid, 13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester (300 mg, 0.409 mmol), methyl l-ethyl-5-iodo-3-methyl-lH-pyrazole-4- carboxylate (169 mg, 0.573 mmol), bis(triphenylphosphine)palladium(II) dichloride (29.6 mg, 0.042 mmol) and Ig of activated 3A molecular sieves. Cap reaction vessel and evacuate and fill with nitrogen through three cycles. Dioxane was added to the reaction and the reagents dissolved at room temperature. The sealed reaction was heated at 120C for 17hrs. Ethyl acetate was added to the reaction and the reaction filtered through a 0.45uM Whatman autovial filter. The filter cake was rinsed with ethyl acetate and the volatiles were removed from the filtrate in vacuuo to give a 508mg of yellow oil. The crude product with an odor of tin was dissolved in 13ml of dioxane and stirred for 2hrs with a aqueous solution of potassium fluoride. An attempt to filter the solution was unsuccessful and the aqueous /organic suspension was poured into a separatory funnel and ethyl acetate added and the aqueous layer extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate, filtered and volatiles removed in vacuuo to obtain 446mg of amber oil that still has an odor of tin. The crude product was adsorbed onto 1. Ig of silica gel using dichloromethane and purified on a 15.Og of silica gel column slurry loaded in dichloromethane. The column was eluted with a step gradient of dichloromethane to 2% ethyl acetate in dichloromethane and finally flushed with 5% ethyl acetate in dichloromethane. The product fraction were combined and solvent removed in vacuuo to give the title compound (152mg, 61%) as a amorphous yellow solid. The compound had a faint odor indicating trace amount of tin may be present. The product was used in subsequent steps without further purification.

IH NMR shows sample probably contains a butyl tin impurity. IH NMR

(500 MHz, CHLOROFORM-D) δ ppm 0.64 (s, 3 H) 0.81 - 0.89 (m, 2 H) 0.91 (t, J=7.32 Hz, 2.5 H, Sn compound?) 1.20 - 1.31 (m, 7 H) 1.31 - 1.41 (m, 3 H) 1.43 - 1.55 (m, 3 H) 1.56 (s, 5 H) 1.58 (s, 8 H) 1.60 - 1.68 (m, 2 H) 1.77 (d, J=9.46 Hz, 2 H) 1.94 (d, J=7.63 Hz, 1 H) 2.03 (s, 0.9 H, EtOAc) 2.07 (s, 2 H) 2.45 (s, 0.4 H) 2.47 (s, 3 H) 2.53 (s, 0.3 H) 2.85 (t, J=I 1.90 Hz, 1 H) 3.50 (d, J=54.93 Hz, 3 H) 3.73 - 3.85 (m, 3 H) 3.90 (s, 3 H) 4.08 - 4.14 (m, 0.8 H, EtOAc and impurity) 4.59 (q, J=7.22 Hz, 1 H) 4.66 (d, J=13.43 Hz, 1 H) 4.95 (d, J=14.04 Hz, 1 H) 6.72 (s, 1 H) 6.92 (d, J=2.44 Hz, 1 H) 7.05 (dd, J=8.70, 2.59 Hz, 1 H) 7.51 (d, J=8.54 Hz, 1 H) 7.63 (dd, J=8.55, 1.53 Hz, 1 H) 7.78 - 7.83 (m, 1 H) 7.85 (s, 1 H).

LC-MS retention time 2.74 min; 610 m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[l- ethyl-4-(methoxycarbonyl)-3-methyl-lH-pyrazol-5-yl]-3-methox y-

7H-indolo [2, 1 -a] [2]benzazepine- 10-carboxylic acid, 13 -cyclohexyl-6-[ 1 - ethyl-4-(methoxycarbonyl)-3-methyl-lH-pyrazol-5-yl]-3-methox y-, 1,1- dimethylethyl ester (151mg, 0.248 mmol) was dissolved in 1,2-dichloroethane (2ml) and TFA (2.000 ml) added. The reaction was stirred under a nitrogen atmosphere at room temperature for 2.5hrs. Volatiles from the reaction were removed in vacuuo using a rotary evaporator to give a orange/amber oil. The oily product was dissolved in a mixture of dichloromethane and benzene and the volatiles were removed in vacuuo to obtain a yellow amorphous solid. The solid was suspended in benzene- dichloromethane and again volatiles removed in vacuuo. The product was dried in vacuuo at room temperature to give 15 lmg of a yellow solid with a trace odor of tin. The product was triturated with the addition of 1.5 to 2mls of dichloromethane and several milliliters of hexanes. The suspension was heated to reflux then allowed to cool. The product as a pale yellow amorphous solid was filtered and rinsed with hexanes and dried in vacuuo at room temperature to yield 114.7mg of the title compound.

1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 0.60 (s, 3 H) 0.88 (t, J=7.02 Hz, 1 H) 1.19 - 1.33 (m, 3 H) 1.34 - 1.58 (m, 3 H) 1.79 (d, J=8.85 Hz, 2 H) 1.96 (s, 1 H) 2.08 (s, 3 H) 2.51 (s, 3 H) 2.86 (t, J=I 1.60 Hz, 1 H) 3.41 - 3.71 (m, 3 H) 3.73 - 3.89 (m, 2 H) 3.91 (s, 3 H) 4.49 (s, 6 H) 4.70 (d, J=12.21 Hz, 1 H) 4.96 (d, J=12.21 Hz, 1 H) 6.76 (s, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.08 (dd, J=8.70, 2.59 Hz, 1 H) 7.54 (d, J=8.54 Hz, 1 H) 7.76 (dd, J=8.39, 1.37 Hz, 1 H) 7.89 (d, J=8.54 Hz, 1 H) 7.95 (s, I H).

LC-MS retention timel.87 min;552 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl] amino] carbonyl] -7H-indolo[2,l-a] ' [2]benzazepin-6-yl]-l-ethyl- 3 -methyl-, methyl ester

7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[l- ethyl-4-(methoxycarbonyl)-3-methyl-lH-pyrazol-5-yl]-3-methox y- (109.4 mg, 0.198 mmol) was suspended in dichloromethane (2ml) and propane-2-sulfonamide (82 mg, 0.666 mmol) and DMAP (77.8 mg, 0.637 mmol) were added to the reaction. Upon addition of DMAP the reaction became a homogeneous yellow solution. EDC (57.7 mg, 0.301 mmol) was added to the reaction and the reaction was capped under a nitrogen atmosphere and stir at room temperature for 2 days. The reaction was diluted with ethyl acetate and washed sequentially with 1.0N aqueous hydrochloric acid and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuuo to obtain 128mg of product as a yellow foam.

IH NMR analysis shows the presence of ethyl acetate and approximately 0.24 equivilents of propane-2-sulfonamide reagent. The material was used without further purification.

LC-MS retention time 1.84min; 657m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.66 (s, 2 H) 0.79 - 0.94 (m,

2 H) 1.28 - 1.39 (m, 2 H) 1.45 - 1.49 (m, 6 H) 1.50 - 1.56 (m, 1 H) 1.79 (d, J=8.85 Hz, 2 H) 1.96 (s, 2 H) 2.05 - 2.11 (m, 2 H) 2.26 (s, 7 H, H2O peak) 2.49 (s, 3 H) 2.81 - 2.91 (m, 1 H) 3.38 - 3.71 (m, 4 H) 3.74 - 3.88 (m, 2 H) 3.91 (s, 3 H) 4.01 - 4.08 (m, 1 H) 4.69 (d, J=15.26 Hz, 1 H) 4.94 (d, J=12.51 Hz, 1 H) 6.76 (s, 1 H) 6.94 (d, J=2.75 Hz, 1 H) 7.08 (dd, J=8.70, 2.59 Hz, 1 H) 7.38 (d, J=8.55 Hz, 1 H) 7.53 (d, J=8.55 Hz, 1 H) 7.76 (s, 1 H) 7.89 (d, J=8.54 Hz, 1 H) 8.30 (s, 1 H).

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a] [2]benzazepin-6-yl]-l-ethyl- 3-methyl- lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l-ethyl- 3-methyl-, methyl ester (127mg, 0.193 mmol) was dissolved in TΗF (3ml) and methanol (3 ml) added to the solution.. Sodium hydroxide (3 ml, 3.00 mmol, 1.0N aqueous solution) was added to the homogeneous yellow solution reaction. The reaction turned to a rose-reddish cloudy color after complete addition of sodium hydroxide solution. The reaction was stirred at room temperature under a nitrogen atmosphere and eventually became a clear rose colored solution. The reaction was stirred at room temperature under a nitrogen atmosphere. ΗPLC analysis after 40hours revealed 78% conversion to product. Sodium hydroxide (1.0ml, l.OOmmol, 1.0N aqueous solution) was added to the reaction and the reaction stirred under a nitrogen atmosphere for an additional 24hrs. The reaction was concentrated to dryness in vacuuo using a rotary evaporator with bath at ambient temperature. The pink solid residue was partitioned between ethyl acetate and 1.0N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the organic layers combined and washed sequentially with 1.0N aqueous hydrochloric acid and brine. The organic layer was dried over magnesium sulfate, filtered and solvents removed in vacuuo to give a yellow solid which was dried in vacuuo at room temperature to give 108mg of the title compound as a amorphous yellow solid.

1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 0.71 (s, 3 H) 0.81 - 0.94 (m, 2 H) 0.96 - 1.20 (m, 3 H) 1.23 - 1.27 (m, 3 H) 1.27 - 1.37 (m, 3 H) 1.41 (t, J=IAl Hz, 6 H) 1.45 - 1.53 (m, 2 H) 1.60 - 1.73 (m, 1 H) 1.77 (d, J=I 1.90 Hz, 2 H) 1.86 - 2.02 (m, 2 H) 2.04 - 2.08 (m, 1 H) 2.47 (s, 2 H) 2.77 - 2.89 (m, 1 H) 3.43 - 3.69 (m, 4 H) 3.70 - 3.86 (m, 2 H) 3.99 - 4.06 (m, 2 H) 4.61 (d, J=10.07 Hz, 1 H) 4.95 (d, J=13.73 Hz, 1 H) 6.75 (s, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.03 - 7.10 (m, 1 H) 7.42 (d, J=8.24 Hz, 1 H) 7.47 - 7.54 (m, 1 H) 7.79 - 7.91 (m, 2 H) 8.76 (s, 1 H). LC-MS retention time 1.50 min; 643 m/z (MH-). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[4- f[(2R,6S)-2,6-dimethyl-4-morpholinylJcarbonylJ-l-ethyl-3-met hyl-lH-pyrazol-5-ylJ- 3-methoxy-N-[(l-methylethyl)sulfonyl]- lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l-ethyl- 3 -methyl- (61.1 mg, 0.095 mmol) was dissolved in DMF (948 μL) and ΗATU (80 mg, 0.210 mmol) added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for lhr. DMAP (36.7 mg, 0.300 mmol) was added to the reaction followed by the amine reagent, (2R,6S)-2,6- dimethylmorpholine (35.2 μL, 0.284 mmol). The clear yellow reaction solution was capped under a nitrogen atmosphere and the reaction stirred at room temperature for 42 hours. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL- 1OA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile purified using a Waters Sunfire Prep C 18 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 50% solvent A / 50% solvent B to 0% solvent A / 100% solvent B, a gradient time of 25 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product was from 16.16 to 17.47 minutes. The product fractions were combined and volatiles removed in vacuuo using a rotary evaporator. The title compound was dried in vacuuo at room temperature to yield 36.3mg as a yellow amorphous solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.68 (s, 4 H) 0.75 - 0.93 (m, 2 H) 1.05 (s, 1 H) 1.30 - 1.45 (m, 6 H) 1.51 (dd, J=IlXl, 6.26 Hz, 7 H) 1.79 (d, J=10.68 Hz, 2 H) 1.89 - 2.02 (m, 3 H) 2.03 - 2.16 (m, 3 H) 2.26 (s, 12 H) 2.88 (t, J=10.68 Hz, I H) 2.95 - 3.31 (m, 3 H) 3.34 - 3.75 (m, 1 H) 3.94 (s, 3 H) 4.03 - 4.11 (m, 1 H) 4.17 (s, 2 H) 4.57 (d, J=14.65 Hz, 1 H) 4.87 (d, J=15.56 Hz, 1 H) 6.74 -

6.86 (m, 1 H) 6.93 (s, 1 H) 7.12 (d, J=7.02 Hz, 1 H) 7.58 (d, J=8.54 Hz, 1 H) 7.66 (s, 1 H) 7.73 (s, 1 H) 7.90 (d, J=8.24 Hz, 1 H) 10.66 (s, 1 H).

LC-MS retention time 1.93 min; 740m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide, 13-cyclohexyl-6-[l-ethyl- 3-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylcarbonyl)-lH-py razol-5-yl]-3- methoxy-N-[(l-methylethyl)sulfonyl]- lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l-ethyl- 3-methyl- (45.8mg, 0.071 mmol) was dissolved DMF (710 μL) and ΗATU (62.7 mg, 0.165 mmol) was added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred for lhr at room temperature. DMAP (37.1 mg, 0.304 mmol), was added to the reaction followed by the amine reagent 8-oxa-3- azabicyclo[3.2. l]octane hydrochloride (23.3 mg, 0.156 mmol). The reaction was again capped under a nitrogen atmosphere and stirred at room temperature for 42hrs. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 50% solvent A / 50% solvent B to 0% solvent A / 100% solvent B, a gradient time of 25 minutes with a run time of 35 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system.

Retention time of product was from 14.77 to 15.57 minutes. Volatiles were removed from the product fraction in vacuuo using a rotary evaporator. The title compound was dried in vacuuo at room temperature to yield 28.2mg of a yellow amorphous solid. 1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 0.68 (s, 1 H) 1.14 - 1.30 (m,

2 H) 1.32 - 1.55 (m, H H) 1.55 - 1.72 (m, 3 H) 1.80 (t, J=10.68 Hz, 2 H) 1.90 - 2.02 (m, 2 H) 2.11 (s, 12 H) 2.19 - 2.34 (m, 4 H) 2.85 (t, J=I 1.75 Hz, 1 H) 2.98 (d, ./=11.90 Hz, I H) 3.13 (s, 1 H) 3.25 - 3.68 (m, 2 H) 3.74 - 3.91 (m, 2 H) 3.94 (s, 3 H) 4.00 - 4.10 (m, 1 H) 4.19 (d, J=27.77 Hz, 2 H) 4.55 (d, J=14.95 Hz, 1 H) 4.80 (d, J=14.65 Hz, 1 H) 5.03 (s, 0.15 H) 6.82 (s, 1 H) 6.93 (s, 1 H) 7.11 (dd, J=8.70, 2.59 Hz, 1 H) 7.54 (d, J=8.55 Hz, 1 H) 7.62 (d, J=7.63 Hz, 2 H) 7.81 - 8.01 (m, 1 H) 10.51 (s, 1 H). LC-MS retention time 1.79 min; 738 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-ethyl-3-methyl-lH-pyrazol-5-yl]-3-methoxy -, 1,1-dimethylethyl ester

7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-

(tributylstannyl)-, 1,1-dimethylethyl ester (2.025 g, 2.764 mmol) was charged into a 20ml microwave reaction vessel with a magnetic stir bar along with copper (I) chloride (1.368 g, 13.82 mmol), tetrakis(triphenylphosphine)palladium (0) (0.319 g, 0.276 mmol) and lithium chloride (0.926 g, 21.84 mmol) (LiCl, flame dried then vacuum overnight). The reaction vessel was capped and evacuated/filled with nitrogen three times. To the reaction vessel was added a solution of l-ethyl-5-iodo-3- methyl-lH-pyrazole-4-carboxylate (1.022 g, 3.32 mmol) in DMSO (13.5 mL). Sparge the reaction for approx 3 minutes with nitrogen then heat to 120C in oil bath. The initial solution was dark in color and became light green color of CuCl during sparging with nitrogen. The reaction was heated for 4hrs at 120C. Dilute reaction with approximately 40OmL of ethyl acetate, and wash with 5% aqueous ammonium hydroxide solution. Back extract deep blue aqueous layer with diethyl ether. Combine organic phases and wash with brine, filter through ceilite plug and rinse ceilite with ethyl acetate. Dry filtrate over magnesium sulfate, filter and remove solvent in vacuuo using a rotary evaporator. Reaction produced 2.83g of crude product as a yellow oil. The crude product was combined with 2.04g of a previous reaction and adsorbed onto 14.8g of silica gel and purified by column chromatography on 186g of silica gel slurry packed in dichloromethane. The column was eluted with 1500ml of dichloromethane then 2% ethyl acetate in dichloromethane (>3L) and then 5% ethyl acetate in dichloromethane and finally eluted with 10% ethyl acetate in dichloromethane.

Product fractions indicated pure by TLC (2% ethyl acetate in dichloromethane) were combined and solvent removed in vacuuo using a rotary evaporator to give a yellow amorphous solid when dried in vacuuo at room temperature yielded 2.149g (71% yield) of pure product IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.65 (s, 3 H) 1.21 - 1.44 (m, 7 H) 1.44 - 1.54 (m, 2 H) 1.56 (s, 3 H) 1.58 (s, 9 H) 1.77 (d, J=10.07 Hz, 2 H) 1.94 (s, 1 H) 1.99 - 2.15 (m, 3 H) 2.48 (s, 3 H) 2.80 - 2.90 (m, 1 H) 3.43 (s, 1 H) 3.54 (s, 1 H) 3.90 (s, 3 H) 4.19 - 4.36 (m, 2 H) 4.65 (d, ./=12.21 Hz, 1 H) 4.96 (d, J=14.95 Hz, 1 H) 6.72 (s, 1 H) 6.92 (d, J=2.75 Hz, 1 H) 7.05 (dd, J=8.70, 2.59 Hz, 1 H) 7.51 (d, J=8.85 Hz, 1 H) 7.63 (d, J=8.55 Hz, 1 H) 7.81 (d, J=8.24 Hz, 1 H) 7.85 (s, 1 H) LC-MS retention time 2.98min; 624m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 7H-indolo[2, 1-a] [2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-ethyl-3-methyl-lH-pyrazol-5-yl]-3-methoxy -

7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)- 1 -ethyl-3 -methyl- 1 H-pyrazol-5 -yl] -3 -methoxy-, 1 , 1 -dimethylethyl ester (2.134 g, 3.42 mmol) was dissolved in 1 ,2-dichloroethane (17 mL) then TFA (17 mL) was added and the reaction stirred at room temperature under a nitrogen atmosphere for 2hrs. Volatiles were removed from the reaction in vacuuo using a rotary evaporator. The orange-amber reaction residue was dissolved in dichloromethane and benzene added. The solvents and residual TFA was removed in vacuuo using the rotary evaporator. The product was dried in vacuuo at room temperature to give 2.309g of an amorphous yellow solid. Analysis of the product by IH NMR and 19F NMR indicated TFA still present. The product was then dissolved in ethyl acetate and washed with 1.0N aqueous hydrochloric acid. The aqueous phases were combined and back extracted with ethyl acetate. The organic extracts were combined and washed with brine, dried over magnesium sulfate, filtered and volatiles removed in vacuuo to yield to give a yellow foam which was dissolved in dichloromethane and benzene and volatiles again removed in vacuuo using the rotary evaporator. The product ,as a light yellow amorphous solid, was dried in vacuuo to give 1.962 g of product. The product was sufficiently pure to use without further purification.

IH NMR showed a broad baseline shift (4.5 to 5ppm, water , H+ from acid function group) causing larger integration values for the bridge methylene protons. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.63 (s, 3 H) 1.12 - 1.60 (m, 9 H) 1.78 (d, J=9.16 Hz, 2 H) 1.95 (s, 1 H) 2.00 - 2.19 (m, 3 H) 2.50 (s, 3 H) 2.86 (t,

J=I 1.90 Hz, 1 H) 3.51 (d, J=34.79 Hz, 2 H) 3.90 (s, 3 H) 4.19 - 4.40 (m, 2 H) 4.68 (d, J=14.65 Hz, 2 H) 4.96 (d, J=12.21 Hz, 2 H) 6.73 (s, 1 H) 6.93 (d, J=IAA Hz, 1 H) 7.07 (dd, J=8.55, 2.14 Hz, 1 H) 7.53 (d, J=8.85 Hz, 1 H) 7.76 (d, J=8.55 Hz, 1 H) 7.88 (d, J=8.55 Hz, 1 H) 7.96 (s, 1 H).

LC-MS retention time2.94 min; 568m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Sunfire Cl 8 5u 4.6x50mm column using a SPD-10AV UV -Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% TFA and solvent B was 90% H2O / 10% acetonitrile / 0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a] [2]benzazepin-6-yl]-l-ethyl- 3-methyl-, ethyl ester

7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-ethyl-3 -methyl- lH-pyrazol-5-yl] -3 -methoxy- (1.965g, 3.46 mmol) was dissolved in dichloromethane (35 mL). Propane-2-sulfonamide (1.415 g, 11.49 mmol) and DMAP (1.355 g, 11.09 mmol) were added to the reaction followed by EDC (1.046g, 5.46 mmol). The reaction was stirred under a nitrogen atmosphere for 2 days. Remove volatiles/solvent from reaction in vacuuo using a rotary evaporator. Partition the reaction between ethyl acetate and 1.0N aqueous hydrochloric acid.

Wash organic layer sequentially with 1.0N aqueous hydrochloric acid, 0. IN aqueous NaH2PO4 and brine. Dry organic layer over magnesium sulfate, filter and remove solvent in vacuuo to obtain a yellow foam which was dried in vacuuo at room temperature to give 2.12g of crude product as an amber-orange amorphous foam. Dissolve the crude product in dichloromethane and adsorb onto 5.3g of silica gel. The product was purified by column chromatography on 7 Ig of silica gel slurry loaded in 2% methanol in dichloromethane. The product was eluted with 2% methanol in dichloromethane and after collecting 40 18x150mm fraction tubes 3% methanol in dichloromethane. The pure product fractions were combined and solvent removed in vacuuo using a rotary evaporator. The title compound (1.482g) was obtained as a amorphous yellow solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.66 (s, 3 H) 1.12 - 1.44 (m, 6 H) 1.46 (d, J=7.02 Hz, 6 H) 1.49 - 1.55 (m, J=I 9.99, 6.56 Hz, 1 H) 1.55 - 1.63 (m, 4 H) 1.78 (d, J=9.16 Hz, 2 H) 1.87 - 2.17 (m, 4 H) 2.48 (s, 3 H) 2.80 - 2.92 (m, 1 H) 3.37 - 3.66 (m, 2 H) 3.90 (s, 3 H) 3.99 - 4.09 (m, 1 H) 4.15 - 4.35 (m, 1 H) 4.68 (d, J=14.04 Hz, 1 H) 4.95 (d, J=13.73 Hz, 1 H) 6.74 (s, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.07 (dd, J=8.55, 2.44 Hz, 1 H) 7.37 (d, J=8.24 Hz, 1 H) 7.51 (d, J=8.54 Hz, 1 H) 7.77 (s, 1 H) 7.88 (d, J=8.24 Hz, 1 H) 8.29 (s, 1 H).

LC-MS retention time 2.02min; 671m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 5-[10-(aminocarbonyl)-13-cyclohexyl-3-methoxy- 7H-indolo[2, 1-a] [2]benzazepin-6-yl] -l-ethyl-3-methyl-, ethyl ester

The title compound was isolated as a minor impurity in the purification of IH- pyrazole-4-carboxylic acid, 5- [ 13 -cyclohexyl-3 -methoxy- 10- [ [[( 1 - methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2, 1-a] [2]benzazepin-6-yl]- l-ethyl- 3-methyl-, ethyl ester in the above example. IH NMR had indicated that ammonium chloride as an impurity contained in reactant propane-2-sulfonamide was most likely responsible for the formation to the title compound. The title compound, IH- pyrazole-4-carboxylic acid, 5-[10-(aminocarbonyl)-13-cyclohexyl-3-methoxy-7H- indolo[2,l-a][2]benzazepin-6-yl]-l-ethyl-3-methyl-, ethyl ester, trailed the major product, 4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][2]benz azepin-6-yl]-l-ethyl- 3-methyl-, ethyl ester of the reaction in the above chromatography conditions. The title compound (153mg) was isolated as a light yellow solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.64 (s, 2 H) 0.80 - 0.97 (m, 1 H) 1.13 - 1.57 (m, 7 H) 1.60 (s, 3 H) 1.78 (d, J=10.07 Hz, 2 H) 1.95 (s, 1 H) 2.08 (s, 3 H) 2.47 (s, 3 H) 2.80 - 2.92 (m, 1 H) 3.50 (d, J=39.67 Hz, 2 H) 3.90 (s, 3 H) 4.28 (s, 2 H) 4.67 (d, J=13.43 Hz, 1 H) 4.98 (d, J=12.21 Hz, 1 H) 5.58 (s, 1 H) 6.01 (s, 1 H) 6.72 (s, 1 H) 6.93 (d, J=2.14 Hz, 1 H) 7.06 (dd, J=8.55, 2.44 Hz, 1 H) 7.34 (d, J=8.24 Hz, 1 H) 7.52 (d, J=8.85 Hz, 1 H) 7.80 (s, 1 H) 7.85 (d, J=8.55 Hz, 1 H). NMR results for sample in DMSO were not satisfactory. All peaks were broad (including solvent peak). Likewise NMR taken in acetonirtile exhibited broad peak shape. IH NMR (500 MHz, ACETONITRILE-D3) δ ppm 0.55 (s, 2 H) 0.78 - 1.00 (m, 1 H) 1.10 - 1.35 (m, 4 H) 1.38 - 1.58 (m, 3 H) 1.69 - 1.83 (m, 2 H) 2.03 - 2.13 (m, 5 H) 2.15 (s, 3 H) 2.41 (s, 3 H) 2.78 - 2.92 (m, 1 H) 3.48 (s, 2 H) 3.90 (s, 3 H) 4.21 (d, J=30.21 Hz, 2 H) 4.62 (s, 1 H) 5.01 (s, 1 H) 5.82 (s, 1 H) 6.67 (s, 1 H) 6.84 (s, 1 H) 7.05 (d, J=2.75 Hz, 1 H) 7.13 (dd, J=8.55, 2.75 Hz, 1 H) 7.47 (dd, J=8.39, 1.37 Hz, 1 H) 7.59 (d, J=8.55 Hz, 1 H) 7.74 (s, 1 H) 7.89 (d, J=8.24 Hz, 1 H). LC-MS retention time 2.19 min; 567 m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-3- methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl ]-lH-pyrazol-5-yl]-3- methoxy-N-f(l-methylethyl)sulfonylJ-

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l-ethyl- 3 -methyl- (40.8 mg, 0.063 mmol) was dissolved in DMF (633 μL) and ΗATU (49.2 mg, 0.129 mmol) added to the reaction. The reaction was stirred for lhr at room temperature under a nitrogen atmosphere then DMAP (39.2 mg, 0.321 mmol) was added to the reaction followed by the amine reagent, 3-methyl-3,8- diazabicyclo[3.2.1]octane dihydrochloride (29.5 mg, 0.148 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 19hr. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 50% solvent A / 50% solvent B to 0% solvent A / 100% solvent B, a gradient time of 25 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product was 4.34min. Volatiles were removed from the product fraction in vacuuo using a Speed-vac using a medium heat setting. The product was transferred to a vial in acetonitile, solvent removed using a nitrogen sweep then the sample was dried in vacuuo at room temperature to yield 32.3mg of the title compound as a yellow amorphous solid. IH NMR exhibits broad peaks characteristic of salt formation and/or restricted rotation.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.87 (s, 0.2 H) 1.24 (s, 2 H) 1.32 - 1.63 (m, 9 H) 1.79 (d, J=10.99 Hz, 2 H) 1.88 - 2.15 (m, 4 H) 2.19 - 2.75 (m, 12 H) 2.80 - 2.99 (m, 2 H) 3.11 (s, 2 H) 3.42 (d, J=70.19 Hz, 3 H) 3.80 - 3.90 (m, 1 H) 3.94 (s, 3 H) 4.03 (s, 1 H) 4.20 (s, 2 H) 4.57 (d, J=15.56 Hz, 1 H) 4.81 (s, 1 H) 6.98 (s, 1 H) 7.12 (d, J=8.55 Hz, 1 H) 7.54 (d, J=7.93 Hz, 1 H) 7.63 (s, 1 H) 7.91 (d, J=8.24 Hz, I H) 10.16 (s, I H). LC-MS retention time2.04 min; 75 lm/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-3- methyl-4-[[(3R, 5S)-3, 4, 5-trimethyl-l-piperazinyl] carbonyl] -lH-pyrazol-5-yl] -3- methoxy-N-[(l-methylethyl)sulfonyl]-

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l-ethyl- 3-methyl- (39.8 mg, 0.062 mmol) was dissolved in DMF (617 μL) and ΗATU (47.9 mg, 0.126 mmol) added to the reaction. The reaction was stirred for lhr at room temperature under a nitrogen atmosphere then DMAP (47.7 mg, 0.390 mmol) was added to the reaction followed by the amine reagent, (2R,6S)- 1,2,6- trimethylpiperazine dihydrochloride (29.4 mg, 0.146 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 19hr. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 25 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product is 8.08min, Remove volatiles from product fractions in vacuuo overnight using speed-vac at medium heating setting. The product fraction were combined in acetonitrile, transferred into a vial and solvent removed using a nitrogen sweep. The product was dried overnight at room temperature to yield 32.5mg of the title compound as a yellow amorphous solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.27 (s, 1.5 H) 1.04 (s, 6 H) 1.21 - 1.46 (m, 6 H) 1.50 (s, 6 H) 1.81 (d, J=9.77 Hz, 2 H) 1.90 - 2.13 (m, 4 H) 2.25 (s, 3 H) 2.36 (s, 2 H) 2.92 (s, 8 H) 3.08 - 3.65 (m, 5 H) 3.84 (s, 1 H) 3.94 (s, 3 H) 4.00 - 4.10 (m, 1 H) 4.15 (s, 2 H) 4.60 (d, J=14.34 Hz, 1 H) 4.72 - 4.98 (m, 2 H) 6.89 (s, 1 H) 6.95 (d, J=2.44 Hz, 1 H) 7.13 (d, J=7.63 Hz, 1 H) 7.56 (d, J=7.32 Hz, 1 H) 7.61 - 7.88 (m, 2 H) 7.94 (d, J=8.55 Hz, 1 H) 10.19 (s, 1 H). LC-MS retention timel.26 min; 753 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-3- methyl-4-[(lS, 4S)-2-oxa-5-azabicyclo[2.2. l]hept-5-ylcarbonyl]-lH-pyrazol-5-yl]-3- methoxy-N-f(l-methylethyl)sulfonylJ-

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-l-ethyl- 3 -methyl- 41.7mg, 0.065 mmol) was dissolved in DMF (647 μL) and ΗATU (49.8 mg, 0.131 mmol) added to the reaction. The reaction was stirred for lhr at room temperature under a nitrogen atmosphere then DMAP (53.5 mg, 0.438 mmol) was added to the reaction followed by the amine reagent, (lS,4S)-(+)-2-Aza-5- oxabicyclo(2.2.1)-heptane hydrochloride (22.6 mg, 0.167 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 19hr. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile and a few drops of water purified using a Waters Sunfire Prep C 18 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 25 minutes with a run time of 35 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Retention time of product is 18.9min. Remove volatiles from product fractions in vacuuo overnight using speed-vac at medium heating setting. The product fraction was dissolved in dichloromethane and transferred into a vial and solvent removed using a nitrogen sweep. The product was dried overnight at room temperature to yield 3 l.Omg of the title compound as a yellow amorphous solid. IH NMR data shows characteristics of restricted rotation with broadening and splitting of some peaks.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.15 (s, 0.6 H) 0.94 (s, 0.4 H) 1.08 - 1.34 (m, 2.6 H) 1.34 - 1.60 (m, 12.4 H) 1.79 (d, J=10.38 Hz, 2.1 H) 1.97 (d, J=9.77 Hz, 1.3 H) 2.00 - 2.16 (m, 3.0 H) 2.29 (s, 3.0 H) 2.71 (d, J=6.71 Hz, 0.2 H) 2.81 - 2.94 (m, 1.4 H) 3.03 (d, J=I 1.90 Hz, 1.0 H) 3.09 - 3.67 (m, 8.7 H) 3.83 - 4.02 (m, 4.4 H) 4.01 - 4.11 (m, 1.4 H) 4.13 - 4.31 (m, 2.2 H) 4.53 - 4.65 (m, 1.0 H) 4.92 (dd, J=15.26, 5.49 Hz, 0.9 H) 6.84 (d, J=18.62 Hz, 0.6 H) 6.89 - 6.97 (m, 1.5 H) 7.12 (t, J=8.09 Hz, 1.0 H) 7.55 (q, J=7.73 Hz, 1.0 H) 7.59 - 7.66 (m, 0.8 H) 7.67 - 7.76 (m, 0.9 H) 7.83 (s, 0.3 H) 7.86 - 7.99 (m, 1.0 H) 10.41 - 10.82 (m, 0.8 H). LC-MS retention time 1.71min; 724 m/z (MH-). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

The compounds below were synthesized by identical coupling methodology used in the above examples.

7H-indolo[2, 1-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-4-[(5- ethyl-2, 5-diazabicyclo[2.2.1] hept-2-yl)carbonyl] -3-methyl-lH-pyrazol-5-yl] -3- methoxy-N-[(l-methylethyl)sulfonyl]-

HPLC purification method:

The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile with a couple drops of TFA and water, filtered through a 0.45uM syringe filter and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product was collected between 6.62minutes and 8.81 minutes. The title compound was isolated (86.7mg) as a yellow amorphous solid. IH NMR is characteristic of restricted rotation and/or salt formation with splitting/broadening of peaks- appears rotomeric.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.29 - 0.58 (m, 0.5 H) 0.87 (s, 0.2 H) 0.96 - 1.07 (m, 0.2 H) 1.17 (s, 2.1 H) 1.23 - 1.34 (m, 1.2 H) 1.34 - 1.57 (m, 10.7 H) 1.58 - 1.74 (m, 1.0 H) 1.81 (d, J=9.46 Hz, 1.9 H) 1.96 (d, ./=14.34 Hz, 1.1 H) 2.04 (d, J=8.55 Hz, 2.8 H) 2.19 - 2.34 (m, 3.1 H) 2.60 - 2.98 (m, 8.3 H) 3.03 - 3.57 (m, 3.7 H) 3.59 - 3.87 (m, 1.9 H) 3.94 (s, 3.0 H) 4.03 (s, 0.8 H) 4.09 - 4.36 (m, 2.3 H) 4.58 (t, J=15.26 Hz, 1.0 H) 4.78 (d, J=14.34 Hz, 0.9 H) 6.90 - 7.23 (m, 3.0 H) 7.45 - 7.67 (m, 2.6 H) 7.92 (d, J=7.63 Hz, 0.9 H) 8.32 (s, 0.1 H) 9.29 (s, 0.1 H) 9.92 - 10.87 (m, 0.95 H).

LC-MS retention time 1.73 min; 751m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-3- methyl-4-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl ]-lH-pyrazol-5-yl]-3- methoxy-N-[(l-methylethyl)sulfonyl]-

HPLC purification method: The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile with the addition of a couple drops of TFA and water then filtered through a 0.45uM syringe filter and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product fractions were collected between 6.79 and 8.69 minutes.

The title compound was isolated (80.0mg) as a yellow amorphous solid. INMR exhibits characteristics of restricted rotation and/or salt formation. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.87 (s, 2.0 H) 1.23 (s, 2.2 H) 1.30 - 1.62 (m, 10.5 H) 1.76 (s, 2.7 H) 1.86 - 2.10 (m, 5.5 H) 2.14 - 2.47 (m, 4.6 H) 2.55 - 2.93 (m, 7.7 H) 3.14 - 3.86 (m, 5.2 H) 3.85 - 3.94 (m, 3.6 H) 3.98 (dd, J=12.67, 6.56 Hz, 1.8 H) 4.08 - 4.40 (m, 1.4 H) 4.44 - 5.09 (m, 2.0 H) 6.95 (s, 1.5 H) 7.01 - 7.14 (m, 1.2 H) 7.50 (d, J=7.63 Hz, 1.0 H) 7.58 (d, J=7.93 Hz, 1.0 H) 7.66 - 7.82 (m, 0.7 H) 7.87 (d, J=8.55 Hz, 1.0 H) 8.24 (s, 0.1 H) 8.67 (s, 0.1 H) 10.18 (s, 0.6 H) LC-MS retention time 1.80min; 75 lm/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-3- methyl-4-(4-morphoHnylcarbonyl)-lH-pyrazol-5-yl]-3-methoxy-N -[(l- methylethyl)sulfonyl] -

HPLC purification method:

The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile with a few drops of TFA and water, then filtered through a 0.45uM syringe filter and purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product fractions were collected between 15.62 and 16.66 minutes.

The title compound was isolated (67.0mg) as a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.14 - 1.29 (m, 1 H) 1.34 - 1.46 (m, 5 H) 1.51 (dd, J=22.89, 6.71 Hz, 7 H) 1.79 (d, J=10.38 Hz, 2 H) 1.91 - 2.01 (m, 2 H) 2.02 - 2.20 (m, 7 H) 2.27 (s, 3 H) 2.50 - 2.77 (m, 2 H) 2.78 - 2.93 (m, 3 H) 3.08 (s, 2 H) 3.94 (s, 3 H) 4.01 - 4.09 (m, 1 H) 4.11 - 4.24 (m, 2 H) 4.57 (d, J=I 5.26 Hz, 1 H) 4.84 (d, J=14.95 Hz, 1 H) 6.81 (s, 1 H) 6.93 (d, J=2.44 Hz, 1 H) 7.12 (dd, J=8.70, 2.59 Hz, 1 H) 7.57 (d, J=8.55 Hz, 1 H) 7.62 (d, J=8.24 Hz, 1 H) 7.67 (s, 1 H) 7.92 (d, J=8.24 Hz, 1 H) 10.60 (s, 1 H). LC-MS retention time 1.83 min; 712 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-3- methyl-^S-oxa^-azabicycloβ.S.lJnon-^ylcarbonylJ-lH-pyrazol- S-ylJS-methoxy- N-[(l-methylethyl)sulfonyl]-

HPLC purification method:

The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile with a few drops of TFA and water, then filtered through a 0.45uM syringe filter and purified using a Waters Sunfire Prep C 18 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product fractions were collected between 18.65 and 19.75 minutes.

The title compound was isolated (63.2mg) as a yellow amorphous solid. IH NMR exhibits some charasteristics of restricted rotation with the splitting of some peaks- rotomeric.

IH NMR (SOO MHz ₁ CHLOROFORM-D) O pPm L H - 1.27 (m, 2.0 H) 1.28 - 1.51 (m, 12.8 H) 1.51 - 1.58 (m, J=6.56, 6.56 Hz, 3.3 H) 1.68 (t, J=13.73 Hz, 0.9 H) 1.77 (d, J=10.38 Hz, 2.0 H) 1.90 - 2.27 (m, 8.6 H) 2.30 (s, 3.2 H) 2.32 - 2.45 (m, 1.1 H) 2.83 - 2.92 (m, 1.0 H) 3.05 (d, J=9.16 Hz, 0.7 H) 3.16 (s, 0.8 H) 3.23 (s, 0.8 H) 3.32 (d, J=10.99 Hz, 1.2 H) 3.43 - 3.80 (m, 1.2 H) 3.94 (s, 3.0 H) 3.99 - 4.09 (m, 1.1 H) 4.10 - 4.26 (m, 2.0 H) 4.58 (d, J=15.26 Hz, 1.0 H) 4.89 (d, J=14.95 Hz, 0.7 H) 4.95 (d, J=14.65 Hz, 0.3 H) 6.75 - 6.85 (m, 1.0 H) 6.91 (d, ./=2.14 Hz, 1.0 H) 7.08 - 7.14 (m, 1.0 H) 7.57 (t, J=8.70 Hz, 1.0 H) 7.65 (d, J=8.24 Hz, 1.0 H) 7.74 (s, 0.7 H) 7.81 (s, 0.3 H) 7.89 (t, J=8.24 Hz, 1.0 H) 10.86 (s, 0.8 H).

LC-MS retention time 2.15 min; 752 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-4-[[(2S)- 2-(methoxymethyl)-4-morphoHnyl] carbonyl] -3-methyl-lH-pyrazol-5-yl] -3-methoxy- N-[(l-methylethyl)sulfonyl]-

HPLC purification method:

The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile with a few drops of TFA and water, then filtered through a 0.45uM syringe filter and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product fractions were collected between 15.58 and 16.76 minutes. The title compound was isolated (65.1mg) as a yellow amorphous solid.

IH NMR exhibits some charasteristics of restricted rotation with the splitting of some peaks- rotomeric.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.15 - 1.30 (m, 1.3 H) 1.31 - 1.46 (m, 4.9 H) 1.49 (d, J=6.41 Hz, 3.9 H) 1.53 (d, J=6.41 Hz, 3.3 H) 1.79 (d, J=9.77 Hz, 2.4 H) 1.83 - 2.03 (m, 4.9 H) 2.02 - 2.18 (m, 3.1 H) 2.26 (s, 3.0 H) 2.29 - 2.52 (m, 1.3 H) 2.68 (s, 0.5 H) 2.80 - 3.02 (m, 3.8 H) 3.05 (s, 1.9 H) 3.12 - 3.30 (m, 3.3 H) 3.29 - 3.51 (m, 1.4 H) 3.94 (s, 2.9 H) 4.00 - 4.10 (m, 1.1 H) 4.10 - 4.24 (m, 1.9 H) 4.56 (d, J=15.26 Hz, 1.0 H) 4.74 - 4.92 (m, 0.9 H) 6.81 (d, J=17.09 Hz, 1.0 H) 6.92 (s, 1.0 H) 7.11 (dd, J=8.55, 2.14 Hz, 1.0 H) 7.50 - 7.77 (m, 3.0 H) 7.89 (t, J=9.00 Hz, 1.0 H) 10.74 (s, 0.6 H). LC-MS retention timel.88 min; 756 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4-

(ethoxycarbonyl)- 1 -ethyl- lH-pyrazol-5-yl] -3-methoxy-, 1, 1 -dimethylethyl ester

In a 20ml microwave vessel suspend tert-butyl 13-cyclohexyl-6-((2E,Z)-3-

(dimethylamino)-2-(ethoxycarbonyl)-2-propenoyl)-3-methoxy -7H-indolo[2,l- a][2]benzazepine-10-carboxylate (2.056 g, 3.36 mmol) in ethanol (9 mL) and dioxane (2.2 mL). To the reaction was added ethylhydrazine oxalate (0.533 g, 3.55 mmol) followed by triethyl amine (1.4 mL, 10.04 mmol). The reaction was capped under a nitrogen atmosphere and heated using microwave to 160C for 40min. The reaction was diluted with ethyl acetate and washed with 1.0N aqueous hydrochloric acid and the aqueous layer extracted with ethyl acetate. The organic extracts were combined and washed sequentially with saturated aqueous sodium bicarbonate and then 1.0N aqueous hydrochloric acid and brine. The organic phase was dried over magnesium sulfate, filtered and solvent removed in vacuuo using a rotary evaporator to give 2.02g of crude product. The crude product was combined with 500mg of crude product from an analogous reaction in dichloromethane and adsorbed onto 6.3g of silica gel. The title compound was purified by silica column chromatography (89g slurry loaded in dichloromethane), eluting with dichloromethane then 2% ethyl acetate in dichloromethane. Note the first major UV adsorbing spot is that of the regio-ethyl pyrazole isomer and the second larger spot on TLC is that of the title compound.

The pure product fractions were collected and solvent removed in vacuuo to give 1.006g of the title compound as a yellow amorphous solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.70 (s, 3 H) 1.28 - 1.51 (m, 7 H) 1.57 (s, 9 H) 1.77 (d, J=9.16 Hz, 2 H) 1.94 (s, 1 H) 2.07 (s, 3 H) 2.79 - 2.94 (m, 1 H) 3.53 - 3.71 (m, 2 H) 3.90 (s, 3 H) 4.21 - 4.33 (m, 2 H) 4.69 (d, J=I 1.90 Hz, 1 H) 4.99 (d, J=12.51 Hz, 1 H) 6.76 (s, 1 H) 6.93 (d, J=2.44 Hz, 1 H) 7.06 (dd, J=8.55, 2.44 Hz, 1 H) 7.52 (d, J=8.85 Hz, 1 H) 7.63 (d, J=8.55 Hz, 1 H) 7.79 - 7.84 (m, 2 H) 7.93 (s, 1 H). LC-MS retention time2.91 min; 610m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-ethyl-lH-pyrazol-3-yl]-3-methoxy-, 1,1-dimethylethyl ester

The above compound was isolated as a minor component of the reaction mixture for the above experimental for 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-6- [4-(ethoxycarbonyl)- 1 -ethyl- 1 H-pyrazol-5 -yl]-3 -methoxy-, 1,1- dimethylethyl ester and is described in the text as the regio-ethyl pyrazole isomer. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.17 - 1.27 (m, 2 H) 1.31 (t, J=7.17 Hz, 3 H) 1.34 - 1.51 (m, 3 H) 1.51 - 1.57 (m, 7 H) 1.61 (s, 9 H) 1.61 - 1.66 (m, 1 H) 1.75 (d, J=I 1.29 Hz, 2 H) 1.93 (d, J=7.02 Hz, I H) 1.97 - 2.16 (m, 3 H) 2.81 - 2.91 (m, 1 H) 3.90 (s, 3 H) 4.13 - 4.31 (m, 4 H) 4.39 (d, J=14.34 Hz, 1 H) 5.84 (d, J=14.04 Hz, 1 H) 6.96 - 7.06 (m, 2 H) 7.51 (d, J=8.24 Hz, 1 H) 7.64 (d, J=8.24 Hz, 1 H) 7.79 (d, J=8.55 Hz, 1 H) 7.94 (d, J=7.32 Hz, 1 H) 8.29 (s, 1 H).

LC-MS retention time 3.06 min; 6 lOm/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-ethyl-lH-pyrazol-5-yl]-3-methoxy-

7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4-

(ethoxycarbonyl)- 1 -ethyl- lH-pyrazol-5-yl]-3 -methoxy-, 1 , 1 -dimethylethyl ester (0.984 g, 1.614 mmol) was dissolved in 1,2-dichloroethane (10 mL) and TFA (10.00 mL) added to the reaction. The reaction was placed under a nitrogen atmosphere and stirred at room temperature for 3.5 hours. Volatiles were removed from the reaction in vacuuo using a rotary evaporator. Dissolve product in ethyl acetate and wash sequentially with 1.0N aqueous hydrochloric acid and brine, dry over magnesium sulfate, filter and remove solvents in vacuuo. The title compound was dried in vacuuo to yield 978mg as a amorphous yellow solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.69 (s, 3 H) 1.14 - 1.28 (m, 2 H) 1.28 - 1.39 (m, 4 H) 1.37 - 1.61 (m, 3 H) 1.78 (d, J=9.46 Hz, 2 H) 1.95 (s, 1 H) 2.08 (s, 3 H) 2.80 - 2.95 (m, 1 H) 3.65 (s, 2 H) 3.91 (s, 3 H) 4.19 - 4.36 (m, 2 H) 4.73 (d, ./=12.21 Hz, 1 H) 4.99 (d, J=10.38 Hz, 1 H) 6.78 (s, 1 H) 6.94 (d, J=2.75 Hz, 1 H) 7.08 (dd, J=8.55, 2.75 Hz, 1 H) 7.53 (d, J=8.55 Hz, 1 H) 7.75 (dd, J=8.55, 1.22 Hz, 1 H) 7.88 (d, J=8.55 Hz, 1 H) 7.93 (s, 1 H) 7.99 (s, 1 H). LC-MS retention time 2.03min; 552m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

Ethyl 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy -7H-indolo[2,l- a][2]benzazepin-6-yl)-l-ethyl-lH-pyrazole-4-carboxylate

In a 100ml round bottom flask dissolve 13-cyclohexyl-6-(4-(ethoxycarbonyl)-l- ethyl- 1 H-pyrazol-5-yl)-3 -methoxy-7H-indolo [2, 1 -a] [2]benzazepine- 10-carboxylic acid (950mg, 1.680 mmol), propane-2 -sulfonamide (652 mg, 5.29 mmol) and DMAP (655 mg, 5.36 mmol) in dichloromethane (16.8 mL). To the reaction add EDC (508 mg, 2.65 mmol). Place the reaction under a nitrogen atmosphere and stir a room temperature for 64 hours.

Remove solvent in vacuuo using a rotary evaporator and partition the reaction between ethyl acetate and 1.0N aqueous hydrochloric acid. Wash the organic extract sequentially with 1.0N aqueous hydrochloric acid and brine then dry over magnesium sulfate. Filter off the magnesium sulfate from the organic extract rinsing with ethyl acetate then remove the solvent in vacuuo from the filtrate using a rotary evaporator. The product was dried in vacuuo at room temperature to yield 1.009g of the title compound as a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.69 (s, 3 H) 1.18 - 1.36 (m, 6 H) 1.41 (d, J=6.71 Hz, 2 H) 1.45 (d, J=6.71 Hz, 6 H) 1.48 - 1.61 (m, 2 H) 1.79 (d,

J=9.46 Hz, 2 H) 1.90 - 2.15 (m, 4 H) 2.46 (s, 4 H) 2.82 - 2.93 (m, 1 H) 3.66 (s, 2 H) 3.90 (s, 3 H) 4.00 - 4.08 (m, 1 H) 4.26 (dd, J=13.73, 6.71 Hz, 2 H) 4.72 (d, J=13.73 Hz, 1 H) 4.99 (d, J=12.21 Hz, 1 H) 6.79 (s, 1 H) 6.94 (d, J=I.83 Hz, 1 H) 7.08 (dd, J=8.39, 1.98 Hz, 1 H) 7.37 (d, J=8.55 Hz, 1 H) 7.52 (d, J=8.55 Hz, 1 H) 7.76 (s, 1 H) 7.88 (d, J=8.55 Hz, 1 H) 7.95 (s, 1 H) 8.31 (s, 1 H).

LC-MS retention time 1.95min; 657m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 5-(l 3-cyclohexyl-l 0-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2, 1- a] [2] benzazepin-6-y I)-I -ethyl- 1 H-pyrazole-4-carboxylic acid

Ethyl 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy -7H- indolo[2,l-a][2]benzazepin-6-yl)-l-ethyl-lH-pyrazole-4-carbo xylate was dissolved in THF (14 mL) and methanol (14 mL) then sodium hydroxide(15 mL, 15.00 mmol) (1.0N aqueous) was added to the reaction. The reaction was placed under a nitrogen atmosphere and stirred at room temperature for 16.5hrs. The reaction was concentrated in vacuuo using a rotary evaporator (bath temp equal to less than 26C) then partitioned between ethyl acetate and 1.0N aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the organic extracts combined, washed with brine and dried over magnesium sulfate. The organic solution was filtered and solvents removed in vacuuo to give amorphous amber-orange solid (902mg) after drying at room temperature in vacuuo.. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.79 (s, 3 H) 1.12 - 1.21 (m, 1 H) 1.28 - 1.38 (m, 2 H) 1.41 (d, J=6.71 Hz, 6 H) 1.43 - 1.57 (m, 2 H) 1.66 - 1.83 (m, 2 H) 1.87 - 2.07 (m, 4 H) 2.77 - 2.89 (m, 1 H) 3.71 (s, 3 H) 3.90 (s, 3 H) 3.98 - 4.07 (m, 1 H) 4.63 (d, J=13.43 Hz, 1 H) 4.99 (d, J=12.82 Hz, 1 H) 6.79 (s, 1 H) 6.94 (d, J=2.44 Hz, 1 H) 7.07 (dd, J=8.70, 2.29 Hz, 1 H) 7.43 (d, J=8.24 Hz, 1 H) 7.51 (d, J=8.85 Hz, 1 H) 7.80 - 7.87 (m, 2 H) 7.95 (s, 1 H) 8.86 (s, 1 H).

LC-MS retention time 1.35 min; 629m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

B-cyclohexyl-ό-μ-tfβRόS^ό-dimethyl^-morpholinytycarb onyiyi-ethyl-lH- pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy-7H-indolo[2,l- a] [2]benzazepine-10- carboxamide

5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-meth oxy-7H-indolo[2,l- a][2]benzazepin-6-yl)-l -ethyl- lH-pyrazole-4-carboxylic acid (75 mg, 0.119 mmol) was dissolved in DMF (1.2ml) and HATU (103 mg, 0.271 mmol) added to the reaction. The reaction was capped and stirred at room temperature for 1.5hrs then DMAP (44.3 mg, 0.363 mmol) and the amine reagent (2R,6S)-2,6- dimethylmorpholine (0.044 ml, 0.357 mmol) were added to the reaction. The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 2 days. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL- 1OA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile with 2 drops of water added to aid solubility then purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Product eluted between 17.39 and 18.20 minutes. Volatiles from the product fraction were removed in vacuuo overnight using a Speed-Vac set at medium heat. The title compound (54.3mg ) was isolated as a yellow amorphous solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.69 (s, 4 H) 0.82 (d, J=33.57 Hz, 2 H) 1.15 - 1.31 (m, I H) 1.31 - 1.59 (m, 12 H) 1.79 (d, J=10.68 Hz, 2 H) 1.88 - 2.32 (m, 13 H) 2.88 (t, J=I 1.14 Hz, I H) 2.96 - 3.31 (m, 2 H) 3.95 (s, 3 H) 4.04 - 4.12 (m, 1 H) 4.22 (s, 2 H) 4.60 (d, J=14.95 Hz, 1 H) 4.90 (d, J=15.56 Hz, 1 H) 6.77 - 6.86 (m, 1 H) 6.94 (s, 1 H) 7.10 - 7.17 (m, 1 H) 7.61 (dd, J=27.62, 7.17 Hz, 2 H) 7.70 (d, J=19.23 Hz, 2 H) 7.92 (d, J=7.93 Hz, 1 H) 10.49 (s, 1 H). LC-MS retention time 1.93min; 726m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

The following compounds were prepared from 5-(13-cyclohexyl-10- ((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,l-a][2] benzazepin-6-yl)-l- ethyl-lH-pyrazole-4-carboxylic acid by identical coupling methodology used in the above example for 13-cyclohexyl-6-(4-(((2R,6S)-2,6-dimethyl-4- morpholinyl)carbonyl)-l -ethyl- lH-pyrazol-5-y l)-N-(isopropylsulfony l)-3-methoxy- 7H-indolo[2,l-a][2]benzazepine-10-carboxamide.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-4-(8- oxa-3-azabicyclo[3.2.1]oct-3-ylcarbonyl)-lH-pyrazol-5-yl]-3- methoxy-N-[(l- methylethyl)sulfonyl] -

HPLC purification method:

The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile and a few drops of water added to solubilize. The sample was then filtered through a 0.45uM syringe filter and purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product fraction was collected between 16.30min and 17.11min.

The title compound was isolated (61.7mg) as a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.24 (dd, J=21.67, 10.38 Hz, 2 H) 1.39 (s, 4 H) 1.46 (d, J=5.80 Hz, 6 H) 1.52 - 1.72 (m, 4 H) 1.78 (d, J=8.85 Hz, 2 H) 1.90 - 2.03 (m, 2 H) 2.08 (s, 3 H) 2.27 (s, 1 H) 2.85 (t, J=I 1.60 Hz, 1 H) 2.97 - 3.13 (m, 1 H) 3.31 (s, 1 H) 3.86 (s, 1 H) 3.93 (s, 3 H) 3.98 - 4.09 (m, 2 H) 4.22 (s, 2 H) 4.57 (d, J=15.26 Hz, I H) 4.81 - 5.07 (m, 1 H) 6.71 - 6.92 (m, 3 H) 6.94 (s, I H) 7.11 (d, J=7.93 Hz, 1 H) 7.54 (d, J=8.55 Hz, 1 H) 7.72 (s, 1 H) 7.82 - 8.02 (m, 1 H) 9.63 - 10.11 (m, I H). LC-MS retention time 1.80min;724 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, l-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-4-[(8- methyl-3, 8-diazabicyclo[3.2.1] oct-3-yl)carbonyl] -lH-pyrazol-5-yl] -3-methoxy-N-[(l- methylethyl)sulfonyl] -

HPLC purification method:

The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 4ml with acetonitrile / DMF (1 : 1) and a couple drops of TFA added, the sample was filtered through a 0.45uM syringe filter and the filtrate injected in two injections and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 20 minutes using %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid solvent system.

The title compound was isolated (55.5mg) as a yellow-greenish amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) d ppm 0.74 (s, 3 H) 1.12 - 1.29 (m, 2 H) 1.30 - 1.41 (m, 4 H) 1.42 - 1.57 (m, 4 H) 1.77 (d, J=8.55 Hz, 2 H) 1.86 - 2.10 (m, 4 H) 2.18 (s, 1 H) 2.24 - 2.50 (m, 2 H) 2.78 - 2.95 (m, 4 H) 3.03 (s, 5 H) 3.73 (s, 1 H) 3.81 - 3.88 (m, 1 H) 3.90 (s, 3 H) 3.93 (s, 1 H) 3.99 - 4.08 (m, 2 H) 4.10 - 4.37 (m, 3 H) 4.40 - 4.69 (m, 3 H) 6.90 (s, 1 H) 6.96 (d, J=2.44 Hz, 1 H) 7.07 (dd, J=8.70, 2.29 Hz, 1 H) 7.49 - 7.55 (m, 2 H) 7.57 - 7.65 (m, 1 H) 7.67 (s, 1 H) 7.86 (d, J=8.24 Hz, 1 H) 10.64 (s, 1 H) 11.24 (s, 1 H).

LC-MS retention time 1.74 min;737m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

ethyl 5-(l 3-cyclohexyl-l 0-((dimethylsulfamoyl)carbamoyl)-3-methoxy- 7H- indolo[2,l-a] [2]benzazepin-6-yl)-l-ethyl-3-methyl-lH-pyrazole-4-carboxyla te

7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-ethyl-3 -methyl- lH-pyrazol-5-yl] -3 -methoxy- (0.603 g, 1.062 mmol) was dissolved in dichloromethane (10.6 mL) with DMAP (0.417 g, 3.41 mmol) and N,N-dimethylsulfamide (0.394 g, 3.17 mmol). EDC (0.336 g, 1.753 mmol) was added to the reaction and the reaction was stirred under a nitrogen atmosphere at room temperature for 40 hours. Solvent was removed from the reaction in vacuuo using a rotary evaporator. The residue was partitioned between ethyl acetate and 1.0N aqueous hydrochloric acid. The organic phase was sequentially washed with 1.0N aqueous hydrochloric acid, a mixture of 0.1 M aqueous NaH2P04 / 1.0N aqueous hydrochloric acid and again with 1.0N aqueous hydrochloric acid and finally with brine. The organic phase was dried over magnesium sulfate, filtered and solvent removed in vacuuo using a rotary evaporator. The yellow amorphous solid was dried in vacuuo at room temperature to yield 669mg of the title compound.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.53 - 0.90 (m, 3 H) 1.15 - 1.46 (m, 7 H) 1.47 - 1.66 (m, 4 H) 1.78 (d, J=8.85 Hz, 2 H) 1.91 - 2.15 (m, 4 H) 2.48 (s, 3 H) 2.86 (t, J=16.02 Hz, 1 H) 3.04 (s, 6 H) 3.52 (d, J=38.76 Hz, 2 H) 3.90 (s, 3 H) 4.26 (s, 2 H) 4.67 (d, J=14.34 Hz, 1 H) 4.95 (d, J=13.73 Hz, 1 H) 6.73 (s, 1 H) 6.93 (d, J=2.44 Hz, 1 H) 7.06 (dd, J=8.55, 2.44 Hz, 1 H) 7.33 (d, J=8.55 Hz, 1 H) 7.51 (d, J=8.55 Hz, 1 H) 7.78 (s, 1 H) 7.87 (d, J=8.55 Hz, 1 H) 8.46 (s, 1 H) LC-MS retention time2.23 min; 672 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 5-/73-cyclohexyl-l 0-

[ [ [(dimethylamino)sulfonyl] amino] carbonyl] -3-methoxy-7H-indolo [2, 1 - a] [2] benzazepin-6-yl] -1 -ethyl-3-methyl-

In a 100ml rb flask dissolve lH-pyrazole-4-carboxylic acid, 5 -[13-cyclohexyl-l 0- [[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indo lo[2,l- a][2]benzazepin-6-yl]-l-ethyl-3 -methyl-, ethyl ester (652mg, 0.968 mmol) in THF (10 mL) and methanol (10.00 mL). Sodium hydroxide (10 mL, 10.00 mmol), 1.0N aqueous solution was added to the reaction and the reaction was stirred under a nitrogen atmosphere at room temperature for 7 days.

The reaction was concentrated using rotary evaporator keeping the water heating bath temperature at or below 25C. The remaining reaction solution was partitioned between ethyl acetate and 1.0N aqueous hydrochloric acid. Extract aqueous phase with ethyl acetate and combine the organic extracts and wash with brine, dry over magnesium sulfate, filter and remove solvent in vacuuo using a rotary evaporator. The amorphous film residue was dissolved in dichloromethane and the solvent and volatiles were removed in vacuuo using a rotary evaporator. The yellow amorphous solid was broken up into a more finely divided solid and dried in vacuuo at room temperature to yield 600mg of the title compound as a yellow amorphous solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.71 (s, 3 H) 0.86 (s, 1 H) 1.10 - 1.58 (m, 6 H) 1.69 (s, I H) 1.76 (d, J=10.99 Hz, I H) 1.86 - 2.15 (m, 5 H) 2.47 (s, 3 H) 2.84 (t, J=I 1.90 Hz, 1 H) 3.00 (s, 6 H) 3.59 (s, 2 H) 3.90 (s, 3 H) 4.64 (d, J=13.43 Hz, 1 H) 4.97 (d, J=13.73 Hz, 1 H) 6.75 (s, 1 H) 6.95 (d, J=2.75 Hz, 1 H) 7.06 (dd, J=8.55, 2.44 Hz, 1 H) 7.35 (d, J=8.24 Hz, 1 H) 7.50 (d, J=8.54 Hz, 1 H) 7.77 - 7.86 (m, 2 H) 8.68 (s, 1 H). LC-MS retention time 1.75min; 644 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

13-cyclohexyl-6-(4-(((2R,6S)-2,6-dimethyl-4-morpholinyl)c arbonyl)-l-ethyl-3- methyl-1 H-pyrazol-5-yl)-N-(dimethylsulfamoyl)-3-methoxy-7H-indolo[2, 1 - a] [2]benzazepine-10-carboxamide

CAS Name for 77778-062 (126 mg, 0.195 mmol) was dissolved in DMF (1.95ImL) and

HATU (167 mg, 0.439 mmol) was added to the reaction. The reaction was capped and stirred at room temperature for 1.5hrs then DMAP (72.1 mg, 0.590 mmol) was added to the reaction followed by the amine reagent, (2R,6S)-2,6- dimethylmorpholine (72.5 μL, 0.585 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 2 days. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 4ml with acetonitrile with a few drops of water to dissolve then filtered through a 0.45uM syringe filter and purified (2 x 2ml injections) using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The product fractions were collected and volatiles removed in vacuuo overnight using a speed-vac set on medium heating. The product fractions were analyzed by LCMS and the pure fractions were combined in dichloromethane and transferred to a vial. The solvent was removed using a nitrogen sweep and the product dried in vacuuo at room temperature to yield 89.2mg of the title compound as amorphous yellow solid.

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.68 (s, 3 H) 0.73 - 1.08 (m, 3 H) 1.15 - 1.29 (m, 1 H) 1.31 - 1.54 (m, 6 H) 1.79 (d, J=10.99 Hz, 2 H) 1.88 - 2.18 (m, 6 H) 2.26 (s, 3 H) 2.58 - 2.99 (m, 7 H) 3.07 (s, 5 H) 3.10 - 3.27 (m, 2 H) 3.94 (s, 3 H) 4.19 (s, 2 H) 4.57 (d, J=14.95 Hz, 1 H) 4.90 (d, J=15.26 Hz, 1 H) 6.70 - 6.88 (m, 1 H) 6.93 (s, 1 H) 7.12 (d, J=7.63 Hz, 1 H) 7.45 - 7.67 (m, 2 H) 7.73 (s, 1 H) 7.91 (d, J=8.24 Hz, I H) 10.61 (s, I H)

LC-MS retention time 2.13 min; 741m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C 18 3.0x50mm column using a SPD- 1 OAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. lH-pyrazole-4-carboxylic acid, 5-/73-cyclohexyl-l 0-

[[(cyclopropylsulfonyl)amino] carbonyl] -3-methoxy-7H-indolo[2,l-a] [2]benzazepin- 6-yl] -l-ethyl-3-methyl-, ethyl ester.

Dissolve 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4- (ethoxycarbonyl)-l-ethyl-3 -methyl- lH-pyrazol-5-yl] -3 -methoxy- (110 mg, 0.194 mmol) in THF (0.646 mL). Carbonyldiimidazole (94 mg, 0.581 mmol) was added to the reaction. The reaction was placed under a nitrogen atmosphere and heated to 60 deg C for 1 hour. The reaction was cooled under a nitrogen atmosphere and cyclopropanesulfonamide (94 mg, 0.775 mmol) was added to the reaction followed by DBU (0.088 mL, 0.581 mmol). The reaction was immerse in oil bath at 60 deg C under nitrogen atmosphere and heated overnight at 60 deg C. The reaction was diluted with chloroform (50 mL) and the organic layer washed sequentially with 1.0N aqueous hydrochloric acid (50 mL), 0. IM aqueous NaH2PO4 (50 mL) and brine (25 mL). The organic layer was dried over MgS 04, filtered and volatiles removed in vacuuo to yield a yellow foam which was dried in vacuuo at room temperature overnight to yield 130 mg (0.194 mmol, 90% crude) of the title compound as a yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.67 (br.m, 3H) 1.12 - 1.59 (m, 9 H) 1.62 - 2.16 (m, 8 H) 2.49 (s, 3 H) 2.87 (m, 1 H) 3.91 (s, 3 H) 4.11 (m, 2 H) 4.27 (m, 3 H) 4.69 (br.d, 1 H) 4.97 (br.d, 1 H) 6.72 (s, 1 H) 6.94 (s, 1 H) 7.07 (dd, J=8.55, 2.14 Hz, 1 H) 7.37 (dd, J=8.55, 2.14 Hz, 1 H) 7.51 (d, J=8.24 Hz, 1 H) 7.82 (d, J=2.14 Hz, 1 H) 7.89 (d, J=8.24 Hz, 1 H) 8.59 (br. s, 1 H). LCMS 671 m/z (MH+). lH-pyrazole-4-carboxylic acid, 5-/73-cyclohexyl-l 0-

[[(cyclopropylsulfonyl)amino] carbonyl] -3-methoxy-7H-indolo[2,l-a] [2]benzazepin- 6-ylJ-l-ethyl-3-methyl-.

Dissolve lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-10- [[(cyclopropylsulfonyl)amino]carbonyl]-3-methoxy-7H-indolo[2 ,l-α][2]benzazepin- 6-yl]-l-ethyl-3-methyl-, ethyl ester (130 mg, 0.194 mmol) was dissolved in dioxane (0.969 mL) and methanol (0.969 mL) was added to the reaction followed by IN aqueous sodium hydroxide (1.94 mL). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 72 hrs. The reaction was diluted with chloroform (50 mL) and washed with 1.0N aqueous hydrochloric acid (50 mL). The organic layer was concentrated in vacuuo using a rotary evaporator to yield the title compound as a yellow solid (125 mg, 100% crude). 1Η NMR (500 MHz,

CHLOROFORM-D) δ ppm 0.72 (br.m, 3H) 1.12 - 1.59 (m, 6 H) 1.62 - 2.16 (m, 8 H) 2.51 (s, 3 H) 2.87 (m, 3 H) 3.91 (s, 3 H) 4.12 (m, 1 H) 4.69 (br.d, 1 H) 5.01 (br.d, 1 H) 6.74 (s, 1 H) 6.96 (s, 1 H) 7.08 (dd, J=8.55, 2.14 Hz, 1 H) 7.41 (dd, J=8.55, 2.14 Hz, 1 H) 7.52 (d, J=8.24 Hz, 1 H) 7.88 (m, 2 H) 8.92 (br. s, 1 H). MS m/z 643 (MH ⁺ ).

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-N-

(cyclopropylsulfonyl)-6-[4-[[(2R,6S)-2,6-dimethyl-4-morph olinyl]carbonyl]-l-ethyl-

3-methyl-lH-pyrazol-5-yl]-3-methoxy-

lH-pyrazole-4-carboxylic acid, 5-[13-cyclohexyl-10-

[[(cyclopropylsulfonyl)amino]carbonyl]-3-methoxy-7H-indol o[2,l-α][2]benzazepin- 6-yl]-l-ethyl-3-methyl- was dissolved in DMF (1.9mL) and ΗATU (160 mg, 0.421 mmol) added to the reaction. The reaction was stirred at room temperature for 1.5hrs then DMAP (70.7 mg, 0.579 mmol) was added to the reaction followed by (2R,6S)- 2,6-dimethylmorpholine (71.1 μL, 0.574 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 17hrs. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 4ml with acetonitrile with a few drops of water to dissolve then filtered through a 0.45uM syringe filter and purified (2 x 2ml injections) using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. The title compound was dried in vacuuo at room temperature to yield 71.8mg of yellow amorphous solid. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.68 (s, 4 H) 0.81 (d, J=33.27 Hz, 2 H) 0.93 - 1.18 (m, 3 H) 1.20 - 1.30 (m, 1 H) 1.33 - 1.48 (m, 6 H) 1.50 - 1.61 (m, 1 H) 1.79 (d, J=10.99 Hz, 2 H) 1.97 (d, J=9.77 Hz, 3 H) 2.04 - 2.17 (m, 3 H) 2.26 (s, 3 H) 2.88 (t, J=I 1.29 Hz, 1 H) 3.05 - 3.29 (m, 3 H) 3.53 (s, 5 H) 3.95 (s, 3 H) 4.20 (s, 2 H) 4.57 (d, J=14.95 Hz, 1 H) 4.89 (d, J=15.56 Hz, 1 H) 6.75 - 6.87 (m, 1 H) 6.93 (s, 1 H) 7.13 (d, J=8.24 Hz, 1 H) 7.52 - 7.60 (m, 1 H) 7.63 - 7.77 (m, 2 H) 7.86 - 7.99 (m, 1 H) 10.72 (s, 1 H)

LC-MS retention time 1.50min; 738m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou C18 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 0 min, and an analysis time of 3min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

methyl l-isopropyl-5(3)-methyl-lH-pyrazole-4-carboxylate

Dissolve methyl 3 -methyl- lH-pyrazole-4-carboxy late (2.375g, 16.95 mmol) in DMF (85 mL), sodium hydride (0.471 g, 18.64 mmol) (95% in mineral oil) was added portion wise under nitrogen. The reaction was stirred for approximately 10 minutes and 2-iodopropane (1.861 mL, 18.64 mmol) was added to the reaction. The reaction was stirred at room temperature under a nitrogen atmosphere overnight (23hr). Solvent was removed from the reaction in vacuuo using a rotary evaporator. The orange residue was partitioned between 1.0N aqueous hydrochloric acid (~30ml) and ethyl acetate. The yellow colored aqueous solution was extracted with ethyl acetate and the organic extracts were combined and washed Ix with saturated aqueous sodium bicarbonate solution. The aqueous hydrochloric acid washes were neutralized to pH of ~4 with ION aqueous sodium hydroxide then saturated aqueous sodium bicarbonate added to make the solution basic. The basic aqueous solutions were combined and extracted with ethyl acetate. The organic extracts were combined and washed with brine and dried over magnesium sulfate, filtered and solvent removed in vacuuo to yield a yellow oil (4.4g). The yellow oil was dissolved in benzene and volatiles removed in vacuuo using a rotary evaporator (bath temp= 40C) to obtain a yellow oil (weight= 2.964g). The material was dissolved in a small amount of dichloromethane and applied to a silica gel column (105g) slurry loaded in dichloromethane. The product was eluted with dichloromethane to yield a mixture of isomers as a yellow oil (1.736g).

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.46 (s, 2.29 H) 1.47 (s, 5.08 H) 1.48 (s, 3.03 H) 2.45 (s, 3.00 H) 2.54 (s, 1.99 H) 3.79 (s, 3.15 H) 3.79 (s, 1.91 H) 4.34 - 4.49 (m, 1.80 H) 7.83 (s, 1.02 H) 7.85 (s, 0.65 H).

methyl 3(5)-iodo-l-isopropyl-5(3)-methyl-lH-pyrazole-4-carboxylate

Vasilevskii, S. F.; Gerasimov,V.A.; Shvartsbert, M.S.; Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 30 (4) 683-685 (1981), ISSN: 0568-5230; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 4, 902-904 (1981). In a 25ml flask dissolve methyl l-isopropyl-3(5)- methyl-lH-pyrazole-4-carboxylate mixture (550mg, 3.02 mmol) in acetic acid (3.2 ml), then add sulfuric acid (1.22ml, 6.87 mmol) (30% w/w) followed by iodine (620 mg, 2.443 mmol) and iodic acid (250 mg, 1.421 mmol). The reaction was heated at 95C under a nitrogen atmosphere for approximately 21hrs. The reaction was cooled and sodium acetate (750mg, 9.14 mmol) to the reaction. The reaction was transferred to a sepratory funnel in ethyl acetate and washed with 10% aqueous sodium sulfite. The organic layer was washed in an erlenmeyer with saturated aqueous sodium bicarbonate (Caution: CO2 evolution). The organic phase was decanted and washed with saturated aqueous sodium bicarbonate then brine. The organic extract was dried over magnesium sulfate, filtered and solvent removed in vacuuo using a rotary evaporator to give the product as a yellow oil (598mg). The crude mixture was used without further purification.

LC-MS retention time 1.4min unresolved peaks; 309m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Sunfire Cl 8 5u 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 1OmM ammonium acetate and solvent B was 95% H2O / 5% acetonitrile / 1OmM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[4- (methoxycarbonyl)-5-methyl-l-(l-methylethyl)-lH-pyrazol-3-yl ]-, 1,1-dimethylethyl ester

7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6- (tributylstannyl)-, 1,1-dimethylethyl ester (679 mg, 0.927 mmol) was charged into a 20ml microwave vessel with copper(I) chloride (468 mg, 4.73 mmol), tetrakis(triphenylphosphine)palladium(0) (106.8 mg, 0.092 mmol) and lithium chloride (312 mg, 7.36 mmol) (lithium chloride flame dried and stored in vacuum at room temperature overnight). The reaction vessel was capped with a teflon lined septa and evacuated and back filled with nitrogen three times. A mixture containing methyl 3(5)-iodo-l-isopropyl-5(3)-methyl-lH-pyrazole-4-carboxylate (356 mg, 1.155 mmol) in DMSO (6.2mL) was added to the reaction vessel. The reaction was sparged for approximately 2 minutes with nitrogen and stirred for 5 minutes at room temperature then heated to 120C in an oil bath for 5hrs. Dilute reaction with ethyl acetate and wash sequentially with 5% aqueous ammonium hydroxide then brine. Back extract aqueous layer with diethyl ether. Combine organic extracts and wash sequentially with water then brine. Filter off a fine precipitate suspension in the organic layer then dry filtrate using magnesium sulfate. Filter drying agent and remove volatiles to yield the crude reaction products as a yellow oil (825mg). The crude product was adsorbed onto 2g of silica gel using dichloromethane and purified by column chromatography using 25.8g of silica gel slurry loaded in 30% hexanes in dichloromethane. The products were eluted from the column with 30% hexanes in dichloromethane then a gradient to dichloromethane, continued elution with 1% ethyl acetate in dichloromethane and finally a gradient to 5% ethyl acetate in dichloromethane. Pure fractions of the title compound were combined and volatiles removed to yield the title compound (165mg) a yellow film. LC-MS retention time 3.91min; 624m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Sunfire Cl 8 5u 4.6x50mm column using a SPD-10AV UV -Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 70% solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 3 min, and an analysis time of 6 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% TFA and solvent B was 90% H2O / 10% acetonitrile / 0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.

IH NMR indicates some impurities present. The material was used without further purification. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.91 (t, J=7.48 Hz, 1.2 H) 1.16 - 1.41 (m, 5.6 H) 1.44 (d, J=6.71 Hz, 2.2 H) 1.46 - 1.53 (m, 4.5 H) 1.55 (s, 6.8 H) 1.60 (s, 9.2 H) 1.61 - 1.67 (m, 1.7 H) 1.69 - 1.81 (m, 2.3 H) 1.93 (d, J=10.99 Hz, 1.2 H) 2.06 (s, 3.1 H) 2.48 - 2.50 (s, 0.7 H) 2.51 (s, 2.8 H) 2.77 - 2.83 (m, 0.4 H) 2.83 - 2.92 (m, 1.0 H) 3.70 (s, 2.9 H) 3.80 (s, 0.6 H) 3.90 (s, 3.0 H) 4.35 - 4.53 (m, 2.2 H) 5.59 (d, J=14.95 Hz, 0.9 H) 6.95 (d, J=2.75 Hz, 1.0 H) 6.99 (dd, J=8.55, 2.75 Hz, 1.0 H) 7.36 (s, 1.0 H) 7.50 (d, J=8.55 Hz, 1.1 H) 7.64 (dd, J=8.39, 1.37 Hz, 1.0 H) 7.80 (d, J=8.55 Hz, 1.0 H) 8.19 (s, 0.9 H). 7H-indolo[2, 1-a] [2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[4- (methoxycarbonyl)-5-methyl-l-(l-methylethyl)-lH-pyrazol-3-yl ]-

7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[4- (methoxycarbonyl)-5 -methyl- 1 -( 1 -methylethyl)- lH-pyrazol-3 -yl] -, 1 , 1 -dimethylethyl ester (152mg, 0.244 mmol) was dissolved in 1 ,2-dichloroethane (1.2 mL), then TFA (1.2 mL) was added to the reaction. The reaction was stirred at room temperature under a nitrogen atmosphere for 2hrs. Volatiles were removed from the reaction in vacuuo using a rotary evaporator. Dissolve residue in dichloromethane and benzene then remove volatiles in vacuuo using a rotary evaporator, repeat sequence. The resulting yellow foam was dissolved in dichloromethane and transferred to a tared round bottom flask. The volatiles were removed in vacuuo an the resulting yellow foam was dried in vacuuo at room temperature to yield 147mg of the title compound. The material was used without further purification.LC-MS retention time 2.24min; 566m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. LC-MS retention time3.09 min; 568m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Sunfire Cl 8 5u 4.6x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% TFA and solvent B was 90% H2O / 10% acetonitrile / 0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 3-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a] [2]benzazepin-6-yl]-5- methyl- l-(l-methylethyl)-, methyl ester

In a 2 dram vial suspend 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-5-methyl-l-(l-me thylethyl)-lH- pyrazol-3-yl]- in dichloromethane (2.5ml). To the reaction as a fine yellow suspension add propane-2-sulfonamide (96.7 mg, 0.785 mmol) and DMAP (105 mg, 0.859 mmol). Upon addition of DMAP, the reaction became a homogeneous clear yellow solution. EDC (77 mg, 0.402 mmol) was added to the reaction and the reaction was capped under a nitrogen atmosphere and stir at room temperature for 39hrs. The solvent was removed in vacuuo using a rotary evaporator and the reaction residue partitioned between ethyl acetate and 1.0N aqueous hydrochloric acid. The organic layer was washed sequentially with 1.0N aqueous hydrochloric acid, 0. IM aqueous NaΗ2PO4 and 1.0N aqueous hydrochloric acid then brine. The organic layer was dried over magnesium sulfate, filtered and solvent remove in vacuuo to yield a yellow amorphous solid. The product was dried in vacuuo at room temperature to give 154mg of the title compound as an amorphous yellow solid. The product was used without further purification. LC-MS retention time 3.14min; 673m/z (MH+). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Sunfire Cl 8 5u 4.6x50mm column using a SPD-10AV UV -Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 2 min, and an analysis time of 5 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% TFA and solvent B was 90% H2O / 10% acetonitrile / 0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. LC-MS retention time 2.16 min;671 m/z (MH-). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

lH-pyrazole-4-carboxylic acid, 3-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a] [2]benzazepin-6-yl]-5- methyl-1- (1 -methylethyl) -

lH-pyrazole-4-carboxylic acid, 3-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-5- methyl-1 -(I -methylethyl)-, methyl ester (153mg, 0.227 mmol) was dissolved in TΗF (2.2 mL) and Methanol (2.2 mL). To the clear orange/amber solution aqueous 1.0N sodium hydroxide (2.2 mL, 2.200 mmol) was added. The reaction mixture turned a rose/red color and was slightly cloudy which became clear within 24hrs. The reaction was stirred under a nitrogen atmosphere at room temperature for 14 days. Progression of the reaction was measured at intervals of every few days by taking a 15ul aliquot diluting in acetonitrile and adding 1 to 2 drops of water to dissolve salts then analyzing the solution by LCMS.

The reaction was partitioned between 1.0N aqueous hydrochloric acid and ethyl acetate. The aqueous phase was extracted Ix using ethyl acetate and the organic extracts combined and washed with brine and dried over magnesium sulfate.

Filtering and removing solvents in vacuuo using a rotary evaporator gave a orange amorphous solid. The crude product was dried in vacuuo at room temperature to yield 151mg of amorphous amber-orange solid. The crude product was used without further purification. LC-MS retention time 2.85min; 659m/z (MH+). LC data was recorded on a

Shimadzu LC-IOAS liquid chromatograph equipped with a Waters Sunfire Cl 8 5u 4.6x50mm column using a SPD-10AV UV -Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 4 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile / 90% H2O / 0.1% TFA and solvent B was 90% H2O / 10% acetonitrile / 0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[4-[[(2R,6S)-2,6- dimethyl^-morpholinylJcarbonylJS-methyl-l-fl-methylethylj-lH -pyrazol-S-ylJS- methoxy-N-[(l-methylethyl)sulfonyl]-

In a 2 dram vial, lH-pyrazole-4-carboxylic acid, 3-[13-cyclohexyl-3-methoxy-10- [[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α] [2]benzazepin-6-yl]-5- methyl- l-(l-methylethyl)- (50 mg, 0.076 mmol) was dissolved in DMF (759 μL) then ΗATU (66 mg, 0.174 mmol) was added to the reaction. The reaction was stirred at room temperature under a nitrogen atmosphere for 20 minutes and DMAP (30.3 mg, 0.248 mmol) was added to the reaction followed by the amine reagent, (2R,6S)- 2,6-dimethylmorpholine (28.2 μL, 0.228 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature overnight (16hrs).

The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 50% solvent A / 50% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system. Volatiles from the product fraction at retention time 15.9 minutes were removed in vacuuo and the title compound was dried in vacuuo at room temperature to yield 25.9mg of a yellow amorphous solid.

1Η NMR of sample shows characteristics of restricted rotation. 1Η NMR (500 MHz, CHLOROFORM-D) δ ppm 0.80 (s, 1.2 H) 0.96 (d, J=4.58 Hz, 0.4 H) 1.07 (d, J=5.80 Hz, 2.3 H) 1.17 - 1.29 (m, 1.2 H) 1.31 - 1.40 (m, 1.1 H) 1.39 - 1.45 (m, 1.1 H) 1.46 - 1.54 (m, 9.9 H) 1.56 (d, J=12.51 Hz, 0.6 H) 1.61 (d, J=6.41 Hz, 0.8 H) 1.65 (d, J=6.10 Hz, 0.5 H) 1.72 (t, J=6.41 Hz, 2.0 H) 1.78 (d, J=10.99 Hz, 2.0 H) 1.89 - 2.02 (m, 2.0 H) 2.02 - 2.17 (m, 2.8 H) 2.20 (s, 0.9 H) 2.27 (s, 2.0 H) 2.30 - 2.44 (m, 1.5 H) 2.49 (d, J=13.12 Hz, 0.5 H) 2.71 (br.s, 4.2 H) 2.81 - 3.01 (m, 2.3 H) 3.15 (s, 0.4 H) 3.27 (d, J=12.82 Hz, 0.5 H) 3.35 - 3.43 (m, 0.7 H) 3.47 - 3.57 (m, 0.5 H) 3.90 (d, J=4.58 Hz, 3.0 H) 4.01 - 4.15 (m, 1.1 H) 4.32 (dd, J=20.29, 14.19 Hz, 0.7 H) 4.38 - 4.55 (m, 2.0 H) 5.15 (d, J=15.56 Hz, 0.2 H) 5.46 (d, J=15.26 Hz, 0.1 H) 5.80 (d, J=14.34 Hz, 0.4 H) 5.93 (d, J=14.34 Hz, 0.3 H) 6.75 (s, 0.4 H) 6.83 - 6.93 (m, 0.6 H) 6.94 - 7.01 (m, J=22.89 Hz, 1.0 H) 7.03 (dd, J=8.55, 2.14 Hz, 1.0 H) 7.39 (t, J=7.17 Hz, 0.7 H) 7.52 (d, J=8.55 Hz, 1.1 H) 7.60 (d, J=8.24 Hz, 0.2 H) 7.82 - 7.98 (m, 1.5 H) 8.02 - 8.11 (m, 0.4 H) 8.34 (d, J=19.84 Hz, 0.6 H) 9.17 (s, 0.1 H) 10.02 (s, 0.2 H).

LC-MS retention time 1.96 min; 754m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-N-[(l- methylethyl)sulfonyl]-6-[5-methyl-4-[(3-methyl-3, 8-diazabicyclo[3.2. lJoct-8- yl)carbonyl] -l-(l-methylethyl)-lH-pyrazol-3-yl] -

lH-pyrazole-4-carboxylic acid, 3-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-5- methyl- l-(l-methylethy I)- (50 mg, 0.076 mmol) was dissolved in DMF (759 μL) and ΗATU (59.6 mg, 0.157 mmol) to the reaction. The reaction was stirred under a nitrogen atmosphere for 55 minutes then DMAP (52.0 mg, 0.426 mmol) was added to the reaction followed by the amine reagent, 3-methyl-3,8- diazabicyclo[3.2.1]octane dihydrochloride (37.8 mg, 0.190 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 63 hours.

The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile with 2 drops of trifluoroacetic acid added, filtered through a syringe filter and the filtrate purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 30 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system.

The retention time of the product was 8.84min. The volatiles/solvents were removed in vacuuo from the product fraction using a rotary evaporator and the product dried in vacuuo at room temperature to yield 27.4mg of the title compound as a yellow solid. The 1Η NMR shows characteristics of restricted rotation and/or salt formation exhibiting broadening of peaks and multiple peak sets, integrals rounded to nearest whole number. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.59 (s, 1 H) 0.89 (s, 1 H) 1.22 (d, J=20.14 Hz, I H) 1.29 - 1.66 (m, 12 H) 1.77 (d, J=10.38 Hz, 4 H) 1.87 - 2.14 (m, 5 H) 2.16 - 2.48 (m, 4 H) 2.79 - 3.07 (m, 3 H) 3.10 - 3.81 (m, 7 H) 3.90 (s, 3 H) 4.04 (d, J=39.06 Hz, 2 H) 4.48 (s, 2 H) 4.67 (s, 1 H) 4.99 (d, J=94.00 Hz, 1 H) 5.71 (s, 1 H) 5.98 (s, 1 H) 6.70 - 6.97 (m, 2 H) 7.04 (d, J=7.63 Hz, 1 H) 7.34 - 7.63 (m, 2 H) 7.76 - 7.94 (m, 2 H) 8.06 (s, 1 H) 9.34 (s, 1 H) 9.70 (s, 1 H) LC-MS retention time 2.01min;765 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-3-methoxy-N-[(l- methylethyl)sulfonyl]-6-[5-methyl-l-(l-methylethyl)-4-[[(3R, 5S)-3, 4, 5-trimethyl-l- piperaziny I] 'car bony I]-I H-pyrazol-3-y I]-

lH-pyrazole-4-carboxylic acid, 3-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-α][2]ben zazepin-6-yl]-5- methyl-l-(l-methylethyl)- (46 mg, 0.070 mmol) was dissolved in DMF (698 μL) and ΗATU (61.6 mg, 0.162 mmol) was added to the reaction. The reaction was capped and stirred for 68 minutes at room temperature then DMAP (44.5 mg, 0.364 mmol) was added to the reaction followed by (2R,6S)-l,2,6-trimethylpiperazine dihydrochloride (35.9 mg, 0.178 mmol). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 17hrs. The product was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The reaction was diluted to 2ml with acetonitrile and 2 drops of TFA added to ensure protonation then filtered through a 0.45uM syringe filter and purified using a Waters Sunfire Prep Cl 8 OBD, 5uM 19mm x 150mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 70 solvent A / 30% solvent B to 0% solvent A / 100% solvent B, a gradient time of 20 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system.

Volatiles were removed from the product fractions in vacuuo overnight using a speed-vac on the medium heating setting. The product fraction were combined in dichloromethane then solvent removed in vacuuo and the product was dried in vacuuo at room temperature to give 27.0mg of the title compound as a brown-tan amorphous solid.

IH NMR is characteristic of restricted rotation and or salt formation. IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0 - 0.61 (m, 2.7 H) 0.91 (t, J=7.32 Hz, 0.8 H) 0.98 - 1.14 (m, 2.6 H) 1.17 - 1.44 (m, 5.9 H) 1.48 (s, 10.7 H) 1.57 - 1.86 (m, 5.3 H) 1.88 - 2.12 (m, 4.2 H) 2.13 - 2.38 (m, 5.0 H) 2.40 - 2.82 (m, 9.1 H) 2.84 - 3.06 (m, 1.9 H) 3.09 - 3.80 (m, 2.7 H) 3.91 (d, J=10.07 Hz, 3.0 H) 4.07 (d, J=10.99 Hz, 1.3 H) 4.22 - 4.40 (m, 0.6 H) 4.42 - 4.51 (m, 1.0 H) 4.55 (d, J=13.73 Hz, 0.3 H) 4.68 (dd, J=30.98, 14.80 Hz, 0.5 H) 5.04 (d, J=15.87 Hz, 0.3 H) 5.83 (d, J=15.26 Hz, 0.3 H) 6.01 (d, J=15.56 Hz, 0.2 H) 6.68 - 6.78 (m, 0.3 H) 6.91 (d, J=27.47 Hz, 0.7 H) 6.96 - 7.11 (m, 1.9 H) 7.38 (dd, J=15.26, 7.93 Hz, 0.6 H) 7.48 - 7.58 (m, 1.0 H) 7.72 (d, J=7.93 Hz, 0.3 H) 7.86 (d, J=8.24 Hz, 0.8 H) 7.93 (s, 0.9 H) 8.08 (s, 0.3 H) 8.37 (d, J=33.57 Hz, 0.5 H) 9.94 (s, 0.3 H) 11.49 (s, 0.4 H). LC-MS retention time 2.04min;767 m/z (MH-). LC data was recorded on a Shimadzu LC-IOAS liquid chromatograph equipped with a Phenomenex-Luna 1Ou Cl 8 3.0x50mm column using a SPD-IOAV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 5 ml/min , a gradient of 100% solvent A / 0% solvent B to 0% solvent A / 100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile / 95% H2O / 10 mM ammonium acetate and solvent B was 5% H2O / 95% acetonitrile / 10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.

7H-indolo[2, 1-a] [2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[l-ethyl-5- (methoxycarbonyl) -3 -methyl- lH-pyrazol-4-yl) '-3-methoxy-, 1 , 1 -dimethylethyl ester

In a microwave tube, 7H-indolo[2,l-α][2]benzazepine-10-carboxylic acid, 13- cyclohexyl-3 -methoxy-6-(tributylstannyl)-, 1 , 1 -dimethylethyl ester ( 1.1 Og, 1.50 mmol), methyl 4-bromo- 1 -ethyl-3 -methyl- lΗ-pyrazole-5-carboxylate (482 mg, 1.92 mmol) and bis(triphenylphosphine)palladium II chloride (105 mg, 0.150 mmol), LiCl (318 mg, 7.51 mmol), CuCl (624 mg, 6.31 mmol) were added. It was then sealed, degassed and flushed with nitrogen. 1,4-Dioxane (7.51 mL) was added. The reaction mixture was heated at 12O ⁰ C under microwave condition for 1 hour. It was then filtered and the filtrate was concentrated. The residue was purified on a Shimadzu high pressure liquid chromatography system employing Discovery VP software interfaced with a SCL-IOA controller, SIL-IOA autosampler and FRC-IOA fraction collector. The sample was dissolved in acetonitrile / DMF (1 :1) (8ml) purified using a Waters Sunfire Prep C18 OBD, 5uM 19mm x 100mm column and monitored using a SPD-10AV UV-Vis detector at a detector wave length of 22OnM. The elution conditions employed a flow rate of 25 mL / min , a gradient of 25% solvent A / 75% solvent B to 0% solvent A / 100% solvent B, a gradient time of 10 minutes with a run time of 20 minutes using %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA solvent system.

The product-containing fractions were collected and concentrated to give title compound as a yellow oil (916 mg, 0.150 mmol, 40% yield). MS m/z 610 (MH ⁺ ).

7H-indolo[2, l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[l-ethyl-5- (methoxycarbonyl)-3-methyl-lH-pyrazol-4-yl]-3-methoxy-

To a solution of 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl- 6-[l-ethyl-5-(methoxycarbonyl)-3-methyl-lH-pyrazol-4-yl]-3-m ethoxy-, 1,1- dimethylethyl ester (290 mg, 0.476 mmol) in 1,2-dichloroethane (0.951 mL), TFA (0.951 mL) was added. The reaction mixture was stirred at RT for 2 hours. Volatiles were removed on a rotary evaporator to give the title compound as a brownish thick oil as crude product (263 mg, 0.476 mmol, 100 % yield). MS m/z 568(MH ⁺ ).

lH-pyrazole-5-carboxylic acid, 4-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl] amino] carbonyl] -7H-indolo[2,l-a] ' [2]benzazepin-6-yl]-l-ethyl- 3 -methyl-, methyl ester

To a solution of 7H-indolo[2,l-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl- 6-[l-ethyl-5-(methoxycarbonyl)-3-methyl-lH-pyrazol-4-yl]-3-m ethoxy-(260 mg, 0.470 mmol) in tetrahydrofuran (1.57 mL) was added carbonyldiimidazole (228 mg,

1.41 mmol). The reaction mixture was heated at 6O ⁰ C for one hour. Propane-2- sulfonamide (231 mg, 1.88 mmol) and DBU (0.212 mL, 1.41 mmol) were added at room temperature. The reaction mixture was then heated at 6O ⁰ C for 2 hours. The reaction mixture was diluted with IN HCl (50 mL) solution and extracted with chloroform (5OmL). The organic layers were combined and concentrated on a rotory evaporator to give an orange oil as crude product. It was purified through silica gel using 90/9/1 methylene chloride/MeOH/AcOH as the eluent to give the title compound (269 mg, 0.409 mmol, 87 % yield) as a yellow oil. MS m/z 659 (MH ⁺ ).

lH-pyrazole-5-carboxylic acid, 4-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a] [2]benzazepin-6-yl]-l-ethyl- 3-methvl-

To a mixture of lH-pyrazole-5-carboxylic acid, 4-[13-cyclohexyl-3-methoxy-10- [[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][ 2]benzazepin-6-yl]-l- ethyl-3 -methyl-, methyl ester (260 mg, 0.395 mmol) was dissolved in dioxane (1.97 mL) and methanol (1.97 mL) was added to the reaction followed by IN aqueous sodium hydroxide (3.95 mL). The reaction was capped under a nitrogen atmosphere and stirred at room temperature for 72 hrs. The reaction was diluted with chloroform (50.0 mL) and washed with 1.0N aqueous hydrochloric acid (50ml). The organic layer was concentrated in vacuuo using a rotary evaporator to yield the title compound as a yellow solid (252 mg, 0.391 mmol, 99%). MS m/z 645 (MH ⁺ ).

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-3- methyl-5-(4-morphoHnylcarbonyl)-lH-pyrazol-4-yl]-3-methoxy-N -[(l- methylethyl)sulfonyl] -

To a solution of lH-pyrazole-5-carboxylic acid, 4-[13-cyclohexyl-3-methoxy-10- [[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][ 2]benzazepin-6-yl]-l- ethyl-3 -methyl- (35 mg, 0.054 mmol) in DMF (0.54 mL), TBTU (35 mg, 0.109 mmol) and DIPEA (0.028 mg, 0.22 mmol) were added. The reaction mixture was stirred at RT for 15 min. Then morpholine (19 mg, 0.22 mmol) was added. The solution was stirred at RT for overnight. The reaction mixture was purified by prep HPLC column using CH3CN/H2O/TFA as solvent system. Fractions were collected and concentrated under speedvac overnight to yield the title compound as a beige solid (26 mg, 0.036 mmol, 81 % yield). MS m/z 714 (MH ⁺ )

IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.19 - 1.62 (m, 13 H) 1.76 - 2.30 (m, 6 H) 2.41 (s, 3 H) 2.60 (m, 1 H) 2.77 - 3.22 (m, 8 H) 3.94 (s, 3 H) 4.13 (m, 2 H) 4.30 (m, 1 H) 4.63 (br d, 1 H) 4.83 (br d, 1 H) 6.72 (s, 1 H) 6.97 (s, 1 H) 7.12 (d, J=8.24 Hz, 1 H) 7.65-7.70 (m, 3 H) 7.98 (d, J=8.24 Hz, 1 H) 10.38 (s, 1 H).

The following compounds were synthesized by an analogous method as described above for 7H-indolo[2,l-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l- ethyl-3 -methyl-5-(4-morpholinylcarbonyl)- 1 H-pyrazol-4-yl] -3 -methoxy-N- [( 1 - methylethyl)sulfonyl]-:

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[5-[[(2R,6S)-2,6- dimethyl-4-morpholinyl]carbonyl]-l-ethyl-3-methyl-lH-pyrazol -4-yl]-3-methoxy-N- [(l-methylethyl)sulfonyl]-

MS m/z 742 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 0.75 (m, 6 H) 1.05 - 1.62 (m, 13 H) 1.76 - 2.26 (m, 6 H) 2.33 (m, 1 H) 2.39 (s, 3 H) 2.81 - 3.29 (m, 4 H) 3.70-4.01 (m, 5 H) 4.14 (m, 2 H) 4.27 (m, 1 H) 4.63 (br d, 1 H) 4.83 (br d, 1 H) 6.70 (s, 1 H) 6.98 (s, 1 H) 7.18 (br d, 1 H) 7.65-7.81 (m, 3 H) 7.96 (d, J=8.24 Hz, 1 H) 10.49 (s, 1 H). 7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-3- methyl-5-[(4-methyl-l-piperazinyl)carbonyl]-lH-pyrazol-4-yl] -3-methoxy-N-[(l- methylethyl)sulfonyl] -

MS m/z 727 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.22 - 1.62 (m, 13 H) 1.76 - 2.20 (m, 6 H) 2.39 (br s, 6 H) 2.78 - 3.90 (m, 9 H) 3.96 (s, 3 H) 4.08- 4.25 (m, 3 H) 4.63 (br d, 1 H) 4.73 (br d, 1 H) 6.78 (s, 1 H) 6.99 (s, 1 H) 7.12 (br d, 1 H) 7.62-7.82 (m, 3 H) 7.98 (br d, 1 H) 10.02 (br s, 1 H).

7H-indolo[2,l-a] [2]benzazepine-10-carboxamide, 13-cyclohexyl-6-[l-ethyl-3- methyl-5-[[(3R, 5S)-3, 4, 5-trimethyl-l-piperazinyl] carbonyl] -lH-pyrazol-4-yl] -3- methoxy-N-f(l-methylethyl)sulfonylJ-

MS m/z 755 (MH ⁺ ). IH NMR (500 MHz, CHLOROFORM-D) δ ppm 1.04 (m, 6 H) 1.25 - 1.62 (m, 13 H) 1.76 - 2.13 (m, 6 H) 2.31 (br s, 3 H) 2.40 (s, 3 H) 2.99-3.12 (m, 3 H) 3.35 - 3.52 (m, 2 H) 3.90-3.99 (m, 4 H) 4.05-4.25 (m, 4 H) 4.64 (br d, 1 H) 4.85 (br d, 1 H) 6.76 (s, 1 H) 6.98 (s, 1 H) 7.13 (d, J=8.24 Hz, 1 H) 7.59 (d, J=8.24 Hz, 1 H) 7.82 (m, 2 H) 8.00 (d, J=8.24 Hz, 1 H) 10.05 (s, 1 H).

7H-indolo[2, 1 -a] [2] benzazepine-6-propanoic acid, 13-cyclohexyl-3-methoxy- 10-[[[(l-methylethyl)sulfonyl] amino] carbonyl]-beta-oxo-, ethyl ester.

To a stirred solution of 7H-indolo[2,l-a][2]benzazepine-6-carboxylic acid, 13-cyclohexyl-3-methoxy-10-[[[(l-methylethyl)sulfonyl]amino] carbonyl]- (4 g, 7.45 mmol) in THF (20 mL) was added CDI (1.151 g, 7.10 mmol) and the mixture was heated at 45 ⁰ C for 0.5 h and the reaction mixture was cooled and transferred into a suspension of magnesium chloride (1.419 g, 14.91 mmol) and potassium ethyl malonate (2.54 g, 14.91 mmol) in THF (15 mL). Additional THF (40 mL) was added to dissolve the ensuing precipitation. The reaction mixture was stirred for 0.5 h at r. t. and then heated at 60 ⁰ C overnight. Rxn mixture was cooled to rt and diluted with EtOAc, washed with IN HCl, brine and dried (Mg2SO4). Crude product was purified on a Thomson 16Og column (MeOH/DCM: 0 to 25%) to afford the product as a reddish solid (3.8 g, 84%). LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.418 min, m/z 607 (MH ⁺ ). lH-pyrrole-3-carboxylic acid, 2-fl i-cyclohexyl-i-methoxy-10-[[[(l- methylethyl)sulfonyl] amino] carbonyl] -7H-indolo[2,l-a] ' [2]benzazepin-6-yl]-l-(l- methylethyl)-, ethyl ester. To a solution of 7H-indolo[2,l-a][2]benzazepine-6-propanoic acid, 13- cyclohexyl-3-methoxy-10-[[[(l-methylethyl)sulfonyl]amino]car bonyl]-beta-oxo-, ethyl ester (0.8 g, 1.055 mmol) in THF (3 mL) was added propan-2-amine (0.624 g, 10.55 mmol) and Tosic Acid (10.03 mg, 0.053 mmol). The mixture was stirred at r.t. for 0.5 h and 1 ,2-dibromoethyl acetate (0.337 g, 1.371 mmol) was added at 0 ⁰ C. The reaction mixture was stirred at r.t. for 0.5 h and then sodium hydride (0.051 g, 2.110 mmol) was added and stirred for 10 min at r.t. The mixture was heated at 60 ⁰ C for 3 h and cooled to r.t., diluted with EtOAc and washed with ice cold HCl (IN), brine and dried (MgSO4). Crude product was purified on a Biotage 25M column, (EtOAc/hexane: 5-100%) to afford the compound as a beige foam (0.26 g, 35%). LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.631 min, m/z 672 (MH ⁺ ).

lH-pyrrole-3-carboxylic acid, 2-[l 3-cyclohexyl-3-methoxy-l 0-[[[(l- methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][2]benz azepin-6-yl]-l-(l- methylethyl)-.

To a solution of lH-pyrrole-3-carboxylic acid, 2-[13-cyclohexyl-3-methoxy- 10-[[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l- a][2]benzazepin-6-yl]- l-(l-methylethyl)-, ethyl ester (80 mg, 0.119 mmol) in THF (2 mL) and was added potassium trimethylsilanolate (45.8 mg, 0.357 mmol). The mixture was stirred under nitrogen for 30 min and another portion of potassium trimethylsilanolate (100 mg) was added. The reaction mixture was stirred at r.t. for 2 days and diluted with EtOAc, washed with cold 1 N HCl, brine, dried (MgSO4) and removed the solvent to afford the acid as a beige solid (71 mg, 88%). IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.80 (1 H, br. s.), 7.81 - 7.89 (1 H, m), 7.76 (1 H, s), 7.45 - 7.52 (1 H, m), 7.42 (1 H, d, J=6.29 Hz), 7.03 (1 H, dd, J=8.69, 2.64 Hz), 6.93 (1 H, d, J=2.27 Hz), 6.47 - 6.76 (3 H, m), 4.98 (1 H, d, J=13.85 Hz), 4.61 (1 H, d, J=14.60 Hz), 3.97 - 4.07 (1 H, m), 3.89 (1 H, s), 3.34 - 3.52 (1 H, m), 2.73 - 2.89 (1 H, m), 1.87 - 2.12 (4 H, m), 1.66 - 1.84 (2 H, m), 0.81 - 1.55 (19 H, m). LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.503 min, m/z 644 (MH ⁺ ).

13-Cyclohexyl-6-(l-isopropyl-3-(3-methyl-3, 8-diazabicyclo[3.2. l]octane-8- carbonyl)-lH-pyrrol-2-yl)-3-methoxy-N-(isopropylsulfonyl)-7H -indolo[2,l- a] [2]benzazepine-10-carboxamide.

IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87 (1 H, d, J=8.56 Hz), 7.78 (1 H, s), 7.66 (1 H, d, J=8.06 Hz), 7.54 (1 H, d, J=8.31 Hz), 7.02 - 7.09 (1 H, m), 6.89 (1 H, d, J=2.77 Hz), 6.83 (1 H, br. s.), 6.69 (1 H, br. s.), 6.48 (1 H, br. s.), 4.91 (1 H, d, J=15.36 Hz), 4.55 (1 H, d, J=15.61 Hz), 4.48 (1 H, br. s.), 4.01 - 4.13 (1 H, m), 3.93 (3 H, s), 3.58 (1 H, br. s.), 3.12 (1 H, br. s.), 2.78 - 2.92 (1 H, m), 1.70 - 2.34 (14 H, m), 1.13 - 1.68 (16 H, m), 1.05 (1 H, br. s.), 0.52 (1 H, br. s.), -0.30 (1 H, br. s.). LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.331 min, m/z 752 (MH ⁺ ).

13-Cyclohexyl-6-(l-isopropyl-3-(4-propylpiperazine-l-carb onyl)-lH-pyrrol- 2-yl)-3-methoxy-N-(isopropylsulfonyl)- 7H-indolo[2,l-a] [2]benzazepine-10- carboxamide. IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87 (1 H, d, J=8.56 Hz), 7.79 (1 H, s), 7.59 (1 H, d, J=8.31 Hz), 7.53 (1 H, d, J=8.56 Hz), 7.05 (1 H, dd, J=8.69, 2.64 Hz), 6.90 (1 H, d, J=2.52 Hz), 6.78 (1 H, br. s.), 6.68 (1 H, s), 6.32 (1 H, d, J=2.27 Hz), 4.91 (1 H, d, J=14.60 Hz), 4.55 (2 H, d, J=14.86 Hz), 3.99 - 4.50 (2 H, m), 3.95 - 4.32 (1 H, m), 3.92 (3 H, s), 2.70 - 3.19 (5 H, m), 1.86 - 2.16 (8 H, m), 1.67 - 1.84 (2 H, m), 1.09 - 1.64 (18 H, m), 0.65 - 0.83 (3 H, m). LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.330 min, m/z 754 (MH ⁺ ).

13-Cyclohexyl-6-(3-((2S,6R)-2,6-dimethylmorpholine-4-carb onyl)-l- isopropyl-lH-pyrrol-2-yl)-3-methoxy-N-(isopropylsulfonyl)-7H -indolo[2,l- a][2]benzazepine-10-carboxamide. IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87 - 7.93 (1 H, m), 7.75 (1 H, br. s.), 7.44 - 7.66 (2 H, m), 7.01 - 7.12 (1 H, m), 6.90 (1 H, br. s.), 6.83 (1 H, br. s.), 6.64 (1 H, br. s.), 6.37 (1 H, br. s.), 4.90 (0 H, d,

J=14.86 Hz), 4.57 (1 H, s), 4.31 - 4.50 (1 H, m), 4.05 - 4.16 (1 H, m), 3.94 (3 H, s), 3.85 - 3.92 (1 H, m), 2.70 - 3.74 (5 H, m), 1.84 - 2.25 (7 H, m), 1.66 - 1.84 (2 H, m), 0.97 - 1.66 (20 H, m), 0.53 - 0.93 (5 H, m); LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.550 min, m/z 741 (MH ⁺ ).

13-Cyclohexyl-6-(l-isopropyl-3-(morpholine-4-carbonyl)-lH-py rrol-2-yl)-3- methoxy-N-(isopropylsulfonyl)- 7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.21 (1 H, br. s.), 7.92 (1 H, d, J=8.56 Hz), 7.84 (1 H, s), 7.61 (1 H, d, J=8.31 Hz), 7.56 (1 H, d, J=8.81 Hz), 7.09 (1 H, dd, J=8.69, 2.64 Hz), 6.90 (1 H, d, J=2.77 Hz), 6.82 (1 H, br. s.), 6.69 (1 H, s), 6.36 (1 H, d, J=2.52 Hz), 4.94 (1 H, d, J=14.86 Hz), 4.56 (1 H, d, J=15.11 Hz), 4.38 (1 H, br. s.), 4.02 - 4.12 (1 H, m), 3.94 (3 H, s), 3.58 - 4.14 (2 H, m), 2.53 - 3.28 (6 H, m), 1.95 (1 H, br. s.), 1.88 - 2.30 (4 H, m), 1.72 - 1.85 (2 H, m), 1.08 - 1.64 (16 H, m).

3-Furancarboxylic acid, 2-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl) sulfony IJ amino] carbonylj- 7H-indolo[2, 1-a] [2]benzazepin-6-yl]-, ethyl ester

lH-pyrrole-3-carboxylic acid, 2-fl 3-cyclohexyl-3-methoxy-l 0-[[[(l- methylethyl) sulfony I] amino] carbonyl] - 7H-indolo[2, 1-a] [2]benzazepin-6-yl]-, ethyl ester

To a solution of starting 7H-indolo[2,l-a][2]benzazepine-6-propanoic acid, 13-cyclohexyl-3-methoxy-10-[[[(l-methylethyl)sulfonyl]amino] carbonyl]-beta-oxo-, ethyl ester (1.200 g, 1.978 mmol) in THF (20 mL) was added 1,2-dibromoethyl acetate in THF (0.26 M, 9.13 mL, 2.373 mmol). NH ₃ was then bubbled through the mixture for 10 min and the reaction was maintained under ammonia (1 atmosphere) overnight. The mixture was then heated at 60° C for 2 h and then cooled to room termperature., diluted with EtOAc and washed with cold 0.5 N HCl (3x) and brine. The organic layer was then dried (MgSO ₄ ) and filtered and the filtrate evaporated under reduced pressure. The crude product was purified on a Biotage 4OM Column (EtOAc/hexane 0% to 100%) to afford a yellow solid which was further purified by preparative HPLC to afford the title furan (65 mg, 5%) and title pyrrole (145 mg, 11%). Furan product: IH NMR (400 MHz, METHANOL-d _A ) δ ppm 8.10 (1 H, s), 7.90 (1 H, d, J=8.56 Hz), 7.81 (1 H, s), 7.49 - 7.63 (3 H, m), 7.05 - 7.18 (2 H, m), 6.86 (1 H, d, J=2.01 Hz), 5.93 (1 H, d, J=14.35 Hz), 4.28 - 4.47 (3 H, m), 3.94 - 4.02 (1 H, m), 3.92 (3 H, s), 2.79 - 2.96 (1 H, m), 1.86 - 2.23 (4 H, m), 1.69 - 1.84 (2 H, m), 1.44 (6 H, d, J=6.80 Hz), 1.35 (3 H, t, J=7.05 Hz), 1.27 - 1.60 (4 H, m). LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.736 min, m/z 631 (MH ⁺ ). Pyrrole product: IH NMR (400 MHz, MeOD) δ ppm 11.02 (1 H, br. s.), 8.03 (1 H, br. s.), 7.84 (1 H, d, J=8.56 Hz), 7.81 (1 H, s), 7.47 - 7.56 (2 H, m), 7.01 - 7.11 (2 H, m), 6.90 (1 H, s), 6.58 - 6.64 (2 H, m), 5.44 (1 H, d, J=17.63 Hz), 4.51 (1 H, d, J=14.10 Hz), 4.18 - 4.35 (2 H, m), 3.87 (3 H, s), 3.81 - 3.97 (1 H, m), 2.82 - 2.95 (1 H, m), 1.86 - 2.20 (4 H, m), 1.68 - 1.84 (2 H, m), 1.12 - 1.55 (13 H, m). LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.475 min, m/z 630 (MH ⁺ ).

3-Furancarboxylic acid, 2-[13-cyclohexyl-3-methoxy-10-[[[(l- methylethyl)sulfonyl] amino] carbonyl] -7H-indolo[2,l-a] ' [2]benzazepin-6-yl]-.

To a mixture of 3-Furancarboxylic acid, 2-[13-cyclohexyl-3-methoxy-10- [[[(l-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,l-a][ 2]benzazepin-6-yl]-, ethyl ester (63 mg, 0.100 mmol) and potassium trimethylsilanolate (128 mg, 0.999 mmol) was added THF (2 mL). The mixture was stirred at r. t. under nitrogen for 2 h. Diluted with EtOAc and washed with cold IN HCl and dried (MgSO4), removed the solvents to afford acid (48 mg, 80%). LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.558 min, m/z 603 (MH ⁺ ).

13-cyclohexyl-6-(3-(morpholine-4-carbonyl)furan-2-yl)-3-m ethoxy-N- (isopropylsulfonyl)- 7H-indolo[2, 1-a] [2]benzazepine-l O-carboxamide.

IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.08 (1 H, d, J=LOl Hz), 7.86 (1 H, d, J=8.56 Hz), 7.66 (1 H, dd, J=8.44, 1.38 Hz), 7.49 (1 H, d, J=8.56 Hz), 7.40 (1 H, d, J=1.76 Hz), 7.33 (1 H, s), 7.04 (1 H, dd, J=8.56, 2.77 Hz), 6.96 (1 H, d, J=2.52 Hz), 6.48 (1 H, d), 5.23 (1 H, d), 4.40 (1 H, d), 3.99 - 4.18 (2 H, m), 3.90 (3 H, s), 3.79 - 3.95 (1 H, m), 3.67 - 3.78 (2 H, m), 3.42 - 3.51 (2 H, m), 3.33 - 3.41 (1 H, m), 3.19 - 3.31 (1 H, m), 2.75 - 2.88 (1 H, m), 1.86 - 2.13 (4 H, m), 1.14 - 1.83 (12 H, m); LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.276 min, m/z 711 (MH ⁺ ).

13-cyclohexyl-6-(3-(3-methyl-3, 8-diazabicyclo[3.2. l]octane-8- carbonyl)furan-2-yl)-lH-pyrrol-2-yl)-3-methoxy-N-(isopropyls ulfonyl)-7H- indolo[2,l-a][2]benzazepine-10-carboxamide. LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5. LC/MS: retention time 3.503 min, m/z 644 (MH ⁺ ).

5H-indolo[2, 1 -a] [2] benzazepine-1 O-carboxamide, 13-cyclohexyl-6-[3- [(dimethylamino)carbonyl] -5-methyl-4H- 1 ,2,4-triazol-4-yl] -N- [(dimethylamino)sulfonyl]-6, 7-dihydro-3-methoxy-. To a mixture of ethanediamide, N'-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbon yl]-6,7-dihydro-3- methoxy-5H-indolo[2,l-α][2]benzazepin-6-yl]-N,N-dimethyl- (19.9 mg, 0.033 mmol) in CH ₂ Cl ₂ (1 mL) at 0 ⁰ C under N ₂ was added phosphorus pentachloride (20.4 mg, 0.098 mmol). The mixture was stirred at 0 ⁰ C for 2 hours, and then added with acetylhydrazine (7.25 mg, 0.098 mmol). The mixture was stirred at 0 ⁰ C for 1 hour, and then at r.t. for 21 hours. The mixture was added another 14.5 mg (0.196 mmol) of acetylhydrazine, evaporated to dryness, added PI1CH3 (1 mL), and then stirred at 120 ⁰ C for 6 hours. The mixture was cooled to r.t. and then evaporated. The residue was diluted with MeOH and purified by using Shimadzu-VP preparative reverse phase HPLC to obtain the TFA salt of the product using the separation method: Solvent A = 10% MeOH-90% H ₂ O-0.1% TFA, Solvent B = 90%

MeOH- 10%H ₂ O-0.1% TFA, Start %B = 60, Final %B = 90, Gradient time = 10 min, Stop time = 12 min, Flow Rate = 30 mL/min, Column: Xterra Prep MS Cl 8 5u 30x50mm, Fraction Collection: 7.02 - 7.62 min. (UV detection at 220 nm). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A = 10% MeOH-90% H ₂ O-0.1% TFA, Solvent B = 90% MeOH- 10%H ₂ O-0.1% TFA, Start %B = 0, Final %B = 100, Gradient time = 2 min, Stop time = 3 min, Flow Rate = 5 ml/min, Column: Xterra MS C18 S7 3.0 x 50mm; (ES+) m/z (M+H) ⁺ = 648.41, HPLC R _t = 1.787 min. HPLC method: Solvent A = 5% MeCN-95% H ₂ O-IO mM NH ₄ OAc, Solvent B = 95% MeCN-5%H ₂ O-10 mM NH ₄ OAc, Start %B = 0, Final %B = 100, Gradient time = 2 min, Stop time = 3 min, Flow Rate = 5 ml/min, Column: Phenomenex Lina C18 5um 3.0 x 50mm; (ES+) m/z (M+H) ⁺ = 648.38, HPLC R _t = 1.260 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 254 nm and 256 nm. Analytical HPLC method: Solvent A = 5% MeCN-95% H ₂ O-0.1% TFA, Solvent B = 95% MeCN-5%H ₂ O-0.1% TFA, Start %B = 10, Final %B = 100,

Gradient time = 10 min, Stop time = 20 min, Flow Rate = 1 ml/min, Column: Waters Sunfire C- 18, 4.6 x 150 mm, 3.5 um; R _t = 10.46 min; Column: Waters Xbridge Phenyl 4.6 x 150 mm, 3.5 um; R _t = 9.42 min.

5H-indolo[2, 1 -a] [2] benzazepine-10-carboxamide, 13-cyclohexyl-6-[3- [(dimethylamino)carbonyl] -4H-1 , 2, 4-triazol-4-yl]-N-[(dimethylamino)sulfonyl]-6, 7- dihydro-3-methoxy-. This example was prepared in a similar manner as described by using formylhydrazine as the coupling partner. Purification by Shimadzu-VP preparative reverse phase HPLC to obtain the TFA salt of the product using the separation method: Solvent A = 10% MeOH-90% H ₂ O-0.1% TFA, Solvent B = 90% MeOH- 10%H ₂ O-0.1% TFA, Start %B = 40, Final %B = 90, Gradient time = 10 min, Stop time = 12 min, Flow Rate = 30 mL/min, Column: Xterra Prep MS Cl 8 5u 30x50mm, Fraction Collection: 9.57 - 9.99 min. (UV detection at 220 nm). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A = 10% MeOH-90% H ₂ O-0.1% TFA, Solvent B = 90% MeOH-10%H ₂ O-0.1% TFA, Start %B = 0, Final %B = 100, Gradient time = 2 min, Stop time = 3 min, Flow Rate = 5 ml/min, Column: Xterra MS C18 S7 3.0 x 50mm; (ES+) m/z (M+H) ⁺ = 634.45, HPLC R _t = 1.785 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 254 nm and 256 nm. Analytical HPLC method: Solvent A = 5% MeCN-95% H ₂ O-0.1% TFA, Solvent B = 95% MeCN-5%H ₂ O-0.1% TFA, Start %B = 10, Final %B = 100, Gradient time = 10 min, Stop time = 20 min, Flow Rate = 1 ml/min, Column: Waters Sunfire C- 18, 4.6 x 150 mm, 3.5 urn; R _t = 10.33 min; Column: Waters Xbridge Phenyl 4.6 x 150 mm, 3.5 um; R _t = 9.44 min.

All the Prep HPLC purifications were run at following conditions except for the other conditions that mentioned in individual procedures. Solvent A: 10% MeOH-90% H ₂ O-0.1% TFA; Solvent B: 90% MeOH-10% H ₂ O-0.1% TFA; Column: XTERRA 30xl00mm S5. LCMS methods: All LCMS analysis conditions used method 1 except mentioned in individual procedure. Method 1 : Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 ml/min; Wavelength: 220; Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5; Method 2: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 5 min; Flow rate: 4 ml/min; Wavelength: 220; Solvent A: 10% MeOH / 90% H ₂ O / 0.1% Trifluoroacetic Acid; Solvent B: 10% H ₂ O / 90% MeOH / 0.1% Trifluoroacetic Acid; Column: XBridge 4.6 x 50 mm S5.

Preparation of compound 1: 13-cyclohexyl-6-[l-cyclopropyl-4-[[(2R,6S)-2,6- dimethyl-4-morpholinyl] carbonyl] -lH-imidazol-5-yl] -3-methoxy-N-[(l- methylethyl)sulfonyl] - 7H-indolo[2, 1-a] [2]benzazepine-10-carboxamide

Step 1: Preparation of compound 1-1

To a solution of ethyl 2-amino-2-cyanoacetate (1.8 g, 15 mmol) in Acetonitrile (25 mL) was added triethoxymethane (2.7 mL, 16.3 mmol). The clear brown solution was refluxed for 1 h, removed the solvent in vacuum to afford a residue. A mixture of the above residue and cyclopropanamine (1.2 mL, 17.32 mmol) in Acetonitrile (15 mL) in a sealed tube was heated at 50 ⁰ C for 0.5 h and 85 ⁰ C for 3h, cooled and then removed the solvents. The residue was dissolved in DCM, washed with 2 N NaOH, dried (MgSO4), removed the solvent to afford compound 1-1 as a beige solid (1.8 g, 62%). The crude product was directly used in next reaction.

Step 2: Preparation of compound 1-2

To a solution of isopentyl nitrite (3.70 mL, 27.7 mmol) in CH ₂ I ₂ (10 mL, 124 mmol) was added dropwise a solution of compound 1-1 (1.8 g, 9.22 mmol) in chloroform (10 mL) at 90 ⁰ C (bath temperature) over 5 min, 5 ml CHCI3 was used to washed the flask to complete the transfer. After the reaction mixture was stirred for Ih at 90 ⁰ C, the solvents were partially removed and the remaining mixture was purified on Thomson 80g column (EtOAc/hexane: 0 to 100%) to afford compound 1-2 as a reddish semi-solid (0.71g, 25%). LC-MS retention time: 1.682 min; MS m/z 307 (M+H) ⁺ . IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.69 (1 H, s), 4.39 (2 H, q, J=7.05 Hz), 3.12 - 3.27 (1 H, m), 1.41 (3 H, t, J=7.18 Hz), 1.16 - 1.26 (2 H, m), 0.96 - 1.07 (2 H, m).

Step 3: Preparation of compound 1-4

Compound 1-2 (0.6 g, 1.960 mmol), Tetrakis (0.158 g, 0.136 mmol), copper (I) iodide (0.260 g, 1.365 mmol) and compound 1-3 (1 g, 1.365 mmol) was added in a microwave vial. Capped the vessel, evacuated and filled with nitrogen. Dioxane (5 ml) was added and the mixture was evacuated and refilled with nitrogen. The reaction mixture was heated in oil bath at 120 ⁰ C for 4 h. Removed the solvent and the residue was purified on Thomson 80g column (EtOAc/hexane: 0 to 80%) to afford compound 1-4 as a pale yellow solid (0.24 g, 28%). LC-MS retention time: 3.603 min; MS m/z 622 (M+H) ⁺ . IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.78 - 7.84 (2 H, m), 7.37 - 7.70 (2 H, m), 7.04 (1 H, dd, J=8.69, 2.64 Hz), 6.92 (1 H, d, J=2.52 Hz), 6.82 (1 H, s), 5.09 (1 H, d, J=14.35 Hz), 4.70 (1 H, d, J=15.61 Hz), 4.38 (1 H, q, J=7.05 Hz), 3.89 (3 H, s), 2.77 - 2.91 (2 H, m), 1.99 - 2.17 (2 H, m), 1.85 - 1.98 (1 H, m), 1.67 - 1.83 (2 H, m), 1.57 (9 H, s), 1.39 (3 H, t, J=7.05 Hz), 1.12 - 1.65 (7 H, m), 0.70 (1 H, br. s.), 0.59 (1 H, br. s.), 0.03 (1 H, br. s.), -0.66 (1 H, br. s.). Step 4: Preparation of compound 1-5

To a solution of compound 1-3 (0.24 g, 0.386 mmol) in DCM (0.5 mL) was added TFA (1 mL, 12.98 mmol). The mixture was stirred at rt for 1.5 h, removed the solvents in vacuum to afford compound 1-5 as a brown foam (0.218 g, 100%). LC- MS retention time: 3.300 min; MS m/z 566 (M+H) ⁺ .

Step 5: Preparation of compound 1-6

A mixture of compound 1-4 (0.218 g, 0.385 mmol) and CDI (0.125 g, 0.771 mmol) in THF (5ml) was stirred at 50 ⁰ C for 0.5 h, cooled down and added propane-2- sulfonamide (0.100 g, 0.812 mmol) and DBU (0.2 ml, 1.327 mmol). The mixture was stirred at ambient temperature for 3 days and diluted with EtOAc and washed with HCl (0.1 N), brine, removed the solvent, purified on Thomson 25g column (MeOH/DCM: 0 to 25%) to afford compound 1-6 (0.136 g, 53%). LC-MS retention time: 3.208 min; MS m/z 671 (M+H) ⁺ . IH NMR (500 MHz, CHLOROFORM-d) δ ppm 8.12 (1 H, br. s.), 7.89 (1 H, d, J=8.55 Hz), 7.52 (2 H, d, J=8.55 Hz), 7.32 (1 H, br. s.), 7.06 (1 H, dd, J=8.70, 2.59 Hz), 6.93 (1 H, d, J=2.44 Hz), 6.82 (1 H, s), 5.23 (1 H, d, J=14.65 Hz), 4.71 (1 H, d, J=14.34 Hz), 4.29 (2 H, br. s.), 3.97 - 4.06 (1 H, m), 3.90 (3 H, s), 2.78 - 2.93 (2 H, m), 1.86 - 2.23 (4 H, m), 1.12 - 1.84 (15 H, m), 0.72 (1 H, br. s.), 0.59 (1 H, br. s.), 0.03 (1 H, br. s.), -0.50 (1 H, br. s.).

Step 6: Preparation of compound 1-7

A mixture of compound 1-5 (0.136 g, 0.203 mmol) in THF (3 mL), NaOH (1.5 mL, 1.500 mmol), and MeOH (1.5 mL) was stirred at rt over night, diluted with EtOAc and washed with 0.2 N HCl, brine, dried (MgSO4), removed the solvent to afford compound 1-7 as a yellow solid (0.102 g, 78%). LC-MS retention time: 3.055 min; MS m/z 643 (M+H) ⁺ . IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (1 H, br. s.), 7.84 (2 H, br. s.), 7.37 - 7.47 (1 H, m), 7.08 (1 H, br. s.), 6.97 (1 H, dd, J=8.69, 2.39 Hz), 6.71 - 6.84 (1 H, m), 5.81 (1 H, d, J=14.60 Hz), 4.68 (1 H, d, J=15.11 Hz), 3.89 - 3.97 (1 H, m), 3.83 (3 H, s), 2.85 (2 H, br. s.), 1.12 - 2.22 (17 H, m), 0.74 (1 H, br. s.), 0.46 (1 H, br. s.), -0.12 (1 H, br. s.), -0.30 (1 H, br. s.). Step 7: Preparation of compound 1

A mixture of compound 1-6 (0.082 g, 0.128 mmol), DCM (1 mL), TEA (0.1 ml, 0.717 mmol), (2R,6S)-2,6-dimethylmorpholine (0.03 mL, 0.244 mmol), and TBTU (0.060 g, 0.187 mmol) was stirred for 3 h and quenched with MeOH and then removed the solvents. The residue was purified by Prep-HPLC to afford compound 1 and isolated as mono TFA salt (0.0361 g, 31%). LC-MS retention time: 3.170 min; MS m/z 740 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.88 (1 H, br. s.), 7.89 - 8.11 (2 H, m), 7.72 (1 H, d, J=8.56 Hz), 7.62 (1 H, d, J=8.31 Hz), 7.54 - 7.65 (1 H, m), 7.05 - 7.19 (2 H, m), 7.00 (1 H, br. s.), 5.03 - 5.19 (1 H, m), 4.62 (1 H, d, J=14.35 Hz), 4.01 - 4.12 (1 H, m), 3.97 (3 H, s), 3.02 - 3.61 (4 H, m), 2.85 - 2.99 (1 H, m), 1.65 - 2.55 (9 H, m), 0.97 - 1.63 (14 H, m), 0.89 - 0.97 (1 H, m), 0.73 - 0.86 (3 H, m), 0.66 (2 H, br. s.).

Preparation of compound 2: 13-cyclohexyl-6-fl-cyclopropyl-4-(4- morpholinylcarbonyl)-lH-imidazol-5-yl]-3-methoxy-N-[(l-methy lethyl)sulfonyl]- 7H- indolo[2,l-a] [2]benzazepine-10-carboxamide

A mixture of compound 1-6 (0.020 g, 0.031 mmol), DCM (1 mL), morpholine (0.0ImL, 0.115 mmol), TEA (0.05 ml, 0.359 mmol), and TBTU (0.030 g, 0.093 mmol) was stirred at rt for 3 h and quenched with MeOH, and then removed the solvents. The residue was purified by Prep-HPLC to afford compound 2 and isolated as mono TFA salt (0.0072 g, 28%). LC-MS retention time: 3.071 min; MS m/z 712 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.69 (1 H, br. s.), 7.88 - 7.97 (2 H, m), 7.63 (1 H, d, J=8.56 Hz), 7.57 (1 H, d, J=8.81 Hz), 7.13 (1 H, dd, J=8.56, 2.52 Hz), 7.06 (1 H, s), 6.96 (1 H, d, J=2.52 Hz), 5.06 (1 H, d, J=14.60 Hz), 4.61 (1 H, d, J=15.36 Hz), 3.95 - 4.05 (1 H, m), 3.93 (3 H, s), 2.71 - 3.55 (10 H, m), 2.44 (1 H, br. s.), 1-89 - 2.21 (4 H, m), 1.71 - 1.85 (2 H, m), 1.14 - 1.63 (10 H, m), 0.92 - 1.11 (4 H, m).

Preparation of compound 3: 6-[l-cyclobutyl-4-[[(2R,6S)-2,6-dimethyl-4- morpholinyl] carbonyl] -lH-imidazol-5-yl] -13-cyclohexyl-3-methoxy-N-[(l- methylethyl)sulfonyl]- 7H-indolo[2, l-a][2]benzazepine-10-carboxamide

Step 1: Preparation of compound 3-1

Compound 3-1 was prepared by using a similar method as described in synthesis of compound 1-1 except cyclobutanamine (1.4 mL, 16.40 mmol) was used in place of cyclopropanamine (1.8g, 62%). The crude product was directly used in the next reaction. Step 2: Preparation of compound 3-2

To a solution of isopentyl nitrite (3.26 mL, 24.37 mmol) in diiodomethane (10 mL, 124 mmol) was added dropwise a solution of ethyl 5-amino-l-cyclobutyl-lH- imidazole-4-carboxylate (1.7 g, 8.12 mmol) in chloroform (10 mL) at 90 ⁰ C (bath temperature) over 5 min, 5 ml CHC13 was used to washed the flask to complete the transfer. The mixture was stirred for Ih at the temperature. The solvent was partially removed and then purified on Thomson 11Og column (EtOAc/hexane:0 to 100%) to afford a reddish oil which was re-purified on Thomson 90g column (EtOAc/hexane: 0 to 100%) to afford compound 3-2 as a brown solid (0.8 g, 31%). LC-MS retention time: 1.888 min; MS m/z 321 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.83 (1 H, s), 4.58 - 4.71 (1 H, m), 4.37 (2 H, q, J=7.22 Hz), 2.56 - 2.68 (2 H, m), 2.25 - 2.42 (2 H, m), 1.88 - 2.00 (2 H, m), 1.39 (3 H, t, J=7.18 Hz).

Step 3: Preparation of compound 3-3 In a microwave vial was added ethyl l-cyclobutyl-5-iodo-lH-imidazole-4- carboxylate (0.7 g, 2.187 mmol), Tetrakis (0.158 g, 0.136 mmol), copper (I) iodide (0.260 g, 1.365 mmol) and compound 1-3 (1 g, 1.365 mmol). Capped the vessel evacuated and filled with nitrogen. Dioxane (10 ml) was added and the mixture was evacuated and refilled with nitrogen. The reaction mixture was heated in a oil bath at 120 ⁰ C for 4 h, concentrated and the residue was purified on Thomson 80g column (EtOAc/hexane; 0 to 100%) to afford compound 3-3 as a beige solid (0.22 g, 25%). LC-MS retention time: 3.636 min; MS m/z 636 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 - 7.83 (2 H, m), 7.57 - 7.70 (1 H, m), 7.41 - 7.56 (1 H, m), 7.04 (1 H, dd, J=8.56, 2.77 Hz), 6.90 (1 H, d, J=2.52 Hz), 6.68 (1 H, s), 5.02 (1 H, d, J=14.10 Hz), 4.68 (1 H, d, J=14.35 Hz), 4.37 (2 H, br. s.), 3.89 - 4.00 (1 H, m), 3.89 (3 H, s), 2.76 - 2.93 (1 H, m), 2.26 - 2.43 (1 H, m), 1.65 - 2.21 (9 H, m), 1.58 (9 H, s), 0.84 - 1.52 (10 H, m).

Step 4: Preparation of compound 3-4 To a solution of compound 3-3 (0.24 g, 0.377 mmol) in DCM (0.5 mL) was added TFA (1 mL, 12.98 mmol). The mixture was stirred at rt for 2h, and then removed the solvents in vacuum to afford the compound 3-4 as a brown foam (0.219 g, 100%). LC-MS retention time: 3.320 min; MS m/z 580 (M+H) ⁺ . Step 5: Preparation of compound 3-5

A mixture of compound 3-4 (0.219 g, 0.378 mmol) and CDI (0.122 g, 0.752 mmol) in THF (5ml) was stirred at 50 ⁰ C for 0.5 h, cooled and added propane-2-sulfonamide (0.100 g, 0.812 mmol) and DBU (0.2 ml, 1.327 mmol). The mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with EtOAc, washed HCl (0.1N), brine and dried (MgSO4). Crude product was purified on a Thomson 25g column (MeOH/DCM: 0 to 25%) to afford the compound 3-5 (0.087 g, 34%). LC-MS retention time: 3.230 min; MS m/z 685 (M+H) ⁺ ; IH NMR (500 MHz, CHLOROFORM-d) δ ppm 8.30 (1 H, br. s.), 7.89 (1 H, d, J=8.55 Hz), 7.54 (1 H, br. s.), 7.52 (1 H, d, J=8.85 Hz), 7.28 - 7.36 (1 H, m), 7.06 (1 H, dd, J=8.55, 2.44 Hz), 6.92 (1 H, d, J=2.44 Hz), 6.70 (1 H, s), 5.24 (1 H, br. s.), 4.69 (1 H, d, J=14.04 Hz), 4.29 (2 H, br. s.), 3.91 - 4.07 (2 H, m), 3.91 (3 H, s), 2.82 - 2.94 (1 H, m), 1.88 - 2.24 (6 H, m), 1.00 - 1.85 (19 H, m).

Step 6: Preparation of compound 3-6

A mixture of compound 3-5 (0.087 g, 0.127 mmol) in THF (3 mL), NaOH (1.5 mL, 1.500 mmol), and MeOH (1.5 mL) was stirred at rt overnight, diluted with EtOAc and washed with HCl (0.2N), brine, dried (MgSO4), removed the solvent to afford compound 3-6 as a yellow solid (0.079 g, 95%). LC-MS retention time: 3.108 min; MS m/z 657 (M+H) ⁺ .

Step 7: Preparation of compound 3

A mixture of compound 3-6 (0.059 g, 0.090 mmol), TEA (0.06 ml, 0.430 mmol),

(2R,6S)-2,6-dimethylmorpholine (0.03mL, 0.244 mmol), DCM (1 mL) and TBTU (0.060 g, 0.187 mmol) was stirred at rt for 5 h and quenched with MeOH (1 mL), removed the solvent, purified by Prep-HPLC to afford compound 3 and isolated as mono TFA salt (0.0311 g, 37%). LC-MS retention time: 3.181 min; MS m/z 754 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 9.04 (1 H, br. s.), 7.87 - 8.12 (2 H, m), 7.74 (1 H, d, J=8.06 Hz), 7.61 (1 H, br. s.), 7.18 (1 H, d, J=8.56 Hz), 6.98 (2 H, br. s.), 5.01 - 5.17 (1 H, m), 3.99 (3 H, s), 3.94 - 4.78 (8 H, m), 3.05 - 3.54 (2 H, m), 2.83 - 2.97 (1 H, m), 2.34 - 2.75 (5 H, m), 1.73 - 2.24 (9 H, m), 1.16 - 1.67 (10 H, m), 0.65 - 1.07 (4 H, m). Preparation of compond 4: 6-[l-cyclobutyl-4-(4-morpholinylcarbonyl)-lH-imidazol-

5-yl]-13-cyclohexyl-3-methoxy-N-[(l-methylethyl)sulfonyl] -7H-indolo[2,l- a] [2]benzazepine-10-carboxamide

A mixture of compound 3-6 (0.020 g, 0.030 mmol), DCM (1 mL), TEA (0.05 ml, 0.359 mmol), morpholine (0.0 ImL, 0.115 mmol), and TBTU (0.030 g, 0.093 mmol) was stirred at rt for 5 h and quenched with MeOH (1 mL), removed the solvents and purified by Prep-HPLC to afford compound 4 and isolated as mono TFA salt (0.0046 g, 17%). LC-MS retention time: 3.100 min; MS m/z 726 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.87 (1 H, br. s.), 8.03 (1 H, br. s.), 7.97 (1 H, d, ./=8.31 Hz), 7.70 (1 H, d, J=8.56 Hz), 7.60 (1 H, d, J=8.56 Hz), 7.17 (1 H, dd, J=8.69, 2.64 Hz), 6.93 - 7.00 (2 H, m), 5.08 (1 H, d, J=14.10 Hz), 4.52 - 4.66 (2 H, m), 3.99 - 4.09 (1 H, m), 3.98 (3 H, s), 2.27 - 3.46 (14 H, m), 1.73 - 2.25 (8 H, m), 1.13 - 1.68 (10 H, m).

Preparation of compound 5: l3-cyclohexyl-3-methoxy-6-fl-(l-methylethyl)-4-(4- morpholinylcarbonyl)-lH-imidazol-5-yl]-N-[(l-methylethyl)sul fonyl]-7H-indolo[2,l- a] [2]benzazepine-10-carboxamide

N _A compound 5-1 compound 5-2

(Ph ₃ P) ₄ Pd, CuI, dioxaπe, 12O ⁰ C

Step 1 : Preparation of compound 5-1

To a solution of ethyl 2-amino-2-cyanoacetate (3.5 g, 27.3 mmol) in Acetonitrile (50 mL) was added triethoxymethane (5.00 mL, 30.0 mmol). The clear brown solution was refluxed for 50 min and then removed the solvent in vacuum to afford a brown residue. The residue and propan-2 -amine (2.56 mL, 30.0 mmol) were dissolved in Acetonitrile (50 mL), heated at 50 ⁰ C in a seal tube for 30 min, and at 85 ⁰ C for 30 min. The reaction mixture was cooled and removed the solvent. The residue was dissolved in DCM and washed with 2 N NaOH, dried (MgSO4), removed the solvent. The resultant residue was dissolved in DCM (~5 ml) and enough hexane was added to precipitate out the product which was filtered to afford the compound 5- 1 as a brown solid (1.6 g, 30%). The crude product was directly used in next step. Step 2: Preparation of compound 5-2

To a solution of isopentyl nitrite (3.25 mL, 24.34 mmol) in CH2I2 (30 mL, 372 mmol) was added dropwise a solution of compound 5-1 (1.6 g, 8.11 mmol) in chloroform (8 mL) at 90 ⁰ C (bath temperature) over 5 min. The reaction mixture was stirred at 90 ⁰ C for 1 h, and concentrated, purified on Thomson 11Og column (EtOAc/hexane:0 to 100%) and re-purified on Thomson 90g column (EtOAc/hexane: 0 to 100%) to afford compound 5-2 as a brown solid (1.18 g, 47%). LC-MS retention time: 1.677 min; MS m/z 309 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.81 (1 H, s), 4.45 - 4.60 (1 H, m), 4.40 (2 H, q, J=I A3 Hz), 1.53 (6 H, d, J=6.80 Hz), 1.42 (3 H, t, ./=7.18 Hz).

Step 3: Preparation of compound 5-3

Compound 5-2 (0.290 g, 0.941 mmol), Tetrakis (0.095 g, 0.082 mmol), compound 1-

3 (0.600 g, 0.819 mmol) and CuI (0.03g) were added in a microwave vial, capped, evacuated and filled with nitrogen. Dioxane (3.5 ml) was added and the mixture was evacuated and refilled with nitrogen and then heated in a oil bath at 120 ⁰ C for 2 h. Removed the solvent, and the residue was purified on Thomson 90 g column (EtOAc/hexane: 5 to 100%) to afford compound 5-3 (0.3 Ig, 61%). LC-MS retention time: 3.573 min; MS m/z 624 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.75 - 7.85 (2 H, m), 7.59 - 7.70 (1 H, m), 7.41 - 7.57 (2 H, m), 7.04 (1 H, dd, J=8.69, 2.64 Hz), 6.93 (1 H, d, J=2.52 Hz), 6.67 (1 H, s), 4.98 (1 H, d, ./=14.10 Hz), 4.67 - 4.77 (1 H, m), 4.31 - 4.46 (2 H, m), 3.89 (3 H, s), 3.45 - 3.61 (1 H, m), 2.72 - 2.90 (1 H, m), 1.05 - 2.23 (25 H, m), 0.89 - 0.93 (3 H, m).

Step 4: Preparation of compound 5-4

A mixture of compound 5-3 (0.430 g, 0.689 mmol) in DCM (1 mL) and TFA (5 ml, 64.9 mmol) was stirred for 0.5 h. The reaction mixture was concentrated in vacuum to afford compound 5-4 (0.391 g, 100%). LC-MS retention time: 3.278 min; MS m/z 568 (M+H) ⁺ .

Step 5: Preparation of compound 5-5

A mixture of compound 5-4 (0.391 g, 0.689 mmol), propane-2-sulfonamide (0.255 g,

2.066 mmol), DMAP (0.589 g, 4.82 mmol), and N-(3-Dimethylaminopropy I)-N'- ethylcarbodiimide hydrochloride (0.180 g, 0.939 mmol) in DCM (1 mL) was stirred at rt for 3 days. MeOH (ImL) was added and the mixture was stirred for 0.5 h, diluted with EtOAc, washed with satd. NH4C1, brine, dried (Na2SO4) and purified on Thomson 25g column (MeOH/DCM: 0 to 25%) to afford the compound 5-5 as a yellow glass (0.255 g, 55%). LC-MS retention time: 3.191 min; MS m/z 673 (M+H) ⁺ .

Step 6: Preparation of compound 5-6

A mixture of compound 5-5 (0.25 g, 0.372 mmol) in THF (3 mL), MeOH (1.5 mL) and NaOH (1.5 mL, 1.500 mmol) was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with 0.2 N HCl, brine, dried (MgSO4), removed the solvent to afford compound 5-6 as a yellow solid (0.172 g, 72%). LC-MS retention time: 3.070 min; MS m/z 645 (M+H) ⁺ .

Step 7: Preparation of compound 5

A mixture of compound 5-6 (0.040 g, 0.062 mmol), morpholine (0.04 mL, 0.459 mmol), TBTU (0.0398 g, 0.124 mmol) in DCM (ImL) was stirred at rt for 1 h. Quenched with MeOH, removed the solvents and purified by prep HPLC to afford the compound 5 as a yellow solid and isolated as mono TFA salt (0.0135 g, 24%). LC-MS retention time: 3.060 min; MS m/z 714 (M+H) ⁺ ; IH NMR (400 MHz,

CHLOROFORM-d) δ ppm 8.04 (1 H, br. s.), 7.92 (1 H, d, J=8.56 Hz), 7.64 (1 H, d, J=7.05 Hz), 7.55 (1 H, d, J=8.56 Hz), 7.12 (1 H, dd, J=8.69, 2.64 Hz), 6.95 (1 H, d, J=2.52 Hz), 6.92 (1 H, br. s.), 5.08 (1 H, d, J=14.86 Hz), 4.58 (1 H, d, J=15.36 Hz), 4.26 (1 H, br. s.), 3.94 - 4.03 (1 H, m), 3.93 (3 H, s), 2.75 - 3.79 (8 H, m), 1.87 - 2.18 (4 H, m), 1.69 - 1.84 (2 H, m), 1.08 - 1.60 (18 H, m).

Preparation of compound 6: 13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-3,8- diazabicyclo[3.2.1]oct-8-yl)carbonyl]-l-(l-methylethyl)-lH-i midazol-5-yl]-N-[(l- methylethyl)sulfonyl]- 7H-indolo[2, l-a][2]benzazepine-10-carboxamide

The compound 5-6 (0.046 g, 0.071 mmol ) was dissolved in DCM (2 ml) and added TEA (0.1 ml, 0.717 mmol), 3-methyl-3,8-diazabicyclo[3.2.1]octane, 2 HCl (0.020 g, 0.100 mmol) and TBTU (0.035 g, 0.109 mmol). The mixture was stirred for 1.5 h, quenched with MeOH, removed the solvent and purified by prep HPLC to afford the compound 6 and isolated as bis-TFA salt (0.023 g, 32%). LC-MS retention time: 3.056 min; MS m/z 753 (M+H) ⁺ .

Preparation of compound 7: 13-cyclohexyl-3-methoxy-N-[(l-methylethyl)sulfonyl]-6- [l-(l-methylethyl)-4-[[(3R, 5S)-3, 4, 5-trimethyl-l-piperazinyl]carbonyl]-lH-imidazol- 5-ylJ- 7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxamide

The compound 5-6 (0.046 g, 0.071 mmol) was dissolved in 2 ml of DCM and added TEA (0.1 ml, 0.717 mmol), (2R,6S)-l,2,6-trimethylpiperazine, 2 HCl (0.030 g, 0.149 mmol) and TBTU (0.035 g, 0.109 mmol). The mixture was stirred for 1.5 h, quenched with MeOH, removed the solvent and purified by prep HPLC to afford the compound 6 and isolated as bis-TFA salt (0.0264 g, 36%). LC-MS retention time: 3.035; MS m/z 755 (M+H) ⁺ . Preparation of compound 8: 13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4- morpholinyl] carbonyl] -l-(l-methylethyl)-lH-imidazol-5-yl] -3-methoxy-N-[(l- methylethyl)sulfonyl] - 7H-indolo[2, 1-a] [2]benzazepine-10-carboxamide

To a mixture of compound 5-6 (0.040 g, 0.062 mmol) and (2R,6S)-2,6- dimethylmorpholine (0.04 mL, 0.325 mmol) in DCM was added (2R,6S)-2,6- dimethylmorpholine (0.04 mL, 0.325 mmol) and TBTU (0.0398 g, 0.124 mmol). The reaction mixture was stirred at rt for 1.5 h. Quenched with MeOH, removed the solvent, and purified by prep HPLC to afford the compound 8 as a yellow solid and isolated as mono TFA salt (0.0105 g, 19%).

Preparation of compound 9: 13-cyclohexyl-N- [(dimethylamino)sulfonyl] -3-methoxy- 6-[l-(l-methylethyl)-5-(4-morpholinylcarbonyl)-lH-imidazol-4 -yl]- 7H-indolo[2, 1- a] [2]benzazepine-10-carboxamide

compound 9-1 compound 9-2

Step 1 : Preparation of compound 9-1

A solution of ethyl N-cyanoformimidate (1.095 g, 11.16 mmol) in Ether (5 ml) was added dropwise to a solution of ethyl 2-(isopropylamino)acetate (1.62 g, 11.16 mmol) in ether (5 ml). The reaction mixture was stirred at rt for 1 h and removed the solvent. To the residue was added EtOH (10.00 mL) and potassium ethoxide (1.127 g, 13.39 mmol). The reaction mixture was stirred for 1 h, removed the solvents to afford a tan solid (1.9 g, 86%). The crude product was used in next step.

Step 2: Preparation of compound 9-2

To a solution of isopentyl nitrite (3.86 mL, 28.9 mmol) in CH ₂ L; (20 mL, 248 mmol) was added ethyl 4-amino-l-isopropyl-lH-imidazole-5-carboxylate (1.9 g, 9.63 mmol) in chloroform (8 mL) at 90 ⁰ C over 5 min. To complete the addition CHC13 (1OmL) was used to wash down the solid. After the reaction mixture was stirred for 1 h, the solvent was partially removed and purified on Thomson 9Og column (EtOAc/hexane: 0 to 60%) to afford the compound 9-2 as a brown solid (0.739 g, 25%). LC-MS retention time: 2.098 min; MS m/z 309 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.65 (1 H, s), 5.22 - 5.30 (1 H, m), 4.36 (2 H, q, J=7.22 Hz), 1.47 (6 H, d, J=6.80 Hz), 1.43 (3 H, t, J=7.18 Hz).

Step 3: Preparation of compound 9-3

In a microwave vial was added ethyl 4-iodo-l-isopropyl-lH-imidazole-5-carboxylate (0.389 g, 1.263 mmol), Tetrakis (0.142 g, 0.123 mmol), CuI (0.03 g) and compound

1-3 (0.9 g, 1.228 mmol). Capped the vial evacuated and filled with nitrogen.

Dioxane (3.5 ml) was added and evacuated, filled with nitrogen. The reaction mixture was heated in a oil bath at 120 ⁰ C for 2 h. Cooled and removed the solvent and the residue was purified on Thomson 80g column (EtOAc/hexane: 0 to 80%) to afford compound 9-3 as a pale yellow solid (0.364 g, 47%). LC-MS retention time:

3.588 min; MS m/z 624 (M+H) ⁺ .

Step 4: Preparation of compound 9-4

A mixture of compound 9-3 (0.364 g, 0.584 mmol) and TFA (2 ml, 26.0 mmol) in DCM (1 mL) was stirred at rt for 0.5 h and removed the excess TFa and solvent in vacuum to afford compound the compound 9-4 as a yellow solid (0.33 Ig, 100%). LC-MS retention time: 3.265 min; MS m/z 568 (M+H) ⁺ .

Step 5: Preparation of compound 9-5 A mixture of compound 9-4 (0.331 g, 0.583 mmol), N,N-dimethyl sulfamide (0.22 g, 1.772 mmol), DMAP (0.499 g, 4.08 mmol), and N-(3-Dimethylaminopropy I)-N'- ethylcarbodiimide hydrochloride (0.22 g, 1.148 mmol) in DCM (4 mL) was stirred at rt for 3 days and quenched with 1 ml of MeOH, stirred for 5 min, removed the solvents. The residue was purified on Thomson 4Og column (EtOAc/hexane: 5 to 100%) to afford the compound 9-5 as a DMAP salt (0.42g, 90%). LC-MS retention time: 3.221 min; MS m/z 674 (M+H) ⁺ . Step 6: Preparation of compound 9-6

A mixture of compound 9-5 (0.42 g, 0.528 mmol) in THF (5 mL), MeOH (3 mL) and sodium hydroxide (3 mL, 3.00 mmol) was stirred at rt for 16 h. The reaction mixture was partially concentrated, diluted with EtOAc, washed with pH 4 buffer, dried (MgSO4), and removed the solvent to afford the compound 9-6 as a yellow solid. LC-MS retention time: 2.981 min; MS m/z 646 (M+H) ⁺ .

Step 7: Preparation of compound 7

A mixture of compound 9-6 (0.040 g, 0.062 mmol), morpholine (0.03 mL, 0.344 mmol) and TBTU (0.035 g, 0.109 mmol) in DCM (1 mL) was stirred for 1.5 h, and diluted with MeOH (1 ml), removed the solvent and purified by Prep-HPLC to afford the compound 9 as a yellow solid and isolated as mono TFA salt (0.0091 g, 18%). LC-MS retention time: 3.061 min; MS m/z 715(M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.50 (1 H, br. s.), 8.25 (1 H, br. s.), 7.88 (1 H, d, J=8.31 Hz), 7.67 (1 H, br. s.), 7.48 - 7.56 (1 H, m), 7.09 (1 H, dd, J=8.56, 2.52 Hz), 7.01 (1 H, br. s.), 6.92 (1 H, br. s.), 5.51 (1 H, d, J=14.35 Hz), 4.59 - 4.71 (2 H, m), 4.53 (1 H, d, J=13.35 Hz), 3.89 (3 H, s), 3.74 - 3.83 (1 H, m), 3.42 (2 H, br. s.), 3.21 - 3.30 (1 H, m), 3.03 (6 H, s), 2.83 - 2.95 (1 H, m), 2.28 (1 H, br. s.), 1.86 - 2.20 (7 H, m), 1.73 - 1.83 (2 H, m), 1.09 - 1.72 (9 H, m).

Preparation of compound 10: 13-cyclohexyl-N- [(dimethylamino)sulfonyl] -6- [5- [[(2R,6S)-2,6-dimethyl-4-morphotinyl]carbonyl]-l-(l-methylet hyl)-lH-imidazol-4- yl]-3-methoxy-7H-indolo[2,l-a] [2]benzazepine-10-carboxamide

TEA

A mixture of compound 9-6 (0.04 g, 0.062 mmol), (2R,6S)-2,6-dimethylmorpholine (0.03 mL, 0.244 mmol), and TBTU (0.035 g, 0.109 mmol) in DCM (1 mL) was stirred for 1 h, quenched with MeOH, removed the solvent and purified by Prep- HPLC to afford compound 10 as a yellow solid and isolated as mono TFA salt (0.011 g, 19%). LC-MS retention time: 3.188 min; MS m/z 743 (M+H) ⁺ ; compound 10 exists as rotamers as observed by IH NMR; major rotamer: IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.21 - 8.44 (2 H, m), 7.82 - 7.92 (1 H, m), 7.61 - 7.74 (1 H, m), 5.47 - 5.68 (1 H, m), 4.62 - 4.83 (1 H, m), 4.24 - 4.56 (1 H, m), 3.84 - 3.89 (3 H, m), 3.20 - 3.79 (7 H, m), 3.03 (6 H, s), 2.74 - 2.96 (2 H, m), 2.28 - 2.56 (1 H, m), 1.89 - 2.17 (4 H, m), 1.11 - 1.81 (15 H, m), 0.63 - 1.05 (3 H, m), -0.04 (1 H, d, J=5.79 Hz).

Prpeparation of compound 11: 13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4- morpholinyl] carbonyl] -l-(l-methylethyl)-lH-l ,2,3-triazol-5-yl] -3-methoxy-N-[(l- methylethyl)sulfonyl] - 7H-indolo[2, 1-a] [2]benzazepine-10-carboxamide

compound 11-1

Step 1: Preparation of compound 11-1

To a solution of 2-azidopropane (0.5 g, 5.87 mmol) in THF (20 mL) was added methyl propiolate (0.631 mL, 7.05 mmol) under N2 and followed by addition of TEA (0.983 mL, 7.05 mmol) dropwise. Iodine monochloride (1.145 g, 7.05 mmol) was added (washed with 3 mL of THF to complete the transfer) and added powdered copper (I) iodide (1.343 g, 7.05 mmol) at -30 ⁰ C bath temperature. The reaction mixture was stirred at -30 ⁰ C for 5 min, removed the bath and stirred at rt for 20 h. The reaction mixture was concentrated and directly purified on Thomson 80g column (EtOAc/hexane: 0 to 80%) to afford the compound 10-1 as a yellow solid (0.257 g, 15%). LC-MS retention time: 1.727 min; MS m/z 296 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 4.71 - 4.90 (1 H, m), 3.96 (3 H, s), 1.63 (6 H, d, J=6.80 Hz).

Step 2: Preparation of compound 11-2 Powdered 3A molecular sieve (0.75 g) was added into a 20 ml microwave viall, flame dried under vacuum, refilled with N2 and cooled. Compound 1-3 (0.682 g, 0.931 mmol), methyl 5-iodo-l-isopropyl-lH-l,2,3-triazole-4-carboxylate (0.229 g, 0.776 mmol), and Bis(triphenylphosphine)palladium(II) dichloride (0.055 g, 0.078 mmol) were added. Capped the vial, evacuated and filled with nitrogen. Dioxane (5 ml) was added and the mixture was evacuated and filled with nitrogen and heated in a oil bath at 120 ⁰ C for 2Oh. The reaction mixture was cooled down and filtered through celite, removed the solvent and the residue was purified on Thomson 25g column (EtOAc/hexane: 0 to 100%) to afford the compound 10-2 as a dark brown solid (0.269 g, 57%). LC-MS retention time: 3.743 min; MS m/z 611 (M+H) ⁺ ;1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.81 (1 H, d, J=8.31 Hz), 7.74 (1 H, s), 7.64 (1 H, dd, J=8.56, 1.26 Hz), 7.51 (1 H, d, J=8.56 Hz), 7.08 (1 H, dd, J=8.56, 2.77 Hz), 6.93 (1 H, d, J=2.77 Hz), 4.87 - 5.00 (1 H, m), 4.79 - 4.87 (1 H, m), 4.67 - 4.78 (1 H, m), 3.96 (3 H, s), 3.90 (3 H, s), 2.76 - 2.87 (0 H, m), 1.98 - 2.17 (3 H, m), 1.86 - 1.98 (1 H, m), 1.69 - 1.84 (2 H, m), 1.63 (6 H, d, J=6.80 Hz), 1.56 (9 H, s), 1.13 - 1.70 (6 H, m). Step 3: Preparation of compound 11-3

A mixture of compound 11-2 (0.269 g, 0.440 mmol), DCM (0.5 mL), and TFA (1 ml, 12.98 mmol) was stirred at rt for 1 h. Removed the solvents in vacuum to afford the compound 10-3 (0.244 g, 100%). LC-MS retention time: 3.575 min; MS m/z 555 (M+H) ⁺ .

Step 4: Preparation of compound 11-4

A mixture of compound 11-1 (0.244 g, 0.440 mmol), propane-2-sulfonamide (0.163 g, 1.320 mmol) and DMAP (0.376 g, 3.08 mmol), N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (0.180 g, 0.939 mmol) in DCM (1 mL) was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with cold 0.1 N HCl, water, brine, dried (MgSO4), removed the solvent, and purified on Thomson 12 g column [EtOAc-MeOH (9-l)/hexane: 5 to 100%] to afford the compound 10-4 as a glass (0.150 g, 52%). LC-MS retention time: 3.310 min; MS m/z 660 (M+H) ⁺ .

Step 5: Preparation of compound 11-5

A mixture of compound 11-4 (0.15 g, 0.227 mmol) in THF (2 mL), NaOH (0.909 mL, 0.909 mmol), and MeOH (ImL) was stirred at rt for 20 h, diluted with EtOAc and washed with 0.2 N HCl brine, dried (MgSO4), removed the solvent to afford the compound 10-5 as a yellow solid (0.134 g, 91%). LC-MS retention time: 3.233 min; MS m/z 646 (M+H) ⁺ .

Step 6: Preparation of compound 11 A mixture of compound 11-5 (0.0446 g, 0.069 mmol), (2R,6S)-2,6- dimethylmorpholine (0.008 g, 0.069 mmol),TEA (0.03 mL, 0.215 mmol), and TBTU (0.022 g, 0.069 mmol) in DCM was stirred at rt for 2 h. Quenched with MeOH, removed the solvent and purified by prep HPLC to afford the compound 11 as a yellow solid (0.0122 g, 23%). LC-MS retention time: 3.273 min; MS m/z 743 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.89 (1 H, d, J=8.56 Hz), 7.41 - 7.59 (2 H, m), 7.08 (1 H, d, J=8.56 Hz), 6.94 (1 H, d, J=2.27 Hz), 6.74 (1 H, s), 4.91 - 5.13 (1 H, m), 4.53 - 4.74 (1 H, m), 3.96 - 4.35 (2 H, m), 3.90 (3 H, s), 3.34 - 3.60 (1 H, m), 2.40 - 2.99 (11 H, m), 1.89 - 2.17 (4 H, m), 1.67 - 1.84 (2 H, m), 0.66

- 1.56 (18 H, m).

Preparation of compound 12: 13-cyclohexyl-3-methoxy-N-f(l-methylethyl)sulfonylJ- 6-fl-(l-methylethyl)-4-ff(3R, 5S)-3, 4, 5-trimethyl-l-piperazinyl]carbonyl]-lH-l,2, 3- triazol-5-yl]-7H-indolo[2,l-a][2]benzazepine-10-carboxamide

A mixture of compound 11-5 (0.0446 g, 0.069 mmol), (2R, 6S)-1,2,6- trimethylpiperazine (0.0124 g, 0.097 mmol),TEA (0.1 mL, 0.717 mmol) and TBTU (0.031 g, 0.097 mmol) in DCM was stirred at rt for 1 h. Quenched with MeOH, removed the solvent and purified by prep HPLC to afford the compound 12 as a yellow solid (0.0129 g, 21%) and isolated as mono TFA salt. LC-MS retention time: 3.081 min; MS m/z 756 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.76 - 7.92 (2 H, m), 7.41 - 7.56 (2 H, m), 7.06 (1 H, dd, J=8.69, 2.39 Hz), 6.98 (1 H, br. s.), 6.75 (1 H, s), 5.33 (1 H, br. s.), 5.02 (1 H, br. s.), 4.66 (1 H, d, J=13.85 Hz), 3.99 (1 H, br. s.), 3.89 (3 H, s), 2.63 - 3.78 (10 H, m), 1.00 - 2.21 (28 H, m).

Preparation of compound 13: 13-cyclohexyl-N- [(dimethylamino)sulfonyl] -3- methoxy-6-[l-(l-methylethyl)-4-(4-morpholinylcarbonyl)-lH-l, 2,3-triazol-5-yl]-7H- indolo[2, l-a][2]benzazepine-10-carboxamide

Step 1: Preparation of compound 13-1

A mixture of compound 11-3 (0.296 g, 0.534 mmol) and CDI (0.169 g, 1.042 mmol) in THF (5ml) was stirred at 50 ⁰ C for 0.5 h, cooled and added N ₅ N- dimethylsulfamide (0.129 g, 1.039 mmol) and DBU (0.4 ml, 2.65 mmol). The mixture was stirred at ambient temperature overnight. Removed the solvent in vacuum and added DCM (5mL) and DMAP (0.250 g, 2.046 mmol), and l-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.140 g, 0.730 mmol). The reaction mixture was stirred overnight, concentrated and directly loaded on

Thomson 4Og column (EtOAc/Hexane: 5 to 100%). The collection was dissolved in EtOAc and washed with cold HCl (IN), brine, dried (MgSO4), removed the solvent to afford compound 13-1 as a yellow solid (0.240 g, 68%). LC-MS retention time: 3.250 min; MS m/z 661 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 9.06 (1 H, br. s.), 8.21 (1 H, br. s.), 7.90 (1 H, d, J=8.56 Hz), 7.48 - 7.57 (1 H, m), 7.19 (1 H, br. s.), 7.09 (1 H, dd, J=8.69, 2.64 Hz), 6.95 (1 H, d, J=2.52 Hz), 6.75 (1 H, s), 5.21 (1 H, br. s.), 4.76 (1 H, br. s.), 3.93 - 4.02 (1 H, m), 3.91 (3 H, s), 3.77 (3 H, s), 2.92 (6 H, s), 2.81 - 2.89 (1 H, m), 1.09 - 2.27 (16 H, m).

Step 2: Preparation of compound 13-2

A mixture of compound 13-1 (0.24 g, 0.363 mmol) in THF (4 mL), NaOH (2 mL, 2.000 mmol) and MeOH (2mL) was stirred at rt for 20 h. Diluted with EtOAc and washed with 0.2 N HCl, brine, dried (MgSO4), removed the solvent to afford a brown solid. LC-MS retention time: 3.220 min; MS m/z 647 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.51 (1 H, br. s.), 7.89 (1 H, d, J=8.56 Hz), 7.65 (1 H, d, J=IM Hz), 7.43 (1 H, d, J=8.56 Hz), 6.99 (1 H, d, J=9.32 Hz), 6.93 (1 H, d, J=2.52 Hz), 6.77 (1 H, s), 5.47 (1 H, br. s.), 4.66 (1 H, d, J=14.86 Hz), 3.91 - 4.00 (1 H, m), 3.80 (3 H, s), 2.83 (6 H, s), 1.04 - 2.24 (16 H, m).

Step 3: Preparation of compound 13

To a mixture of compound 13-2 (0.040 g, 0.062 mmol) and morpholine (0.02ml, 0.230 mmol) in DCM (1 mL) was added TEA (0.03 ml, 0.215 mmol) and TBTU (0.028 g, 0.087 mmol). The reaction mixture was stirred at rt for 2 h and another portion of morpholine (0.02ml, 0.230 mmol) and TBTU (0.028 g, 0.087 mmol) was added and stirred for 1 h. Quenched with MeOH, removed the solvents, and the residue was dissolved in MeOH, filtered and purified by prep-HPLC to afford a yellow solid which was re-purified by prep TLC (MeOH/DCM: 2 to 10%) to afford the compound 13 as a glass (0.0028 g, 6%). LC-MS retention time: 3.198 min; MS m/z 716 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87 (1 H, d, J=8.06 Hz), 7.75 (1 H, br. s.), 7.50 (1 H, d, J=8.81 Hz), 7.36 (1 H, d, J=7.81 Hz), 7.04 - 7.09 (1 H, m), 6.93 (1 H, br. s.), 6.70 (1 H, s), 5.04 (1 H, d, J=18.63 Hz), 4.66 - 4.78 (1 H, m), 4.27 (1 H, br. s.), 4.11 (1 H, br. s.), 3.90 - 4.01 (1 H, m), 3.89 (3 H, s), 3.50 - 3.75 (4 H, m), 3.02 (6 H, s), 2.83 (1 H, br. s.), 2.67 (2 H, br. s.), 1.86 - 2.14 (4 H, m), 0.74 - 1.82 (12 H, m).

Preparation of compound 14: 13-cyclohexyl-6-[4-[(3-methyl-3,8- diazabicyclo[3.2.1]oct-8-yl)carbonyl]-l-(l-methylethyl)-lH-l ,2,3-triazol-5-yl]-N-

[(dimethylamino)sulfonyl]-3-methoxy-7H-indolo[2,l-a] [2]benzazepine-10- carboxamide

To a mixture of compound 13-2 (0.040 g, 0.062 mmol) and 3-methyl-3,8- diazabicyclo[3.2.1]octane, HCl (0.025 g, 0.154 mmol) in DCM (1 mL) was added TEA (0.10 ml, 0.717 mmol) and TBTU (0.028 g, 0.087 mmol). The reaction mixture was stirred at rt for 2 h and another portion of 3-methyl-3,8- diazabicyclo[3.2.1]octane, HCl (0.025 g, 0.154 mmol) and TBTU (0.028 g, 0.087 mmol) were added and stirred for Ih. Quenched with MeOH, removed the solvent, and purified by prep HPLC to afford the compound 14 (0.0223 g, 41.5%) as a yellow solid and isolated as mono TFA salt. LC-MS retention time: 3.086 min; MS m/z 755 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.66 (1 H, br. s.), 7.87 (1 H, d, J=8.56 Hz), 7.79 (1 H, br. s.), 7.46 - 7.56 (1 H, m), 7.32 (1 H, d, J=8.31 Hz), 7.08 (1 H, dd, J=8.69, 2.64 Hz), 6.92 (1 H, br. s.), 6.69 (1 H, br. s.), 5.81 (1 H, br. s.), 5.10 (1 H, d, J=15.36 Hz), 4.82 - 5.04 (2 H, m), 4.71 (1 H, d, J=14.86 Hz), 3.89 (3 H, s), 3.64 - 3.84 (3 H, m), 3.57 (1 H, d, J=I 1.58 Hz), 3.01 (6 H, s), 2.70 - 3.28 (5 H, m), 1.87 - 2.59 (8 H, m), 1.71 - 1.85 (2 H, m), 1.03 - 1.58 (6 H, m), 0.39 - 0.88 (2 H, m).

Preparation of compound 15: 13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4- morphoHnyl]carbonyl]-l-l-(l-methylethyl)-lH-l,2,3-triazol-5- yl]-N- [(dimethylamino)sulfonyl]-3-methoxy-7H-indolo[2,l-a] [2]benzazepine-10- carboxamide

DCM

To a mixture of compound 13-2 (0.040 g, 0.062 mmol) and (2R,6S)-2,6- dimethylmorpholine (0.02 ml, 0.163 mmol) in DCM (1 mL) was added TEA (0.03 ml, 0.215 mmol) and TBTU (0.0278 g, 0.087 mmol). The reaction mixture was stirred at rt for 2 h. Quenched with MeOH, removed the solvents. The residue was dissolved in MeOH, filtered, and purified by prep HPLC to afford the compound 15 as a yellow solid (0.0193 g, 41%). LC-MS retention time: 3.253 min; MS m/z 744 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.89 (1 H, d, J=8.56 Hz), 7.78 (1 H, br. s.), 7.35 - 7.56 (2 H, m), 7.09 (1 H, d, J=8.56 Hz), 6.93 (1 H, br. s.), 6.74 (1 H, br. s.), 4.94 - 5.09 (1 H, m), 4.67 (1 H, d, J=14.60 Hz), 3.94 - 4.36 (2 H, m), 3.90 (3 H, s), 3.43 - 3.64 (1 H, m), 3.02 (6 H, s), 2.51 - 3.38 (7 H, m), 1.87 - 2.19 (4 H, m), 1.78 (2 H, d, J=9.32 Hz), 0.70 - 1.56 (14 H, m).

Preparation of compound 16: 13-cyclohexyl-6-[4-[(6,6-difluorohexahydro-4-methyl- IH-1, 4-diazepin-l-yl)carbonyl]-l-(l-methylethyl)-lH-l, 2, 3-triazol-5-yl]-N- [(dimethylamino)sulfonyl]-3-methoxy-7H-indolo[2,l-a] [2]benzazepine-10- carboxamide

To a mixture of compound 13-2 (0.040 g, 0.062 mmol) and 6,6-difluoro-l,4- diazepane, hydrobromide (0.0268 g, 0.124 mmol) in DCM (1 mL) was added TEA (0.10 ml, 0.717 mmol) and TBTU (0.0278 g, 0.087 mmol). The reaction mixture was stirred at rt for 1 h. MeI (0.06 ml, 0.960 mmol) was injected to the reaction mixture and stirred at rt for 1.5 h. Quenched with MeOH, removed the solvents, the residue was dissolved in MeOH, filtered, and purified by prep HPLC to afford a yellow solid which was re-purified by prep TLC to afford the compound 16 as a glass (0.0073 g, 15%). LC-MS retention time: 3.076 min; MS m/z 779 (M+H) ⁺ .

Preparation of compound 17: 13-cyclohexyl-6-[4-[[(3R,5S)-3,4,5-trimethyl-l- piperazinyl] carbonyl] -l-(l-methylethyl)-lH-l ,2,3-triazol-5-yl] -N- [(dimethylamino)sulfonyl]-3-methoxy-7H-indolo[2,l-a] [2]benzazepine-10- carboxamide DCM

To a mixture of compound 13-2 (0.040 g, 0.062 mmol) and (2R,6S)- 1,2,6- trimethylpiperazine, 2 HCl (0.025 g, 0.124 mmol) in DCM (1 mL) was added TEA (0.10 ml, 0.717 mmol) and TBTU (0.028 g, 0.087 mmol). The reaction mixture was stirred at rt for 2 h and another portion of TEA (0.10 ml, 0.717 mmol) and TBTU (0.028 g, 0.087 mmol) were added and stirred for 1 h. Quenched with MeOH, removed the solvents, the residue was dissolved in MeOH, filtered, and purified by prep-HPLC to afford the compound 17 as a yellow solid and isolated as mono TFA salt (0.0293 g, 54%). LC-MS retention time: 3.060 min; MS m/z 757 (M+H) ⁺ .

Preparation of compound 18: 13-cyclohexyl-6-[5-cyclopropyl-3-[[(2R,6S)-2,6- dimethyl-4-morpholinyl] carbonyl] -4-isoxazolyl] -N-[(dimethylamino)sulfonyl] -3- methoxy- 7H-indolo[2, 1-a] [2]benzazepine-l 0-carboxamide

compound 18-1 CuI tetrakis dioxane 120 ⁰ C

Stepl : Preparation of compound 18-1

To a solution of S-cyclopropylisoxazole-S-carboxylic acid (0.5 g, 3.27 mmol) in CHC13 (3 mL) was added a solution of iodine chloride (0.69 g, 4.25 mmol) in CHC13 (6 mL) at 0 ⁰ C. The reaction mixture was stirred at 70 ⁰ C for 5 h. Removed the solvent and the residue was dissolved in ethanol (5 mL, 3.27 mmol) was added S0C12 (0.5 mL, 6.85 mmol). The mixture was stirred at 70 ⁰ C for 1 h, cooled, diluted with EtOAc and washed with cold IN NaOH, brine, dried (MgSO4), and purified by Thomson 25g column (EtOAc/hexane:0 to 100%) to afford the compound 18-1 as an oil. LC-MS retention time: 2.502 min; MS m/z 309 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 4.43 (2 H, q, J=7.22 Hz), 2.10 - 2.21 (1 H, m), 1.41 (3 H, t, J=7.05 Hz), 1.11 - 1.21 (4 H, m). Step 2: Preparation of compound 18-2

In a microwave vial were added ethyl 5-cyclopropyl-4-iodoisoxazole-3-carboxylate (0.360 g, 0.879 mmol), Tetrakis (0.095 g, 0.082 mmol), CuI (0.03 g) and compound 1-3 (0.600 g, 0.819 mmol). Capped the vial evacuated and filled with nitrogen. Dioxane (3.5 ml) was added and the mixture was evacuated and filled with nitrogen. The reaction mixture was heated in a oil bath at 120 ⁰ C for 2 h. Cooled and removed the solvent. The residue was purified on Thomson 40 g column (EtOAc/hexane: 5 to 100%) to afford the compound 18-2 (0.094 g, 18%). LC-MS retention time: 4.04 min; MS m/z 623 (M+H) ⁺ (Method 2); IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.85 (1 H, d, J=I 26 Hz), 7.81 (1 H, d, J=8.31 Hz), 7.64 (1 H, dd, J=8.44, 1.38 Hz), 7.50 (1 H, d, J=8.56 Hz), 7.02 (1 H, dd, J=8.56, 2.77 Hz), 6.90 (1 H, d, J=2.77 Hz), 6.74 (1 H, s), 4.85 - 5.02 (1 H, m), 4.51 - 4.65 (1 H, m), 4.34 - 4.42 (2 H, m), 3.89 (3 H, s), 2.78 - 2.91 (1 H, m), 1.86 - 2.17 (3 H, m), 1.74 (1 H, d, J=3.27 Hz), 1.58 (9 H, s), 1.37 (3 H, t, J=7.05 Hz), 0.49 - 1.67 (11 H, m).

Step 3: Preparation of compound 18-3

To a solution of compound 18-2 (0.094 g, 0.151 mmol) in DCM (0.5 mL) was added TFA (0.5 mL, 6.49 mmol). The mixture was stirred at rt for 1 h and then removed the solvent in vacuum to afford the compound 18-3 as brown foam (0.086 g, 100%). LC-MS retention time: 3.548 min; MS m/z 567 (M+H) ⁺ .

Step 4: Preparation of compound 18-4

To a mixture of compound 18-3 (0.086 g, 0.152 mmol) in and THF (ImI) was added

CDI (0.050 g, 0.308 mmol) the mixture was stirred at 50 ⁰ C for 0.5 h, cooled down and added N,N-dimethylsulfamide (0.040 g, 0.322 mmol) and DBU (0.1 ml, 0.663 mmol). The mixture was stirred at ambient temperature overnight and directly loaded on Thomson 25 g column (MeOH/DCM: 0 to 25%) to afford the compound 18-4 as a yellow glass (0.086 g, 84%). LC-MS retention time: 3.438 min; MS m/z 673 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44 (1 H, br. s.), 7.87 (1 H, d, J=8.31 Hz), 7.82 (1 H, d, J=1.51 Hz), 7.48 - 7.54 (1 H, m), 7.33 - 7.38 (1 H, m), 7.03 (1 H, dd, J=8.56, 2.77 Hz), 6.91 (1 H, d, J=2.52 Hz), 6.75 (1 H, s), 4.92 (1 H, br. s.), 4.63 (1 H, br. s.), 4.23 - 4.45 (2 H, m), 3.90 (3 H, s), 3.03 (6 H, s), 2.82 - 2.90 (1 H, m), 1.11 - 2.16 (14 H, m), 0.46 - 0.94 (4 H, m). Step 5: Preparation of compound 18-5

A suspension of compound 18-4 (0.086 g, 0.128 mmol) in THF (2 mL), MeOH (1 ml) and NaOH (1 ml, 1.000 mmol) was stirred overnight and diluted with EtOAc, washed with pH 4.0 buffer, brine, dried (MgSO4) removed the solvent to afford compound 18-5 as a yellow solid (0.083 g 100%). LC-MS retention time: 3.331 min; MS m/z 645 (M+H) ⁺ .

Step 6: Preparation of compound 18

A mixture of compound 18-5 (0.039 g, 0.060 mmol), TEA (0.15 ml, 1.076 mmol), (2R,6S)-2,6-dimethylmorpholine (0.03 mL, 0.244 mmol), TBTU (0.035 g, 0.109 mmol) in 2 ml of DCM was stirred for 3 h and quenched with MeOH, removed the solvent, and purified by Prep-HPLC to afford the compound 18 (0.0159 g, 34%). LC- MS retention time: 3.271 min; MS m/z 742 (M+H) ⁺ .

Preparation of compound 19: 13-cyclohexyl-6-[5-cyclopropyl-3-(4- morpholinylcarbonyl)-4-isoxazolyl] -N- [(dimethylamino)sulfonyl] -3-methoxy-7H- indolo[2, 1-a] [2]benzazepine-10-carboxamide

TEA

A mixture of compound 18-5 (0.039 g, 0.060mmol), TEA (0.15 m, 0.1076 mmoll), morpholine (0.03 mL, 0.244 mmol), TBTU (0.035 g, 0.109 mmol) in 2 ml of DCM was stirred for 3 h and quenched with MeOH, removed the solvent. The residue was dissolved in MeOH and purified by Prep-HPLC to afford a solid which was re- purified by Prep-HPLC (Solvent A: 10 mM Ammonia Acetate in 95:5 H2O/ACN; 10 mM Ammonia Acetate in 5:95 H2O/ACN; Start B%30 end B% 100, gradient time 16 min; end time 20 min, Column: XTERRA 30xl00mm S5) to afford the compound 19 as a yellow solid (0.0048 g, 11%). LC-MS retention time: 3.190 min; MS m/z 714 (M+H) ⁺ ; IH NMR (400 MHz, CHLOROFORM-d) δ ppm 7.91 (1 H, d, J=8.56 Hz), 7.80 (1 H, d, J=1.51 Hz), 7.55 (1 H, dd, J=8.56, 1.51 Hz), 7.51 (1 H, d, J=8.81 Hz), 7.05 (1 H, dd, J=8.69, 2.64 Hz), 6.89 (1 H, d, J=2.77 Hz), 6.86 (1 H, s), 4.96 (1 H, d, J=15.86 Hz), 4.58 (1 H, d, J=14.86 Hz), 3.91 (3 H, s), 3.13 - 3.30 (2 H, m), 3.06 (2 H, s), 2.78 - 3.10 (6 H, m), 2.66 (1 H, br. s.), 1-84 - 2.28 (7 H, m), 1.68 - 1.82 (2 H, m), 1.00 - 1.55 (10 H, m).

Biological Methods

The compounds demonstrated activity against HCV NS5B as determined in the following HCV RdRp assays.

HCVNS5B RdRp cloning, expression, and purification. The cDNA encoding the NS5B protein of HCV, genotype Ib, was cloned into the pET21a expression vector. The protein was expressed with an 18 amino acid C-terminal truncation to enhance the solubility. The E. coli competent cell line BL21(DE3) was used for expression of the protein. Cultures were grown at 37 ⁰ C for ~ 4 hours until the cultures reached an optical density of 2.0 at 600 nm. The cultures were cooled to 20 ⁰ C and induced with 1 mM IPTG. Fresh ampicillin was added to a final concentration of 50 μg/ml and the cells were grown overnight at 20 ⁰ C.

Cell pellets (3L) were lysed for purification to yield 15-24 mgs of purified

NS5B. The lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500 mM NaCl, 0.5% triton X-100, 1 mM DTT, ImM EDTA, 20% glycerol, 0.5 mg/ml lysozyme, 10 mM MgC12, 15 ug/ml deoxyribonuclease I, and Complete TM protease inhibitor tablets (Roche). After addition of the lysis buffer, frozen cell pellets were resuspended using a tissue homogenizer. To reduce the viscosity of the sample, aliquots of the lysate were sonicated on ice using a microtip attached to a Branson sonicator. The sonicated lysate was centrifuged at 100,000 x g for lhr at 4 ⁰ C and filtered through a 0.2 μm filter unit (Corning).

The protein was purified using three sequential chromatography steps:

Heparin sepharose CL-6B, polyU sepharose 4B, and Hitrap SP sepharose (Pharmacia). The chromatography buffers were identical to the lysis buffer but contained no lysozyme, deoxyribonuclease I, MgC12 or protease inhibitor and the NaCl concentration of the buffer was adjusted according to the requirements for charging the protein onto the column. Each column was eluted with a NaCl gradient which varied in length from 5-50 column volumes depending on the column type. After the final chromatography step, the resulting purity of the enzyme is >90% based on SDS-PAGE analysis. The enzyme was aliquoted and stored at -80 ⁰ C.

Standard HCVNS5B RdRp enzyme assay. HCV RdRp genotype Ib assays were run in a final volume of 60 μl in 96 well plates (Costar 3912). The assay buffer is composed of 20 mM Hepes, pH 7.5, 2.5 mM KCl, 2.5 mM MgC12, 1 mM DTT, 1.6 U RNAse inhibitor (Promega N2515), 0.1 mg/ml BSA (Promega R3961), and 2 % glycerol. All compounds were serially diluted (3 -fold) in DMSO and diluted further in water such that the final concentration of DMSO in the assay was 2%. HCV RdRp genotype Ib enzyme was used at a final concentration of 28 nM. A polyA template was used at 6 nM, and a biotinylated oligo-dT12 primer was used at 180 nM final concentration. Template was obtained commercially (Amersham 27- 4110). Biotinylated primer was prepared by Sigma Genosys. 3H-UTP was used at 0.6 μCi (0.29 μM total UTP). Reactions were initiated by the addition of enzyme, incubated at 30 ⁰ C for 60 min, and stopped by adding 25 μl of 50 mM EDTA containing SPA beads (4 μg/μl, Amersham RPNQ 0007). Plates were read on a Packard Top Count NXT after >lhr incubation at room temperature.

Modified HCVNS5B RdRp enzyme assay. A modified enzyme assay was performed essentially as described for the standard enzyme assay except for the following: The biotinylated oligo dT12 primer was precaptured on streptavidin- coated SPA beads by mixing primer and beads in assay buffer and incubating at room temperature for one hour. Unbound primer was removed after centrifugation. The primer-bound beads were resuspended in 20 mM Hepes buffer, pH 7.5 and used in the assay at final concentrations of 20 nM primer and 0.67 μg/μl beads. Order of addition in the assay: enzyme (14 nM) was added to diluted compound followed by the addition of a mixture of template (0.2 nM) , 3H-UTP (0.6 μCi, 0.29 μM), and primer-bound beads, to initiate the reaction; concentrations given are final. Reactions were allowed to proceed for 4 hours at 30° C. IC50 values for compounds were determined using seven different [I]. IC50 values were calculated from the inhibition using the formula y = A+((B-

A)/(l+((C/x) ^Λ D))).

FRET Assay Preparation. To perform the HCV FRET screening assay, 96- well cell culture plates were used. The FRET peptide (Anaspec, Inc.) (Taliani et al, Anal. Biochem. 1996, 240, 60-67) contains a fluorescence donor, EDANS, near one end of the peptide and an acceptor, DABCYL, near the other end. The fluorescence of the peptide is quenched by intermolecular resonance energy transfer (RET) between the donor and the acceptor, but as the NS3 protease cleaves the peptide the products are released from RET quenching and the fluorescence of the donor becomes apparent. The assay reagent was made as follows: 5X cell Luciferase cell culture lysis reagent from Promega (#E153A) diluted to IX with dH ₂ O, NaCl added to 150 mM final, the FRET peptide diluted to 20 μM final from a 2 mM stock.

To prepare plates, HCV replicon cells, with or without a Renilla luciferase reporter gene, were trypsinized and placed into each well of a 96-well plate with titrated test compounds added in columns 3 through 12; columns 1 and 2 contained a control compound (HCV protease inhibitor), and the bottom row contained cells without compound. The plates were then placed in a CO ₂ incubator at 37 ⁰ C.

Assays. Subsequent to addition of the test compounds described above (FRET Assay Preparation), at various times the plate was removed and Alamar blue solution (Trek Diagnostics, #00-100) was added per well as a measure of cellular toxicity. After reading in a Cytoflour 4000 instrument (PE Biosystems), plates were rinsed with PBS and then used for FRET assay by the addition of 30 ul of the FRET peptide assay reagent described above (FRET Assay Preparation) per well. The plate was then placed into the Cytoflour 4000 instrument which had been set to 340 excite/490 emission, automatic mode for 20 cycles and the plate read in a kinetic mode. Typically, the signal to noise using an endpoint analysis after the reads was at least three-fold. Alternatively, after Alamar blue reading, plates were rinsed with PBS, 50 ul of DMEM (high glucose) without phenol red was added and plates were then used for luciferase assay using the Promega Dual-Glo Luciferase Assay System. Compound analysis was determined by quantification of the relative HCV replicon inhibition and the relative cytotoxicity values. To calculate cytoxicity values, the average Alamar Blue fluorescence signals from the control wells were set as 100% non-toxic. The individual signals in each of the compound test wells were then divided by the average control signal and multiplied by 100% to determine percent cytotoxicity. To calculate the HCV replicon inhibition values, an average background value was obtained from the two wells containing the highest amount of HCV protease inhibitor at the end of the assay period. These numbers were similar to those obtained from naϊve Huh-7 cells.

The background numbers were then subtracted from the average signal obtained from the control wells and this number was used as 100% activity. The individual signals in each of the compound test wells were then divided by the averaged control values after background subtraction and multiplied by 100% to determine percent activity. EC50 values for a protease inhibitor titration were calculated as the concentration which caused a 50% reduction in FRET or luciferase activity. The two numbers generated for the compound plate, percent cytoxicity and percent activity were used to determine compounds of interest for further analysis.

Representative data for some compounds are reported in Table 1.

Table 1.

A>0.5 μM; B 0.001 μM - 0.5 μM; C <0.02 μM but an exact value was not determined; D>0.04 μM; but an exact value was not determined.

Pharmaceutical Compositions and Methods of Treatment

The compounds demonstrate activity against HCV NS5B and can be useful in treating HCV and HCV infection. Therefore, another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Another aspect of the invention is a composition further comprising a compound having anti-HCV activity.

Another aspect of the invention is a composition where the compound having anti-HCV activity is an interferon. Another aspect of the invention is where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compound having anti-HCV activity is a cyclosporin. Another aspect of the invention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'- monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compound having anti-HCV activity is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an interferon and ribavirin.

Another aspect of the invention is a method of inhibiting the function of the HCV replicon comprising contacting the HCV replicon with a compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of inhibiting the function of the HCV NS5B protein comprising contacting the HCV NS5B protein with a compound or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof. In another embodiment the compound is effective to inhibit the function of the HCV replicon. In another embodiment the compound is effective to inhibit the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in conjunction with (prior to, after, or concurrently) another compound having anti-HCV activity.

Another aspect of the invention is the method where the other compound having anti-HCV activity is an interferon.

Another aspect of the invention is the method where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is the method where the other compound having anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin is cyclosporin A.

Another aspect of the invention is the method where the other compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of target in the HCV life cycle other than the HCV NS5B protein.

"Therapeutically effective" means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of hepatitis and HCV infection.

"Patient" means a person infected with the HCV virus and suitable for therapy as understood by practitioners in the field of hepatitis and HCV infection.

"Treatment," "therapy," "regimen," "HCV infection," and related terms are used as understood by practitioners in the field of hepatitis and HCV infection.

The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. A therapeutically effective amount is that which is needed to provide a meaningful patient benefit. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions.

Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit. Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally.

The specific dosing regime, however, will be determined by a physician using sound medical judgement.

The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating hepatitis and HCV infection. In these combination methods, the compound will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regime, however, will be determined by a physician using sound medical judgement.

Some examples of compounds suitable for compositions and methods are listed in Table 2.

Table 2.