NZ714201B2 - Pyrazole compounds as modulators of fshr and uses thereof - Google Patents

Abstract

The present invention relates to pyrazole compounds of general formula I or a pharmaceutically acceptable salts thereof, wherein each of Ring A, X, Y, Z, R1, R2, R3, R4, R5,R6, n and p is as defined and described in embodiments herein. The compounds of the invention, and pharmaceutically acceptable compositin thereof are useful as positive allosteric modulators of follicle stimulating hormone receptor (FSHR), for example in the treatment of fertility disorders. compositin thereof are useful as positive allosteric modulators of follicle stimulating hormone receptor (FSHR), for example in the treatment of fertility disorders.

Description

PYRAZOLE COMPOUNDS AS TORS OF FSHR AND USES THEREOF RELATED ATIONS The present invention claims the benefit of US provisional application 61/838,460, filed on June 24, 2013, and US. provisional application 61/898,608, filed on November 1, 2013.

The contents of the aforementioned ations are hereby incorporated by reference in their ties.

TECHNICAL FIELD OF THE INVENTION The present invention relates to le compounds useful as agonists of follicle stimulating hormone receptor (FSHR). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the ent of various disorders.

BACKGROUND OF THE INVENTION Gonadotropins serve important functions in a variety of bodily functions including metabolism, temperature regulation and the reproductive process. Gonadotropins act on specific gonadal cell types to initiate ovarian and testicular differentiation and steroidogenesis. The gonadotropin FSH (follicle stimulating hormone) is released from the or pituitary under the influence of gonadotropin—releasing hormone and estrogens, and from the placenta during pregnancy. FSH is a heterodimeric rotein e that shares structural similarities with luteinizing hormone (LH) and thyroid stimulating e (TSH), both of which are also produced in the pituitary gland, and chorionic gonadotropin (CG), which is produced in the placenta. In the female, FSH plays a pivotal role in the stimulation of follicle development and maturation and in addition, it is the major hormone regulating secretion of estrogens, s LH induces ovulation. In the male, FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis.

The hormones are relatively large (28—38 kDa) and are composed of a common 06— subunit non—covalently bound to a distinct B—subunit that confers or binding specificity.

The cellular receptor for these es is expressed on testicular Sertoli cells and n granulosa cells. The FSH receptor is known to be members of the G protein—coupled class of membrane—bound receptors, which when activated stimulate an increase in the activity of adenylyl cyclase. This results in an increase in the level of the intracellular second messenger ine 3', 5'—monophosphate (CAMP), which in turn causes increased steroid synthesis and secretion. Hydropathicity plots of the amino acid sequences of these receptors reveal three general domains: a hydrophilic terminal region, ered to be the amino—terminal extracellular domain; seven hydrophobic segments of membrane—spanning length, considered to be the transmembrane domain; and a carboxy—terminal region that contains ial phosphorylation sites (serine, threonine, and tyrosine residues), considered to be the y— terminal ellular or cytoplasmic domain. The glycoprotein hormone receptor family is distinguished from other G protein—coupled ors, such as the renergic, sin, and substance K receptors, by the large size of the hilic amino-terminal domain, which is involved in hormone binding.

Annually in the U.S. there are 2.4 million couples experiencing infertility that are potential candidates for treatment. FSH, either extracted from urine or produced by recombinant DNA technology, is a parenterally—administered protein product used by specialists for ovulation induction and for controlled ovarial hyperstimulation. Whereas ovulation induction is directed at achieving a single follicle to ovulate, controlled ovarial hyperstimulation is directed at harvesting multiple oocytes for use in various in-vitro assisted reproductive technologies, e.g. in-vitro fertilization (IVF). FSH is also used clinically to treat male hypogonadism and male infertility, e.g. some types of failure of spermatogenesis.

FSHR is a highly ic target in the ovarian follicle growth process and is ively expressed in the ovary. However, the use of FSH is limited by its high cost, lack of oral dosing, and need of extensive monitoring by specialist physicians. Hence, identification of a non—peptidic small molecule substitute for FSH that could ially be developed for oral stration is desirable. Low molecular weight FSH mimetics with agonistic properties are disclosed in the international applications and WC 2010/ 136438 as well as the patent US 6,653,338. There is still a need for low molecular weight hormone cs that selectively activate FSHR.

SUMMARY OF THE INVENTION It has now been found that nds of this invention, and pharmaceutically acceptable compositions thereof, are ive as modulators of FSHR. Such compounds have general formula I: or a pharmaceutically acceptable salt thereof, wherein each of Ring A, X, Y, Z, R1, R2, R3, R4, R5, R6, n, and p, is as defined and described in embodiments herein. [0007a] In particular provided herein are compounds selected from: O O N N N N N N N S S 1 2 O O N Br N N O N O N N N 3 4 (followed by page 3A) O O O N N N N N N 6 N HN S NH O O N HN O N N HN S OH 9 10 O O N HN N O NH N N N N S 11 12 wed by page 3B) O O N N N HN O O S N O 13 14 O O O O O O N N N N N N S S O O HO O 17 18 O O O O O O N N N N O N N N S S 19 20 O O N N S HN N O N NH O S 21 22 wed by page 3C) O O O O N N N O S N N O S N O O 23 24 O O N N N O O O O O O O O O N N N N N S N S O 29 30 O O O O N N N N N S S O N 31 32 wed by page 3D) O O O O O O N N N N N O S N O O 33 34 N N O N N O NH 36 N O N N S HO O NH N N 37 38 O O N N N N N S OH 39 40 wed by page 3E) N N N N N N O N O 41 42 O O N O N N N O N N H O 43 44 O O O O O O N N N N N N S S N O N O 45 46 O O N N N N N S OH 47 48 wed by page 3F) O O O H N N N O S N O N N D S D D 49 50 O O D S O O N N N N N N S S 51 52 O O O O N F N N N N N N S S 53 54 O O O O N O N N N N O S N S D 55 56 wed by page 3G) O O N HN N S N N S O D D 57 58 N D N HN D N HN S O D S N D D O 59 60 O O D HN D O N N N O S N D N D N HN O D D S N 61 62 O O O O O O N N N N N N N N N S S 63 64 wed by page 3H) O O O O O O N N N N N N N N N N S S 65 66 O O O O N N O N N N N S S 67 68 O O O O N N N S D O N N N D D N N 69 70 O O O O O O N N N N N N N O N S S 71 72 wed by page 3I) O O O O O O S O N N N N N N S S 73 74 O O O O S N N N N N N S S 75 76 O O O D O O D D N O N N N N N N N O O S N S D 77 78 O O S N O O O HN N N N N N 79 80 wed by page 3J) O O O O O N D N N N N D N N D N S S D 81 82 O O N D N D O S D O O HN O N O N N N N S N S D D O 85 86 O O O O S N N N N N S NH D D S 87 88 wed by page 3K) O O O O N N N N N S S 89 90 O O O O O N N N S N N N 91 92 O O O O S O N N N N N N N S S O 93 94 O O O N O N N N N N N N S O D S 95 96 wed by page 3L) O O O O O O N N N N N N N O O S S 97 98 O O O O O O O O N N N N H N N N N N H S S 99 100 O O O O O O N N N N N N N N S O 101 102 O O O O N O N N N N N N N S S 103 104 wed by page 3M) O O O O O O O N N S N N N N N S O 105 106 O O N N N O O O O N N N N N H N N N N S O 109 110 O O O O O O O O S N O N N N N N H N N S S 111 112 wed by page 3N) O O O O O O O O N N N N N N N N D O D O S D D S D D D D D D D 113 114 O O O O O O O O N N N N N N N N D D S D D S D 115 116 O O O N N N N N N D S D S D 117 118 O O O O N N N N D N O N N N S D D D O 119 120 wed by page 3O) O O O O N N N N N N N S O 121 122 O O O O O O N N N N N N N N N N S O 123 124 O O O O N N N N N N N N N S O 125 126 O O O O N N N N N N N N N S S 129 130 wed by page 3P) O O O O HO O N N N O N N S O 131 132 O O O O N N N N N S S 133 134 O O O O O O HN OH N N N N H N N N N H S S 135 137 O O O O O O N O N N N N N N N N N Si D S S D 139 140 wed by page 3Q) O O N N N H O O O O O F N N D N N N F D N N N N N D S S D D O 143 144 O O O O O O N N N N H N N N S S D 145 146 O O O O O O O O N N N N N S S 147 148 wed by page 3R) O O O O N N N N N N S S 149 150 O O O O O O N N N N N N S O 151 152 O O O O N N N N O N N N N 153 154 N N N N wed by page 3S) O O N O N N N N N N N O O 157 158 O O O O N N N N N N N N S S N N 159 160 O O O O N O N‐ N N N N N N N D O S D S D D 161 162 O O O O O O O OH N N N N N N N H S D O D S 163 164 wed by page 3T) O O NH2 N N S O O O O O O O D D O D N O N N N N N D N N N D D D S D O D S D O 167 168 O O N N N N N N N S S NH NH 169 170 O O O O O N N N N N N N N N N 171 174 wed by page 3U) O O O O O O O NH N N N N N N N OH S O 175 176 O O O O N N N N N O N N N N O D D S D D D D S D D D D D D 177 178 O O O O N N H N N N O N NH S S 179 180 O O O O O O N N O N NH N N 2 N N N O S S 181 182 O O O O O O D D N N N N N N O N O D D D D S S 183 184 wed by page 3V) O O O O O OH O N N N N N N H N N N H S S 185 186 O O N N N N O N N 189 190 O O O O O O N N N N N N N N N N O S 191 192 O O O O O N N N N N S O 194 195 wed by page 3W) O O O O N N N N N N N O D S D D D O D S D D D D D D D 197 198 O O O O O O O S O S O O N O N N N N N D O S D D D S D D D D 199 200 O O O O O O O N N N N N N O 201 202 O O O O N N N N N N N N N N S 203 204 wed by page 3X) O O O O N N N N N N N N O S S N 205 206 O O O O N N N N N N N N N S O 207 208 O O O O O O N N N N N N N O N N N S O 209 210 O O O O O O N N N N N N N N S O 211 212 wed by page 3Y) O O O O O O N N N N N N N D O S D 213 214 O O O O O O N N N N N N N N O O 215 216 O O O O N N N N N N N N D OH O S D D S 217 , and 218, or a pharmaceutically acceptable salt thereof. However, the invention is also described more broadly with regard to other s and embodiments. (followed by page 3Z) [0007b] Further provided herein are pharmaceutical compositions sing the compounds of formula (I), or a pharmaceutically acceptable salt f, as described herein, and a pharmaceutically acceptable adjuvant, carrier or vehicle.

Compounds of the present invention, and ceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with abnormal cellular responses triggered by follicle stimulating e events.

Such diseases, disorders, or conditions include those described herein. [0008a] In particular embodiments provided herein is the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, in the production of a medicament for modulating FSHR, or a mutant thereof, activity in a patient, for treating fertility disorders in a subject, or for the prophylactic or therapeutic treatment of a FSHR-mediated disorder. [0008b] In another the embodiment provided herein is a method for modulating FSHR, or a mutant thereof, in a biological , sing the step of contacting said biological sample with a compound or a pharmaceutically acceptable salt thereof as described herein.

DETAILED DESCRIPTION OF N EMBODIMENTS 1. General Description of Compounds of the ion In certain embodiments, the present invention provides modulators of follicle stimulating hormone or (FSHR). In certain embodiments, the present invention provides positive allosteric modulators of FSHR. In some embodiments, such nds include those of the formulae described herein, or a ceutically acceptable salt thereof, n each variable is as d and described . 2. Compounds and Definitions Compounds of this invention include those bed generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, ito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and (followed by page 4) March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by nce.

The term “aliphatic” or “aliphatic group”, as used herein, means a straight—chain (i.e., unbranched) or ed, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a clic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle77 4‘cycloaliphatic” or “cycloalkyl”), that has a single point of ment to the rest of the molecule. Unless ise specified, aliphatic groups contain 1—6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1—5 aliphatic carbon atoms. In other ments, aliphatic groups n 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other ments, aliphatic groups contain 1—2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. ary aliphatic groups are linear or ed, substituted or unsubstituted C1—C3 alkyl, C2—C3 alkenyl, C2—C3 alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alky1 or (cycloalkyl)alkeny1.

The term “lower alkyl” refers to a C1_4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, , isopropyl, butyl, isobutyl, and tert—butyl.

The term “lower haloalkyl” refers to a C1_4 straight or branched alkyl group that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, or phosphorus (including, any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen or; a tutable nitrogen of a heterocyclic ring, for example N (as in 3,4- dihydro—2H—pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N—substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

As used herein, the term “bivalent C1-s (0r C1_6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a thylene group, i.e., —(CH2)n—, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a thylene group in which one or more ene hydrogen atoms are ed with a substituent. Suitable substituents e those described below for a substituted aliphatic group.

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

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is ic and wherein each ring in the system contains three to seven ring members. The term “aryl” is used interchangeably with the term “aryl ring”. In certain ments of the present invention, “aryl” refers to an aromatic ring system. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl and the like, which optionally includes one or more substituents. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non—aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, thridinyl, or tetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar—”, used alone or as part of a larger , e. g., “heteroaralkyl”, or “heteroaralkoxy”, refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 TC electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any nized form of a basic nitrogen. Heteroaryl groups include, t limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. iting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, lyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H—quinolizinyl, carbazolyl, nyl, inyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3—b]—l,4—oxazin— 3(4H)—one. A heteroaryl group is optionally mono— or bicyclic. The term “heteroaryl” is used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are ally substituted. The term oaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, ocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 5— to 7—membered monocyclic or 7—lO—membered bicyclic cyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0—3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen is N (as in 3,4—dihydro— rolyl), NH (as in pyrrolidinyl), or +NR (as in N—substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that s in a stable structure and any of the ring atoms can be optionally substituted.

Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or liphatic rings, such as indolinyl, olyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of ment is on the heterocyclyl ring. A heterocyclyl group is optionally mono— or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, n the alkyl and heterocyclyl portions independently are optionally substituted.

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

As described , certain compounds of the invention contain “optionally substituted” moieties. In general, the term “substituted”, r preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either | —R1 explicit or implicit from the structure (e.g., refers to at least ; and NH N’ NH N” '_R1 refers to at least ,R1 R1 or R1 , . Unless otherwise ted, an “optionally substituted” group has a suitable substituent at each substitutable position of the group, and when more than one on in any given structure is substituted with more than one substituent ed from a specified group, the substituent is either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an nally substituted” group are independently deuterium; halogen; —(CH2)MR°; —(CH2)04OR°; -O(CH2)0_ 4R0, —O—(CH2)04C(O)OR°; —(CH2)04CH(OR°)2; —(CH2)MSR°; MPh, which are optionally substituted with R0; —(CH2)MO(CH2)(HPh which is optionally tuted with RO; — CH=CHPh, which is optionally substituted with RO; —(CH2)04O(CH2)0_1—pyridyl which is optionally substituted with R°; —N02; —CN; —N3; —(CH2)MN(R°)2; —(CH2)04N(R°)C(O)R°; — (S)R°; 04N(R°)C(0)NR°2; -N(R°)C(S)NR°2; ‘(CH2)0—4N(R°)C(O)OR°§ — N(R°)N(R°)C(0)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(0)0R°; —(CH2)MC(0)R°; — C(S)R°; —(CH2)04C(O)OR°; —(CH2)MC(O)SR°; —(CH2)MC(O)OSiR°3; —(CH2)MOC(O)R°; — OC(O)(CH2)0_4$R°, R°; —(CH2)04SC(O)R°; 0_4C(O)NR°2; —C(S)NR°2; —C(S)SR°; —SC(S)SR°, —(CH2)(HOC(O)NR°2; —C(O)N(OR°)R°; —C(O)C(O)R°; —C(O)CH2C(O)R°; — C(NOR°)R°; -(CH2)04SSR°; —(CH2)04S(O)2R°; —(CH2)MS(O)2OR°; —(CH2)MOS(O)2R°; — S(O)2NR°2; -(CH2)MS(O)R°; S(O)2NR°2; —N(R°)S(O)2R°; —N(OR°)R°; —C(NH)NR°2; — P(O)2R°; —P(O)R°2; —OP(O)R°2; —OP(O)(OR°)2; SiR°3; —(CH straight or branched alkylene)O— N(R°)2; or —(C14 straight or branched alkylene)C(O)O—N(R°)2, wherein each R° is optionally tuted as d below and is independently hydrogen, C14 aliphatic, —CH2Ph, —O(CH2)(n 1Ph, —CH2—(5—6 membered aryl ring), or a 5—6—membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a embered saturated, partially unsaturated, or aryl mono— or bicyclic ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is optionally substituted as defined below.

Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently deuterium, halogen, —(CH2)0_2R', R'), —(CH2)0_20H, —(CH2)0_20R', —(CH2)0_2CH(OR')2; 0R'), —CN, —N3, d2C(0)R', —(CH2)072C(0)OH, d2C(0)0R', —(CH2)d2$R', —(CH2)0—2$H, —(CH2)o—2NH2, —(CH2)o—2NHR., —(CH2)O—2NR.2, —N02, —SiR'3, 3, —C(O)SR', —(C14 straight or branched alkylene)C(O)OR', or —SSR' wherein each R' is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from CM aliphatic, —CH2Ph, —O(CH2)(HPh, or a 5—6—membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable nt substituents on a saturated carbon atom of R° include =0 and 2S.

Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: :0, =3, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, O)2R*, =NR*, =NOR*, —0(C(R*2))2,3o—, or —S(C(R*2))2,3s—, wherein each independent occurrence of R* is selected from hydrogen, C14 tic which is substituted as defined below, or an unsubstituted 5—6—membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*2)2,3O—, wherein each independent occurrence of R* is selected from hydrogen, C1,6 aliphatic which is optionally substituted as d below, or an unsubstituted 5—6— membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently ed from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include n, —R', —(haloR'), —OH, —OR', —O(haloR'), —CN, —C(O)OH, —C(O)OR', —NH2, —NHR', —NR'2, or —N02, wherein each R' is tituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C14 aliphatic, —CH2Ph, —O(CH2)(HPh, or a 5—6—membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, or .

Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —Rl, —NR*2, —C(O)Rl, —C(O)0Rl, —C(O)C(O)Rl, —C(O)CH2C(O)RT, —S(O)2Rl, —S(O)2NRT2, —C(S)NRl2, —C(NH)NRT2, or —N(RT)S(O)2RT; wherein each RT is independently hydrogen, C1_6 tic which is optionally substituted as d below, unsubstituted —OPh, or an unsubstituted 5—6—membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the tion above, two independent occurrences of RT, taken er with their intervening atom(s) form an unsubstituted 3—12—membered saturated, partially rated, or aryl mono— or bicyclic ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. le substituents on the aliphatic group of R] are independently halogen, —R', R'), —OH, —OR', —O(haloR'), —CN, H, —C(O)OR', —NH2, —NHR', —NR'2, or —N02, wherein each R' is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1_4 aliphatic, —CH2Ph, —O(CH2)(HPh, or a 5—6— membered ted, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, the terms “optionally substituted”, “optionally substituted alkyl,” “optionally substituted “optionally tuted alkenyl,” “optionally tuted alkynyl”, “optionally substituted carbocyclic,77 4‘optionally substituted aryl”, ll optionally substituted heteroaryl," “optionally substituted heterocyclic,” and any other optionally substituted group as WO 09980 used herein, refer to groups that are substituted or unsubstituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with typical substituents including, but not limited to: -F, —Cl, -Br, —I, deuterium, —OH, protected hydroxy, alkoxy, oxo, thiooxo, —N02, -CN, CF3, N3, —NH2, protected amino, —NH alkyl, —NH alkenyl, —NH alkynyl, —NH cycloalkyl, —NH — aryl, —NH —heteroaryl, —NH —heterocyclic, —dialkylamino, —diarylamino, —diheteroarylamino, —0— alkyl, —0— l, —O— alkynyl, —O— cycloalkyl, —O—aryl, —O—heteroary1, —O— heterocyclic, -C(O)- alkyl, -C(O)- l, -C(O)- l, -C(O)- carbocyclyl, -C(O)-aryl, -C(O)- heteroaryl, —C(O)—heterocyclyl, -CONH2, —CONH— alkyl, —CONH— alkenyl, -CONH— alkynyl, —CONH—carbocyclyl, — CONH—aryl, —CONH—heteroaryl, —CONH—heterocyclyl, -OC02— alkyl, —OC02— alkenyl, —OC02- alkynyl, -OCOZ— carbocyclyl, —OC02—aryl, — eteroaryl, -OCOz—heterocyclyl, 2, —OCONH— alkyl, — l, — OCONH— alkynyl, —OCONH— carbocyclyl, —OCONH— aryl, —OCONH— heteroaryl, —OCONH— heterocyclyl, —NHC(O)— alkyl, —NHC(O)— alkenyl, —NHC(O)— alkynyl, —NHC(O)— carbocyclyl, — NHC(O)—aryl, -NHC(O)—heteroaryl, —NHC(O)-heterocyclyl, -NHCOZ- alkyl, —NHC02— alkenyl, — NHCOZ— alkynyl, —NHC02 — carbocyclyl, — aryl, —NHC02— heteroaryl, — heterocyclyl, —NHC(O)NH2, —NHC(O)NH— alkyl, —NHC(O)NH— alkenyl, )NH— alkenyl, — NHC(O)NH— carbocyclyl, —NHC(O)NH—aryl, —NHC(O)NH—heteroaryl, —NHC(O)NH— heterocyclyl, NHC(S)NH2, —NHC(S)NH— alkyl, —NHC(S)NH— alkenyl, —NHC(S)NH— alkynyl, — NHC(S)NH— carbocyclyl, -NHC(S)NH-aryl, -NHC(S)NH—heteroaryl, -NHC(S)NH-heterocyclyl, —NHC(NH)NH2, —NHC(NH)NH- alkyl, -NHC(NH)NH- -alkenyl, -NHC(NH)NH- alkenyl, - )NH- carbocyclyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, —NHC(NH)NH— cyclyl, —NHC(NH)— alkyl, —NHC(NH)— alkenyl, —NHC(NH)— alkenyl, —NHC(NH)— carbocyclyl, —NHC(NH)—aryl, —NHC(NH)—heteroaryl, —NHC(NH)—heterocyclyl, —C(NH)NH— alkyl, —C(NH)NH— alkenyl, —C(NH)NH— alkynyl, —C(NH)NH— carbocyclyl, — C(NH)NH—aryl, —C(NH)NH—heteroaryl, —C(NH)NH—heterocyclyl, —S(O)— alkyl, - S(O)— l, — S(O)— alkynyl, — S(O)— carbocyclyl, — S(O)—aryl, — S(O)— heteroaryl, - S(O)—heterocyclyl —SOzNH2, —SOZNH— alkyl, —SOzNH— alkenyl, — alkynyl, - SOZNH— carbocyclyl, —SOZNH— aryl, — heteroaryl, —SOZNH— heterocyclyl, -NHSOZ- alkyl, — alkenyl, — NHSOz- alkynyl, —NHSOZ— carbocyclyl, —NHSOZ— aryl, -NHSOg—heteroaryl, —NHSOg—heterocyclyl, —CH2NH2, —CH2802CH3, —mono—, di—, or tri—alkyl silyl, —alkyl, —alkenyl, —alkynyl, —aryl, —arylalkyl, —heteroaryl, —heteroarylalkyl, — heterocycloalkyl, —cycloalkyl, —carbocyclic, ocyclic, polyalkoxyalkyl, polyalkoxy, - methoxymethoxy, —methoxyethoxy, -SH, —S- alkyl, -S— alkenyl, —S— alkynyl, —S— carbocyclyl, —S— aryl, eroary1, -S-heterocyclyl, or methylthiomethyl.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals t undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, l—l9, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, oric acid, ic acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.

Other pharmaceutically acceptable salts include adipate, alginate, ate, aspartate, benzenesulfonate, benzoate, bisulfate, , butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2—hydroxy—ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, esulfonate, thalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3—phenylpropionate, phosphate, te, propionate, stearate, succinate, sulfate, tartrate, anate, p—toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases e alkali metal, alkaline earth metal, ammonium and N+(CHalkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lkyl ate and aryl ate.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S urations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. ore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present nds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more ically enriched atoms.

For example, compounds having the present ures ing the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C— or 14C—enriched carbon are within the scope of this invention. In some embodiments, the group comprises one or more deuterium atoms.

There is rmore intended that a compound of the formula I includes isotope— d forms thereof. An isotope—labeled form of a compound of the formula I is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally. Examples of isotopes which are readily commercially available and which can be incorporated into a nd of the formula Iby well— known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phos—phorus, fluo—rine and chlorine, for example 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32F, 358, 18F and 36CI, respectively.

A compound of the formula I, a prodrug, thereof or a pharmaceutically acceptable salt of either which ns one or more of the above—mentioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention. An isotope—labeled compound of the formula I can be used in a number of beneficial ways. For example, an isotope—labeled compound of the formula I into which, for example, a radioisotope, such as 3H or 14C, has been orated, is suitable for medicament and/or substrate tissue distribution assays. These radioisotopes, i.e. tritium (3H) and —l4 (14C), are particularly preferred owing to simple preparation and excellent detectability. Incorporation of heavier isotopes, for example deuterium (2H), into a compound of the formula I has therapeutic advantages owing to the higher metabolic stability of this isotope—labeled compound. Higher lic stability translates directly into an increased in vivo half—life or lower dosages, which under most circumstances would represent a preferred embodiment of the t invention. An e—labeled compound of the a I can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related ption, in the e part and in the preparation part in the present text, replacing a otope—labeled reactant by a readily available isotope—labeled reactant. ium (2H) can also be incorporated into a compound of the formula I for the purpose in order to manipulate the oxidative metabolism of the compound by way of the primary c isotope effect. The y kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exchange.

Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate in rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle—point region along the coordinate of a multi— product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom at a non—exchangeable position, rate differences of kM/kD = 2—7 are typical. If this rate ence is successfully applied to a com—pound of the formula I that is susceptible to oxidation, the profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilled in the art is able to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic es are susceptible to oxidative metabolism. In vitro liver microsomal assays currently available provide le information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of the formula I with ed stability through ance to such ive metabolism. Significant improvements in the pharmacokinetic profiles of compounds of the formula I are thereby obtained, and can be expressed quantitatively in terms of ses in the in vivo half—life (t/2), concen-tra—tion at m eutic effect (me), area under the dose response curve (AUC), and F; and in terms of reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of the formula I which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and en atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of en atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favorable and accurate determination of the extent of the extent to which the improvement in resistance to oxidative lism has improved. In this way, it is ined that the half—life of the parent compound can be extended by up to 100% as the result of deuterium—hydrogen exchange of this type.

Deuterium—hydrogen exchange in a compound of the formula I can also be used to achieve a favorable modification of the metabolite spectrum of the ng compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon—hydrogen (C—H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium—hydrogen exchange may be found, for example in k et al., J. Org. Chem. 55, 3992—3997, 1990, Reider et al., J. Org. Chem. 52, 3326—3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et a1, Biochemistry 33(10) 2927—2937, 1994, and Jarman et a1. Carcinogenesis 16(4), 683-688, 1993.

As used herein, the term “modulator” is defined as a compound that binds to and /or inhibits the target with measurable affinity. In certain embodiments, a modulator has an IC50 and/or binding constant of less about 50 MM, less than about 1 MM, less than about 500 nM, less than about 100 nM, or less than about 10 nM.

The terms “measurable affinity” and rably inhibit,” as used herein, means a able change in FSHR activity between a sample comprising a compound of the present W0 20141209980 invention, or composition thereof, and FSHR, and an equivalent sample comprising FSHR, in the absence of said compound, or composition thereof.

Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which ins the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

The recitation of a listing of chemical groups in any definition of a variable herein es definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in ation with any other embodiments or portions thereof. 3. Descrigtion 0t Exemglary Comgounds According to one aspect, the t invention provides a compound of formula I, X (R4)n / R5 R2 / 2’ /N\N (R6)p or a pharmaceutically able salt thereof, wherein: X is O, S, SO, S02, or NR; Yis O, S, or NR; Z is O, S, SO, S02, or N; wherein when Z is O, S, SO, or S02, then p is 0; each R is ndently hydrogen, C14 aliphatic, C340 aryl, a 3—8 membered saturated or partially unsaturated carbocyclic ring, a 3—7 membered heterocylic ring having 1—4 heteroatoms independently ed from nitrogen, oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently ed from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or two R groups on the same atom are taken together with the atom to which they are attached to form a C3_10 aryl, a 3-8 membered saturated or partially unsaturated yclic ring, a 3-7 membered heterocylic ring having 1—4 heteroatoms ndently ed from nitrogen, 2014/043838 oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; Ring A is a fused C340 aryl, a fused 3-8 membered saturated or partially unsaturated carbocyclic ring, a fused 3—7 membered heterocylic ring having 1—4 atoms independently selected from en, oxygen, or sulfur, or a fused 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently ed from nitrogen, oxygen, or sulfur; R1 is —OR, —SR, —CN, —N02, —SOZR, -SOR, -C(O)R, —C02R, —C(O)N(R)2, —NRC(O)R, -NRC(O)N(R)2, -NRSOZR, or —N(R)2; R2 is —R, halogen, lkyl, —OR, —SR, —CN, —N02, —SOgR, -SOR, —C(O)R, —C02R, -C(O)N(R)2, -NRC(O)R, )N(R)2, -NRSOzR, or —N(R)2; R3 is en, CM aliphatic, C340 aryl, a 3—8 membered ted or partially unsaturated carbocyclic ring, a 3—7 membered heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; each R4 is independently —R, halogen, —haloalkyl, —OR, —SR, —CN, —N02, —SOZR, -SOR, —C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSOZR, or —N(R)2; R5 is C14 aliphatic, C340 aryl, a 3—8 ed saturated or partially unsaturated carbocyclic ring, a 3—7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or ; each of which is optionally substituted; R6 is hydrogen, C14 aliphatic, C340 aryl, a 3—8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 atoms ndently selected from nitrogen, oxygen, or , or a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or R5 and R6, er with the atom to which each is attached, form a 3—8 membered heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3—8 membered heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; n is 0, l, or 2; and p is 0 or 1.

In certain embodiments, X is O. In certain embodiments, X is S. In certain embodiments, X is SO, or S02. In certain embodiments, X is NR.

In certain ments, Y is O. In certain embodiments, Y is S. In certain embodiments, Y is NR.

In n embodiments, Z is O. In certain embodiments, Z is S. In n ments, Z is S0 or S02. In certain embodiments, Z is N.

In certain embodiments, Ring A is a fused C3_10 aryl. In certain embodiments, Ring A is a fused 3—8 membered saturated or partially unsaturated carbocyclic ring. In certain embodiments, Ring A is a fused 3—7 membered heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In n embodiments, Ring A is a fused 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, Ring A is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, furanyl, nyl, imidazolidinyl, imidazolinyl, imidazolyl, lH—indazolyl, indolenyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3—oxadiazolyl, oxadiazolyl;— 1,2,50xadiazolyl, 1,3,4—oxadiazolyl, idinyl, oxazolyl, idinyl, dinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, lidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, inyl, 2H—pyrrolyl, pyrrolyl, tetrahydrofuranyl, thiazolyl, thienyl, thiophenyl, oxetanyl, or azetidinyl.

In certain embodiments, Ring A is phenyl.

In certain embodiments, R1 is —OR, —SR, -S02R, -SOR, -C(O)R, -C02R, -C(O)N(R)2, —NRC(O)R, -NRC(O)N(R)2, —NRS02R, or —N(R)2. In certain embodiments, R1 is —OR, —SR, -S02R, or —SOR. In certain embodiments, R1 is —C(O)R, -C02R, or —C(O)N(R)2. In certain embodiments, R1 is —NRC(O)R, )N(R)2, —NRS02R, or —N(R)2.

In certain embodiments, R1 is —OR, and R is hydrogen.

In certain embodiments, R1 is —OR, and R is C14 aliphatic, C340 aryl, a 3—8 ed saturated or partially unsaturated carbocyclic ring, a 3—7 membered heterocylic ring having 1—4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R1 is —OR, and R is C14 aliphatic. In certain embodiments, R is methyl, ethyl, propyl, i—propyl, butyl, s—butyl, t—butyl, straight or branched pentyl, or straight or branched hexyl; each of which is optionally substituted.

In n embodiments, R1 is —OR, and R is C340 aryl, a 3—8 membered ted or partially rated carbocyclic ring, a 3—7 membered heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5—6 membered monocyclic aryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, R is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, ctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, ]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH—carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, droquinolinyl, 2H, 6H—l,5,2—dithiazinyl, dihydrofuro [2,3—[9] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, nolinyl, isothiazolyl, isoxazolyl, morpholinyl, yridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3—oxadiazolyl, l,2,4—oxadiazolyl;— 1,2,50xadiazolyl, l,3,4—oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, lyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, idinyl, pyrrolinyl, 2H—pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, nolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H—l,2,5-thiadiazinyl, 1,2,3— azolyl, l,2,4—thiadiazolyl, l,2,5—thiadiazolyl, l,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, enyl, triazinyl, 1,2,3—triazolyl, 1,2,4—triazolyl, 1,2,5—triazolyl, l,3,4—triazolyl, oxetanyl, azetidinyl, or nyl; each of which is ally substituted.

WO 09980 In certain embodiments, R2 is hydrogen.

In certain embodiments, R2 is C1_6 tic. In certain embodiments, R2 is C14 aliphatic wherein the tic group is a C14 alkyl. In certain embodiments, R2 is , ethyl, propyl, i-propyl, butyl, l, t—butyl, straight or branched pentyl, or straight or branched hexyl; each of which is optionally substituted. In certain embodiments, R2 is C14 aliphatic wherein the aliphatic group is a C14 alkenyl.

In certain embodiments, R2 is C340 aryl, a 3—8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring haVing 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring haVing 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R2 is phenyl, yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, nyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, idazolinyl, carbazolyl, NH—carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H—1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, l, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH—indazolyl, nyl, indolinyl, indolizinyl, indolyl, 3H—indolyl, olinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3—oxadiazolyl, l,2,4—oxadiazolyl;— 1,2,50xadiazolyl, 1,3,4—oxadiazolyl, idinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H—pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, ydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, ,5—thiadiazinyl, 1,2,3— thiadiazolyl, 1,2,4—thiadiazolyl, 1,2,5—thiadiazolyl, hiadiazolyl, thianthrenyl, lyl, thienyl, thienothiazolyl, oxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3—triazolyl, l,2,4—triazolyl, l,2,5—triazolyl, l,3,4—triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted.

In n embodiments, R2 is halogen, —haloalkyl, —OR, —SR, —CN, —N02, —SOZR, -SOR, -C(O)R, -C02R, -C(O)N(R)2, -NRC(O)R, —NRC(O)N(R)2, —NRSOZR, or —N(R)2.

In certain embodiments, R2 is F, Cl, Br, I, or haloalkyl.

In certain embodiments, R2 is —OR, —SR, —CN, —N02, -SOzR, —SOR, —C(O)R, —C02R, —C(O)N(R)2, )R, -NRC(O)N(R)2, —NRSOZR, or —N(R)2. In certain embodiments, R is C1, 6 aliphatic, C340 aryl, a 3—8 membered saturated or partially unsaturated carbocyclic ring, a 3—7 ed heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R is methyl, ethyl, propyl, yl, butyl, s—butyl, t—butyl, straight or branched pentyl, or straight or branched hexyl; each of which is optionally substituted. In other embodiments, R is , naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecany1, [2.2.2]bicyclooctany1, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, oxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, bazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H—l,5,2—dithiazinyl, ofuro [2,3—19] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, olyl, lH—indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, olyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3—oxadiazolyl, l,2,4—oxadiazolyl;— 1,2,50xadiazolyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, thridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, azinyl, phthalazinyl, piperazinyl, piperidinyl, inyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, oxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H—pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H—quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H—l,2,5—thiadiazinyl, 1,2,3— thiadiazolyl, 1,2,4—thiadiazolyl, l,2,5—thiadiazolyl, l,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, nyl, 1,2,3—triazoly1, 1,2,4—triazolyl, 1,2,5—triazolyl, 1,3,4—triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted.

In n embodiments, R2 is hydrogen, Br, CN, f0 )V‘Zi X/E AO/‘ZS. AS/K As/E o’ “O $85771o/ O Ys/ Ho E E H N2 \n/‘LLL AS)" /O\/\/3L O ” ‘o OH OH In certain embodiments, R2 is H H I I 'l“ I a, a" it“ “at "“t a ”a / \ W N‘Nfiat 0—K / N‘N N\N\ N‘N\ N‘N\ N{N\ N{N\/_§ N{N\ 2 H A Y C” H g N N H| W0 20142’209980 “at “a at a.

\ \ N N\ / \ 4 \ N \O O S S o A w “L “L NCS fl “a “a NW “a “a a \ NFg fig a I N H Y N r \N rN N N O 0 CD3 CD3 /SI /0 O In certain embodiments, R2 is In n embodiments, R2 is In certain embodiments, R3 is hydrogen.

In certain embodiments, R3 is C145 aliphatic, C340 aryl, a 3—8 membered ted or partially rated carbocyclic ring, a 3—7 membered heterocylic ring having 1—4 heteroatoms independently selected from en, oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

In n ments, R3 is an optionally substituted C14 aliphatic. In certain embodiments, R3 is an ally substituted C340 aryl. In certain embodiments, R3 is an optionally substituted 3—8 membered saturated or partially unsaturated carbocyclic ring. In certain embodiments, R3 is an optionally substituted 3—7 membered heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, R3 is an optionally substituted 5—6 membered monocyclic aryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, is R3 is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, uranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, trazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH—carbazolyl, carbolinyl, nyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H—l,5,2—dithiazinyl, dihydrofuro [2,3—b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, olinyl, imidazolyl, lH—indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, nolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, zolyl, l,2,3-oxadiazolyl, l,2,4-oxadiazolyl;— l,2,50xadiazolyl, 1,3,4—oxadiazolyl, idinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, inyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, zinyl, pyridooxazole, pyridoimidazole, WO 09980 pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H—pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H—quinoliziny1, quinoxalinyl, quinuclidinyl, ydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H— l ,2,5—thiadiazinyl, l,2,3—thiadiazolyl, 1,2,4—thiadiazolyl, thiadiazolyl, 1,3,4thiadiazolyl, hrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3—triazolyl, 1,2,4—triazolyl, 1,2,5—triazolyl, 1,3,4—triazoly1, yl, azetidinyl, or xanthenyl; each of which is optionally substituted.

In certain embodiments, is R3 is dihydrofuro [2,3—19] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H—indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H—indolyl, isoindolinyl, olenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, olyl, oxadiazolyl, 1,2,3—oxadiazolyl, l,2,4—oxadiazolyl;— 1,2,50xadiazolyl, 1,3,4—oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, zinyl, pyrrolidinyl, pyrrolinyl, 2H—pyrroly1, pyrrolyl, tetrahydrofuranyl, 6H-l,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, hiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, l,2,3—triazolyl, l,2,4—triazolyl, l,2,5—triazolyl, l,3,4—triazolyl, or xanthenyl; each of which is optionally substituted.

In certain embodiments, R3 is ”5L “LL Cl vN In certain embodiments, each R4 is independently en.

In certain embodiments, each R4 is independently C14 aliphatic, C340 aryl, a 3—8 membered saturated or lly unsaturated carbocyclic ring, a 3-7 ed heterocylic ring having 1—4 heteroatoms independently selected from en, oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, each R4 is independently an optionally substituted C145 aliphatic. In certain embodiments, each R4 is independently an optionally substituted C340 aryl.

In certain embodiments, each R4 is ndently an ally substituted 3-8 ed saturated or partially unsaturated carbocyclic ring. In certain embodiments, each R4 is 2014/043838 independently an optionally substituted 3—7 membered heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain ments, each R4 is independently an ally tuted 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In n embodiments, each R4 is independently halogen, —haloalkyl, —OR, —SR, — CN, —N02, -SOzR, —SOR, —C(O)R, —C02R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRS02R, or —N(R)2.

In certain embodiments, R5 is Cm aliphatic, C340 aryl, a 3—8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1—4 atoms independently selected from nitrogen, oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R5 is an ally substituted C14 aliphatic. In certain embodiments, R5 is an optionally substituted C340 aryl. In certain embodiments, R5 is an optionally substituted 3—8 membered saturated or partially unsaturated carbocyclic ring. In certain embodiments, R5 is an optionally substituted 3—7 membered heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, R5 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, R5 is CH; aliphatic. In certain embodiments, R5 is methyl, ethyl, propyl, i—propyl, butyl, s—butyl, t—butyl, straight or branched pentyl, or straight or branched hexyl; each of which is optionally substituted In certain ments, R5 is phenyl, yl, cyclopropyl, utyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, l, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, hiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH—carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H—l,5,2—dithiazinyl, dihydrofuro [2,3—19] tetrahydrofuran, l, nyl, imidazolidinyl, imidazolinyl, imidazolyl, azolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H—indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, omanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3—oxadiazolyl, 1,2,4—oxadiazolyl;— 1,2,50xadiazolyl, 1,3,4—oxadiazolyl, oxazolidinyl, oxazolyl, idinyl, pyrimidinyl, thridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H—pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H—quinolizinyl, alinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, ydroquinolinyl, 6H—l,2,5—thiadiazinyl, 1,2,3— azolyl, 1,2,4-thiadiazolyl, thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, oxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3—triazolyl, 1,2,4-triazoly1, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted.

In certain embodiments, R5 and R6, together with the atom to which each is attached, form a 3—8 membered heterocylic 1 ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5—6 membered heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or ; each of which is optionally substituted.

In certain embodiments, R5 is methyl, t—butyl, or -CD3.

In certain embodiments, R5 is H I 9D3 ii/VN ENNm/HAA/Nm/ \n/ E 0Y0 O O O 0 H M Eméo‘tw myvowyvcrN\,\]’N\ OH s s 5 5 5‘0 EXO\CD3 no], nO/CDs \QOH \QO—CD3 [’O—CDs ‘0 0w 0 H e“ in I? 511 0+??? ”,chch EEO f>CO No?OH CD3 f om SCbHO OCEFOE;OgrS>C\NH In n embodiments, Z is N and the ring formed by Z, R5 and R6 is ”33:” x\ OH O ROYO CF3 \N stfi AN>§ 5\N& :1NWMYANK ANK ANK o oK/o K/o‘riN o K/NH K/NH K/N\ ANK \N M K/NTO-t-Bu :35 \n/O-t-Bu O 0\ :iN e‘LN Oe’iN eiN NH ONN:> N90/’/—N:> RN 0QNN<O Q:1 O 0 ;\N/\\N H ACNOO NH2 N O—t—Bu V Jfij In certain embodiments, R6 is hydrogen.

In certain embodiments, R6 is C14 aliphatic, C340 aryl, a 3—8 membered saturated or partially unsaturated carbocyclic ring, a 3—7 ed heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R6 is an optionally substituted C14 aliphatic. In certain embodiments, R6 is an optionally substituted C340 aryl. In certain embodiments, R6 is an optionally substituted 3—8 membered saturated or partially unsaturated carbocyclic ring. In certain embodiments, R6 is an optionally substituted 3—7 membered cylic ring having 1—4 atoms independently selected from nitrogen, oxygen, or . In certain embodiments, R6 is an optionally substituted 5—6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In n embodiments, R6 is C14 aliphatic. In certain embodiments, R6 is , ethyl, propyl, yl, butyl, s-butyl, l, straight or branched pentyl, or ht or branched hexyl; each of which is optionally substituted.

In certain embodiments, R5 is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, ]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, othiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H—l,5,2—dithiazinyl, dihydrofuro [2,3—[9] tetrahydrofuran, l, nyl, olidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H—indolyl, isoindolinyl, isoindolenyl, zofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, nolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3—oxadiazolyl, 1,2,4—oxadiazolyl;— 1,2,50xadiazolyl, 1,3,4—oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, zinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, rolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H—quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H—l,2,5—thiadiazinyl, 1,2,3— thiadiazolyl, 1,2,4—thiadiazolyl, 1,2,5—thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, l, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3—triazolyl, l,2,4—triazolyl, 1,2,5—triazolyl, l,3,4—triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally substituted.

In certain embodiments, R6 is hydrogen.

In certain embodiments, R6 is methyl, t—butyl, or —CD3.

In certain embodiments, n is 0. In certain embodiments, n is 1. In certain ments, n is 2.

In certain ments, p is 0. In certain embodiments, p is l.

In certain embodiments, each of R1, R2, R3, R4, R5, R6, X, Y, Z, n, and p is as defined above and described in embodiments, s and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a nd of formula 1-3, r X v // / ,R5 R2 Z R3,N\N (R6)p 1-3; or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R5, R6, X, Y, Z, and p is as defined above and bed in embodiments, classes and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound of formula I-b, R1 o (R4)n R2 / ,R5 / Z R3/N\N (R6)p I-b; or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R4, R5, R6, Y, Z, n, and p is as d above and described in embodiments, classes and subclasses above and herein, singly or in combination.

In certain ments, the compound is of formula LC: 2014/043838 I 0 / / / R5 R2 Z R3/N\N (R6)p or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R5, R6, Z, and p is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound of formula I-d: R1 o R2 / zR5 / N ,N\N R6 I-d; or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R5, and R6 is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

In certain ments, the invention es a compound of formula I-e: R1 o R2 / /R5 / O ,N\N I-e; or a pharmaceutically acceptable salt f, wherein each of R1, R2, R3, and R5 is as defined above and described in embodiments, classes and subclasses above and herein, singly or in ation.

In other embodiments, the invention provides a compound of formula I-f: MeO O R2 / / N ,N\N R6 I-f; or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, R5, and R6 is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

In other embodiments, the invention provides a compound of formula I-g: MeO O R2 / O/R5 R3/N\N I-g; or a pharmaceutically able salt thereof, wherein each of R2, R3, and R5 is as defined above and described in embodiments, classes and subclasses above and herein, singly or in ation.

] In certain embodiments, the invention provides a compound of formula I-h: R1 o R2 // (Rs N‘N (Rm or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R5, R6, Z, and p is as defined above and described in embodiments, s and subclasses above and herein, singly or in combination.

] In certain embodiments, the invention provides a compound of formula I-f, wherein R2 is 5—6 membered monocyclic heteroaryl ring having 1—4 atoms independently selected from nitrogen, oxygen, or sulfur; which is optionally substituted; R3 is an optionally substituted —6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Z is N.

In certain embodiments, R5 is an optionally tuted C14 aliphatic.

] In certain embodiments, R5 and R6, together with the atom to which each is attached, form a 3—8 membered heterocylic 1 ring having 1—4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur, which is optionally substituted.

In certain embodiments, R6 is an optionally substituted C145 aliphatic.

In certain embodiments, the invention provides a compound of formula I-h, wherein R1 is —OR and R is C1_6 aliphatic; R2 is 5-6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; which is ally substituted; and Z is N.

In n embodiments, R5 is an optionally substituted CM aliphatic.

In certain ments, R5 and R6, together with the atom to which each is attached, form a 3—8 ed heterocylic 1 ring having 1—4 atoms independently selected from nitrogen, oxygen, or sulfur, which is optionally substituted.

In certain embodiments, R6 is an optionally substituted C14 aliphatic.

In certain embodiments, the invention provides a nd selected from Table 1: Table 1 \ / H N\ / N/ N‘N 1 2 WO 09980 WO 09980 16 / / O O / O O / / / “ “ Cr“ “ \O O HO O 17 18 WO 09980 AW9SWWl HT 36/ )V 5 19 20 21 22 A / / O \N // \ o>\O 5gN\N N \ / —\_”\J \O O 23 24 O/ o 26 WO 09980 4% * W5 27 28 29 30 0/ / / 0 ° / / / N\N/ S/CK /PK C(M/ r\1 o N——< / \ / o 31 32 0/ / / O / l O / / WO 09980 O O\ 39 40 o J / O // / 0 Cf” “ Cr“ “ \T 0 \N o 41 42 WO 09980 43 44 /0 /O / O l O / / \N/ N \ <:|/N\N/ N E“ O DAG 45 46 47 48 / O HZN / O 5g / N N \ O\o 0 )VD S O/NN/\ /“1% D / 49 50 WO 09980 57 58 59 60 WO 09980 65 66 WO 09980 69 70 77 78 WO 09980 81 82 o l O O 83 84 / /0 N/ O H N\ \ o / N- O / / N N \ >\o \ 85 86 WO 09980 89 90 WO 09980 99 100 101 102 WO 09980 109 110 WO 09980 WO 09980 133 134 135 136 137 138 WO 09980 o o o o ”4 / / / 0 I / I / Ar N N N\N N/N N~N \ K»NJi / \ \ D/KD / / D 139 140 ° L o 145 146 /° \ 147 148 WO 09980 //o ' O 0 I / N‘N /N 149 150 155 156 WO 09980 157 158 161 162 0 0 / / / O / I OH N‘N D/K/g N‘N/ d /N [El/h on Q 163 164 WO 09980 169 170 o /o / 0 / / / & N—N I / / / N/N “N H OH Cf”\N N < / ‘ N H / 171 172 WO 09980 2\ j\\ 3 \\ \zfi. T\2\ z <05 181 182 /0 /0 o o / D / / D N‘N/ O/K I N N \N/ 0/A \ D / \ D / / 183 184 WO 09980 WO 09980 201 202 WO 09980 203 204 213 214 217 218.

In some embodiments, the present invention provides a nd selected from those depicted above, or a pharmaceutically acceptable salt thereof.

] Various structural depictions may show a heteroatom without an attached group, radical, charge, or counterion. Those of ordinary skill in the art are aware that such ions are meant to indicate that the heteroatom is attached to hydrogen (e.g., 11/ is understood to be ELL/OH).

In certain embodiments, the compounds of the invention were synthesized in accordance with Schemes A-C below. More specific examples of compounds made utilizing Schemes A—C are provided in the Examples below.

SchemeA *1:er —> R1 R1 X (R4)n X (R4)n AW —> AW / Z6R5 / Z6x N»: f hal / R2 N N N [G (R), R Ry (R), Ry H II—a I SchemeB O OH [NxN \N , (R6)p R3 R3 III-a I Scheme C R1 R1 R1 X (R4)n x (R4)n X (R4)n A Y LG / / hal hal / LG R2 / LG 0 OH ,N\N /N\N R3 R3 lV-a lV-b X (R4)n ' A ,R5 / R2 / Z R3’N\N (R6)p 4. Uses ation and Administration Pharmaceutically Acceptable Compositions According to r embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably modulate FSHR, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this ion is such that is effective to measurably modulate FSHR, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a ition of this invention is formulated for administration to a patient in need of such composition.

The term “patient” or “subject”, as used herein, means an , preferably a mammal, and most preferably a human.

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

A aceutically acceptable derivative” means any non—toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a ent, is capable of providing, either ly or indirectly, a compound of this invention or an torily active lite or residue thereof.

Compositions of the t invention are administered orally, erally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an ted reservoir.

The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra—synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the itions of this invention include aqueous or oleaginous sion. These suspensions are formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

The sterile injectable preparation is also be a sterile injectable solution or suspension in a non— toxic parenterally acceptable diluent or solvent, for e as a on in 1,3—butanediol.

Among the acceptable vehicles and ts that are employed are water, Ringer’s solution and isotonic sodium chloride solution. In on, sterile, fixed oils are conventionally ed as a solvent or suspending medium.

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

Pharmaceutically acceptable compositions of this invention are orally administered in any orally acceptable dosage form. Exemplary oral dosage forms are capsules, tablets, aqueous suspensions or ons. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating , such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When s suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, ng or coloring agents are optionally also added.

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

Pharmaceutically acceptable compositions of this invention are also administered topically, especially when the target of treatment includes areas or organs readily ible by topical application, ing diseases of the eye, the skin, or the lower inal tract. Suitable l formulations are y prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository ation (see above) or in a suitable enema formulation. Topically—transdermal patches are also used.

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

Pharmaceutically able itions of this invention are optionally administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques nown in the art of pharmaceutical formulation and are prepared as solutions in , employing benzyl alcohol or other suitable vatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food.

In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

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

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

Uses of Comgounds and Pharmaceutically Accegtable Comgositions In certain ments, the invention provides a method for allosterically agonising FSHR, or a mutant f, in a positive manner in a t or in a biological sample comprising the step of administering to said patient or contacting said biological sample with a compound according to the invention.

In certain ments, the invention is directed to the use of compounds of the invention and/or physiologically acceptable salts thereof, for modulating a FSH receptor, particularly in the presence of FSH. The term ation” denotes any change in FSHR— mediated signal uction, which is based on the action of the specific inventive compounds capable to interact with the FSHR target in such a manner that makes recognition, binding and activating possible. The compounds are characterized by such a high affinity to FSHR, which ensures a reliable binding and preferably a positive eric modulation of FSHR. In certain embodiments, the substances are pecific in order to guarantee an exclusive and directed recognition with the single FSHR target. In the context of the present invention, the term “recognition” — without being limited thereto — s to any type of interaction between the specific compounds and the target, particularly nt or non-covalent binding or association, such as a covalent bond, hydrophobic/ hydrophilic interactions, van der Waals , ion pairs, hydrogen bonds, ligand—receptor interactions, and the like. Such association may also encompass the presence of other molecules such as peptides, proteins or nucleotide sequences. The present receptor/ligand—interaction is characterized by high affinity, high selectivity and minimal or even lacking cross—reactivity to other target molecules to exclude unhealthy and harmful impacts to the treated subject.

In certain embodiments, the present invention relates to a method for modulating an FSH receptor, and in particular in a positive allosteric manner, wherein a system capable of expressing the FSH receptor is contacted, in the presence of FSH, with at least one compound of a (I) according to the invention and/or physiologically acceptable salts thereof, under conditions such that said FSH receptor is modulated. In certain embodiments, modulation is in a positive eric manner. In n embodiments, the system is a ar system. In other embodiments, the system is an in—vitro translation which is based on the protein synthesis t living cells. The cellular system is defined to be any t provided that the subject comprises cells. Hence, the cellular system can be selected from the group of single cells, cell cultures, tissues, organs and animals. In certain embodiments, the method for modulating an FSH receptor is performed in—Vitro. The prior teaching of the present specification concerning the nds of formula (I), including any embodiments thereof, is valid and applicable without ctions to the compounds according to formula (I) and their salts when used in the method for ting FSHR. The prior teaching of the present specification concerning the compounds of formula (I), including any embodiments thereof, is valid and applicable without ctions to the nds according to formula (I) and their salts when used in the method for modulating FSHR.

In certain embodiments, the compounds according to the invention exhibit an advantageous biological activity, which is easily demonstrated in cell culture—based assays, for example assays as described herein or in prior art (cf. e.g. , which is incorporated herein by reference). In such , the compounds according to the invention preferably exhibit and cause an tic effect. In certain embodiments, the compounds of the invention have an FSHR agonist activity, as expressed by an EC50 rd, of less than 5 uM. In certain embodiments, less than 1 uM. In certain embodiments, less than 0.5 uM. In certain embodiments, less than 0.1 uM. “EC50” is the effective concentration of a nd at which 50 % of the maximal response of that obtained with FSH would be obtained.

As discussed herein, these signaling pathways are relevant for various diseases, including fertility disorders. Disorders/diseases treated by the methods of the invention include but are not limited to, hypogonadotropic hypogonadism, Isolated idiopathic hypogonadotropic nadism, Kallmann syndrome, Idiopathic hypogonadotropic hypogonadism, Craniopharyngiomas, Combined pituitary hormone deficiency, Fertile eunuch syndrome, Abnormal beta subunit of LH, Abnormal beta subunit of FSH, mass lesions, pituitary adenomas, cysts, metastatic cancer to the sella (breast in women, lung and prostate in men), Infiltrative lesions, Hemochromatosis, sarcoidosis, histiocytosis, lymphoma, Lymphocytic ysitis, Infections, Meningitis, Pituitary apoplexy, Hyperprolactinemia, yroidism, Intentional genic) secondary nadism, Empty sella, Pituitary infarction, Sheehan syndrome, Anorexia a, Congenital adrenal hyperplasia, and disorders related to GnRH deficiency.

Accordingly, the compounds according to the ion are useful in the prophylaxis and/or treatment of diseases that are dependent on the said signaling pathways by interaction with one or more of the said signaling pathways. The present invention therefore relates to compounds according to the invention as tors, preferably agonists, more preferably positive allosteric modulators, of the signaling pathways described herein, preferably of the FSHR—mediated signaling pathway. The compounds of the ion are supposed to bind to the intracellular receptor domain without a competitive ction with FSH, but they act as an allosteric er of FSH on its receptor. The mpetitive interaction refers to the nature of the t activity exhibited by the compounds of the invention, n the compounds activate FSHR t substantially reducing the magnitude of binding of FSH to FSHR.

In n embodiments, the invention is directed towards the stimulation of follicular development, ovulation induction, lled ovarial hyperstimulation, assisted reproductive technology, including in—vitro fertilization, male hypogonadism and male infertility, including some types of failure of spermatogenesis.

] It is another object of the invention to e a method for treating diseases that are caused, mediated and/or propagated by FSHR activity, wherein at least one compound of formula (I) according to the invention and/or physiologically acceptable salts thereof is administered to a mammal in need of such treatment. In certain embodiments, the invention provides a method for treating fertility disorders, wherein at least one compound of formula (I) according to the invention and/or physiologically acceptable salts thereof is administered to a mammal in need of such ent. In certain embodiments, the compound is stered in an effective amount as defined above. In certain embodiments, the treatment is an oral administration.

In certain embodiments, the method of treatment aims to achieve ovulation ion and/or controlled ovarian hyperstimulation. In still another embodiment, the method of treatment forms the basis for a method for in-Vitro fertilization sing the steps of: (a) treating a mammal ing to the method of treatment as described above, (b) collecting ova from said mammal, (c) izing said ova, and (d) implanting said fertilized ova into a host mammal. The host mammal can be either the treated mammal (i.e. the patient) or a surrogate. The prior teaching of the invention and its embodiments is valid and applicable without restrictions to the methods of treatment if expedient.

The method of the invention can be med either in—vitro or o. The susceptibility of a particular cell to treatment with the compounds according to the invention can be particularly determined by in—vitro tests, whether in the course of ch or clinical application. Typically, a culture of the cell is combined with a compound according to the invention at various concentrations for a period of time which is sufficient to allow the active agents to modulate FSHR activity, usually between about one hour and one week. In-vitro treatment can be carried out using cultivated cells from a biopsy sample or cell line. In a preferred aspect of the invention, a follicle cell is stimulated for maturation. The viable cells remaining after the treatment are counted and further processed.

] The host or patient can belong to any mammalian species, for example a primate s, particularly humans; rodents, including mice, rats and hamsters; s; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease.

For identification of a signal transduction pathway and for detection of interactions between various signal transduction pathways, various scientists have developed suitable models or model systems, for e cell culture models and models of transgenic animals. For the determination of certain stages in the signal transduction cascade, interacting compounds can be utilized in order to modulate the signal. The compounds according to the invention can also be used as reagents for g ependent signal transduction pathways in animals and/or cell culture models or in the clinical diseases mentioned in this application.

The use according to the previous paragraphs of the specification may be either performed in—vitro or in—vivo models. The modulation can be monitored by the techniques described in the course of the present specification. In n embodiments, the in—vitro use is preferably applied to samples of humans suffering from fertility disorders. Testing of several specific compounds and/or tives thereof makes the selection of that active ingredient possible that is best suited for the treatment of the human subject. The in—vivo dose rate of the chosen derivative is advantageously pre—adjusted to the FSHR susceptibility and/or severity of e of the respective subject with regard to the in—vitro data. Therefore, the therapeutic efficacy is remarkably enhanced. er, the subsequent ng of the t specification concerning the use of the nds according to a (I) and its derivatives for the production of a medicament for the prophylactic or therapeutic ent and/or monitoring is considered as valid and applicable without restrictions to the use of the compound for the modulation of FSHR activity if expedient.

The invention also relates to the use of compounds according to formula (1) and/or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or propagated by FSHR activity.

Furthermore, the invention relates to the use of compounds according to formula (1) and/or physiologically acceptable salts thereof for the tion of a medicament for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or propagated by FSHR activity. In certain embodiments, the invention es the use of a compound according to formula I or physiologically acceptable salts thereof, for the production of a medicament for the prophylactic or therapeutic ent of a FSHR—mediated disorder.

Compounds of formula (1) and/or a physiologically acceptable salt thereof can furthermore be employed as intermediate for the preparation of further medicament active ingredients. The medicament is ably ed in a non—chemical manner, e.g. by ing the active ingredient with at least one solid, fluid and/or semi—fluid carrier or ent, and optionally in conjunction with a single or more other active substances in an riate dosage form.

Another object of the present invention are nds of a (I) according to the invention and/or physiologically acceptable salts thereof for use in the prophylactic or therapeutic treatment and/or monitoring of diseases that are , mediated and/or propagated by FSHR activity. Another preferred object of the invention ns compounds of formula (1) according to the invention and/or physiologically acceptable salts thereof for use in the prophylactic or therapeutic treatment and/or monitoring of fertility disorders. The prior teaching of the present specification concerning the compounds of formula (1), including any preferred embodiment thereof, is valid and applicable without restrictions to the compounds according to a (I) and their salts for use in the prophylactic or therapeutic treatment and/or monitoring of fertility disorders.

The compounds of formula (1) according to the invention can be administered before or following an onset of disease once or several times acting as therapy. The aforementioned compounds and l products of the inventive use are particularly used for the therapeutic treatment. A therapeutically relevant effect relieves to some extent one or more symptoms of a er, or returns to normality, either partially or completely, one or more physiological or biochemical parameters associated with or causative of a disease or pathological condition. ring is considered as a kind of treatment provided that the compounds are administered in distinct intervals, e.g. in order to booster the response and eradicate the pathogens and/or symptoms of the disease completely. Either the identical compound or different compounds can be applied. The methods of the invention can also be used to reducing the likelihood of developing a disorder or even prevent the initiation of disorders associated with FSHR activity in advance or to treat the arising and continuing symptoms. In certain embodiments, the ers are fertility disorders.

In the meaning of the invention, prophylactic treatment is advisable if the subject possesses any preconditions for the aforementioned physiological or pathological conditions, such as a familial disposition, a genetic defect, or a previously passed disease.

The invention furthermore relates to a medicament comprising at least one compound ing to the ion and/or pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios. In certain embodiments, the invention relates to a medicament sing at least one compound according to the invention and/or logically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the field of medicine, which comprises one or more compounds of formula (I) or preparations thereof (e. g. a pharmaceutical composition or pharmaceutical formulation) and can be used in prophylaxis, therapy, follow—up or aftercare of patients who suffer from diseases, which are associated with FSHR ty, in such a way that a pathogenic modification of their overall condition or of the condition of particular regions of the organism could establish at least temporarily.

In various ments, the active ingredient may be stered alone or in combination with other ents. A synergistic effect may be achieved by using more than one compound in the ceutical composition, i.e. the compound of formula (I) is combined with at least another agent as active ingredient, which is either another nd of formula (I) or a compound of different structural scaffold. The active ingredients can be used either simultaneously or sequentially. The present compounds are le for combination with known fertility—inducing agents. In certain embodiments, the other active pharmaceutical ingredient is selected from the group of FSH, Ot—FSH (Gonal F), B—FSH, LH, hMG and 2—(4—(2—chloro—l,2— diphenylethenyl)-phenoxy)-N,N-diethyl-ethanamine citrate (Chlomifene citrate). r ovulation adjuncts are known to those of skill in the art (cf. e.g. , which is incorporated herein by nce) and are useful with the compounds of the present invention.

In another , the invention provides for a kit consisting of separate packs of an effective amount of a compound according to the invention and/or pharmaceutically acceptable salts, derivatives, solvates and isomers thereof, including mixtures thereof in all ratios, and ally, an effective amount of a further active ingredient. The kit comprises suitable containers, such as boxes, individual bottles, bags or ampoules. The kit may, for example, comprise separate ampoules, each containing an effective amount of a compound according to the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an ive amount of a r active ingredient in dissolved or lyophilized form.

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

The nds and compositions, according to the method of the present invention, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided above. The exact amount required will vary from t to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the ular agent, its mode of administration, and the like.

Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically te unit of agent appropriate for the patient to be d. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the ing physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the ty of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body , general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific nd employed, and like factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can be administered to humans and other s orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by s, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being d. In certain embodiments, the compounds of the invention are administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 100 mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

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

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

Injectable formulations can be sterilized, for e, by filtration through a bacterial—retaining filter, or by orating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of the present ion, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection.

This is accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or ding the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in radable polymers such as ctide— polyglycolide. Depending upon the ratio of compound to polymer and the nature of the ular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are ible with body tissues.

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

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

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

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

Dosage forms for topical or transdermal stration of a compound of this invention include ointments, pastes, creams, s, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.

Additionally, the present invention contemplates the use of ermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate lling membrane or by sing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method of allosterically modulating FSHR activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

According to another ment, the invention relates to a method of allosterically modulating FSHR, or a mutant thereof, activity in a biological sample in a positive manner, comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

] The compounds of the invention are strong and selective tors of the FSH receptor. Their selectivity to the FSH receptor is 3 to 10—fold over the LH receptor and even 10 to lOO—fold over the TSH receptor While the EC50 or IC50 amounts to more than 10 uM on unrelated G protein—coupled receptors (GPCR) or non—GPCR targets. The current invention comprises the use of the compounds of the invention in the regulation and/or modulation of the FSHR signal cascade, which can be ageously applied as research tool, for diagnosis and/or in ent of any disorder arising from FSHR signaling.

For example, the compounds of the invention are useful in—vitro as unique tools for understanding the biological role of FSH, including the tion of the many factors thought to influence, and be influenced by, the production of FSH and the interaction of FSH with the FSHR (e. g. the mechanism of FSH signal transduction/receptor activation). The present compounds are also useful in the development of other compounds that ct with FSHR since the present compounds provide important structure—activity relationship (SAR) information that facilitate that development. nds of the present ion that bind to FSHR can be used as reagents for detecting FSHR on living cells, fixed cells, in biological fluids, in tissue homogenates, in purified, natural biological materials, etc. For example, by labeling such compounds, one can identify cells having FSHR on their surfaces. In addition, based on their y to bind FSHR, nds of the present invention can be used in in—situ staining, FACS (fluorescence—activated cell sorting), n blotting, ELISA (enzyme—linked immunoadsorptive assay), etc., receptor purification, or in purifying cells sing FSHR on the cell surface or inside permeabilized cells.

The compounds of the invention can also be utilized as commercial research reagents for various medical ch and stic uses. Such uses can include but are not limited to: use as a calibration standard for quantifying the activities of candidate FSH agonists in a variety of functional assays; use as blocking reagents in random nd screening, i.e. in looking for new families of FSH receptor s, the compounds can be used to block recovery of the presently claimed FSH compounds; use in the co—crystallization with FSHR receptor, i.e. the compounds of the present invention will allow formation of ls of the compound bound to FSHR, enabling the ination of receptor/compound structure by x—ray crystallography; other research and diagnostic applications, n FSHR is preferably activated or such activation is conveniently calibrated against a known quantity of an FSH agonist, etc.; use in assays as probes for ining the sion of FSHR on the e of cells; and developing assays for detecting compounds which bind to the same site as the FSHR binding ligands.

The compounds of the invention can be applied either themselves and/or in combination with physical measurements for diagnostics of treatment effectiveness.

Pharmaceutical itions containing said compounds and the use of said compounds to treat FSHR-mediated conditions is a promising, novel approach for a broad spectrum of therapies causing a direct and immediate improvement in the state of health, whether in human or animal.

The impact is of special benefit to efficiently combat infertility, either alone or in combination with other fertility—inducing treatments. In particular, the compounds of the invention potentiate the native FSH effect for both ovulation induction and assisted reproductive technology. The orally bioavailable and active new chemical entities of the invention improve convenience for patients and compliance for physicians.

The compounds of the invention are active in the primary screen (CHO with or without FSH), selective in secondary screen (no or low activity t TSHR and LHR) and potent in the granulosa cell iol assay. Neither hERG nor any toxic s could be observed in—vitro.

In certain embodiments, the invention provides a method for in—vitro fertilization comprising the steps of: (a) treating a mammal according to the method as described above, (b) collecting ova from said , (c) fertilizing said ova, and (d) implanting said fertilized ova into a host mammal.

The compounds of formula (1), their salts, isomers, tautomers, enantiomeric forms, diastereomers, racemates, derivatives, prodrugs and/or metabolites are characterized by a high specificity and stability, low manufacturing costs and convenient handling. These features form the basis for a reproducible action, wherein the lack of cross—reactivity is included, and for a le and safe interaction with the target structure.

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

Modulation of FSHR, or a mutant thereof, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. es of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

IFICATION As ed in the Examples below, in certain exemplary embodiments, nds are ed according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the ing general methods, and other s known to one of ordinary skill in the art, can be d to all compounds and subclasses and species of each of these compounds, as described herein.

Compound numbers utilized in the Examples below correspond to nd numbers set forth supra. 1H NMR was recorded on a Bruker 400 MHz spectrometer, using residual signal of deuterated solvent as internal reference. Chemical shifts (8) are reported in ppm ve to the residual solvent signal (8 = 2.49 ppm for 1H NMR in DMSO—d6). 1H NMR data are reported as follows: chemical shift (multiplicity, coupling constants, and number of hydrogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

LCMS—Analysis was performed under the following conditions: Method : A: 0.1 % TFA in H20, B:0.l % TFA in ACN: Runtime: 6.5 min Flow Rate: 1.0 mL/min Gradient: 5—95% B in 4.5 min, wavelength 254 and 215 nM.

Column: Waters Sunfire C18, 3.0X50mm, 3.5um, + ve mode Mass Scan: 100—900 Da c—Sheme1: O—>CFsoH :)TN:EIH0 01°)H2804 aq.0 HO 0 K2003 /O NBS (I) 0 Mel S'I'Ca O )DIPEA nBuLi 2)Diethyloxalate Br GET 0 OH I/ / :C'H o 0 LiOH NHRR o // Br 0 E‘OH ACOH UM DIPEA DCM OH // coupling agent N‘N CV\ NR1R2 R3-Br O Suzuki coupling _, 0 Example 1 7-Methoxy(1H-pyrazolyl)thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methyl-amide (1) Step1: 3-Bromo(2,4-dihydroxyphenyl)propanone HO OH Br 0 CF3SO3H + VY HO OH Br To a stirred suspension of inol (25 g, 0.22 mol) and 3—Bromopropanoic acid (38.3 g, 0.25 mol) was added trifluoromethanesulfonic acid (75 mL, 0.84 mol) drop Wise at 0 0C WO 09980 under nitrogen here. After the addition, the reaction mixture was heated to 80 0C for 30 min. The reaction e was cooled to RT and ed with ice water (200 mL) and extracted with DCM (500 mL). The aqueous layer was re—extracted with DCM (2 x100 mL); the combined c layer was dried over sodium sulphate and concentrated under vacuum to afford the desired compound (40 g, 72 %) as an orange solid. 1H NMR (400 MHz, DMSO-d6) 5 12.2 (bs, 1H), 10.6 (bs, 1H), 7.77-7.75 (d, J = 8 Hz, 1H), 6.38-6.35 (dd, J = 2.0, 8.8 Hz, 1H), 6.26-6.26 (d, J = 4.0 Hz, 1H), 3.74 (t, J = 6.8 Hz, 2H), .57 (dd, J: 6.0, 11.2 Hz, 2H).

Step2: 7-Hydr0xy-2, 3-dihydro-4H-chromenone 1)NaOH.OOCto HO O RT,2H 2) H 80 a 2 4 q.

HO OH Br To an ice cold solution of 2M NaOH (92 mL, 2.33 mol), was added 3—Bromo—l—(2, 4— dihydroxyphenyl) propan—l—one (38 g, 0.155 mol) in lots over a period of 30 min. The resulting suspension was stirred at RT for 2 h. The reaction mixture was cooled to 00 C; pH was adjusted to ~2 using 50 % aqueous solution of sulfuric acid. The solid separated out was stirred for additional 10 min at RT, filtered and dried under high vacuum to afford the desired compound (16 g, 63 %) as brown solid. 1H NMR (400 MHz, DMSO— d6) 8 10.52 (bs, 1H), 7.61-7.59 (d, J: 8.0 Hz, 1H), 6.48-6.45 (dd, J = 4.0, 12.0 Hz, 1H), 6.29-6.20 (d, J: 4.0 Hz, 1H), 4.44 (t, J = 4.0 Hz, 2H), 2.65 (t, J = 4.0 Hz, 2H).

Step3: 7-Methoxy-2,3-dihydro-4H-chromenone HO 0 o o K2003, Mel O 0 To a stirred solution of 7-Hydroxy—2,3—dihydro—4H—chromen—4—one (27 g, 0.16 mol) in acetone (700 mL) was added dry K2C03 (45.6 g, 0.32 mol) in lots at RT under nitrogen. The reaction mixture was stirred at RT for 10 min and then methyl iodide (65.4 g, 0.46 mol) was added drop wise at RT. The reaction mixture was stirred at RT for 4 h. The reaction mixture was filtered and filtrate was concentrated under vacuum. The crude product was dissolved in DCM (200 mL), washed with water (100 mL), brine (50 mL), dried over sodium te and concentrated under vacuum to afford the desired compound (15 g, 89 %) as light yellow solid. 1H NMR (400 MHZ, CDC13) 8 7.85—7.83 (d, J = 8.0 Hz, 1H), 6.60—6.57 (dd, J = 4.0, 12.0 Hz, 1H), 6.41-6.41 (d, J: 4.0 Hz, 1H), 4.52 (t, J: 8.0 Hz, 2H), 3.77 (s, 3H), 2.76 (t, J: 4.0 Hz, 2H).

Step 4: 6-Br0m0methoxy-2,3-dihydro-4H-chromenone O O (I) O NBS, silica gel 0 0 To a solution of 7—Methoxy—2,3—dihydro—4H—chromen—4—one (30 g, 0.16 mol) in acetonitrile : diethyl ether mixture (100 : 300 mL) was added silica gel 60—120 mesh (1.5 g) and NBS (33 g, 0.18 mol) in lots at RT under nitrogen. The reaction mixture was stirred at RT for 14 h. The reaction mixture was filtered and concentrated under vacuum. The crude product was purified by column chromatography by using pet ether / ethyl acetate (9: 1) as eluent to afford the desired compound (10 g, 72 %) as a light brown solid. 1H NMR (400 MHz, DMSO—d6 ) 8 7.82 (s, 1H), 6.73 (s, 1H), 4.53 (t, J = 8.0 Hz, 2H), 3.89 (s, 3H), 2.72 (t, J: 8.0 Hz, 2H).

Step 5: Ethyl-(6-bromomethoxyoxo-2H-chromen-3(4H)- e)(hydroxy)acetate o o )DIPEA nBuLi O 2)Diethyloxalate Br OEt 0 OH ] Diisopropylamine (7 mL, 0.3958mol) was taken in dry THF (50 mL) at RT under nitrogen atmosphere. The reaction mixture was cooled to —78 OC and n—Butyl lithium (1.6 M solution in hexane, 29.2 mL, 0.04 mol) was added drop wise over a period of 30 min. After the on, the reaction mixture was stirred at the same temperature for 15 min and then slowly warmed to —10 0C and stirred r for 30 min. The reaction mixture was again cooled to —78 OC, 6—Bromo—7-methoxy—2, 3-dihydro-4H—chromen—4-one (10 g, 0.03 mol) in THF (50 mL) was added drop wise over period of 30 min and stirred at —78 0C. After lh, diethyl oxalate (7.8 mL, 0.05 mol) was added drop wise at —78 0C; the reaction mixture was slowly brought to 0 0C and stirred for 1h. The on mixture was cooled to —5 OC, quenched with a solution of 1.5N HCl and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with water (100 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford the desired compound (10 g, 72 %) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) 8.8.04 (s, 1H), 6.43 (s, 1H), 5.32 (s, 2H), .32 (m, 2H), 3.95 (s, 3H), 1.42-1.37 (m, 3H).

Step 6: tert-Butyl 1-(3-thienyl)hydrazinecarboxylate B. 0:03,Cul OYNNi’fl To a solution of o thiophene (10 g, 0.061 mol) in DMSO (100 mL) was added utyl carbazate (16.3 g, 0.122 mol), cesium carbonate (40 g, 0.122 mol ) followed by CuI (1.2 g, 0.006 mol) and 4—Hydroxy—L—Proline (1.6 g, 0.01 mol) at RT under nitrogen. The reaction mixture was stirred at 80 °C for 14 h. The reaction mixture was cooled to RT, quenched with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with water (100 mL x 2), brine (100 mL), dried over sodium sulphate and evaporated under vacuum. The crude product was purified by column chromatography by using pet ether and ethyl acetate (7:3) as eluent to afford the title compound (3.5 g, 27 %) as pale brown liquid. 1H NMR (400 MHz, 6) 8 7.37-7.35 (dd, J: 4.0, 5.2 Hz, 1H), .29 (d, J = 8.0 Hz, 1H), 7.14 -7.13 (dd, J: 4.0, 5.2 Hz, 1H), 5.09 (bs, 2H), 1.47 (s, 9H).

Step7: 3-Thienylhydrazine hydrochloride H2N\ D HCI H To a stirred on of tert—Butyl l—(3—thienyl)hydrazinecarboxylate (3.5 g, 0.0163 mol) in diethyl ether (10 mL) was added HCl in dioxane (30 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 8 h. The organic solvent was removed under reduced pressure to afford the desired compound (2.4 g, 97 %) as pale brown solid. 1H NMR (400 MHz, DMSO-d6) 8 10.08 (bs, 3H), 8.20 (bs, 1H), 7.48—7.46 (dd, J: 3.2, 5.2 Hz, 1H), 6.87-6.85 (dd, J: 1.2, 4.8 Hz, 1H), 6.72-6.71 (dd, J: 1.6, 3.2 Hz, 1H).

Step 8: Ethyl 8-br0m0meth0xy(3-thienyl)-1, 4-dihydrochromeno [4,3- c]pyrazolecarb0xylate ' I o o H2N\NB / o o HCI H 0 Br OEt Br / EtOH, AcOH OH 0 OH N~N To a solution of ethyl—(6—bromo—7—methoxy—4—oxo—2H—chromen—3(4H)— ylidene)(hydroxy)acetate (8.0 g, 0.0224 mol) in a mixture of l (200 mL) and acetic acid (200 mL) was added 3—thienylhydrazine hydrochloride (4.4 g 0.0291 mol) at RT under nitrogen.

The reaction mixture was stirred at 100 0C for 4 h. The reaction e was concentrated under high vacuum. The residue was dissolved with ethyl acetate (40 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated under vacuum. The crude product was ed by column chromatography using pet ether/ethyl acetate as eluent to afford the desired nd (8.5 g, 87 %) as a pale yellow solid. 1H NMR (400 MHz, CDC13 ) 5 7.57-7.55 (dd, J = 4.0, 5.2 Hz, 1H), 7.52—7.50 (dd, J = 4.0, 5.2 Hz, 1H),7.22-7.21 (dd, J: 1.2, 5.2 Hz, 1H), 6.94 (s, 1H), 6.60 (s, 1H), 5.56 (s, 2H), 4.47—4.41 (dd, J: 8.0, 12 Hz. 2H), 3.88 (s, 3H), 1.42 (t, J: 8.0 Hz, 3H).

Step 9: 8-Br0m0meth0xy(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole- 3-carb0xylic acid 0\ O\ LiOH To a solution of Ethyl 8—bromo—7—methoxy—l—(3—thienyl)—l, 4—dihydrochromeno [4, 3— c] pyrazole—3—carboxylate (3 g, 0.0069 mol) in mixture of THF (70 mL), H20 (20 mL), MeOH (10 mL) was added LiOH.H20 (0.857 g, 0.0207 mol) at RT. The reaction mixture was stirred at RT for 4 h. The reaction mixture was evaporated and ied with a solution of 1.5N HCl. The solid was filtered and dried to afford the desired compound (2.8 g, 99 %) as an off—white solid. 1H NMR (400 MHz, DMSO—d6) 8 13.28 (bs, 1H), 8.01—8.00 (dd, J = 1.2, 5.2 Hz, 1H), 7.87— 7.85 (dd, J: 4.0, 5.2 Hz, 1H),7.35—7.33 (dd, J: 4.0, 8.0 Hz, 1H), 6.83 (s, 1H), 6.73 (s, 1H), 5.50 (s, 2H), 3.82 (s, 3H). m/z: 407 [M+H]+ Step 10: 8-Br0momethoxythiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarb0xylic acid tert-butyl-methyl-amide (4) /O /O O XN/ O O H Br // / N4 HATU DIPEA ’ 3::r N OH a ! N~ DCM Si N /N7< / / ] To a solution of 8—bromo—7—methoxy—1—(3—thienyl)—1, 4—dihydrochromeno [4, 3—c] le—3—carboxylic acid (2.8 g, 0.0069 mol) in DCM (50 mL) was added N—tert—butyl methyl amine (718 mg, 0.0083 mol), HATU (3.14 g, 0.0083 mol) and diisopropyl ethyl amine (1.8 mL, 0.0103 mol) at RT under nitrogen. The reaction mixture was d at RT for 16 h. The reaction mixture was quenched to sodium bicarbonate (10 mL, 10 %), extracted with DCM (2 x 50 mL).

The combined organic layer was washed with NaHC03 solution (1 x 100 mL, 10 % solution), brine (100 mL) and dried over anhydrous sodium sulphate. The solvent was removed under vacuum; the crude product was purified by column chromatography by using pet ether and ethyl acetate (9: 1) as eluent to afford the desired compound (3.2 g, 98%) as a white solid. 1H NMR (400 MHz, DMSO'dé) 8 7.98-7.97 (dd, J = 1.4, 3.2 Hz, 1H), 7.80-7.85 (dd, J: 3.2 , 4.7 Hz, 1H), 7.33-7.32 (dd, J: 1.3, 5.1 Hz, 1H), 6.83 (s, 1H), 6.76 (s, 1H), 5.37 (s, 2H), 3.81 (s, 3H), 3.15 (s, 3H), 1.47 (s, 9H). m/z: 476 [M+H]+ Step 11: 7-Meth0xy(1H-pyrazolyl)thiophenyl-1,4-dihydro- chromen0[4,3-c]pyrazolecarboxylic acid tert-butyl-methyl-amide (1) 0\ 540£ 0 N7 \o\N Br o H / —> S\/:|/ / Pdc'2(dppf)CH2C|2, cs]: ] To a solution of 8—bromo—N—(tert—butyl)—7—methoxy—N—methyl—l—(thiophen—3—yl)—1,4— dihydrochromeno[4,3—c]pyrazole—3-carboxamide (1 g, 0.0021 mol) in dioxane (20 mL) was added ,5,5—tetramethyl—l,3,2—dioxaborolan—2—yl)—1H—pyrazole (611 mg, 0.0031 mol), PdC12(dppf)CH2C12 (86 mg, 0.0001 mol) and cesium fluoride (800 mg, 0.0053 mol) at RT under nitrogen. The reaction mixture was degassed with nitrogen for 20 min and water (4 mL) was added at RT. The reaction mixture was stirred at 100 0C for 12 h. The reaction mixture was filtered through celite and washed with DCM (20 mL). The te was concentrated under vacuum; the crude product was dissolved in DCM (200 mL), washed with water (10 ml), brine (10 mL) and dried over sodium sulphate. The organic solvent was removed under ; the crude product was purified by column chromatograph using pet ether: ethyl e as eluent to afford the desired compound (0.5 g, 51 %) as an off-white solid. 1H NMR (400 MHz, DMSO—d6) 8 8.02-8.01 (dd, J = 1.4, 3.2 Hz, 1H), 7.89—7.87 (dd, J: 3.2 .1 Hz, 1H), 7.54 (bs, 2H), 7.37-7.36 (dd, J: 1.4, 5.1 Hz, 1H), 6.85 (s, 1H), 6.74 (s, 1H), 5.35 (s, 2H), 3.83 (s, 3H), 3.16 (s, 3H), 1.42 (s, 9H). m/z: 464 [M+H]+ 7-Meth0xypyridinylthi0phenyl-1,4-dihydro-chromen0[4,3-c]pyrazole carboxylic acid tert-butyl-methyl-amide (2) 0\ OH Br 0 N To a solution of 8—bromo—7—methoxy—1—thiophen—3—yl—1,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid tert—butyl-methyl-amide (Example 1 step10) (100 mg, 0.2 mmol) in DME (10 mL) was added pyridine—3—boronic acid (52 mg, 0.4 mmol), tetra kis (triphenylphospine) palladium (13 mg, 0.01 mmol) and potassium carbonate (90 mg, 0.6 mmol) at RT under nitrogen. The reaction mixture was degassed with nitrogen for 10 min and water was added (1 mL). The reaction mixture was stirred at 90 0C for 16 h. The reaction mixture was filtered through celite. Filtrate was concentrated under vacuum; the crude product was dissolved in DCM (200 mL), washed with water (10 ml), brine (10 mL) and dried over sodium sulphate.

The t was removed under vacuum to provide the crude product. The crude product was slurred with l ether (5 mL), ed and dried to afford the desired compound (95 mg, 98 %) as an off white solid. 1H NMR (400 MHz, CDClg) 6 8.50—8.47 (m, 2H), 7.67-7.64 (m, 1H), 7.53—7.52 (dd, J = 1.2, 3.2 Hz, 1H), 7.49—7.47 (dd, J = 3.2, 5.2 Hz, 1H), 7.27-7.22 (m, 2H), 6.77 (s, 1H), 6.69 (s, 1H), 5.52 (s, 2H), 3.82 (s, 3H), 3.28 (s, 3H), 1.52 (s, 9H). m/z: 475 [M+H]+ Example 3 (4-Cyclobutanecarbonyl-[1,4]diazepanyl)-(7-methoxypyridinylthiophenyl-1,4- dihydro-chromeno[4,3-c]pyrazolyl)-methanone (3) Step 1: (8-Bromomethoxythiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolyl)-(4-cyclobutanecarbonyl-[1,4]diazepanyl)-methanone LN”V O /O /o o Br/Cgég—(O _> NTN/ \ N S::rN~N o T3P, TEA 8:: Q50 To a solution of 8—bromo—7—methoxy—l—(3—thienyl)—l,4—dihydrochromeno[4,3— c]pyrazole—3—carboxylic acid (example 1 step 9) (0.5 g, 0.001 mol) in DCM (10 mL) was added l—(cyclobutyl carbonyl)—1,4 diazepane (0.25 g, 0.001 mol), T3P (1 mL, 0.001 mo], 50% soln in EtOAc) and TEA (0.2 mL, 0.003 mol) at RT under nitrogen. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate (10 mL), extracted with DCM (2 x 25 mL). The ed organic layer was washed with NaHC03 solution (1 x100 mL, 100 %), brine (100 mL) and dried over anhydrous sodium te. The solvent was removed under vacuum, the crude product was purified by column chromatography using pet ether and ethyl acetate (9:1) as eluent to afford the d compound as (0.4 g, 57 %) an off white solid. 1H NMR (400 MHz, CDClg) 8 7.51-7.48 (m, 2H), 7.22-7.20 (m, 1H), 6.99 (t, J = 4.0 Hz, 1H), 6.60 (t, J = 2.4 Hz, 1H), 5.54-5.51 (dd, J = 4.0, 12.0 Hz, 2H), 4.18-4.17 (m, 2H), 3.86 (s, 3H), 3.81—3.79 (m, 3H), 3.71—3.60 (m, 3H), 3.57—3.54 (m, 1H), 2.36—2.34 (m, 2H), 1.99-1.95 (m, 2H), 1.94-1.90 (m, 4H). m/z: 571 [M+H]+ Step 2: (4-Cyclobutanecarbonyl-[l,4]diazepanyl)-(7-methoxy-S-pyridinyl- 1-thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazolyl)-methanone DQ466915)SUN” 0 Pd<PPh3..) K2300 ON 0 E To a on of (4—cyclobutanecarbonyl—[l,4]diazepan—l—yl)—(7—methoxy—8—pyridin—3— ylthiopheny1—1,4-dihydro-chromeno[4,3-c]pyrazoly1)-methanone (250 mg, 0.4 mmol) in DME (10 mL) was added pyridine—3—boronic acid (100 mg, 0.8 mmol), tetra kis (triphenylphospine) palladium (30 mg, 0.02 mmol) and potassium carbonate (150 mg, 0.001 mol) at RT under nitrogen. The reaction mixture was degassed with nitrogen for 10 min and water (2 mL) was added. The reaction mixture was stirred at 90 0C for 16 h. The reaction mixture was filtered through celite and washed with DCM (20 mL). Filtrate was trated under vacuum; crude product was dissolved in DCM (200 mL), washed with water (10 ml), brine (10 mL) and dried over sodium sulphate. The solvent was removed under vacuum; crude product was slurred with diethyl ether (10 mL), filtered and dried to afford the d compound as (240 mg, 96 %) an off white solid. 1H NMR (400 MHz, CDC13) 8 8.49-8.47 (dd, J = 1.6, 4.8 Hz, 2H), 7.67 (t, J = 2.0 Hz, 1H), 7.52-7.47 (m, 2H), 7.27-7.24 (m, 2H), .80 (dd, J = 1.6, 4.8 Hz, 1H), 6.68 (t, J = 4.0, Hz, 1H), 5.59—5.56 (dd, J = 1.6, 10.4 Hz, 2H), 4.18-4.17 (m, 2H), 3.86 (s, 4H), .79 (m, 1H), .60 (m, 2H), 3.57—3.54 (m, 1H), 3.36—3.34 (m, 1H), 2.36-2.34 9m, 2H), 2.12—1.99 (m, 6H), 0.98-0.97 (m, 1H). m/z: 570 [M+H]+ Example 4 8-Is0butylmethoxythi0phenyl-1,4-dihydro-chromeno[4,3-c]pyrazolecarb0xylic acid tert-butyl-methyl-amide (5) WO 09980 Step 1: 7-Meth0xy(2-methyl-propenyl)thiophenyl-1,4-dihydro- chromen0[4,3-c]pyrazolecarboxylic acid ethyl ester l O 83/ ‘N o—\ To a solution of ethyl 8-bromo-7—methoxy—1—(3—thienyl)—1,4—dihydrochromeno[4,3— zole—3-carboxylate (example 1 step 8) (1 g, 0.002 mol) in THF (20 mL) was added 2,4,6— Tris—(2—methyl—propenyl)—cyclotriboroxanepyridine complex (380 mg, 0.001 mol), bis (triphenylphospine) palladium (II) dichloride (80 mg, 0.1 mmol) and potassium tri phosphate (63 mg, 0.004 mol) at RT under nitrogen. The reaction mixture was degassed with nitrogen for 10 min and water (2 mL) was added at RT. The reaction mixture was stirred at 70 O C for 4 h. The on mixture was filtered through celite and washed with DCM (50 mL). The filtrate was concentrated under vacuum; crude t was dissolved in DCM (200 mL), washed with water (20 m1), brine (20 mL) and dried over sodium sulphate. The organic solvent was removed under vacuum; crude product was purified by column chromatograph with pet ether: ethyl acetate as eluent to afford the desired product as (0.9 g, 96 %) a light yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 8.00 (m, 1H), 7.83-7.82 (d, J = 3.2 Hz, 1H), 7.33—7.32 (dd, J = 1.6, 5.2 Hz, 1H), 6.65 (s, 1H), 6.56 (s, 1H), 6.00 (s, 1H), 5.56 (s, 2H), .26 (m, 2H), 3.78 (s, 3H), 1.76 (s, 3H), 4.52 (s, 3H), 1.23-1.18 (m, 3H). m/z: 411.5 [M+H]+ Step 2: 8-Isobutylmeth0xy(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole- 3-carb0xylate ] To a solution of ethyl 7—methoxy—8—(2—methy1prop—1-en—1—y1)—1—(thiophen—3—yl)—1,4— dihydrochromeno[4,3—c]pyrazole—3—carboxylate (step 1) (1 g, 0.02 mol) in methanol and ethyl acetate mixture (40 mL) was added palladium on carbon (10 %, 0.5 g). The reaction mixture was hydrogenated under 3 bar of pressure hydrogen for 4h at RT. The reaction mixture was filtered through a celite bed and filtrate was concentrated under vacuum. The residue was ed by column chromatography using pet ether: ethyl acetate as eluent to afford the title compound (0.7 g, 70 %) as an off white solid. 1H NMR (400 MHz, DMSO-d6) 8 7.97-7.96 (dd, J = 1.2, 3.2 Hz, 1H), 7.83-7.82 (dd, J = 3.2 .2 Hz, 1H), 7.31-7.30 (dd, J = 1.2, 5.2 Hz, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 5.43 (s, 2H), 4.32- 4.27 (m, 2H), 3.75 (s, 3H), 2.12-2.10 (m, 2H), .55 (m, 1H), 1.31—1.22 (m, 3H), .83 (d, J: 4.0 Hz, 6H). m/z: 413 [M+H]+ Step 3: 8-Is0butylmeth0xy(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole- 3-carboxylic acid N OH To a solution of ethyl 8-isobutylmethoxy-l-(thiophenyl)-1,4- dihydrochromeno[4,3—c]pyrazole—3—carboxylate (250 mg, 0.006 mol) in mixture of THF (21 mL) MeOH (3 mL) was added LiOH (0.08 g, 0.001 mol) at RT. The reaction mixture , H20 (6 mL), was stirred at RT for 2 h. The reaction mixture was evaporated and acidified with 1.5N HCl solution. The solid was filtered and dried under high vacuum to afford the desired compound (200 mg, 87 %) as a white solid. 1H NMR (400 MHz, DMSO—d6) 8 13.02 (bs, 1H), 7.96—7.95 (dd, J: 1.6, 3.2 Hz, 1H), 7.83—7.81 (dd, J: 3.2 5.2 Hz, 1H), .29 (dd, J: 1.2, 5.2 Hz, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 5.42 (s, 2H), 3.73 (s, 3H), 2.12—2.11 (m, 2H), 1.62—1.55 (m, 1H), 0.72—.711 (d, J: 4.0 Hz, 6H). m/z: 385 [M+H]+ Step 4: 8-Is0butylmeth0xythi0phenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarboxylic acid tert-butyl-methyl-amide (5) WO 09980 To a solution of 8—isobutyl-7—methoxy—1—(3—thienyl)—1,4—dihydrochromeno[4,3— c]pyrazole—3—carboxylic acid (step 3) (180 mg, 0.4 mmol) in DCM (20 mL) was added N—tert— butyl methyl amine (50 mg, 0.5 mmol), HATU (0.22 g, 5 mmol) and diisopropyl ethyl amine (0.2 mL, 0.7 mmol) at RT under nitrogen. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with sodium onate (10 mL, 10 %), extracted with DCM (2 x 25 mL). The combined organic layer was washed with NaHC03 solution (1 x100 mL, 10 %), brine (100 mL) and dried over anhydrous sodium sulphate. The solvent was removed under vacuum; the crude product was ed by column chromatography using pet ether and ethyl acetate (9:1) as eluent to afford the desired compound (140 mg, 66 %) as a white solid. 1H NMR (400 MHz, 6) 8 7.91-7.90 (dd, J = 1.6, 3.2 Hz, 1H), 7.80—7.85 (dd, J: 3.2 .2 Hz, 1H), 7.29-7.28 (dd, J: 1.2, 5.2 Hz, 1H), 6.64 (s, 1H), 6.40 (s, 1H), 5.29 (s, 2H), 3.73 (s, 3H), 3.14 (s, 3H), 2.13-2.11 (m, 2H), 1.63-1.55 (m, 1H), 1.41 (s, 9H), 0.72-.711 (d, J: 4.0 Hz, 6H). m/z: 454 [M+H]+ Example 5 7-Methoxy(2-methyl-propenyl)thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazole carboxylic acid utyl-methyl-amide (6) Step 1: 8-Bromomethoxy-l-thiophen-S-yl-1,4-dihydro-chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methyl-amide (4) / O Ct“ M To a solution of 8—bromo—7—methoxy—1—(3—thienyl)—1,4—dihydrochromeno[4,3— c]pyrazole—3—carboxylic acid (example 1 step 9) (150.00 mg; 0.37 mmol; 1.00 eq.) in DCM (0.50 ml; 7.80 mmol; 21.18 eq.) was added N,N—Diisopropylamine (0.12 ml; 0.74 mmol; 2.00 eq.), o-(benzotriazol—1—yl)—n,n,n',n'—tetramethyluronium uoroborate (TBTU) (236.53 mg; 0.74 mmol; 2.00 eq.), and n—tert—butyl—methylamine (48.16 mg, 0.55 mmol, 1.5 eq.). The reaction was stirred at RT for 2h. The crude product was purified by column chromatography (Biotage) using EtOAc/Hex as eluent to afford the desired compound (120 mg, 68 %) as a white solid.

Step 2: 0xy(2-methyl-propenyl)thiophenyl-1,4-dihydro- chromeno[4,3-c]pyrazole-S-carboxylic acid tert-butyl-methyl-amide (6) To 8—bromo—7—methoxy—1—thiophen—3—y1—1,4—dihydro—chromeno[4,3—c]pyrazole—3— carboxylic acid tert—butyl—methyl—amide (50.00 mg; 0.10 mmol; 1.00 eq.) (example 5 step 1) in a microwave vial, was added 2,4,6—Tris—(2—methy1—propeny1)—cyclotriboroxane ne (51.14 mg; 0.16 mmol; 1.50 eq.) , [1,1'—bis(dipheny1phosphino)ferrocene]dichloropalladium(ii), complex with dichloromethane (1:1) (8.57 mg; 0.01 mmol; 0.10 eq.), dioxane (1.00 ml; 11.74 mmol; 111.82 eq.) and cesium carbonate (0.16 ml; 0.31 mmol; 3.00 eq., 3M). The vessel was sealed, vacumed and backfilled with en (3 times). Reaction was microwaved at 120°C for 2h. The crude product was purified by column chromatography (Biotage) using EtOAc/Hex as eluent to afford the desired compound (6.6 mg, 14 %) as a white solid. 1H NMR (400 MHz, MeOD) 5 7.75 (dd, J: 3.2, 1.4 Hz, 1H), 7.69 (dd, J: 5.1, 3.2 Hz, 1H), 7.27 (dd, J: 5.1, 1.4 Hz, 1H), 6.70 (s, 1H), 6.63 (s, 1H), 6.07 (s, 1H), 5.33 (s, 2H), 3.80 (s, 3H), 3.20 (s, 3H), 1.80 (d, J: 1.3 Hz, 3H), 1.54 (s, 9H), 1.50 (d, J: 1.2 Hz, 3H). m/z: 452 [M+H]+ Example 6 oxy(2-methyl-propenyl)—1-thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazole carboxylic acid (2-acetylamin0-ethyl)-amide (7) Step 1: Ethyl 7-methoxy(2-methylpropenyl)(thiophenyl)-1,4- dihydrochromeno[4,3-c]pyrazolecarboxylate To a solution of ethyl 8—bromo-7—methoxy—l—(3—thienyl)—l,4—dihydrochromeno[4,3— c]pyrazole—3-carboxylate (6 g, 0.0138 mol) in THF (100 mL) was added 2,4,6—Tris—(2—methyl— propenyl)—cyclotriboroxanepyridine complex (5.8 g, 0.018 mol), bis(triphenylphospine)palladium (II) dichloride (1.0 g, 1.38 mmol) and potassium sphate (3.8 g, 0.0276 mol) at RT under nitrogen. The reaction mixture was degassed with nitrogen for min and water (10 mL) was added at RT. The reaction mixture was d at 80 ° C for 8 h.

The reaction mixture was filtered through celite and washed with DCM (50 mL). The filtrate was concentrated under ; crude product was dissolved in DCM (200 mL), washed with water (20 m1), brine (20 mL) and dried over sodium sulphate. The organic solvent was removed under vacuum; crude t was purified by column chromatograph using pet ether: ethyl acetate as eluent to afford the desired compound as (5.5 g, 98 %) a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) 8 8.00 (m, 1H), 7.83-7.82 (d, J: 3.2 Hz, 1H), 7.33—7.32 (dd, J = 1.6, 5.2 Hz, 1H), 6.65 (s, 1H), 6.56 (s, 1H), 6.00 (s, 1H), 5.56 (s, 2H), 4.32-4.26 (m, 2H), 3.78 (s, 3H), 1.76 (s, 3H), 4.52 (s, 3H), .18 (m, 3H). m/z: 411.5 [M+H]+ Step 2: 7-Meth0xy(2-methyl-propenyl)thiophenyl-1,4-dihydro- chr0meno[4,3-c]pyrazolecarboxylic acid 3:: ‘N OH To a solution of ethyl 7—methoxy—8—(2—methylprop—l—en—l—yl)—1—(thiophen—3—yl)—l,4— dihydrochromeno[4,3—c]pyrazole—3—carboxylate (7 g, 0.0171 mol) in mixture of THF (70 mL), H20 (20 mL), MeOH (10 mL) was added 20 (2.1 g, 0.0512 mol) at RT. The reaction mixture was stirred at RT for 4 h. The reaction mixture was evaporated and acidified with l.5N HCl solution. The solid was ed and dried under high vacuum to afford the desired compound (5.5 g, 85 %) as an off—white solid. 1H NMR (400 MHz, DMSO—dé) 5 13.02 (bs, 1H), 7.96-7.95 (dd, J: 1.6, 3.2 Hz, 1H), 7.83-7.81 (dd, J: 3.2 5.2 Hz, 1H), 7.31-7.29 (dd, J: 1.2, 5.2 Hz, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 5.42 (s, 2H), 3.73 (s, 3H), 2.12-2.11 (m, 2H), 1.62-1.55 (m, 1H), 0.72-.7ll (d, J: 4.0 Hz, 6H). m/z: 383 [M+H]+ Step 3: 7-Meth0xy(2-methyl-pr0penyl)—1-thiophenyl-1,4-dihydr0- no[4,3-c]pyrazolecarboxylic acid (2-acetylamino-ethyl)-amide (7) I / O N‘N/ 83/ NxN>/_ To 7—methoxy(2-methyl-propenyl)—1—thiophenyl— 1,4-dihydro—chromeno[4,3— c]pyrazolecarboxylic acid (30mg 0.08mmol) in DCM (1.00 ml; 15.60 mmol; 198.87 eq.) was added N,N—Diisopropylethylamine (0.02 ml; 0.09 mmol; 1.20 eq.), N—acetylethylenediamine (9.61 mg, 0.09 mmol, 1.2 eq.) and T3P (0.03 ml; 0.12 mmol; 1.50 eq.). The reaction was stirred at RT for 1.5 h. The crude product was purified by column chromatography using EtOAc/Hex as eluent to afford the desired compound (27.4 mg, 73 %) as a white solid. 1H NMR (500 MHz, CD30D) 8 7.74 (dd, J = 3.1, 1.2 Hz, 1H), 7.67 (dd, J = 5.0, 3.2 Hz, 1H), 7.26 (dd, J: 5.1, 1.1Hz, 1H), 6.66 (s, 1H), 6.58 (s, 1H), 6.04 (s, 1H), 5.48 (s, 2H), 3.76 (s, 3H), 3.46 (t, J = 6.0 Hz, 2H), 3.41 — 3.33 (m, 2H), 1.94 (s, 3H), 1.78 (s, 3H), 1.48 (s, 3H). m/z: 467 [M+H]+ The following nds were prepared using procedures analogous to those disclosed in Example 6. 0‘ In/Z: 492 1H NMR (400 MHz, CDC13) 7.59 — 7.56 (m, 1H), 7.54 [M+H]+ (dd, J: 5.0, 3.3 Hz, 1H), 7.40 _ 7.34 (m, 1H), 7.26 (dd, \N N 0M SS J: 5.1, 1.4 Hz, 1H),6.71(s, ‘\_>‘ F F 1H), 6.60 (s, 1H), 6.12 (s, Ni ,1 1H), 5.63 (s, 2H), 3.84 (s, N/ 3H), 3.49 (dd, J: 12.3, 6.5 7—Meth0xy—8—(2—methy1—pr0penyl)—1—t Hz, 2H), 3.15 — 3.09 (m, 2H), hiophen-3 -y1-1 ,4—dihydr0-chr0men0 [4,3 - 1.98 (dtd, J: 8.5, 6.0, 2.6 Hz, c]pyrazole—3-carb0xylic acid [3-(1H— 2H), 1.85 (d, J: 1.2 Hz, 3H), tetrazol-S -yl)-pr0py1]—amide; trifluoro— 1.52 (d, J: 1.1 Hz, 3H). acetic acid salt (11) O\ H NMR (400 MHz, MeOD) 8 7.74 (dd, J: 3.2, 1.4 Hz, 1H), 7.67 (dd, J: 5.1, 3.2 HZ, 1H), 7.26 (dd, J: 5.1, 1.4 Hz, 1H), 6.66 (s, 1H), SCF\/ N4\_\N—<o 6.58 (s, 1H), 6.05 (d, J: 0.6 Hz, 1H), 5.49 (s, 2H), 3.78 (s, 3H), 3.39 (dd, J: 10.1, 3.4 HZ, 2H), 3.26 (t, J = 6.7 Hz, 2H), 1.95 (s, 3H), 1.82 — 1.73 0xy(2-methy1-pr0penyl) (In, 5H), 1.48 (d, J: 1.2 Hz, thiophen-3 -y1—1,4-dihydr0-chr0mcn0[4,3- 3H). zolecarboxylic acid (3- acetylamino-propyl)—amide (8) I 1H NMR (400 MHz, CDC13) o 5 7.55 (dd, J : 3.1, 1.3 Hz, 1H), 7.50 (dd, J: 5.1, 3.2 / / O Hz, 1H), 7.24 (dd, J: 5.1, o 1.4 Hz, 1H), 7.11 (s,1H), N‘N N~\_ >Lo 6.71 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.60 (s, 2H), 4.39 _ 4.31 (m, 2H), 3.82 (s, 3H), 3.72 (dd, J: 8.7, 7.2 7-Meth0xy(2-methy1-pr0peny1) Hz, 2H), 3.66 (dd, J: 12.3, thiophcn-3 —yl-1,4-dihydr0-chr0mcn0[4,3- 6.0 Hz, 2H), 3.52 (t, J: 6.1 c]pyrazole—3—carb0xylic acid [2—(2—0x0— Hz, 2H), 1.85 (d, J: 1.3 Hz, oxazolidin-3—y1) -ethy1] -amide (13) 3H), 1.52 (d, J: 1.2 Hz, 3H).

O\ 1H NMR (400 MHz, CDC13) 8 7.54 (dd, J : 3.2, 1.4 Hz, 1H), 7.49 (dd, J: 5.1, 3.2 Hz, 1H), 7.24 (dd, J: 5.1, 1.4 Hz, 1H), 7.19 (s, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 6.11 (s, 1H), 5.61 (s, 2H), 4.38 — 4.30 (m, 2H), 3.81 (s, 3H), 3.65 — 3.58 (m, 2H), 0xy—8—(2—methy1—pr0penyl)—1 — 3.48 (q, J : 6.7 Hz, 2H), 3.39 thiophen-3 -y1-1,4-dihydro-chromeno[4,3- (t, J = 6.8 Hz, 2H), 1.89 (dd, c]pyrazolecarb0xylic acid [3-(2—0x0- J: 13.7, 6.8 Hz, 2H), 1.84 0xazolidinyl)-pr0pyl] -amide (9) (d, J: 1.2 Hz, 3H), 1.52 (d, J = 1.2 Hz, 3H). m/z: 454 1H NMR (400 MHz, CDC13) 8 7.55 (dd, J : 3.2, 1.4 Hz, [M+H]+ 1H), 7.51 (dd, J: 5.1, 3.2 Hz, 1H), 7.24 (dd, J: 5.1, 1.4 Hz, 1H), 6.95 (s, 1H), 6.68 (s, 1H), 6.57 (s, 1H), 6.11 (s, 1H), 5.59 (s, 2H), 3.82 (s, 3H), 3.72 (s, 2H), 1.85 (d, J: 1.3 Hz, 3H), 1.52 7-Meth0xy-8 -(2-methy1-pr0peny1)-1 - (d, J: 1.2 Hz, 3H), 1.41 (s, thiophen-3 -y1-1,4-dihydr0-chr0men0[4,3- 6H). c]pyrazole—3-carboxylic acid (2-hydr0xy- 1 ,1-dimethyl-ethyl)-amide (10) / ZI m/z: 522 H NMR (400 MHz, CDC13) o 5 7.52 (dd, J : 3.2, 1.4 Hz, [M+H] J" 1H), 7.48 (dd, J: 5.1, 3.2 / / O Hz, 1H), 7.24 (dd, J: 5.1, 1.4 Hz, 1H), 6.74 (s, 1H), N\N 6.58 (s, 1H), 6.12 (s, 1H), CW N .52 (s, 2H), 5.00 (d, J: 13.1 Hz, 1H), 4.55 (d, J: 13.4 Hz, 1H), 4.17 (q, J: 7.1 Hz, 2H), /—0 3.83 (s, 3H), 3.47 _ 3.36 (m, 1H), 3.09 — 2.96 (m, 1H), 2.66 — 2.54 (m, 1H), 2.08 — 1 —[7-Methoxy(2—methy1—pr0penyl)—1 - 1.92 (m, 2H), 1.85 (d, J: 1.3 thiophen-3 -y1-1 ,4-dihydr0-chr0men0[4,3- Hz, 3H), 1.81 (d, J: 11.8 Hz, z01€-3—carbonyl] -piperidine 2H), 1.54 (d, J : 1.2 Hz, 3H), carboxylic acid ethyl ester (14) 1.28 (t, J: 7.1 Hz, 3H).

O\ m/z: 564 1H NMR (400 MHz, CDC13) 8 7.55 (ddd, J: 4.6, 3.2, 1.4 [M+H]+ Hz, 2H), 7.51 (dd, J: 5.1, 3.2 Hz, 1H), 7.25 (td, J: 4.7, 1.4 Hz, 1H), 6.69 (s, 1H), 6.57 (s, 1H), 6.11 (s, 1H), .63 (s, 2H), 4.33 (s, 1H), 3.98 (dd, J: 8.2, 4.0 Hz, 2H), 3.83 (d, J: 3.7 Hz, 3H), .4 (m, 1H), 2.56 (s, 3 —{ [7-Meth0xy(2—rnethyl—pr0penyl)—1 - 1H), 2.42 — 2.26 (m, 2H), thiophen-3 -y1-1,4-dihydr0-chr0men0[4,3- 2.05 (d, J: 13.2 Hz, 1H), c]pyrazoleCarbonyl] -amin0 } - 1.92 (dd, J: 21.8, 15.1 Hz, cyclohexanecarboxylic acid tert-butyl ester 2H), 1.85 (s, 3H), 1.52 (s, (15) 3H), 1.48 : 1.42 (m, 9H).

O\ m/z: 494 1H NMR (400 MHz, CDC13) 8 7.52 (dd, J : 3.2, 1.4 Hz, O [M+H]+ 1H), 7.48 (dd, J: 5.1, 3.3 Hz, 1H), 7.24 (dd, J: 5.1, I / O 1.4 Hz, 1H), 6.73 (s, 1H), N\N 6.58 (s, 1H), 6.12 (s, 1H), CV/ N .52 (s, 2H), 5.12 — 5.03 (m, 2H), 4.62 _ 4.52 (m, 2H), O 3.82 (s, 3H), 3.11 — 3.00 (m, HO 2H), .48 (m, 2H), 2.81 1-[7-Meth0xy(2—methyl-pr0penyl)-1 - _ 2.68 (m, 1H), 1.85 (d, J: thiophen—S—yl—l ,4—dihydr0—Chr0men0[4,3— 1.2 Hz, 3H), 1.53 (d, J: 1.2 c] pyrazole—3-carbonyl] -piperidine Hz, 3H). carboxylic acid (16) O\ ZI m/z: 522 1H NMR (400 MHz, CDC13) 7.51 — 7.49 (m, 1H), 7.47 [M+H] + (dd, J: 5.1, 3.3 Hz, 1H), 7.25 _ 7.22 (m, 1H), 6.76 (d, J: 3.4 Hz, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.55 (d, J: 3.4 Hz, 2H), 4.40 — 4.23 (m, 2H), 4.11 — 4.00 (m, 2H), 3.86 (d, J: 5.2 Hz, 1H), 3.82 (s, 3H), 3.79 — 3.74 (m, 1H), 3.69 (d, J : 5.9 Hz, 3H), 2.62 — 2.54 O O (m, 2H), 2.30 _ 2.20 (m, 1H), 1-[7-Meth0xy(2—methy1—pr0penyl)—1 - 2.04— 1.94 (m, 1H), 1.85 (d, thiophen-3 -y1-1 ,4-dihydr0-Chr0men0[4,3- J: 1.2 Hz,2H), 1.81 : 1.73 C] pyrazoleCarbonyl] -azepane (m, 3H), 1.55 (s, 3H). carboxylic acid methyl ester (17) ZI In/Z: 508 1H NMR (400 MHz, CDC13) 8 7.52 _ 7.47 (m, 1H), 7.46 [M+H]+ (d, J: 4.7 Hz, 1H), 7.23 (d, J = 3.7 Hz, 1H), 6.75 (d, J: 4.3 Hz, 1H), 6.57 (s, 1H), HO O 6.12 (s, 1H), 5.53 (d, J: 6.1 Hz, 2H), 4.35 _ 4.21 (m, 1H), 4.04 (dd, J: 17.7, 16.6 Hz, 1H), 3.91 — 3.73 (m, 5H), 3.51 (s, 1H), 2.68 _ 2.52 (m, 1H), 2.30 — 2.18 (m, 1H), 1-[7-Meth0xy(2-methyl-pr0penyl)-1 - 2.13 — 1.94 (m, 3H), 1.85 (s, thiophen-3 4-dihydr0-chr0men0[4,3- 3H), 1.82 _ 1.72 (m, 1H), c]pyrazolecarbonyl]-azepane 1.54 (s, 3H). carboxylic acid (18) / m/z: 579 1H NMR (400 MHz, CDC13) O 5 7.52 — 7.48 (m, 1H), 7.46 [M+H]+ (dd, J: 5.1, 3.3 Hz, 1H), / / O 7.26 — 7.21 (m, 1H), 6.76 (d, / J: 7.6 Hz, 1H), 6.57 (s, 1H), N N \ 6.12 (s, 1H), 5.53 (s, 2H), / 4.63 — 4.51 (m, 1H),4.51— 4.39 (m, 1H), 4.27 — 4.18 (m, CYN 1H), 4.05 4 3.91 (m, 1H), 3.82 (s, 3H), 3.75 — 3.51 (m, \fio 2H), 2.22 — 2.11 (m, 1H), 2.03 _ 1.90 (m, 2H), 1.85 (s, 3H), 1.82 — 1.68 (m, 2H), { 1-[7-Meth0xy(2—methyl—pr0penyl)-1 - 1.54 (d, J: 1.2 Hz, 3H), 1.45 thiophen-3 -y1-1 ,4-dihydr0-Chr0men0[4,3- (d, J: 8.1 Hz, 9H). c]pyrazole-3—carb0nyl] -azepan—4-yl } - ic acid tert-butyl ester (35) m/z: 479 1H NMR (400 MHz, CDC13) 7.51 (d, J: 10.5 Hz, 1H), [M+H]+ 7.47 — 7.41 (m, 1H), 7.23 (d, J: 5.0 Hz, 1H), 6.76 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), .53 (s, 2H), 4.35 — 4.16 (m, 2H), 4.02 — 3.85 (m, 3H), 3.82 (s, 2H), 3.64 _ 3.50 (m, 2H), 3.29 — 3.19 (m, 2H), 2.34 _ 2.23 (m, 1H), 2.10 _ 1.97 (m, 2H), 1.85 (s, 3H), (4-Amin0-azepany1)-[7-meth0xy(2- 1.54 (s, 3H). methyl-propenyl)-1 -thiophen—3-y1- 1 ,4— dihydro—chromeno[4,3-C]pyrazoly1]- methanone (36) l m/z: 480 1H NMR (400 MHz, CDC13) o N 8 7.51 (dd, J = 3.2, 1.4 Hz, 0 k [M+H]+ 1H), 7.47 (dd, J: 5.1, 3.3 / / O Hz, 1H), 7.22 (dd, J: 5.1, 1.3 Hz, 1H), 6.72 (s, 1H), NW6, 6.58 (s, 1H),6.12(s,1H), 8g\ LON7§ 5.47 (s, 2H), 4.10 _ 4.06 (m, 2H), 3.88 — 3.84 (m, 2H), 3.82 (s, 3H), 3.50 (s, 2H), 1.85 (d, J: 1.0 Hz, 3H), 1.55 (3,3—Dimethy1-morpholinyl)—[7- methoxy-8—(2-methyl-pr0penyl) (s, 6H), 1.53 (d, J: 0.9 Hz, thiophen-3 -y1-1 ,4-dihydr0-Chr0men0[4,3- 3H). zol-3—yl]-methanone (39) O\ H NMR (400 MHz, CDC13) 7.53 (d, J = 2.2 Hz, 1H), 7.48 (dd, J: 5.0, 3.3 Hz, 1H), 7.23 (d, J: 5.1 Hz, 1H), 6.72 (s, 1H), 6.58 (s, 1H), \NNK/N‘ 6.12 (s, 1H), 5.44 (s, 2H), s /o 5.07 (t, J: 6.3 Hz, 1H), 3.83 / (s, 3H), 3.80 (d, J: 6.2 Hz, 2H), 3.32 (s, 3H), 1.85 (s, 7-Meth0xy-8 -(2-methy1-pr0peny1)-1 - 3H), 1.52 (s, 3H), 1.46 (s, thiophen-3 -y1-1,4-dihydr0-chromen0[4,3- 6H). c]pyrazole—3-carboxylic acid (2-hydroxy- 1 ,1-dimethyl-ethyl)-methyl-amide (40) 1H NMR (400 MHz, CDC13) 8 7.51 — 7.44 (m, 2H), 7.22 (d, J: 4.8 Hz, 1H), 6.73 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.64 (s, 2H), 5.62 (d, J: 6.7 Hz, 2H), 4.69 (d, J = 6.8 Hz, 2H), 4.51 _ 4.43 (m, 2H), 3.82 (s, 3H), 2.63 — 2.55 (m, 2H), 1.85 (s, 3H), 1.54 (s, 3H). [7-Meth0xy-8 -(2—methy1-pr0penyl) -1 - thiophen-3 —yl-1,4-dihydr0-chr0men0[ 4,3-c]pyrazol-3 6-0xaaza-sp ir0[3.3]hepty1)-methanone (44) Chiral N In/Z: 547 [M+H]+ EN 0 EN 0 Followed by chiral separation [(R) —4—(Azetidine— l —carb0nyl)—azepan—l — -methoxy-8 -(2—methyl-propenyl)-1 - thiophen-3 —yl-1,4-dihydro-chromeno[4,3- c]pyrazol—3—yl]—methanone (45) Chiral N m/z: 547 [M+H]+ C1“ 0 Followed by chlral separatlon [(S)—4—(Azetidine— l —carbonyl)—azepan—1 — yl]—[7-methoxy-8 -(2—rnethyl-propenyl)-1 - thiophen-3 -yl-1,4-dihydro-chromen0[4,3- c]pyrazol-3—yl]—methanone (46) / m/z: 480 1H NMR (400 MHz, CDC13) O N 5 7.57 — 7.44 (m, 2H), 7.23 O O [M+H]+ (d, J: 5.0 Hz, 1H), 6.72 (s, 1H), 6.58 (s, 1H), 6.12 (s, / / 0 1H), 5.83 (s, 1H), 5.54 (s, / 2H), 4.47 _ 4.37 (m, 1H), 8C1 N N \ 3.99 — 3.88 (m, 1H), 3.82 (s, / 070 3H), 3.68 (d, J: 11.9 Hz, 1H), 2.04 _ 1.87 (m, 3H), (2—Hydroxymethyl-2—methyl-pyrrolidin— l - 1.85 (s, 3H), 1.82— 1.74 (m, yl)—[7-methoxy-8 -(2—methyl—propenyl)-1 - 2H), 1.54 (d, J = 4.6 Hz, 6H). en-3 -yl-1,4-dihydro-chromeno[4,3- c]pyrazol-3—yl]-methanone (48) \ ZI m/Z: 452 1H NMR (400 MHZ, CDCl3) k_> 5 7.52 (dd, J = 3.2, 1.4 Hz, [M+H]+ 1H), 7.48 (dd, J: 5.1, 3.3 Hz, 1H), 7.23 (dd, J: 5.1, 1.4 Hz, 1H), 6.72 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), .55 (s, 2H), 4.32 (t, J: 7.0 Hz, 2H), 3.83 (s, 3H), 3.82 — 3.71 (m, 6H), 1.85 (d, J: 1.0 [7-Methoxy(2-methyl-propenyl) HZ’ 3H)= 1'53 (d= J = 0‘9 HZ’ thiophen-3 4-dihydro-chromeno[4,3- 3H)‘ c]pyrazol-3—yl]-morpholinyl-methanone (117) m/Z: 452 1H NMR (500 MHZ, cdcl3) 5 7.49 (dd, J: 3.1, 1.5 Hz, [M+H]+ 1H), 7.48 — 7.42 (In, 1H), 7.22 (dd, J: 6.5, 2.8 Hz, 1H), 6.71 (d, J: 6.3 Hz, 1H), 6.54 (s, 1H), 6.10 (s, 1H), .65 — 5.54 (m, 1H), 4.57 — 4.50 (m, 1H), 4.16 (t, J: 12.8 Hz, 1H), 4.13 — 4.04 (m, 2H), 3.85 — 3.81 (m, 1H), 3.80 (s, 3H), 3.75 (d, J: 2.7 Hz, 1H), (3—Hydroxy—pyrrolidinyl)—[7-methoxy- 2.10 — 1.94 (m, 2H), 1.83 (s, 8-(2-methyl-propenyl)thiophenyl- 3H), 1.52 (s, 3H). 1 ,4—dihydIo—Chromeno[4,3-C]pyrazol-3—yl] - one (47) The following compounds were prepared using procedures analogous to those disclosed in example 4: Compound Starting LC/MS NMR material N/g m/z = 482 H-NMR (DMSO-d6): 5 [M+H]+ 7.94 (s, 1H), 7.84 — 7.79 to (m, 1H), 7.31 (d, 1H), 6.66 (s, 1H), 6.41 (s, 1H), 5.34 (s, 2H), 3.94 (t, 2H), 3.78 — 3.70 (m, 5H), 3.42 (s, 2H), 2.14 (d, 2H), 1.62 (septet, 1H), 1.42 (s, 6H), 0.74 (d, J (3,3—Dimethyl—morpholin—4—yl)—(8—is = 6.5 Hz, 6H). obutylmethoxy— 1 -thiopheny1— 1, 4—dihydro-chromeno[4,3-c]pyrazol yl)—methanone (77) WO 09980 m/z = 470 1H—NMR (DMSO-d6): 5 wO O Hwfi O [M+H]+ 8.67 (s, 1H), 7.99 (dd, 1H), 7.84 (dd, 1H), 7.34 (dd, / OH O 1H), 6.66 (s, 1H), 6.38 (s, 1H), 5.45 (s, 2H), 5.14 (s, \ O 1H), 4.68 (d, 2H), 4.51 (d, / 2H), 3.76 (s, 3H), 3.68 (s, 8-Isobutyl—7—methoxythiophen-3—y 2H), 2.14 (d, 2H), 1.61 1—1,4—d1hydro—chromeno[4,3—c]pyrazo (septet, 1H), 0.74 (d, 6H). 16carboxylic acid (3-hydroxymeth y1-oxetany1)-amide (141) m/z = 454 lH—NMR (DMSO-d6): 5 WO O [M+H]+ 8.87 (s, 1H), 8.00 (dd, 1H), 7.84 (dd, 1H), 7.35 (dd, N790 1H), 6.66 (s, 1H), 6.38 (s. 7 1H), 5.46 (s, 2H), 4.70 (d, N N O 2H), 4.31 (d, 2H), 3.75 (s, 3H), 2.14 (d, 2H), 1.66 — 1.54 (m, 4H), 0.73 (d, 6H). 8-Isobuty1meth0xythi0pheny 1-1,4—dihydr0—chromeno[4,3—c]pyrazo 16—3—carboxylic acid (3—mcthy1—0xct an—3-y1)-amide (145) Scheme 2: F-—B F (DO/OI \/0 C|\/\§O K2003:m0Pyridine. HCIOH::©:'Q —3> K2CO3 [PH )DIPEAnBuLi 2)Diethyloxa|ate——>:l:)\ s f Hui/2 | l o O O O O o NHRF‘z _HC| NH O LiOH o o / o EtOH,AcOH A W i O DIPEA DCM A 0 coupling agent \ N \ Sir” SUN NFl1Fi2 / / Example 7 8-Isopr0poxymethoxythiophenyl-1,4-dihydro-chr0meno[4,3-c]pyrazole—3— carboxylic acid tert-butyl-methyl-amide (19) Step 1: 3-Chloro(2-hydr0xy-4,5-dimeth0xyphenyl)pr0panone F—B:— F UVYT To a d suspension of 3, 4-dimethoxy phenol (10 g, 0.06 mol) and chloropropanoyl chloride (12.5 g, 0.12 mol) was added boron trifluorideethylethrate (8.8 mL, 0.06 mol) in drops at 60 0C under en atmosphere. After the complete addition, the reaction e was heated to 70 0C for l h. The reaction mixture was cooled to RT and quenched with ice- water (200 mL) and extracted with DCM (500 mL). The aqueous layer was re—extracted (2 x100 mL) DCM, the combined organic layer was dried over sodium sulphate and trated under vacuum. The crude mass was purified by column chromatography using pet ether / ethyl acetate (8:2) as eluent to afford the desired compound (12 g, 76 %) as a light yellow solid. 1H NMR (400 MHz, DMSO—dg) 8 12.2 (bs, 1H), 7.27 (s, 1H), 6.55 (s, 1H), 4.12-4.10 (m, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 2.48-2.43 (m, 2H).

Step 2: 6,7-Dimeth0xy-2,3-dihydro-4H-chromenone To a stirred solution of 3—Chloro—l—(2—hydroxy-4,5—dimethoxyphenyl)propan—l—one (13g, 0.05 mol) in ethanol was added dry K2C03 (16.3 g, 0.10 mol) in lots at RT under nitrogen.

The ing suspension was d at RT for 16 h. The reaction mixture was ed and concentrated under vacuum. The crude mass was dissolved in ethyl acetate (200 mL), washed with 5% sodium bicarbonate (50 mL), brine (50 mL) and dried over sodium sulphate. The organic solvent was concentrated; the residue was purified by column chromatography using pet ether/ ethyl acetate (8:2) as eluent to afford the desired compound (9 g, 81 %) as a light brown solid. 1H NMR (400 MHz, DMSO— d6) 8 7.12 (s, 1H), 6.59 (s, 1H), 4.47-4.44 (m, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 2.69-2.65 (m, 2H).

Step 3: 6,7-Dihydroxy-2,3-dihydro-4H-chromenone cl) 0 ne. HCI pi) HO 0 —>.0339? The mixture of 6,7—dimethoxy—2,3—dihydro—4H—chromen—4—one (2.5 g, 0.01 mol) and pyridine hydrochloride (20 g, 0.20 mol ) was heated at 170 0C under nitrogen for 12 h. The reaction mixture was slurred with DCM (100 mL), the separated solid was filtered and filtrate was concentrated under vacuum. The crude product was ed by column tography using pet ether / ethyl acetate (5:5) as eluent to afford the desired compound (1 g, 50 %) as a light white solid. 1H NMR (400 MHz, DMSO— d6) 8 9.72 (bs, 2H), 7.04 (s, 1H), 6.30 (s, 1H), 4.37—4.34 (m, 2H), 2.60—2.57 (m, 2H).

Step 4: 6-Hydr0xymethoxy-2,3-dihydro-4H-chromenone HOmmo K2C03 0 Mel [mmo 0 O To a stirred solution of 6,7—dihydroxy—2,3—dihydro—4H—chromen—4—one (5.5 g, 0.0305 mol) in DMF (60 mL) was added dry K2C03 (4.2 g, 0.0305 mol) at RT under nitrogen. The reaction mixture was stirred at RT for 15 min and then added methyl iodide (1.3 mL, 0.0214 mol) in drops at RT. The reaction mixture was stirred at RT for 2 h. The reaction mixture was filtered and filtrate was concentrated under . The crude product was purified by column chromatography using pet ether / ethyl acetate (9:1) as eluent to afford the desired compound (4 g, 68 %) as a light brown solid. 1H NMR (400 MHz, DMSO-d6 ) 8 9.05 (bs, 1H), 7.05 (s, 1H), 6.53 (s, 1H), 4.43-4.40 (m, 2H), 3.80 (s, 3H), 2.64-2.61 (m, 2H).

Step 5: 6-Isopr0p0xymethoxy-2,3-dihydro-4H-chromenone O A 0 ] To a d solution of 6—hydroxy—7—methoxy—2,3—dihydro—4H—chromen-4—one (4.0 g, 0.0206 mol) in DMF (80 mL) was added dry K2C03 (5.7 g, 0.0412 mol) at RT under nitrogen.

The reaction mixture was stirred at RT for 15 min and then added 2—Iodo propane (6.2 mL, 0.0618 mol) in drops at RT. The reaction mixture was stirred at 65 0C for 8 h. The reaction mixture was filtered and filtrate was concentrated under vacuum. The crude product was dissolved in ethyl e (2 x 200 mL), washed with water (50 mL), brine (50 mL) and dried over sodium sulphate. The organic solvent was concentrated, crude mass was purified by column chromatography using pet ether / ethyl acetate (8:2) as eluent to afford the desired compound (4.1 g, 87 %) as a light brown solid. 1H NMR (400 MHz, 6 ) 8 7.13 (s, 1H), 6.59 (s, 1H), 4.48—4.40 (m, 3H), 3.80 (s, 3H), 2.68-2.65 (m, 2H), 1.21 (s, 3H), 1.20 (s, 3H).

Step 6: Ethyl ydroxy(6-isopropoxymethoxyoxo-2H-chromen-3(4H)- ylidene)acetate O O A:m;)DIPEA, nBuLi O 2)Diethyloxalate AOWOB O OH Diisopropyl amine (6.9 mL, 0.0495mol) was taken in dry THF (150 mL) at RT under nitrogen atmosphere. The reaction mixture was cooled to —78 0C and n—Butyl lithium (1.6 M solution in hexane, 28.6 mL, 0.0457 mol) was added in drops over a period of 30 min. After the addition, the reaction mixture stirred at same temperature for 15 min and then slowly warmed to —10 OC and stirred further for 30 min. Reaction mixture was again re—cooled to —78 0C, 6— Isopropoxy—7—methoxy—2,3—dihydro—4H—chromen—4—one (9 g, 0.0381 mol) in THF (50 mL) was added in drops over period of 30 min and stirred at —78 0C. Afterlh, diethyl oxalate (7.8 mL, 0.0571 mol) was added in drops at —78 0C; the reaction mixture was slowly t to 0 OC and stirred for lh. The on mixture was cooled to —5 0C, quenched with a solution of 1.5N HCl and extracted with ethyl acetate (100 mL x 2). The combined organic layer was washed with water (100 mL), brine (50 mL), dried over sodium sulphate and concentrated to afford the desired compound (10.5 g, 92 %) as a pale yellow solid. 1H NMR (400 MHz, DMSO—d6) 8.7.17-7.13 (d, J = 16 Hz, 1H), 6.61-6.59 (d, J = 24 Hz, 1H), .16-5.12 (m, 1H), .24 (m, 1H), 4.21 (s, 3H), 2.97 (s, 3H), 2.54-5.53 (m, 1H), 1.21 (s, 6H).

Step 7: 8-Isopr0p0xymethoxy(3-thienyl)-1,4-dihydrochromeno[4,3- c]pyrazolecarb0xylate EtOH AcOH AS/ UN‘N To a solution of (ethyl ydroxy(6-isopropoxy—7—methoxy-4—oxo—2H—chromen— 3(4H)—ylidene)acetate (6.0 mg, 0.0223 mol) in a mixture of l (150 mL) and acetic acid (150, mL) was added 3—thienylhydrazine hydrochloride (2.7 g 0.0223 , mol) at RT under nitrogen. The reaction mixture was stirred at 100 0C for 4 h. The reaction mixture was concentrated under high vacuum. The residue was ved with ethyl acetate (20 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated under vacuum.

The crude product was purified by column tography using pet ether/ethyl acetate as eluent to afford desired nd (6.5 g, 88 %) as an off white solid. 1H NMR (400 MHz, DMSO—dé) 8 8.02-8.01 (dd, J: 1.2, 2.4 Hz, 1H), 7.86—7.83 (dd, J: 4, 16 Hz, 1H), 7.35—7.34 (dd, J: 1.2, 4 Hz, 1H), 6.68 (s, 1H), 6.19 (s, 1H), 5.40 (s, 2H), .26 (m, 2H), 3.94—3.88 (m, 1H), 3.72 (s, 3H), 1.31-1.287 (m, 3H), 1.07 (s, 6H).

Step 8: 8-Is0propoxymethoxy(3-thienyl)-1,4-dihydrochromeno[4,3- c]pyrazolecarb0xylic acid To a solution of 8—isopropoxy—7—methoxy—1—(3—thienyl)—1,4—dihydrochromeno[4,3— c]pyrazole—3—carboxylate (4 g, 0.0108 mol) in mixture of THF (70 mL) MeOH , H20 (20 mL), (10 mL) was added LiOH.HZO ( 1.4 g, 0.0326 mol) at RT. The reaction mixture was stirred at RT for 4 h. The reaction mixture was evaporated and ied with a solution of 1.5N HCl. The te was dried under high vacuum to afford the desired compound (3.3 g, 79 %) as an off white solid. 1H NMR (400 MHz, DMSO'd6) 8 13.16 (bs, 1H), 8.01—8.00 (dd, J: 1.2, 2.4 Hz, 1H), 7.85—7.83 (dd, J: 4, 16 Hz, 1H), 7.35—7.33 (dd, J: 1.2, 4 Hz, 1H), 6.69 (s, 1H), 6.19 (s, 1H), 5.39 (s, 2H), 3.94—3.88 (m, 2H), 3.72 (s, 3H), 1.07 (s, 6H).

Step 9: 8-Isopr0p0xymeth0xythiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarb0xylic acid tert-butyl-methyl-amide (19) Wo o / A M W To a stirred solution of 8—isopropoxy—7—methoxy—1—(3—thienyl)—1,4— dihydrochromeno[4,3-c]pyrazole—3—carboxylic acid (1.1 g, 0.0028 mol) in DCM (50 mL) was added N—tert—butyl methyl amine (0.3 g, 0.0034 mol), HATU (1.3 g, 0.0034 mol) and DIPEA (0.8 mL, 0.0043 mol) at RT under nitrogen. The reaction mixture was stirred at RT for 16 h. The reaction e was quenched to water (20 mL), extracted with dichloromethane (2 x 100 mL).

The combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulphate. The solvent was removed under vacuum; the crude product was purified by column chromatography using pet ether/ ethyl acetate (8:2) as eluent to afford the desired nd (1.1 g, 85 %) as an off white solid. 1H NMR (400 MHz, DMSO—dé) 8 7.97-7.96 (dd, J: 1.2, 2.4 Hz, 1H), 7.82—7.80 (dd, J: 4, 16 Hz, 1H), 7.34-7.32 (dd, J: 1.2, 4 Hz, 1H), 6.69 (s, 1H), 6.22 (s, 1H), 5.27 (s, 2H), 3.39—3.89 (m, 1H), 3.72 (s, 3H), 3.14 (s, 3H), 1.41 (s, 9H), 1.06 (s, 6H). m/z: 456 [M+H]+ The ing compounds were prepared using procedures analogous to those disclosed in example 7. material I H H NMR (400 MHz CDC1) 6 o N 7.—53 7.4,,,6(m2H)725(dJ 526 = 4.9 Hz, 1H), 6.62 (s, 1H), / o 6.44 (d, J = 4.2 Hz, 1H), 5.50 A [M+H]+ (d, J = 3.4 Hz, 2H), 4.39 — N\N N 4.22 (m, 1H), 4.06 (dt, J = s<j \ o O 12.9, 6.4 Hz, 1H), 3.83 (s, 3H), 3.77 (dd, J: 11.0, 5.2 Hz, 1H), 3.69 (d, J: 5.5 Hz, 3H), \0 O 3.60—3.50(m, 1H), 2.63 — 2.53 (m, 1H), 2.30 — 2.16 (m, 1-(8 -Isopropoxymethoxy-1—thiophen-3 - 1H), 2.11 — 1.99 (m, 2H), 1.87 yl- 1 ydro—chromeno [4,3-c]pyrazole- 3-carbonyl)—azepane—4—carboxylic acid — 1.68 (m, 2H), 1.56 (d, J: 6.7 Hz, 1H), 1.47 (d, J: 6.7 Hz, methyl ester (24) 1H), 1.22 (d, J: 6.1 Hz, 6H) H 1H NMR (400 MHz, MeOD) δ m/z: O N 7.74 (d, J = 2.8 Hz, 1H), 7.72 O 512 – 7.66 (m, 1H), 7.28 (dd, J = O O 3.2, 1.9 Hz, 1H), 6.64 (s, 1H), [M+H]+ 6.37 (d, J = 3.3 Hz, 1H), 5.36 N N N O O (d, J = 3.0 Hz, 2H), 4.21 (ddt, S J = 30.6, 14.1, 4.9 Hz, 1H), 4.04 (dt, J = 12.1, 6.1 Hz, 1H), 3.96 – 3.82 (m, 2H), 3.80 (s, O O 3H), 3.71 – 3.58 (m, 1H), 2.58 1-(8-Isopropoxymethoxythiophen – 2.44 (m, 1H), 2.24 – 2.11 yl-1,4-dihydro-chromeno[4,3-c]pyrazole- (m, 1H), 2.11 – 1.91 (m, 3H), onyl)-azepanecarboxylic acid 1.86 – 1.66 (m, 2H), 1.15 (d, J (25) = 6.1 Hz, 6H).

The following compounds were ed using procedures analogous to those disclosed in example 1: Compound Boronic acid Amine LC/MS NMR Starting Starting material material O O m/z: 564 1H NMR (400 MHz, O N O H CDCl3) δ 8.31 (d, J O B N [M+H]+ = 0.6 Hz, 1H), 7.63 N O N O N N N (d, J = 0.7 Hz, 1H), 7.58 (dd, J = 3.2, S 1.4 Hz, 1H), 7.55 – 7.52 (m, 1H), 7.28 – 4-[3-(tert-Butyl-methyl-carbamoyl)- 7.26 (m, 1H), 6.96 7-methoxythiophenyl-1,4- (s, 1H), 6.67 (s, dihydro-chromeno[4,3-c]pyrazol 1H), 5.53 (s, 2H), yl]-pyrazolecarboxylic acid tert- 3.92 (s, 3H), 3.30 (s, butyl ester (20) 3H), 1.70 (s, 9H), 1.54 (s, 9H).

O O 1H-NMR (DMSO- m/z = O d6): δ 7.99 (s, 1H), S O NH 509 S B 7.81 (s, 1H), 7.34 N O [M+H]+ N N N (d, 1H), 6.83 (s, N 1H), 6.66 (s, 1H), S 5.42 (s, 2H), 3.78 (s, 3H), 3.17 (s, 3H), 8-(2,4-Dimethyl-thiazolyl) 2.56 (s, 3H), 2.00 (s, methoxythiophenyl-1,4- 3H), 1.44 (s, 9H). dihydro-chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (53) O O m/z = 1H-NMR (CDCl 3): δ O O NH 498 7.57 (m, 2H), 7.02 S S B [M+H]+ (s, 1H), 6.65-6.62 F F O N N N (m, 2H), 6.38 (s, 1H), 5.52 (s, 2H), S 3.92 (s, 3H), 3.29 (s, 3H), 1.54 (s, 9H). luoro-thiophenyl) methoxythiophenyl-1,4- dihydro-chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (54) O O 1H-NMR (CDCl m/z = 3): δ O 7.50 (s, 1H), 7.45 O NH 477 (d, 1H), 7.23 (d, B [M+H]+ N O 1H), 6.83 (s, 1H), N N N 6.67 (s, 2H), 6.15 (s, 1H), 5.94 (s, 1H), .51 (s, 2H), 3.81 (s, 7-Methoxy(1-methyl-1H-pyrrol 3H), 3.41 (s, 3H), yl)thiophenyl-1,4-dihydro- 3.28 (s, 3H), 1.54 (s, chromeno[4,3-c]pyrazole 9H). carboxylic acid tert-butyl-methylamide (55) O O m/z = 1H-NMR (DMSO- O O NH 478 d6): δ 7.94 (s, 1H), N B [M+H]+ 7.83 (d, 1H), 7.60 N N (s, 1H), 7.48 (s, N N N N 1H), 7.32 (d, 1H), S 6.76 (s, 1H), 6.50 (s, 1H), 5.38 (s, 2H), 7-Methoxy(1-methyl-1H-pyrazol- 3.84 (s, 3H), 3.78 (s, 3-yl)thiophenyl-1,4-dihydro- 3H), 3.19 (s, 3H), chromeno[4,3-c]pyrazole 1.45 (s, 9H). ylic acid tert-butyl-methylamide (63) m/z: 507 1H NMR (400 MHz, O N MeOD) δ 8.35 (t, J O O N O [M+H]+ = 6.4 Hz, 1H), 7.81 N O O (s, 1H), 7.76 (d, J = N O N N 3.7 Hz, 1H), 7.62 (s, N N O 2H), 7.34 (d, J = 4.9 S N Hz, 1H), 6.97 (s, 7-Methoxy(1H-pyrazolyl) 1H), 6.71 (s, 1H), thiophenyl-1,4-dihydro- 5.55 (s, 2H), 4.36 (t, chromeno[4,3-c]pyrazole J = 8.1 Hz, 2H), ylic acid [2-(2-oxo-oxazolidin- 3.91 (s, 3H), 3.76 (t, 3-yl)-ethyl]-amide (62) J = 8.0 Hz, 2H), 3.63 – 3.54 (m, 2H), 3.53 – 3.46 (m, 2H). m/z = O O 1H-NMR (DMSO- O O NH d6): δ 7.96 (s, 1H), [M+H]+ N B 7.82 – 7.77 (m, 1H), N 7.40 – 7.32 (m, 2H), N N N N N 6.87 (s, 1H), 6.61 (s, 1H), 6.01 (s, 1H), S 5.44 (s, 2H), 3.80 (s, 3H), 3.53 (s, 3H), 7-Methoxy(2-methyl-2H-pyrazol- 3.18 (s, 3H), 1.45 (s, 3-yl)thiophenyl-1,4-dihydro- 9H). chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (64) m/z = O O 1H-NMR (DMSO- O O NH d6): δ 12.71 (s, 1H), [M+H]+ N B 8.01-7.33 (m, 4.5H), N 6.96 (s, 0.5H), 6.81 N N N N (d, 1H), 6.56 (s, 0.5H), 5.97 (s, S 0.5H), 5.40 (d, 2H), 3.87 (d, 3H), 3.19 7-Methoxy(1H-pyrazolyl) (s, 3H), 1.45 (s, thiophenyl-1,4-dihydro- 9H). chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (65) O O m/z = 1H-NMR (DMSO-d6): NH 478 δ 8.02 (s, 1H), 7.91 (d, N B 1H), 7.80 (s, 1H), 7.38 N N O [M+H]+ N N N (d, 1H), 7.21 (s, 1H), N 6.85 (s, 1H), 6.77 (s, S 1H), 5.38 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 7-Methoxy(1-methyl-1H-pyrazol- 3.19 (s, 3H), 1.45 (s, 1-thiophenyl-1,4-dihydro- 9H). chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (66) O O m/z = 1H-NMR (DMSO-d6): O 493 δ 8.00 (s, 1H), 7.84 – OH NH [M+H]+ 7.78 (m, 1H), 7.36 (d, N O N 1H), 6.84 (s, 1H), 6.48 O N N N (s, 1H), 5.43 (s, 2H), 3.78 (s, 3H), 3.18 (s, 3H), 2.12 (s, 3H), 1.94 (s, 3H), 1.45 (s, 9H). 8-(3,5-Dimethyl-isoxazolyl) methoxythiophenyl-1,4- dihydro-chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (67) O O m/z = 1H-NMR d6): O NH 493 δ 7.94 (s, 1H), 7.84 – [M+H]+ 7.80 (m, 1H), 7.33 (d, N 1H), 6.68 (s, 1H), 6.56 N N N N (s, 1H), 5.63 (s, 1H), S 5.35 (s, 2H), 3.75 (s, 3H), 3.17 (s, 3H), 2.88 (s, 2H), 2.42 (t, 2H), 7-Methoxy(1-methyl-1,2,3,6- 2.25-2.15 (m, 5H), tetrahydro-pyridinyl)thiophen- 1.44 (s, 9H). 3-yl-1,4-dihydro-chromeno[4,3- c]pyrazolecarboxylic acid tertbutyl-methyl-amide (68) m/z = 1H-NMR (DMSO-d6): O 476 O O NH δ 9.08 (s, 1H), 8.69 (s, B [M+H]+ 2H), 8.00 (s, 1H), 7.82 O O N (t, 1H), 7.38 (d, J = N 5.0 Hz, 1H), 6.91 (s, N N 1H), 6.74 (s, 1H), 5.45 N (s, 2H), 3.83 (s, 3H), 3.23-3.15 (m, 4H), 1.45 (s, 9H). 7-Methoxypyrimidinylthiophen- 3-yl-1,4-dihydro-chromeno[4,3- c]pyrazolecarboxylic acid tert-butylmethyl-amide (70) m/z = 1H-NMR (DMSO- 478 d6): δ 7.97 (s, 1H), O O O NH B [M+H]+ 7.81 (s, 1H), 7.41 – O O N 7.32 (m, 2H), 6.77 (s, 1H), 6.67 (s, N N N 1H), 5.37 (s, 2H), N N N 3.77 (s, 3H), 3.18 (s, S 3H), 1.95 (s, 3H), 1.45 (s, 9H). 7-Methoxy(3-methyl-1H-pyrazol- 4-yl)thiophenyl-1,4-dihydrochromeno [4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (71) m/z = 1H-NMR (DMSO- O O O NH 465 d6): δ 9.04 (s, 1H), O [M+H]+ 8.33 (s, 1H), 8.02 (s, N 1H), 7.90 (s, 1H), N N N O 7.39 (d, 1H), 6.86 N (d, 2H), 5.42 (s, S 2H), 3.90 (s, 3H), 3.19 (s, 3H), 1.45 (s, 8-Isoxazolylmethoxy 9H). enyl-1,4-dihydrochromeno [4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (72) m/z = 1H-NMR (DMSO- O O O NH 495 d6): δ 8.03 (s, 1H), S S B [M+H]+ 7.93 – 7.87 (m, 1H), O 7.48 (s, 1H), 7.38 N N N N N (d, 1H), 6.93 (s, 1H), 6.85 (s, 1H), .43 (s, 2H), 3.89 (s, 3H), 3.19 (s, 3H), 7-Methoxy(2-methyl-thiazolyl)- 2.61 (s, 3H), 1.45 (s, 1-thiophenyl-1,4-dihydro- 9H). chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (73) 1H-NMR (DMSO- O O O NH d6): δ 7.94 (s, 1H), O B 7.83 (s, 1H), 7.31 O O (d, 1H), 7.20 (s, N 1H), 6.82 (s, 1H), N N 5.47 (s, 2H), 4.40 (s, S 1H), 4.08 (s, 1H), 3.88 (s, 3H), 3.18 (s, 3H), 2.79 (t, 2H), 8-(4,5-Dihydro-furanyl) 1.67 – 1.59 (m, 2H), methoxythiophenyl-1,4- 1.44 (s, 9H). dihydro-chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (74) S m/z = 1H-NMR (DMSO- O O NH 494 d6): δ 7.97 (s, 1H), O [M+H]+ 7.81 – 7.76 (m, 1H), B O 7.34 (d, 1H), 7.21 N N N (d, 1H), 6.82 – 6.77 S O (m, 2H), 6.59 (s, S 1H), 5.40 (s, 2H), 3.75 (s, 3H), 3.18 (s, 7-Methoxy(2-methyl-thiophen 3H), 2.12 (s, 3H), yl)thiophenyl-1,4-dihydro- 1.45 (s, 9H). chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methylamide (75) O O 1H-NMR (DMSO-d6): O m/z = δ 7.98 (s, 1H), 7.79 (s, O NH 492 1H), 7.34 (d, 1H), N B [M+H]+ 7.21 (s, 1H), 6.88 (s, N N N N O N N 1H), 6.52 (s, 1H), 5.45 (d, 2H), 3.78 (s, 3H), 3.45 (s, 3H), 3.18 (s, -Dimethyl-2H-pyrazolyl) 3H), 1.71 (s, 3H), 1.45 methoxythiophenyl-1,4-dihydro- (s, 9H). chromeno[4,3-c]pyrazolecarboxylic acid tert-butyl-methyl-amide (76) 1H NMR (400 MHz, m/z: 492 O MeOD) δ 7.85 – 7.80 O O (m, 3H), 7.79 – 7.73 B [M+H]+ (m, 1H), 7.34 (d, J = N O O N O 5.2 Hz, 1H), 6.99 (s, N N 1H), 6.78 (s, 1H), 5.42 N N N (s, 2H), 4.02 – 3.96 S (m, 2H), 3.93 (s, 3H), O 3.87 – 3.81 (m, 2H), (3,3-Dimethyl-morpholinyl)-[7- 1.54 (s, 6H). methoxy(1H-pyrazolyl) thiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolyl]-methanone (80) O O 1H-NMR d6): S m/z = O δ 8.99 (s, 1H), 7.95 (s, NH 481 2H), 7.85 (s, 1H), 7.82 S [M+H]+ – 7.79 (m, 1H), 7.32 N N O B N (d, 1H), 6.86 (s, 1H), O 5.76 (s, 1H), 5.41 (s, S 2H), 4.09 (s, 5H), 3.93 (s, 3H), 3.19 (s, 3H), 7-Methoxythiazolylthiophen 1.45 (s, 9H). yl-1,4-dihydro-chromeno[4,3-c]pyrazole- 3-carboxylic acid tert-butyl-methylamide (81) 1H-NMR (DMSO-d6): O m/z = O O δ 7.97 (d, 1H), 7.81 – S B NH 494 7.76 (m, 1H), 7.35 O [M+H]+ (dd, 2H), 6.87 (d, 1H), S O 6.82 (s, 1H), 6.67 (s, N N 1H), 5.42 (s, 2H), 3.78 (s, 3H), 3.18 (s, 3H), S 1.92 (s, 3H), 1.45 (s, 9H). 7-Methoxy(3-methyl-thiophenyl)- 1-thiophenyl-1,4-dihydrochromeno [4,3-c]pyrazolecarboxylic acid tert-butyl-methyl-amide (88) 1H-NMR (DMSO-d6): O O m/z = δ 7.97 – 7.92 (m, 1H), NH 492 O N 7.81-7.77 (m, 1H), N O [M+H]+ 7.33 (d, 1H), 6.83 (s, N 1H), 6.59 (s, 1H), 6.45 N N N (s, 1H), 5.42 (s, 2H), 3.78 (s, 3H), 3.19 (d, S 6H), 2.27 (s, 3H), 1.45 (s, 9H). 8-(2,3-Dimethyl-3H-imidazolyl) methoxythiophenyl-1,4-dihydrochromeno [4,3-c]pyrazolecarboxylic acid tert-butyl-methyl-amide (92) 1H-NMR d6): O O O m/z = δ 8.04-8.00 (m, 1H), O B NH 494 7.91-7.86 (m, 1H), S O [M+H]+ 7.37 (d, 1H), 6.96 (s, N N 1H), 6.83-6.79 (m, 2H), 6.70 (d, 1H), S 5.40 (s, 2H), 3.87 (s, 3H), 3.19 (s, 3H), 2.41 7-Methoxy(5-methyl-thiophenyl)- (s, 3H), 1.45 (s, 9H). 1-thiophenyl-1,4-dihydrochromeno [4,3-c]pyrazolecarboxylic acid tert-butyl-methyl-amide (93) m/z = 1H-NMR (DMSO-d6): O O 506 δ 7.96 (d, 1H), 7.82 O N N [M+H]+ (dd, 1H), 7.60 (d, 1H), O 7.46 (s, 1H), 7.32 (d, 1H), 6.76 (s, 1H), 6.49 N N N N B O (d, 1H), 5.40 (s, 2H), S O O 3.96 (t, 2H), 3.84 (s, 3H), 3.79 – 3.71 (m, 5H), 3.43 (s, 2H), 1.43 (3,3-Dimethyl-morpholinyl)-[7- (s, 6H). methoxy(1-methyl-1H-pyrazolyl)- 1-thiophenyl-1,4-dihydrochromeno [4,3-c]pyrazolyl]-methanone (94) m/z = 1H-NMR (DMSO-d6): O O 506 δ 12.41 (s, 1H), 7.97 O N [M+H]+ (s, 1H), 7.84-7.79 (m, O O 1H), 7.45-7.30 (m, N N N 2H), 6.77 (s, 1H), 6.64 N N N N (s, 1H), 5.39 (s, 2H), O 3.95 (t, 2H), 3.79 – S 3.70 (m, 5H), 3.42 (s, (3,3-Dimethyl-morpholinyl)-[7- 2H), 1.94 (s, 3H), 1.42 methoxy(3-methyl-1H-pyrazolyl)- (s, 6H). 1-thiophenyl-1,4-dihydrochromeno ]pyrazolyl]-methanone (95) 1H-NMR (DMSO-d6): O O m/z = δ 8.02 (dd, 1H), 7.89 O 505 (dd, 1H), 7.37 (dd, B N [M+H]+ 1H), 7.00 (s, 1H), 6.84 N N O N O (s, 1H), 6.71 (s, 1H), 6.63 (t, 1H), 5.79 (t, S 1H), 5.37 (s, 2H), 3.96 (t, 2H), 3.84 (s, 3H), (3,3-Dimethyl-morpholinyl)-[7- 3.73 (t, 2H), 3.59 (s, methoxy(1-methyl-1H-pyrrol 3H), 3.42 (s, 2H), 1.42 yl)thiophenyl-1,4-dihydro- (s, 6H). chromeno[4,3-c]pyrazolyl]- methanone (98) O O 1H-NMR (DMSO-d6): m/z = O δ 8.89 (s, 1H), 8.08 O 477 (dd, 1H), 7.91 (dd, O B H N 2 O [M+H]+ 1H), 7.41 (dd, 1H), N N N O N N 7.00 (t, 1H), 6.81 (s, 1H), 6.71 (s, 1H), 6.63 (t, 1H), 5.78 (t, 1H), 7-Methoxy(1-methyl-1H-pyrrol 5.48 (s, 2H), 4.71 (d, yl)thiophenyl-1,4-dihydro- 2H), 4.32 (d, 2H), chromeno[4,3-c]pyrazole 3.83 (s, 3H), 3.59 (s, 3H), 1.59 (s, 3H). carboxylic acid (3-methyl-oxetan yl)-amide (99) O O 1H-NMR (DMSO-d6): m/z = O δ 8.90 (s, 1H), 8.02 478 (dd, 1H), 7.85 (dd, O H N [M+H]+ N O 2 O 1H), 7.60 (d, 1H), N N N N B O 7.42 (s, 1H), 7.35 (dd, 1H), 6.76 (s, 1H), 6.49 S (d, 1H), 5.52 (s, 2H), 7-Methoxy(1-methyl-1H-pyrazol- 4.71 (d, 2H), 4.32 (d, N 2H), 3.84 (s, 3H), 3.77 3-yl)thiophenyl-1,4-dihydrochromeno [4,3-c]pyrazole (s, 3H), 1.60 (s, 3H). carboxylic acid hyl-oxetan yl)-amide (100) 1H-NMR (DMSO-d6): O O m/z = δ 8.02 (d, 1H), 7.92 – O 505 7.86 (m, 1H), 7.38 B O N [M+H]+ (dd, 1H), 7.00 (s, 1H), N O N N N H 6.88 (d, 1H), 6.71 (s, N 1H), 6.63 (t, 1H), 5.80 S (s, 1H), 5.39 (s, 2H), 4.54 (dd, 2H), 4.23 – 7-Methoxy(1-methyl-1H-pyrrol 4.10 (m, 3H), 3.84 (s, yl)thiophenyl-1,4-dihydro- 3H), 3.72 (s, 1H), 3.59 chromeno[4,3-c]pyrazole (s, 3H), 3.35 (d, 3H), carboxylic acid methyl-(3-methyl- 2.98 (s, 1H), 1.27 (d, oxetanylmethyl)-amide (101) 3H).

O O m/z = 1H-NMR (DMSO-d6): O 506 δ 7.96 (d, 1H), 7.84 (s, O 1H), 7.60 (s, 1H), 7.50 N [M+H]+ N H (d, 1H), 7.32 (dd, 1H), N N N N B O 6.76 (s, 1H), 6.50 (s, S 1H), 5.43 (s, 2H), 4.55 N (dd, 2H), 4.23 – 4.08 7-Methoxy(1-methyl-1H-pyrazol- N (m, 3H), 3.84 (s, 3H), 3-yl)thiophenyl-1,4-dihydro- 3.78 (s, 3H), 3.72 (s, 1H), 3.37 (s, 3H), 3.18 chromeno[4,3-c]pyrazole (d, 1H), 2.99 (s, 1H), carboxylic acid -(3-methyl- 1.27 (d, 3H). oxetanylmethyl)-amide (102) O O H m/z = 1H-NMR (DMSO-d6): O N O 477 δ 8.05 (d, 1H), 7.91 B [M+H]+ (dd, 1H), 7.40 (d, 1H), O O O 7.00 (d, 1H), 6.87 (s, N N N N N 1H), 6.71 (s, 1H), 6.64 (t, 1H), 5.94 (s, 0.5H), S 5.80 (s, 1H), 5.38 (s, 2H), 5.22 (s, 0.5H), 7-Methoxy(1-methyl-1H-pyrrol 4.71 (s, 4H), 3.84 (s, yl)thiophenyl-1,4-dihydro- 3H), 3.59 (s, 3H), 3.41 chromeno[4,3-c]pyrazole (s, 1H), 3.24-3.12 (m, carboxylic acid methyl-oxetanyl- 2H). amide (103) 1H-NMR d6): O O H m/z = N δ 7.99 (d, 1H), 7.84 O 478 (dd, 1H), 7.60 (d, 1H), O O O [M+H]+ 7.49 (s, 1H), 7.35 (d, N N N N N B O 1H), 6.76 (s, 1H), 6.50 (d, 1H), 5.94 (s, S 0.5H), 5.42 (s, 2H), 7-Methoxy(1-methyl-1H-pyrazol- 5.22 (s, 0.5H), 4.72 (s, 3-yl)thiophenyl-1,4-dihydro- 4H), 4.09 (q, 1H), chromeno[4,3-c]pyrazole 3.84 (s, 3H), 3.78 (s, 3H), 3.41 (s, 1H), 3.18 carboxylic acid methyl-oxetanyl- (d, 5H). amide (104) 1H-NMR (DMSO-d6): m/z = O O δ 8.45 (d, 1H), 8.08 O NH 481 O (dd, 1H), 7.94 (dd, B [M+H]+ 1H), 7.42 (dd, 1H), N 7.15 (s, 1H), 7.02 (d, N S N N N S 1H), 6.95 (s, 1H), 5.49 (s, 2H), 4.01 (s, 3H), 3.20 (s, 3H), 1.45 (s, 8-Isothiazolylmethoxy 9H). thiophenyl-1,4-dihydrochromeno [4,3-c]pyrazolecarboxylic acid tert-butyl-methyl-amide (105) O O m/z = 1H-NMR (DMSO-d6): O 506 δ 7.97 (dd, 1H), 7.79 [M+H]+ (dd, 1H), 7.38 – 7.32 B N N N O N (m, 2H), 6.87 (s, 1H), N N N N O 6.59 (s, 1H), 6.00 (d, 1H), 5.46 (s, 2H), 3.99 S – 3.92 (m, 2H), 3.80 (s, 3H), 3.73 (t, 2H), (3,3-Dimethyl-morpholinyl)-[7- 3.52 (s, 3H), 3.42 (s, methoxy(2-methyl-2H-pyrazol 2H), 1.42 (s, 6H). yl)thiophenyl-1,4-dihydrochromeno [4,3-c]pyrazolyl]- methanone (108) O O 1H-NMR (DMSO-d6): O m/z = δ 8.92 (s, 1H), 8.03 O 478 (dd, 1H), 7.81 (dd, O N N B H N [M+H]+ 1H), 7.39-7.35 (m, N N N O N 2 O N 2H), 6.87 (s, 1H), 6.56 (s, 1H), 5.99 (d, 1H), S 5.57 (s, 2H), 4.71 (d, 7-Methoxy(2-methyl-2H-pyrazol- 2H), 4.32 (d, 2H), 3.80 (s, 3H), 3.52 (s, 3-yl)thiophenyl-1,4-dihydro- 3H), 1.59 (s, 3H). chromeno[4,3-c]pyrazole ylic acid (3-methyl-oxetan yl)-amide (109) O O 1H-NMR (DMSO-d6): m/z = O δ 7.97 (dd, 1H), 7.80 O 506 O (dd, 1H), 7.39 – 7.31 N B N [M+H]+ (m, 2H), 6.86 (s, 1H), N N N N O H N N 6.62 (d, 1H), 6.03- S 6.00 (d, 1H), 5.48 (s, 2H), 4.54 (dd, 2H), 7-Methoxy(2-methyl-2H-pyrazol- 4.25 – 4.09 (m, 3H), 3-yl)thiophenyl-1,4-dihydro- 3.80 (s, 3H), 3.72 (s, chromeno[4,3-c]pyrazole 1H), 3.52 (s, 3H), 3.36 carboxylic acid methyl-(3-methyl- (s, 2H), 2.99 (s, 1H), oxetanylmethyl)-amide (110) 1.26 (d, 3H).

O O 1H-NMR (DMSO-d6): OH m/z = O δ 8.73 (s, 1H), 8.02 O 494 (dd, 1H), 7.82 (dd, O B H N 2 [M+H]+ N 1H), 7.37 (dd, 2H), N N N N O O N N 6.87 (s, 1H), 6.56 (s, O 1H), 5.99 (d, 1H), .56 (s, 2H), 5.15 (s, 7-Methoxy(2-methyl-2H-pyrazol- 1H), 4.68 (d, 2H), 3-yl)thiophenyl-1,4-dihydro- 4.52 (d, 2H), 3.80 (s, no[4,3-c]pyrazole 3H), 3.69 (s, 2H), 3.52 (s, 3H). carboxylic acid (3-hydroxymethyloxetanyl )-amide (111) O O 1H NMR (400 MHz, m/z: 533 O CDCl3) δ 7.50 (dd, J = 3.2, 1.4 Hz, 1H), 7.44 B N N [M+H]+ (dd, J = 5.1, 3.2 Hz, N N O N N O 1H), 7.24 (dd, J = 5.1, O S 1.4 Hz, 1H), 6.81 (s, 1H), 6.66 (s, 1H), 5.83 (3,3-Dimethyl-morpholinyl)-[7- (s, 1H), 5.47 (s, 2H), methoxythiophenyl(1,2,5- 4.11 – 4.05 (m, 2H), trimethyl-1H-pyrrolyl)-1,4- 3.89 – 3.83 (m, 2H), o-chromeno[4,3-c]pyrazol 3.82 (s, 3H), 3.50 (s, yl]-methanone (120) 2H), 3.39 (s, 3H), 2.22 (s, 3H), 2.01 (s, 3H), 1.27 (s, 6H). 1H NMR (400 MHz, O O m/z: 534 CDCl3) δ 7.49 (dd, J = O O N 3.1, 1.2 Hz, 1H), 7.44 N N N [M+H]+ (dd, J = 5.0, 3.3 Hz, N O N N N O 1H), 7.21 (dd, J = 5.1, 1.2 Hz, 1H), 6.68 (s, S 1H), 6.63 (s, 1H), 5.51 (s, 2H), 4.12 – 4.05 (3,3-Dimethyl-morpholinyl)-[7- (m, 2H), 3.90 – 3.84 methoxythiophenyl(1,3,5- (m, 2H), 3.80 (s, 3H), trimethyl-1H-pyrazolyl)-1,4- 3.74 (s, 3H), 3.50 (s, dihydro-chromeno[4,3-c]pyrazol 2H), 2.01 (d, J = 5.5 yl]-methanone (121) Hz, 6H), 1.55 (s, 6H).

O 1H NMR (400 MHz, m/z: 520 CDCl3) δ 7.50 – 7.47 N O (m, 1H), 7.47 – 7.44 N B N [M+H]+ (m, 1H), 7.19 (dd, J = N N N O 5.0, 1.5 Hz, 1H), 6.72 N (s, 1H), 6.68 (s, 1H), S O 5.83 (s, 1H), 5.53 (s, 2H), 4.09 (dd, J = 8.4, (3,3-Dimethyl-morpholinyl)-[8- 3.0 Hz, 2H), 3.88 – (2,5-dimethyl-2H-pyrazolyl) 3.83 (m, 2H), 3.82 (s, methoxythiophenyl-1,4- 3H), 3.56 (s, 3H), 3.49 dihydro-chromeno[4,3-c]pyrazol (s, 2H), 2.27 (s, 3H), yl]-methanone (122) 1.54 (s, 6H). 1H NMR (400 MHz, O O m/z: 520 CDCl3) δ 7.51 (dd, J = O O N 3.2, 1.3 Hz, 1H), 7.46 N N N O [M+H]+ (dd, J = 5.1, 3.3 Hz, N N N O 1H), 7.37 (s, 1H), 7.22 (dd, J = 5.1, 1.3 Hz, S 1H), 6.84 (s, 1H), 6.67 (s, 1H), 5.50 (s, 2H), (3,3-Dimethyl-morpholinyl)-[8-(1,3- 4.13 – 4.06 (m, 2H), dimethyl-1H-pyrazolyl)methoxy- 3.89 – 3.82 (m, 8H), 1-thiophenyl-1,4-dihydro- 3.50 (s, 2H), 2.03 (s, chromeno[4,3-c]pyrazolyl]- 3H), 1.55 (s, 6H). methanone (123) O O 1H NMR (400 MHz, O m/z: 520 O CDCl3) δ 7.53 – 7.49 B (m, 1H), 7.49 – 7.44 N N N N O [M+H]+ N (m, 1H), 7.35 (s, 1H), N N O 7.23 (d, J = 5.0 Hz, S O 1H), 6.70 (s, 1H), 6.67 (s, 1H), 5.50 (s, 2H), imethyl-morpholinyl)-[8- 4.13 – 4.05 (m, 2H), (1,5-dimethyl-1H-pyrazolyl) 3.90 – 3.83 (m, 2H), methoxythiophenyl-1,4- 3.81 (d, J = 8.9 Hz, dihydro-chromeno[4,3-c]pyrazol 6H), 3.50 (s, 2H), 2.07 yl]-methanone (124) (s, 3H), 1.55 (s, 6H).

O 1H NMR (400 MHz, m/z: 505 CDCl3) δ 7.62 (d, J = O O B 7.3 Hz, 1H), 7.51 – N N O [M+H]+ 7.42 (m, 2H), 7.22 (d, N N N N O J = 5.0 Hz, 1H), 6.83 (s, 1H), 6.67 (s, 1H), S O 6.17 – 6.12 (m, 1H), .96 – 5.89 (m, 1H), (3,3-Dimethyl-morpholinyl)-[7- 5.51 (s, 2H), 4.15 – y(1-methyl-1H-pyrrol 4.05 (m, 2H), 3.91 – yl)thiophenyl-1,4-dihydro- 3.84 (m, 2H), 3.82 (s, chromeno[4,3-c]pyrazolyl]- 3H), 3.50 (s, 2H), 3.41 methanone (125) (s, 3H), 1.55 (s, 6H).

O 1H NMR (400 MHz, m/z: 520 MeOD) δ 7.79 – 7.74 N (m, 1H), 7.66 (dd, J = N B N [M+H]+ 5.0, 3.2 Hz, 1H), 7.27 N N N N N O O (d, J = 5.1 Hz, 1H), 6.76 (s, 1H), 6.58 (s, S 1H), 5.42 (s, 2H), 4.01 – 3.95 (m, 2H), 3.86 – (3,3-Dimethyl-morpholinyl)-[8- 3.80 (m, 2H), 3.79 (s, (3,5-dimethyl-1H-pyrazolyl) 3H), 3.51 (s, 2H), 2.01 methoxythiophenyl-1,4- (s, 6H), 1.53 (s, 6H). dihydro-chromeno[4,3-c]pyrazol yl]-methanone (126) 1H-NMR (DMSO- m/z = O O NH d6): δ 7.89 (dd, 1H), O 478 7.79 (dd, 1H), 7.74 N O O B [M+H]+ (s, 1H), 7.47 (s, N N N 1H), 7.39 (d, 1H), 7.30 (dd, 1H), 6.76 S N (s, 1H), 5.33 (s, 7-Methoxy(1-methyl-1H-imidazol- 2H), 3.89 (s, 3H), 4-yl)thiophenyl-1,4-dihydro- 3.64 (s, 3H), 3.18 (s, chromeno[4,3-c]pyrazolecarboxylic 3H), 1.45 (s, 9H). acid tert-butyl-methyl-amide (129) 1H-NMR (DMSO-d6): O O m/z = NH δ 7.95 (d, 1H), 7.79 O 478 O (dd, 1H), 7.59 (s, 1H), N [M+H]+ 7.35 – 7.32 (m, 1H), N 6.84 (s, 1H), 6.62 (d, N N N N 2H), 5.42 (s, 2H), 3.79 (s, 3H), 3.35 (s, 3H), 3.18 (s, 3H), 1.45 (s, 7-Methoxy(3-methyl-3H-imidazol- 9H). 4-yl)thiophenyl-1,4-dihydrochromeno ]pyrazolecarboxylic acid tert-butyl-methyl-amide (130) 1H-NMR (DMSO-d6): O O m/z = δ 8.07 (d, 1H), 7.98 O NH 465 (dd, 1H), 7.83 (dd, N B [M+H]+ 1H), 7.37 – 7.33 (m, O 2H), 7.24 (d, 1H), O N N N O 6.88 (s, 1H), 5.46 (s, 2H), 3.87 (s, 3H), 3.19 (s, 3H), 1.45 (s, 9H). 7-Methoxyoxazolylthiophen- 3-yl-1,4-dihydro-chromeno[4,3- c]pyrazolecarboxylic acid tertbutyl-methyl-amide (132) O O 1H-NMR (DMSO-d6): O m/z = δ 7.96 (dd, 1H), 7.83 N NH 493 (dd, 1H), 7.33 (dd, N N B O [M+H]+ 1H), 6.68 (s, 1H), 6.54 N N (s, 1H), 5.67 – 5.63 S (m, 1H), 5.36 (s, 2H), 3.75 (s, 3H), 3.17 (s, 7-Methoxy(1-methyl-1,2,5,6- 3H), 2.85 (d, 2H), tetrahydro-pyridinyl)thiophen- 2.38 (t, 2H), 2.22 (s, ,4-dihydro-chromeno[4,3- 3H), 2.14 (d, 2H), c]pyrazolecarboxylic acid tert- 1.44 (s, 9H). butyl-methyl-amide (134) 1H-NMR (DMSO-d6): O O H N 2 m/z = O δ 12.45 (s, 1H), 8.43 O O 478 (d, 1H), 8.03 (dd, 1H), O [M+H]+ N B 7.82 (dd, 1H), 7.37 N N N N N (dd, 2H), 6.76 (s, 1H), N 6.62 (s, 1H), 5.52 (s, S 2H), 4.49 – 4.40 (m, 1H), 3.86 – 3.67 (m, 7-Methoxy(3-methyl-1H-pyrazol 6H), 3.56 (dd, 1H), yl)thiophenyl-1,4-dihydro- 2.17-2.06 (m, 1H), no[4,3-c]pyrazolecarboxylic 2.02 – 1.91 (m, 4H). acid (tetrahydro-furanyl)-amide (135) O O 1H-NMR (DMSO-d6): O H N m/z = δ 8.50 (dd, 1H), 8.09- O O 2 477 8.03 (m, 1H), 7.90 (dd, N N N N B OH [M+H]+ 1H), 7.40 (d, 1H), 7.00 (s, 1H), 6.82 (d, 1H), S 6.70 (s, 1H), 6.63 (s, 1H), 5.78 (s, 1H), 5.48 7-Methoxy(1-methyl-1H-pyrrol (s, 2H), 4.97 (dd, 1H), yl)thiophenyl-1,4-dihydro- 4.53-4.43 (m, 1H), chromeno[4,3-c]pyrazole 4.32-4.24 (m, 1H), 3.89 carboxylic acid (3-hydroxy- – 3.76 (m, 4 H), 3.59 cyclobutyl)-amide (136) (s, 3H), 2.37 – 2.29 (m, 1H), 2.15 – 2.07 (m, 1H), 2.03-1.91 (m, 1H). 1H-NMR (DMSO-d6): O O 2 m/z = δ 8.50 (dd, 1H), 8.00 (s, 1H), 7.88 – 7.80 (m, O 478 O OH [M+H]+ 1H), 7.60 (d, 1H), 7.43 N (d, 1H), 7.34 (d, 1H), N O N N N B 6.75 (s, 1H), 6.49 (d, S 1H), 5.52 (s, 2H), 4.99 N (s, 1H), .43 (m, 7-Methoxy(1-methyl-1H-pyrazol N 1H), 4.33-4.24 (m, 1H), yl)thiophenyl-1,4-dihydro- 3.94 – 3.70 (m, 7H), chromeno[4,3-c]pyrazolecarboxylic 2.39 – 2.28 (m, 1H), acid (3-hydroxy-cyclobutyl)-amide (137) 2.16-2.06 (m, 1H), 2.04-1.91 (m, 1H).

H N 1H-NMR (DMSO-d6): O O 2 m/z = O O δ 8.50 (dd, 1H), 8.06- OH 8.01 (m, 1H), 7.82 O B [M+H]+ N O N N (dd, 1H), 7.40-7.35 N N N (m, 2H), 6.76 (s, 1H), 6.62 (d, 1H), 5.51 (d, S 2H), 4.97 (s, 1H), 7-Methoxy(3-methyl-1H-pyrazol 4.51-4.44 (m, 1H), yl)thiophenyl-1,4-dihydro- 4.31-4.23 (m, 1H), chromeno[4,3-c]pyrazolecarboxylic 3.90 – 3.74 (m, 5H), acid (3-hydroxy-cyclobutyl)-amide (138) 2.37 – 2.29 (m, 1H), 2.15 – 2.06 (m, 1H), 2.02 – 1.90 (m, 4H).

O 1H NMR (400 MHz, O F m/z: CDCl3) δ 7.61 – 7.48 F F (m, 3H), 7.32 (d, J = O F F O 546 2.0 Hz, 1H), 6.66 (s, N F B O N 1H), 6.54 (d, J = 1.9 N N O [M+H]+ Hz, 1H), 6.36 (s, 1H), S 5.69 – 5.49 (m, 2H), O N 5.31 (d, J = 13.8 Hz, N 1H), 4.44 – 4.22 (m, [7-Methoxy(1-methyl-1H-pyrazol 2H), 4.04 (dd, J = 43.8, thiophenyl-1,4-dihydro- 13.6 Hz, 1H), 3.90 (s, chromeno[4,3-c]pyrazolyl]-(3- 3H), 3.88 (s, 3H), 3.84 trifluoromethyl-morpholinyl)- – 3.70 (m, 1H), 3.62 methanone (144) (dd, J = 24.9, 12.6 Hz, 1H), 3.36 (t, J = 14.2 Hz, 1H).

O O 468 1H-NMR d6): O [M+H]+ δ 7.99 (dd, 1H), 7.85 O B NH (dd, 1H), 7.35 (dd, N N N 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.61 (d, 1H), S 5.63 (dt, 1H), 5.37 (d, 2H), 3.93 (dd, 2H), 7-Methoxy((E)methoxy-propenyl)- 3.80 (s, 3H), 3.23 (s, 1-thiophenyl-1,4-dihydro- 3H), 3.18 (s, 3H), 1.44 chromeno[4,3-c]pyrazolecarboxylic (s, 9H). acid tert-butyl-methyl-amide (147) O O m/z = 1H-NMR (DMSO-d6): O 480 δ 7.92 (dd, 1H), 7.82 O O NH [M+H]+ (dd, 1H), 7.30 (dd, O B 1H), 6.93 (s, 1H), 6.69 N N O N (s, 1H), 5.38 (s, 2H), .29 (t, 1H), 3.89 (t, S 2H), 3.78 (s, 3H), 3.18 (s, 3H), 2.12-2.03 (m, 8-(5,6-Dihydro-4H-pyranyl) 2H), 1.74 (quintet, methoxythiophenyl-1,4-dihydro- 2H), 1.44 (s, 9H). chromeno[4,3-c]pyrazolecarboxylic acid tert-butyl-methyl-amide (148) 1H-NMR (DMSO-d6): O O m/z = 464 δ 7.97 (dd, 1H), 7.85 O B NH [M+H]+ (dd, 1H), 7.34 (dd, O 1H), 6.71 (s, 1H), 6.68 N N (s, 1H), 6.28 (s, 1H), N 5.38 (s, 2H), 3.82 (s, 3H), 3.18 (s, 3H), 2.46-2.38 (m, 2H), 8-Cyclopentenylmethoxy 2.29-2.19 (m, 2H), thiophenyl-1,4-dihydro-chromeno[4,3- 1.76 (quintet, 2H), c]pyrazolecarboxylic acid tert-butyl- 1.44 (s, 9H). methyl-amide (149) O O 1H-NMR (DMSO-d6): m/z = O δ 7.97 (dd, 1H), 7.80 NH 492 (dd, 1H), 7.56 (s, 1H), N B N N [M+H]+ O 7.33 (dd, 1H), 6.77 (s, N N N N 1H), 6.72 (s, 1H), 5.37 S (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.17 (s, 8-(1,3-Dimethyl-1H-pyrazolyl) 3H), 1.84 (s, 3H), 1.44 methoxythiophenyl-1,4-dihydro- (s, 9H). chromeno[4,3-c]pyrazolecarboxylic acid tert-butyl-methyl-amide (150) O O 1H-NMR (DMSO- m/z = O O d6): δ 7.98 (dd, 1H), NH 466 7.88 (dd, 1H), 7.34 O B O O [M+H]+ N N (dd, 1H), 6.77 (s, 1H), 6.44 (s, 1H), S 6.34 (t, 1H), 5.41 (s, 2H), 4.69-4.62 (m, 8-(2,5-Dihydro-furanyl) 2H), 4.49-4.41 (m, methoxythiophenyl-1,4- 2H), 3.85 (s, 3H), dihydro-chromeno[4,3-c]pyrazole 3.18 (s, 3H), 1.44 (s, carboxylic acid tert-butyl-methyl- 9H). amide (151) m/z = 1H-NMR (DMSO-d6): O O + 523 δ 7.92 (dd, 1H), 7.76 O O N O NH N B [M+H]+ (dd, 1H), 7.60 (s, 1H), N O N 7.30 (dd, 1H), 6.91 (s, N N N N O 1H), 6.67 (s, 1H), 5.48 O S (s, 2H), 5.45 (s, 2H), 3.79 (s, 3H), 3.27 (q, 8-(1-Ethoxymethyl-1H-[1,2,3]triazol- 2H), 3.18 (s, 3H), 1.45 7-methoxythiophenyl-1,4- (s, 9H), 0.92 (t, 3H). dihydro-chromeno[4,3-c]pyrazole ylic acid tert-butyl-methylamide (152) m/z = 1H-NMR (DMSO-d6): O O Li NH 478 δ 8.21 (s, 1H), 7.95 O O N O [M+H]+ (dd, 1H), 7.82 (dd, N B N 1H), 7.72 (s, 1H), 7.33 N (dd, 1H), 6.84 (s, 1H), N N N N N 5.39 (s, 2H), 4.04 (s, 3H), 3.91 (s, 3H), 3.19 S (s, 3H), 1.45 (s, 9H). 7-Methoxy(1-methyl-1H- [1,2,3]triazolyl)thiophenyl- 1,4-dihydro-chromeno[4,3- zolecarboxylic acid tertbutyl-methyl-amide (153) m/z: 1H NMR (400 MHz, O O CDCl3) δ 7.58 (d, J = O 2.0 Hz, 1H), 7.53 – O 520 7.49 (m, 2H), 7.32 (d, O N B O O J = 2.0 Hz, 1H), 7.27 N N O [M+H]+ (s, 1H), 6.67 (s, 1H), N N N 6.54 (d, J = 2.1 Hz, S N 1H), 5.54 (s, 2H), 4.90 O (s, 2H), 4.57 (d, J = (2,8-Dioxaaza-spiro[3.5]nonyl)-[7- 6.6 Hz, 2H), 4.17 (s, methoxy(1-methyl-1H-pyrazolyl)- 3H), 3.90 (s, 3H), 3.88 1-thiophenyl-1,4-dihydro- (s, 3H), 3.63 (t, J = chromeno[4,3-c]pyrazolyl]-methanone 4.5 Hz, 2H). (154) m/z: 518 1H NMR (400 MHz, O N CDCl3) δ 7.59 – 7.53 O (m, 2H), 7.30 (d, J = [M+H]+ O B 1.5 Hz, 1H), 7.06 (s, N O N 1H), 7.01 (s, 1H), 6.65 N N N N (s, 1H), 6.55 (t, J = S 2.4 Hz, 1H), 6.04 (s, N O 1H), 5.55 (s, 2H), 4.40 – 4.25 (m, 2H), 3.89 1-{4-[7-Methoxy(1-methyl-1H-pyrrol- (s, 3H), 3.86 – 3.70 3-yl)thiophenyl-1,4-dihydro- (m, 4H), 3.67 (s, 3H), chromeno[4,3-c]pyrazolecarbonyl]- 3.59 (s, 2H), 2.16 (d, J piperazinyl}-ethanone (155) = 7.8 Hz, 3H). 1H NMR (400 MHz, O O m/z: O N N CDCl3) δ 7.55 (dd, J = O 3.2, 1.3 Hz, 1H), 7.53 O O 605 – 7.47 (m, 2H), 7.32 N N N B O (d, J = 2.2 Hz, 1H), S [M+H]+ 7.29 – 7.24 (m, 1H), O N 6.67 (s, 1H), 6.54 (d, J O N = 2.2 Hz, 1H), 5.52 (s, 2H), 4.35 – 4.26 (m, 2H), 3.89 (s, 3H), 3.88 4-[7-Methoxy(1-methyl-1H-pyrazol (s, 3H), 3.61 – 3.47 yl)thiophenyl-1,4-dihydro- (m, 4H), 1.61 (s, 6H), chromeno[4,3-c]pyrazolecarbonyl]- 1.50 (s, 9H). 3,3-dimethyl-piperazinecarboxylic acid tert-butyl ester (156) m/z: 1H NMR (400 MHz, O O O N N CDCl3) δ 7.58 – 7.51 O 604 O B (m, 2H), 7.28 (d, J = N O 1.5 Hz, 1H), 7.05 (s, N N N N [M+H]+ 1H), 7.00 (t, J = 1.9 S Hz, 1H), 6.64 (s, 1H), O 6.55 (t, J = 2.5 Hz, O 1H), 6.04 (s, 1H), 5.49 (s, 2H), 4.34 – 4.26 (m, 2H), 3.90 (s, 3H), 4-[7-Methoxy(1-methyl-1H-pyrrol 3.66 (s, 3H), 3.61 – yl)thiophenyl-1,4-dihydro- 3.47 (m, 4H), 1.61 (s, chromeno[4,3-c]pyrazolecarbonyl]- 6H), 1.50 (s, 9H). 3,3-dimethyl-piperazinecarboxylic acid tert-butyl ester (157) 1H NMR (400 MHz, O O m/z: O CDCl3) δ 7.59 – 7.48 N O O N 603 (m, 3H), 7.32 (d, J = N N 2.1 Hz, 1H), 7.28 – N N N B O S [M+H]+ 7.25 (m, 1H), 6.66 (s, 1H), 6.54 (d, J = 2.1 O N Hz, 1H), 5.54 (s, 2H), O N 4.42 – 4.23 (m, 2H), 3.90 (s, 3H), 3.88 (s, 4H), 3.63 – 3.41 (m, 4-[7-Methoxy(1-methyl-1H- 4H), 1.61 (s, 3H), 1.48 pyrazolyl)thiophenyl-1,4- (s, 9H). dihydro-chromeno[4,3-c]pyrazole carbonyl]-4,7-diaza-spiro[2.5]octane- 7-carboxylic acid tert-butyl ester (158) m/z: 1H NMR (400 MHz, O CDCl3) δ 7.56 (dd, J = N N O 3.2, 1.4 Hz, 1H), 7.52 O 519 (s, 1H), 7.48 (dd, J = O B O 5.1, 3.2 Hz, 1H), 7.32 N N [M+H]+ (d, J = 2.2 Hz, 1H), N N N 7.27 (d, J = 1.3 Hz, S N 1H), 6.66 (s, 1H), 6.53 N (d, J = 2.2 Hz, 1H), .48 (s, 2H), 4.05 – [7-Methoxy(1-methyl-1H-pyrazol- 3.97 (m, 2H), 3.89 (s, 3-yl)thiophenyl-1,4-dihydro- 3H), 3.88 (s, 3H), 2.56 no[4,3-c]pyrazolyl]-(2,2,4- – 2.51 (m, 2H), 2.33 – trimethyl-piperazinyl)-methanone 2.29 (m, 5H), 1.59 (s, (159) 6H). m/z: 1H NMR (400 MHz, O CDCl3) δ 7.56 (dd, J = O N N O 3.2, 1.4 Hz, 1H), 7.52 B (dd, J = 5.0, 3.3 Hz, O O 2H), 7.06 (s, 1H), 7.00 N N [M+H]+ (t, J = 1.9 Hz, 1H), N N 6.64 (s, 1H), 6.55 (t, J S = 2.5 Hz, 1H), 6.06 – N 6.01 (m, 1H), 5.46 (s, 2H), 4.03 – 3.97 (m, [7-Methoxy(1-methyl-1H-pyrrol- 2H), 3.90 (s, 3H), 3.66 1-thiophenyl-1,4-dihydro- (s, 3H), 2.55 – 2.49 chromeno[4,3-c]pyrazolyl]-(2,2,4- (m, 2H), 2.30 (s, 5H), trimethyl-piperazinyl)-methanone 1.59 (s, 6H). (160) O O 1H-NMR (DMSO-d6): OH m/z = O δ 8.31 (t, 1H), 8.08 O H N 2 493 (dd, 1H), 7.91 (dd, O B O [M+H]+ N N O 1H), 7.41 (dd, 1H), N N N 7.00 (t, 1H), 6.81 (s, S 1H), 6.71 (s, 1H), 6.63 (t, 1H), 5.89 (s, 1H), 7-Methoxy(1-methyl-1H-pyrrol 5.80-5.75 (m, 1H), yl)thiophenyl-1,4-dihydro- 5.51 (s, 2H), 4.48 (d, chromeno[4,3-c]pyrazole 2H), 4.38 (d, 2H), carboxylic acid (3-hydroxy-oxetan 3.84 (s, 3H), 3.61 – ylmethyl)-amide (164) 3.53 (m, 5H). 1H-NMR (DMSO-d6): O O OH 494 O δ 8.32 (t, 1H), 8.03 2 [M+H]+ (dd, 1H), 7.85 (dd, O O O N 1H), 7.60 (d, 1H), N N N N B O 7.42 (s, 1H), 7.35 (dd, S 1H), 6.76 (s, 1H), 6.49 (d, 1H), 5.88 (s, 1H), 7-Methoxy(1-methyl-1H-pyrazol- N 5.55 (s, 2H), 4.48 (d, 3-yl)thiophenyl-1,4-dihydro- 2H), 4.38 (d, 2H), chromeno[4,3-c]pyrazole 3.84 (s, 3H), 3.77 (s, carboxylic acid (3-hydroxy-oxetan 3H), 3.56 (d, 2H). ylmethyl)-amide (165) m/z: 1H NMR (400 MHz, O N N CDCl3) δ 8.39 (s, 1H), O O 7.63 – 7.36 (m, 2H), O 505 7.35 – 7.31 (m, 2H), O B O 6.67 (s, 1H), 6.54 (s, N N [M+H]+ 1H), 5.50 (s, 2H), 4.13 N N N (s, 1H), 3.89 (s, 3H), S N 3.77 – 3.62 (m, 1H), N 3.21 (s, 1H), 3.16 – (2,2-Dimethyl-piperazinyl)-[7- 3.05 (m, 2H), 2.94 (s, y(1-methyl-1H-pyrazol 1H), 1.64 (s, 3H), 1.51 – 1.42 (m, 6H). yl)thiophenyl-1,4-dihydrochromeno [4,3-c]pyrazolyl]- methanone (169) m/z: 1H NMR (400 MHz, O N N CDCl3) δ 7.54 (dd, J = O O O 8.0, 2.4 Hz, 2H), 7.27 B 504 (d, J = 5.0 Hz, 1H), O O N 7.05 (s, 1H), 7.00 (s, N 1H), 6.64 (s, 1H), 6.55 N [M+H]+ N N (d, J = 2.2 Hz, 1H), S 6.03 (d, J = 1.7 Hz, N 1H), 5.48 (s, 2H), 4.28 (2,2-Dimethyl-piperazinyl)-[7- (s, 2H), 3.89 (s, 3H), methoxy(1-methyl-1H-pyrrol 3.66 (s, 3H), 3.34 (s, yl)thiophenyl-1,4-dihydro- 2H), 3.07 (s, 2H), 1.69 chromeno[4,3-c]pyrazolyl]- (s, 6H). one (170) 1H NMR (400 MHz, O m/z: O CDCl3) δ 8.26 (s, 1H), O N O 7.61 – 7.46 (m, 3H), O N 503 O 7.35 – 7.31 (m, 1H), N N B O 6.67 (s, 1H), 6.54 (s, N N N [M+H]+ 1H), 5.54 (s, 2H), 4.37 S N (m, 2H), 3.93 – 3.85 N N (m, 6H), 3.20 – 2.99 (4,7-Diaza-spiro[2.5]octyl)-[7- (m, 4H), 1.16 – 0.95 methoxy(1-methyl-1H-pyrazol (m, 4H). yl)thiophenyl-1,4-dihydrochromeno [4,3-c]pyrazolyl]- methanone (171) 1H-NMR (DMSO-d6): O O H N OH m/z = O 2 δ 8.11 (d, 1H), 8.00 (s, 492 1H), 7.84 (s, 1H), 7.60 O [M+H]+ (s, 1H), 7.42 (s, 1H), N N N N N O B O 7.34 (s, 1H), 6.76 (s, S 1H), 6.49 (s, 1H), 5.54 (s, 2H), 4.75 (s, 1H), 7-Methoxy(1-methyl-1H-pyrazol- N 4.32 (s, 1H), 4.15 (s, 3-yl)thiophenyl-1,4-dihydro- N 1H), 3.84 (s, 3H), 3.78 chromeno[4,3-c]pyrazole (s, 3H), 2.06-1.85 (m, carboxylic acid ((1S,3R)hydroxy- 2H), 1.78-1.53 (m, cyclopentyl)-amide (172) 4H).

O O 1H-NMR (DMSO-d6): O H N OH m/z = 2 δ 8.14 – 8.04 (m, 2H), O 491 7.91 (s, 1H), 7.39 (s, N B N N [M+H]+ 1H), 7.00 (s, 1H), 6.80 N O O N (s, 1H), 6.71 (s, 1H), S 6.63 (s, 1H), 5.78 (s, 1H), 5.50 (s, 2H), 4.75 7-Methoxy(1-methyl-1H-pyrrol (s, 1H), 4.33 (s, 1H), thiophenyl-1,4-dihydro- 4.15 (s, 1H), 3.84 (s, chromeno[4,3-c]pyrazole 3H), 3.59 (s, 3H), carboxylic acid ((1S,3R)hydroxy- 2.06-1.84 (m, 2H), cyclopentyl)-amide (173) 1.78-1.52 (m, 4H).

O O 1H-NMR (DMSO-d6): O O m/z = δ 7.96 (s, 1H), 7.84 (s, O 504 1H), 7.60 (s, 1H), 7.49 O [M+H]+ N N N N (s, 1H), 7.32 (s, 1H), B O N 6.78 (s, 1H), 6.50 (s, S 1H), 5.55 (s, 2H), 5.45 N (s, 2H), 4.31 (s, 2H), [7-Methoxy(1-methyl-1H-pyrazol- N 3.91 (s, 2H), 3.85 (s, 3-yl)thiophenyl-1,4-dihydro- 3H), 3.78 (s, 3H), 2.29 chromeno[4,3-c]pyrazolyl]-(2-oxa- (s, 2H), 1.75 (s, 2H). -aza-spiro[3.4]octyl)-methanone (174) 1H-NMR (DMSO-d6): O O O m/z = δ 8.01 (s, 1H), 7.89 (d, O O 505 1H), 7.37 (s, 1H), 7.00 B N [M+H]+ (s, 1H), 6.85 (s, 1H), N N N N O N 6.71 (s, 1H), 6.63 (s, 1H), 5.80 (s, 1H), 5.44 S (s, 2H), 4.88 (s, 1H), 4.10 (s, 1H), 3.91 – roxymethylmethyl- 3.80 (m, 5H), 3.59 (s, pyrrolidinyl)-[7-methoxy(1- 4H), 2.15-2.06 (m, methyl-1H-pyrrolyl)thiophen 1H), 1.89-1.72 (m, yl-1,4-dihydro-chromeno[4,3- 2H), 1.64-1.54 (m, c]pyrazolyl]-methanone (176) 1H), 1.40 (s, 3H).

O 1H-NMR (DMSO-d6): OH m/z = δ 8.06 (dd, 1H), 7.91 O O H N 507 (dd, 1H), 7.80 (s, 1H), O B [M+H]+ 7.39 (dd, 1H), 7.00 (t, N O N N N N O 1H), 6.81 (s, 1H), 6.71 (s, 1H), 6.63 (t, 1H), O 5.78 (dd, 1H), 5.49 (s, 7-Methoxy(1-methyl-1H-pyrrol 2H), 5.10 (s, 1H), 3.91 – 3.75 (m, 8H), 3.63 – yl)thiophenyl-1,4-dihydro- 3.56 (m, 5H), 2.35- chromeno[4,3-c]pyrazole 2.27 (m, 1H), 2.02- carboxylic acid [3-(2-hydroxy-ethyl)- 1.93 (m, 1H). oxetanyl]-amide (186) O O 1H-NMR (DMSO-d6): O m/z = δ 8.23 (s, 1H), 8.02 O 494 (dd, 1H), 7.86 (dd, O N N B [M+H]+ 1H), 7.60 (d, 1H), N O O 7.42 (s, 1H), 7.34 (dd, S O 1H), 6.76 (s, 1H), 6.49 (d, 1H), 5.54 (s, 2H), [8-(3,6-Dihydro-2H-pyranyl) 5.18 (s, 1H), 3.84 (s, methoxythiophenyl-1,4- 3H), 3.77 (s, 3H), o-chromeno[4,3-c]pyrazol 3.44-3.36 (m, 4H), yl]-(3,3-dimethyl-morpholinyl)- 1.05 (s, 3H). methanone (189) O O m/z = 1H-NMR (DMSO-d6): O O B 545 δ 8.04 (dd, 1H), 7.97 N N N O N (s, 1H), 7.91 (dd, 1H), N N N N [M+H]+ O 7.39 (dd, 1H), 7.28 (s, S O 1H), 6.85 (s, 1H), 6.79 N (s, 1H), 5.41 (s, 2H), N 4.38 (t, 2H), 3.99 – 3-{4-[3-(3,3-Dimethyl-morpholine 3.94 (m, 2H), 3.87 (s, carbonyl)methoxythiophen 3H), 3.76 – 3.71 (m, yl-1,4-dihydro-chromeno[4,3- 2H), 3.43 (s, 2H), 3.06 c]pyrazolyl]-pyrazolyl}- (t, 2H), 1.43 (s, 6H). propionitrile (190) O O 1H-NMR (DMSO-d6): m/z = O δ 8.04 (dd, 1H), 7.92 O 534 B (dd, 1H), 7.78 (s, 1H), N N N N O [M+H]+ 7.39 (dd, 1H), 7.26 (s, N N N N O 1H), 6.82 (s, 1H), 6.76 O (s, 1H), 5.41 (s, 2H), 4.48 (septet, 1H), 3.97 (3,3-Dimethyl-morpholinyl)-[8-(1- (t, 2H), 3.86 (s, 3H), isopropyl-1H-pyrazolyl) 3.73 (t, 2H), 3.43 (s, methoxythiophenyl-1,4- 2H), 1.44 – 1.39 (m, 12H). dihydro-chromeno[4,3-c]pyrazol yl]-methanone (191) O O 1H-NMR (DMSO- m/z = O O d6): δ 8.04 (dd, 1H), B 7.91 (dd, 1H), 7.78 N N N [M+H]+ N N O N (s, 1H), 7.39 (dd, N N O 1H), 7.25 (s, 1H), S O 6.83 (s, 1H), 6.77 (s, 1H), 5.40 (s, 2H), imethyl-morpholinyl)-[8-(1- 3.99 – 3.94 (m, 2H), isobutyl-1H-pyrazolyl) 3.91 – 3.84 (m, 5H), methoxythiophenyl-1,4- 3.76 – 3.71 (m, 2H), o-chromeno[4,3-c]pyrazol 3.43 (s, 2H), 2.08 yl]-methanone (192) (septet, 1H), 1.43 (s, 6H), 0.84 (d, 6H). 1H-NMR (DMSO-d6): O O O m/z = δ 8.05 (dd, 1H), 7.92 O 534 (dd, 1H), 7.78 (s, 1H), O N 7.39 (dd, 1H), 7.26 (s, N N N N [M+H]+ N N N 1H), 6.82 (s, 1H), 6.76 S O (s, 1H), 5.41 (s, 2H), 4.48 (septet, 1H), 4.00 (3,3-Dimethyl-morpholinyl)-[8-(1- – 3.94 (m, 2H), 3.86 isopropyl-1H-pyrazolyl) (s, 3H), 3.76 – 3.71 methoxythiophenyl-1,4- (m, 2H), 3.43 (s, 2H), 1.45 – 1.39 (m, 12H). dihydro-chromeno[4,3-c]pyrazol yl]-methanone (195) 1H-NMR (DMSO-d6): O O m/z = O O δ 8.04 (dd, 1H), 7.92 N 605 O – 7.85 (m, 2H), 7.39 N N N N N [M+H]+ (dd, 1H), 7.22 (s, 1H), N O 6.83 (s, 1H), 6.77 (s, S O O 1H), 5.40 (s, 2H), 4.20 N (t, 2H), 3.99 – 3.94 (m, 2H), 3.86 (s, 3H), (3,3-Dimethyl-morpholinyl)-{7- 3.76 – 3.71 (m, 2H), 3.58 – 3.53 (m, 4H), methoxy[1-(2-morpholinyl- 3.42 (s, 2H), 2.71- ethyl)-1H-pyrazolyl]thiophen- 2.65 (m, 2H), 2.43 – 3-yl-1,4-dihydro-chromeno[4,3- 2.38 (m, 4H), 1.42 (s, c]pyrazolyl}-methanone (202) 6H). 1H-NMR (DMSO-d6): O O O m/z = δ 8.04 (dd, 1H), 7.91 O (dd, 1H), 7.82 (s, 1H), N B N 563 N N O N N [M+H]+ 7.39 (dd, 1H), 7.23 (s, N N 1H), 6.82 (s, 1H), 6.76 O N O S (s, 1H), 5.40 (s, 2H), N 4.16 (t, 2H), 3.98 – {8-[1-(2-Dimethylamino-ethyl)-1H- 3.94 (m, 2H), 3.86 (s, pyrazolyl]methoxythiophen- 3H), 3.76 – 3.71 (m, 3-yl-1,4-dihydro-chromeno[4,3- 2H), 3.42 (s, 2H), 2.62 (t, 2H), 2.16 (s, 6H), c]pyrazolyl}-(3,3-dimethyl- 1.42 (s, 6H). linyl)-methanone (203) O O 1H-NMR (DMSO-d6): O m/z = O δ 7.98 (dd, 1H), 7.79 B (dd, 1H), 7.34 (dd, N N O N [M+H]+ N N N N 1H), 6.77 (s, 1H), 6.46 O (s, 1H), 5.40 (s, 2H), S O 3.97 – 3.91 (m, 4H), 3.75 – 3.70 (m, 5H), (3,3-Dimethyl-morpholinyl)-[8-(1- 3.42 (s, 2H), 1.92 (s, ethyl-3,5-dimethyl-1H-pyrazolyl)- 3H), 1.82 (s, 3H), 1.42 7-methoxythiophenyl-1,4- (s, 6H), 1.27 (t, 3H). dihydro-chromeno[4,3-c]pyrazol yl]-methanone (204) O O 580 1H-NMR (DMSO-d6): O O [M+H]+ δ 8.04 (dd, 1H), 7.90 N B N O (dd, 1H), 7.83 (s, 1H), N N N N N 7.38 (dd, 1H), 7.25 (s, S O O O 1H), 6.83 (s, 1H), 6.77 O O (s, 1H), 5.40 (s, 2H), O 4.52 (s, 2H), 4.26 (t, (3,3-Dimethyl-morpholinyl)-{7- 2H), 3.96 (t, 2H), 3.86 methoxy[1-(2-methoxymethoxy- (s, 3H), 3.80 (t, J = 5.3 ethyl)-1H-pyrazolyl]thiophen- Hz, 2H), 3.73 (t, 2H), ,4-dihydro-chromeno[4,3- 3.42 (s, 2H), 3.16 (s, c]pyrazolyl}-methanone (205) 3H), 1.42 (s, 6H).

O O m/z = 1H-NMR (DMSO-d6): O O 589 δ 8.04 (dd, 1H), 7.90 N O N [M+H]+ (dd, 1H), 7.83 (s, 1H), N N N N N O 7.39 (dd, 1H), 7.23 (s, 1H), 6.83 (s, 1H), 6.76 N (s, 1H), 5.40 (s, 2H), 4.18 (t, 2H), 3.98-3.94 (m, 2H), 3.86 (s, 3H), imethyl-morpholinyl)-{7- 3.75 – 3.71 (m, 2H), methoxy[1-(2-pyrrolidinyl- 3.42 (s, 2H), 2.79 (t, -1H-pyrazolyl]thiophen- 2H), 2.47-2.43 (m, 3-yl-1,4-dihydro-chromeno[4,3- 4H), 1.69-1.64 (m, c]pyrazolyl}-methanone (206) 4H), 1.42 (s, 6H). 1H-NMR (DMSO-d6): O O m/z = O δ 8.03 (dd, 1H), 7.90 O 532 B (dd, 1H), 7.79 (s, 1H), N O N N [M+H]+ N 7.38 (dd, 1H), 7.26 (s, N N N N O 1H), 6.82 (s, 1H), 6.77 (s, 1H), 6.06-5.95 (m, S O 1H), 5.40 (s, 2H), [8-(1-Allyl-1H-pyrazolyl) 5.24-5.11 (m, 2H), methoxythiophenyl-1,4- 4.73 (d, 2H), 3.98 – dihydro-chromeno[4,3-c]pyrazol 3.94 (m, 2H), 3.85 (s, yl]-(3,3-dimethyl-morpholinyl)- 3H), 3.75 – 3.71 (m, 2H), 3.42 (s, 2H), 1.42 methanone (207) (s, 6H). 1H-NMR (DMSO-d6): O O m/z = O δ 8.04 (dd, 1H), 7.91 N 564 O (dd, 1H), 7.80 (s, 1H), N N N N [M+H]+ 7.39 (dd, 1H), 7.23 (s, N N N O O 1H), 6.83 (s, 1H), 6.77 S O (s, 1H), 5.40 (s, 2H), O 4.12 (t, 2H), 3.99 – (3,3-Dimethyl-morpholinyl)-{7- 3.94 (m, 2H), 3.86 (s, methoxy[1-(3-methoxy-propyl)- 3H), 3.76 – 3.70 (m, 2H), 3.42 (s, 2H), 3.29 1H-pyrazolyl]thiophenyl- – 3.23 (m, 5H), 1.98 1,4-dihydro-chromeno[4,3-c]pyrazol- (quintet, 2H), 1.42 (s, 3-yl}-methanone (208) 6H). 1H-NMR (DMSO- O O m/z = O 578 d6): δ 8.04 (dd, 1H), N N [M+H]+ 7.90 (dd, 1H), 7.80 N O N N N N O (s, 1H), 7.39 (dd, O N 1H), 7.26 (s, 1H), S O O O 6.82 (s, 1H), 6.77 (s, O 1H), 5.40 (s, 2H), (3,3-Dimethyl-morpholinyl)-[8-(1- 5.14 (t, 1H), 4.22 (d, [1,3]dioxolanylmethyl-1H- 2H), 3.99 – 3.94 (m, pyrazolyl)methoxythiophen- 2H), 3.88 – 3.81 (m, 3-yl-1,4-dihydro-chromeno[4,3- 7H), 3.76 – 3.71 (m, c]pyrazolyl]-methanone (209) 2H), 3.42 (s, 2H), 1.42 (s, 6H). 1H-NMR (DMSO- O O m/z = O O d6): δ 8.04 (dd, 1H), N 520 B 7.91 (dd, 1H), 7.81 [M+H]+ N N O O (s, 1H), 7.38 (dd, N N N N N 1H), 7.22 (s, 1H), S O 6.83 (s, 1H), 6.76 (s, 1H), 5.40 (s, 2H), 4.14 – 4.06 (m, 6H), (3,3-Dimethyl-morpholinyl)-[8-(1- 3.98 – 3.94 (m, 2H), ethyl-1H-pyrazolyl)methoxy 3.86 (s, 3H), 3.76 – thiophenyl-1,4-dihydro- 3.71 (m, 2H), 3.42 no[4,3-c]pyrazolyl]- (s, 2H), 1.42 (s, methanone (210) 6H), 1.36 (t, 3H). m/z = 1H-NMR (DMSO- O O 534 d6): δ 8.04 (dd, 1H), O O B N [M+H]+ 7.91 (dd, 1H), 7.80 N N N N O (s, 1H), 7.39 (dd, N N N O 1H), 7.23 (s, 1H), S O 6.83 (s, 1H), 6.76 (s, 1H), 5.40 (s, 2H), 4.03 (t, 2H), 3.99 – (3,3-Dimethyl-morpholinyl)-[7- 3.94 (m, 2H), 3.86 methoxy(1-propyl-1H-pyrazol (s, 3H), 3.76 – 3.71 yl)thiophenyl-1,4-dihydro- (m, 2H), 3.42 (s, chromeno[4,3-c]pyrazolyl]- 2H), 1.77 (sextet, methanone (211) 2H), 1.42 (s, 6H), 0.82 (t, 3H). 1H-NMR (DMSO- O O m/z = d6): δ 7.94 (dd, 1H), O 548 N 7.76 (dd, 1H), 7.30 N [M+H]+ (dd, 1H), 6.84 (s, N N N N N O N 1H), 6.55 (s, 1H), S O B O 5.76 (s, 1H), 5.43 (s, 2H), 3.96 – 3.91 (m, (3,3-Dimethyl-morpholinyl)-[7- O 2H), 3.77 – 3.70 (m, methoxy(5-methylpropyl-2H- 5H), 3.60 (t, 2H), pyrazolyl)thiophenyl-1,4- 3.42 (s, 2H), 2.12 (s, dihydro-chromeno[4,3-c]pyrazol 3H), 1.54 (sextet, thanone (212) 2H), 1.42 (s, 6H), 0.62 (t, 3H).

O O m/z = 1H-NMR (DMSO- O N 520 d6): δ 7.96 (dd, 1H), N N [M+H]+ 7.77 (dd, 1H), 7.40 N B O O (d, 1H), 7.32 (dd, N N N N 1H), 6.87 (s, 1H), S O 6.56 (s, 1H), 5.97 (d, 1H), 5.45 (s, imethyl-morpholinyl)-[8-(2- 2H), 3.97 – 3.93 (m, ethyl-2H-pyrazolyl)methoxy 2H), 3.80 – 3.71 (m, thiophenyl-1,4-dihydro- 7H), 3.42 (s, 2H), chromeno[4,3-c]pyrazolyl]- 1.42 (s, 6H), 1.17 (t, methanone (213) 3H).

Example 8 7-Methoxy(2-methyl-propenyl)thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazolecarboxylic acid methyl-[2-(2-oxo-oxazolidinyl)-ethyl]-amide (23) O O O O O + I + Na O O O N N N N O N N O S N S N To 7-methoxy(2-methyl-propenyl)thiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarboxylic acid [2-(2-oxo-oxazolidinyl)-ethyl]-amide (22.00 mg; 0.04 mmol; 1.00 eq.) was added N,N-Dimethyl-formamide (0.50 ml) and sodium hydride (2.67 mg; 0.07 mmol; 1.50 eq.). Reaction was stirred at RT for 10 min then iodomethane (0.00 ml; 0.05 mmol; 1.10 eq.) (1 drop) was added and the reaction was d at RT for 15 min. Water was added and product was extracted with EtOAc and washed with water. Organic layer was dried, filtered, concentrated. e was dried on high vacuum then lyophilized to afford the desired product (22.5mg, 99%) as an off white solid. 1H NMR (400 MHz, CDC13) 5 7.56 — 7.42 (m, 2H), 7.24 (d, J: 4.9 Hz, 1H), 6.73 (d, J = 4.0 Hz, 1H), 6.57 (d, J: 2.8 Hz, 1H), 6.12 (s, 1H), 5.55 (s, 1H), 5.51 (s, 1H), 4.38 — 4.31 (m, 1H), 4.20 — 4.10 (m, 2H), 3.82 (s, 3H), 3.81 — 3.72 (m, 2H), 3.62 — 3.55 (m, 3H), 3.53 (s, 1H), 3.46 — 3.38 (m, 1H), 3.17 (s, 1H), 1.85 (s, 3H), 1.53 (d, J: 3.8 Hz, 3H). m/z: 509 [M+H]+ The following compounds were prepared using procedures analogous to those disclosed in example 8 above: compound LC/MS I H NMR (400 MHZ, CDC13) 0 8 7.60 _ 7.47 (m, 2H), 7.26 (dd, J: 5.0, 1.4 Hz, 1H), 6.61 / 0 A (s, 1H), 6.41 (d, J: 3.6 Hz, sj N 1H), 5.54 _ 5.45 (m, 2H), / _\_N/ 4.10 — 4.00 (m, 1H), 3.98 — 0 3.86 (m, 1H), 3.84 (s, 3H), 3.60 — 3.51(m, 1H), 3.51 — 3.42 (m. 2H), 3.33 — 3.25 (m, 8-Isopropoxymethoxy-1— 1H), 3.15 _ 3.10 (m, 1H), thiophen—3—yl—1,4—dihydro- 2.95 (s, 3H), 2.73 (s, 2H), no[4,3—c]pyrazole-3— 2.42 — 2.23 (m, 2H), 2.23 — carboxylic acid [2- 2.04 (m, 2H), 2.04 _ 1.79 (m, (cyclobutanecarbonyl—methyl- 2H), 1.22 (d, J: 6.1 Hz, 6H). amino)-ethyl]—methyl-amide (29) Ox. 1H NMR (400 MHz, CDC13) 7.59 — 7.44 (m, 2H), 7.26 (dd, J: 5.0, 1.4 Hz, 1H), 6.61 (s, 1H), 6.44 _ 6.32 (m, 1H), .59 — 5.36 (m, 2H), 4.10 — 4.01 (m, 1H), 3.91 (dd, J: 19.2, 11.5 Hz, 2H), 3.84 (s, 3H), 3.59 — 351(m, 1H). 3.47 (dd, J: 19.7, 6.8 Hz, 8-Isopropoxy-7—methoxy 2H), 3.38 (t, J = 7.2 Hz, 1H), 3.33 — 3.26 (m, 1H), 3.16 — thiophen—3—yl—1,4—dihydro— 3.06 (m, 3H), 2.95 (s, 2H), chromeno[4,3-c]pyrazole 2.73 (s, 1H), 2.43 — 2.22 (m, carboxylic acid [3— 2H), 2.21 — 2.06 (m, 2H), (cyclobutanecarbonyl-methyl- WO 09980 amino)-propyl]-methyl-amide 2.06 2 1.76 (m, 2H), 1.22 (d, (30) J: 6.1 Hz, 6H).

I / m/z: 482 1H NMR (400 MHz, CDC13) O O O 6 7.52 (dd, J = 3.2, 1.4 Hz, O [M+H]+ 1H), 7.46 (dd, J = 5.1, 3.2 Hz, / 0 / / o / 1H), 7.23 (dd, J=5.1, 1.4 Hz, , MK NcN 1H), 6.74 (s, 1H), 6.58 (s, N\N {:f N‘K 8g\ 0 1H), 6.12 (s, 1H), 5.45 (s, 0\ 2H), 3.82 (s, 3H), 3.78 (s, 2H), 3.39 (s, 3H), 3.33 (s, 3H), 1.85 (s, 3H), 1.53 (d, J: 7-Meth0Xy(2-methy1- 1.1 Hz, 3H), 1.51 (s, 6H). propeny1)thiophen-3—y1—1,4- dihydro-chromeno[4,3- c]pyrazole—3—carb0xylic acid (2-methoxy-1,1—dimethyl- ethy1)-methyl—amide (31) I H NMR (400 MHz, CDC13) O 6 7.57 — 7.46 (m, 2H), 7.27 — 7.19 (m, 1H), 6.74 (s, 1H), / // O 6.57 (s, 1H), 6.12(s, 1H), N\N N 5.61 — 5.50 (m, 2H), 3.97 — SS / /N-< 3.87 (m, 2H), 3.82 (s, 3H), 3.53 (dd, J = 23.0, 9.4 Hz, 4H), 3.38 (d, J: 6.5 Hz, 2H), 3.28 (s, 1H), 3.12 (d, J: 7.8 7-M6th0Xy(2-methyl- Hz, 3H), 2.97 (d, J = 5.7 Hz, propeny1)—1—thi0pheny1—1,4- 2H), 2.81 (d, J: 12.9 Hz, dihydro—chromeno[4,3— 1H), 1.85 (s, 3H), 1.53 (s, c]pyrazole-3—carboxylic acid 3H). etyl-methyl-amino)- propyl] -methy1-amide (32) i 1H NMR (400 MHz, CDC13) o 8 7.57 — 7.45 (m, 2H), 7.27 _ 7.22 (m, 1H), 6.72 (d, J: l // O 13.8 Hz, 1H), 6.58 (s, 1H), N‘N N 6.12 (S, 1H), 5.54 (d, J: 10.5 8g\ / _\—\ 0 Hz, 2H), 4.40 — 4.34 (m, 1H), {j k, 4.05 — 3.93 (m, 2H), 3.82 (s, 3H), 3.69 — 3.63 (m, 1H), 7-Meth0xy-8—(2-methy1- 3.62 — 3.55 (m, 1H), 3.50 (s, propeny1)—1—thiophen—3-y1—1,4— 2H), 3.43 — 3.28 (m, 3H), dihydro—chromeno[4,3— 3-13 (S, 2H), 2-06 7 194011, c]pyrazole—3-carboxylic acid 1H): 1-85 (S, 3H), 1-53 (S, methyl-[3—(2—oxo-oxazolidin— 3H)- 3-y1)—propy1]—amide (33) 1H NMR (400 MHz, CDC13) £95.54\N 8 7.58 — 7.45 (m, 2H), 7.27 _ 7.17 (m. 1H), 6.74 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), .59 — 5.50 (m, 2H), 4.08 (dd, /N—\_N/ J: 13.5, 6.1 Hz, 1H), 3.82 (s, o)— 3H), 3.67 (dd, J: 13.2, 7.7 Hz, 3H), 3.54 (d, J: 5.3 Hz, 7-Meth0xy—8-(2-methy1- 1H), 3.20 — 3.11 (m, 3H), propeny1)—1—thiopheny1— 1,4- 2.88 (d, J: 2.8 Hz, 3H), 1.97 d1hydro—chromeno[4,3— (s, 2H), 1.85 (s, 3H), 1.52 (d, c]pyrazole—3—carb0xylic acid J: 8.4 Hz, 3H). etyl—methyl—amino)- ethyl] —methyl—amide (34) H NMR (400 MHz, CDC13) 6 7.53 — 7.43 (m, 2H), 7.24 (d, J: 5.0 Hz, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.62 (d, J: 1.6 Hz, 2H), 4.33 — 4.15 (In, 2H), 4.05 (t, J = 9.9 Hz, 2H), 3.82 (s, 3H), )Vo 3.80— 3.66 (111, 2H), 2.14— D 1.92 (m, 1H), 1.85 (s, 3H), [7-Meth0xy(2-methyl- 1.54 (s, 3H). propeny1)-1—thiophen—3-y1-1,4- dihydro-chromen0[4,3- C]pyraz01-3—y1]-(3-meth0xyd3-pyrrolidin -methan0ne H NMR (400 MHZ, CDC13) 8 7.53 — 7.42 (m, 2H), 7.23 (d, J: 5.0 Hz, 1H), 6.73 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.56 (s, 2H), 4.23 — 4.14 (In, 1H), 3.99 (dd, J: 17.8, 7.9 HZ, 2H), 3.82 (S, 3H), 3.71 (d, J: 9.5 HZ, 1H), 2.22 (2-Meth0xy-d3-methyl (dd, J = 13.5, 6.8 Hz, 1H), methyl-pyrrolidin—1—y1)-[7- 1-91 (C111: 6-6 HZ, 2H), 1-85 methoxy-S-(2-methyl- (S, 3H), 1.71 (dd, J: 12.4, 6‘4 HZ” 1H)” 1‘54 (S’ 6H)‘ propeny1)—1-thiopheny1—1,4- d1hydr0—chromeno[4,3— c]pyrazol—3—yl]-methanone (51) m/z: 512 1H NMR (400 MHZ, CDC13) [M+H]+ 8 7.56 _ 7.45 (m, 2H), 7.24 (d, J: 4.7 Hz, 1H), 6.73 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.53 (d, J: 17.1 Hz, 2H), 4.35 (t, J = 8.0 Hz, 1H), 4.22 _ 4.11 (m, 2H), 3.82 (s, 3H), 3.81 — 3.72 (m, 2H), 3.62 — 3.53 (m, 2H), 3.42 (t, J 7-Methoxy(2-methy1-d3- = 7.8 Hz, 1H), 1.85 (s, 3H), y1)thiophenyl-1,4- 1.53 (s, 3H). d1hydr0—chromeno[4,3— c]pyrazole—3—carboxy1ic acid methyl-d3-[2-(2-oxo- oxazolidiny1)-ethy1]-amide (56) / I m/z: 488 1H NMR (400 MHZ, CDC13) O O O O [M+H]+ 8 7.52 (s, 1H), 7.46 (s, 1H), 7.23 (d, J: 4.8 Hz, 1H), 6.74 / / O / / (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.45 (s, 2H), 3.83 (5, N Nw/ Sir N‘K Sir /a 0 0 3H), 3.78 (S, 2H), 1.85 (S, D D 3H), 1.55 — 1.48 (m, 9H).

D )8 D 7—Meth0xy—8—(2—methy1—d3— propeny1)-1—thi0pheny1—1,4- dihydro-chromen0[4,3- c]pyrazolecarboxy1ic acid (2-mcth0xy—d3- 1 , 1 -dimethy1— ethy1)-methyl-amide (58) H NMR (400 MHz, CDC13) 0 6 7.56 — 7.45 (m, 2H), 7.25 (d, J: 4.9 Hz, 1H), 6.96 (s, / / 0 1H), 6.69 (s, 1H), 6.57 (s, 1H), 6.11 (s, 1H), 5.62 (s, 2H), 3.82 (S, 3H), 3.52 (s, 2H), 1.85 (s, 3H), 1.52 (s, D D 3H), 1.48 (s, 6H). 7-Methoxy—8-(2-methy1- propeny1)—1-thiophcny1—1,4- dihydro—chromen0[4,3— c]pyrazole—3-carboxylic acid hoxy—d3-1,1-dimethyl— ethy1)—amide (59) / I m/z: 484 1H NMR (400 MHz, CDC13) O O Mo o [M+H]+ 8 7.98 (s, 1H), 7.59 _ 7.43 / O (m, 2H), 7.24 (d, J: 4.8 Hz, 1H), 6.76 _ 6.66 (m, 1H), D W—fl / D \ —\_ 6.57 (s, 1H), 6.12 (s, 1H), SSS/N\N N_\_N7<D Sq )— 5.50 (s, 2H), 4.01 — 3.87 (m, / >_ 0 1H), 3.82 (s, 3H), 3.62 _ 3.41 o (m, 3H), 2.02 (s, 3H), 1.85 (s, 3H), 1.52 (s, 3H). 7-Methoxy—8—(2-methy1- propeny1)—1—thi0pheny1—1,4- o—chromeno[4,3— c]pyrazole-3—carboxylic acid [2—(acetyl—methyl—d3—amino)— eth 1]-amide (60) H NMR (400 MHz, CDC13) 8 7.51 (dd, J: 14.6, 7.7 Hz, 2H), 7.24 (d, J = 4.9 Hz, 1H), 6.73 (d, J: 5.1 HZ, 1H), 6.57 (s,1H),6.12(s, 1H), 5.53 (dd, J = 16.7, 6.7 Hz, 2H), 4.09 (t, J: 6.9 HZ, 1H), 3.82 (s, 3H), 3.67 (d, J: 19.2 Hz, 3H), 2.00 (s, 3H), 1.85 (s, 7-Methoxy(2-methy1- 3H), 1.56 — 1.46 (m, 3H). propeny1)thiopheny1—1,4- dihydro—Chromeno[4,3— c]pyrazole—3-carboxylic acid [2-(acetyl—methyl—d3—amin0)— —methy1—d3-amide (61) l H NMR (400 MHZ, CDC13) 7.54 (dd, J = 29.4, 18.4 Hz, 2H), 7.25 (d, J: 4.3 HZ, 1H), I ’ O 6.87 _ 6.68 (m, 1H), 6.59 (s, SS N 1H), 6.12 (s, 1H), 5.62 (s, D _\—\ 0 1H), 5.53 (d, J: 6.8 Hz, 1H), D D D7? 400— 3.92 (m, 1H), 3.80 (s, D D 3H), 3.67 — 3.59 (m, 1H), 3.55 — 3.38 (m, 1H), 3.37 — 3.23 (m, 2H), 3.07 (dd, J: 7—Meth0xy—8—(2—methy1— 16.1, 8.8 Hz, 1H), 2.89 (s, propeny1)-1—thiopheny1—1,4- 1H), 2.30 (dd, J: 18.3, 9.1 dihydro-chromen0[4,3— Hz, 1H), 2.19 (d, J: 8.0 Hz, c]pyrazolecarboxylic acid 2H), 2.07 — 1.70 (m, 6H), [3-(cyc10butanecarbony1— 1.48 (s, 3H). methyl-d3-amino)-propy1]- methyl-d3-amide (69) g (1 m/z: 541 1H NMR (400 MHz, CDC13) D o o [M+H]+ 87.66(s,1H),7.60—7.53 D09V! \ / o O (In, 2H), 7.38 (d, J: 9.2 Hz, O N\ \ / / N- 0 N / 1H) 7 7.29 (s 7 1H) 7 6.99 (s 7 s:( D14N_\—N>\j 1H), 6.65 (d, J: 4.5 Hz, 1H), D D SCrN‘N / :j 5.56 (d, J: 16.4 Hz, 2H), 7-Meth0Xy(1-methy1-d3- 4.39 — 4.32 (m, 1H), 4.23 — 1H—pyrazol—4-y1)—1—thiophen- 4.13 (m, 2H), 3.91 (s, 3H), ,4—dihydr0— 3.83 — 3.74 (m, 2H), 3.63 — chromeno[4,3-C]pyrazole 3.53 (m, 2H), 3.49 — 3.41 (m, carboxylic acid methyl-d3—[2- 1H). (2-0X0-oxazolidiny1)-ethy1]- amide (78) H-NMR (DMSO-d6): 5 7.95 (d, 1H), 7.82 (s, 1H), 7.37 — 7.28 (m, 1H), 6.66 (d, 1H), 6.47 — 6.40 (m, 1H), 5.40— .32 (m, 2H), 4.06—3.98 (In, 1H), 3.76 (s, 3H), 3.63 — 3.44 (m, 3H), 2.15 (d, 2H), 1.99 (d, 1H), 1.82 (d, 2H), 1.62 8-180buty1meth0Xy (septet, 1H), 0.74 (d, 6H). thiophen-3—yl-1,4—dihydro— chromeno[4,3-C]pyrazole carboxylic acid ety1— methyl-d3—amino)-ethy1]— methyl-d3-amide (82) 1H—NMR (DMSO-d6): 5 7.96 (s, 1H), 7.82 (s, 1H), 7.34 (s, 1H), 6.66 (d, 1H), 6.44 (d, 1H), 5.35 (s, 2H), 4.23 (s, 1H), 4.06 (s, 2H), 3.76 (s, 3H), 3.71—3.59 (d, 2H), 3.50- 3.38 (m, 3H), 2.15 (d, 2H), 8-Isobuty1—7-methoxy 1.69 — 1.55 (m, 1H), 0.75 (d, thiopheny1—1,4—dihydro- 6H). chromeno[4,3—C]pyrazole-3— carboxylic acid methyl-d3-[2- (2-0X0—0Xazolidin-3—y1)—ethy1]- amide (214) H—NMR (DMSO—d6): 5 7.91 (s, 1H), 7.81 (s, 1H), 7.30 (s, 1H), 6.66 (s, 1H), 6.44 (s, 1H), 5.31 (s, 2H), 3.76 (s, 3H), 3.64 (s, 2H), 2.13 (d, 2H), 1.69 —1.55 (m, 1H), 1.41 (s, 6H), 0.74 (d, 6H). 8-Isobuty1methoxy thiopheny1—1,4—dihydro- chromeno[4,3-c]pyrazole-3— carboxylic acid (2—methoxy— d3— 1, 1-dimethy1—ethy1)—methy1— d3-amide (83) (I) m/Z 2 1H—NMR (DMSO-d6): 5 o 517 8.01-7.92 (m, 1H), 7.82 (s, // [M+H]+ 1H), 7.39-7.29 (In, 1H), 6.66 M N’\/\ J2 (s, 1H), 6.47 — 6.40 (m, 1H), s/j N .38 (s, 2H), 3.77 (s, 4H), 3.50 — 3.38 (m, 1H), 3.27— 3.17 (m, 1H), 2.15 (d, 2H), 8-180buty1m6th0Xy 2.01 — 1.56 (m, 6H), 0.74 (d, thiophcn—3-y1—1,4—dihydr0- 6H). no[4,3-c]pyrazolc-3— carboxylic acid [3-(acety1— methyl—d3—amino)—§;;)py1]—meth mide( / (é m/z: 524 H NMR (400 MHz, CDC13) O ° O [M+H]+ 6 8.42 (s, 1H), 7.98 (s, 1H), )Y ELo ° \ “k—\ // 0 7.66 — 7.53 (m, 2H), 6.95 (s, “{N_ / 0 O SSW“ 78X?" 1H), 6.88 (s, 1H), 6.69 (dd, J / / D \J M DD = 10.0, 5.1 Hz, 1H),5.67— \ N—\_ >40 3g N\J 5.56 (m, 2H), 4.36 (t, J: 7.8 D D Hz, 2H), 4.24 — 4.13 (m, 2H), 7-Methoxy(1H—pyrazol 394(81 3H), 3.85 - 3.74011, y1)—1—thiophcn-3—y1—1,4- 2H), 3-63 - 3-55 (m, 2H)- dihydro—chromcn0[4,3— c]pyrazolecarboxylic acid methyl-d3-[2-(2-oxo— oxazolidin-3—y1)-ethy1] -amide (85) / / m/z = 1H—NMR d6): 5 8.38 0 O O 484 (t, 0.3H), 8.04 — 7.78 (m, 3H), 7.40 — 7.31 (m, 1H), 6.69 — / o [M+H]+ / / o / 6.57 (m, 2H), 6.03 (s, 1H), .53 — 5.36 (m, 2H), 3.93 (t. 1H), 3.75 (s, 3H), 3.49 (t, 1H), 3.30 _3.15 (m, 6H), 1.84 — 1.72 (m, 5H), 1.62 (s, 7-Meth0xy(2-methy1- 1H), 1.43 (d, 3H). propeny1)—1—thiopheny1—1,4- dihydro—chromen0[4,3— c]pyrazolc—3—carboxy1ic acid (2-acety1amino-ethy1)—methy1— d3-amide (87) / I m/z: 509 1H NMR (400 MHZ, c1503) 0 0 o O [M+H]+ 8 7.66 (s, 1H), 7.58 _ 7.53 (m, 2H), 7.38 (s, 1H), 7.28 — N\/ / / o N\ / 7.24 (m, 1H), 6.98 (s, 1H), N , Nw/ 6.66 (s, 1H), 5.51 (s, 2H), N <:§ D7340 CV \N N \ \ sg «—K .08 (m, 2H), 3.91 (8, 3H), 3.89 — 3.85 (61,211), 0 3.51 (s. 2H), 1.55 (s, 6H). (3,3-Dimethy1-morpholin-4— y1)-[7—meth0xy(1—methy1— d3—1H—pyrazol—4—y1)- 1— thiophen—3—y1—1,4—dihydrochromeno [4,3-C]pyraz01yl]- methanone (96) D | m/z = H-NMR (DMSO-d6): 5 7.98 O O I a?”D O 541 (s, 1H), 7.84 — 7.80 (m, 1H), 0 O / ; [M+H]+ 7.69 (s, 1H), 7.57 (s, 1H), o | N_N/ H 7.34 (d, 1H), 6.69 — 6.59 (m, / 55’ 6%D 1H), 6.03 (s. 1H), 5.39 (d, N~N D>< / 2H), 4.71 (s, 1H), 4.39 (s, 85 D D 1H), 4.09 (s, 1 H), 3.76 (s, / 3H), 3.18 (s, 5H), 2.21 (d, 7-Mcth0xy—8-(2-methy1- 1H), 1.88 — 1.19 (m, 6H). propeny1)—1—thi0pheny1—1,4- dihydro—chromeno[4,3— c]pyrazole—3-carboxy1ic acid methyl-d3-((1R,3S)—3—methy1— d3-Carbam0y1-cyc10hexy1)- amide (107) /0 0 /0 0 m/z : lH-NMR d6): 5 8.04 / 527 (dd, 1H), 7.90 (dd, 1H), 7.39 / o I 0 (dd, 1H), 7.00 (t, 1H), 6.85 (s, N N44 [M+H]+ N N—N /N 1H), 6.71 (s, 1H), 6.63 (t, / /j [WAD o s 3 / DJPD / 1H), 5.81 — 5.78 (m, 1H), .40 (s, 2H), 4.69 (d, 2H), D 4.39 (d, 2H), 3.88 (s, 2H), 7-Methoxy(l-methyl-IH- 3.84 (s, 3H), 3.59 (s, 3H). pyrr01y1)thiophenyl- 1,4—dihydro—chromeno[4,3- c]pyrazole—3-carboxylic acid (3-meth0xy-d3-methy1—Oxetan- 3-yl)—methy1—d3-amide (113) /O 0 /0 O m/z 2 1H-NMR (DMSO-d6): a / / 528 8.02—7.95 (m, 1H), 7.84 (dd, / , , Nfio / I N_/ 0 [M+H]+ 1H), 7.60 (d, 1H), 7.47 (s, /N’ N‘N /N’N N 1H), 7.34 (d, 1H), 6.76 (s, 1H), 6.49 (d, 1H), 5.44 (s, 2H), 4.70 (d, 2H), 4.40 (d, 2H), 3.88 (s, 2H), 3.84 (s, 0xy—8-(1-methy1-1H— 3H), 3.78 (s, 3H). pyrazol—3—yl)—1—thi0phen—3—yl— 1,4-dihydro-chromen0[4,3- c]pyrazole-3—carboxylic acid (3-methoxy—d3-methyl-oxetan- 3-y1)—methy1—d3-amide (114) O 0 /O 0 m/z = 1H-NMR (DMSO-d6): 5 O O / 494 8.08—8.00 (m, 1H), 7.90 (dd, / I N—,( [M+H]+ 1H), 7.39 (d, 1H), 7.00 (s, N N—N NWCO NjCO ’4 /N 1 1H), 6.85 (s, 1H), 6.71 (s, / 36 D D 1H), 6.63 (t, 1H), 5.80 (s, / D 3/; 1H), 5.40 (s, 2H), 4.69 (d, 7-Methoxy(1-methy1-1H- 2H), 4-24 (CL 2H), 3.83 (S, pyrroly1)thi0phen-3—yl- 3H), 3.59 (s, 3H), 1.63 (s, 1,4—dihydr0—chr0mcn0[4,3— 3H)‘ c]pyrazolecarboxylic acid methyl—d3—(3—methy1—oxetan—3— 1)-amide (115) /o 0 1H-NMR (DMSO-d6): 5 7.98 o (dd, 1H), 7.84 (dd, 1H), 7.60 / I / Nj/C/O (d, 1H),7.47 (s, 1H),7.34 ,N N~N (dd, 1H), 6.76 (s, 1H), 6.49 f' 0% (d, 1H), 5.43 (s, 2H), 4.69 (d, S5 D / D 2H), 4.24 (d, 2H), 3.84 (s, 7-Meth0xy—8-(l-methyl-IH— 3H), 3-78 (3,311), 1-63 (5’ 3H). pyrazol—3—yl)thi0phen—3-y1— 1,4—dihydr0—chromeno[4,3- zole—3—carboxylic acid —d3—(3—methy1—oxetan—3— y1)-amide (116) /0 o 1H-NMR(DMSO-d6): 5 8.00 0 (dd, 1H), 7.81 (dd, 1H), 7.39— \\ / N/fio 7.34 (m, 2H), 6.87 (s, 1H), N/N\ N—N 7 D 6.60 (s, 1H), 6.01 (d, 1H), 36 D 5.49 (s, 2H), 4.69 (d, 2H), / 4.24 (d, 2H), 3.80 (s, 3H), 7-Meth0xy—8-(2-methy1-2H— 3-52 (s, 3H). 1463 (s. 3H). pyrazolyl)thiopheny1— 1,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid methyl-d3-(3-methy1—0xetan—3— y1)—amide (118) /0 0 /0 O m/z = lH-NMR (DMSO—d6): 5 8.00 0 0 / 528 (dd, 1H), 7.81 (dd, 1H), 7.39- / \ \\ 0 / O \ N 7.34 (dd, 2H), 6.87 (s, 1H), N N [M+H]+ N-N\ N—N ’14 N’ \ N~'\/1 33 6.60 (s, 1H), 6.01 (d, 1H), {j ‘ D O o 5.49 (s, 2H), 4.69 (d, 2H), / D «(D 4.39 (d, 2H), 3.88 (s, 2H), 6 3.80 (s, 3H), 3.53 (s, 3H). 7—Methoxy(2-methy1-2H— pyrazol—3—yl)thiophen—3-yl— 1,4—dihydro—chromeno[4,3- c]pyrazolc—3-carboxylic acid (3-methoxy—d3-methy1—oxetan- 3—yl)—methy1—d3—amide (119) | | m/z = 1H-NMR (DMSO-d6): 8 7.97 0 0 O O 495 (dd, 1H), 7.83 (dd, 1H), 7.60 O O / o O / [M+H]+ (d, 1H), 7.50 (d, 1H), 7.34 (s, / 1 , N0 ’11 N4 N 1H), 6.76 (s, 1H), 6.50 (d, N’N N-N ’1 /‘ \ 1H), 5.59 (s, 1H), 5.43 (s, / 33/ D D 8/; 2H), 5.20 (s, 1H), 4.01-3.91 (m, 1H), 3.89 _ 3.54 (m, 7-Meth0xy(1-methy1-1H- 10H), 2.26 — 2.17 (m, 1H), pyrazol—3-yl)—1-thiophen—3-y1— 1.95 (s, 1H). hydro—chromeno[4,3— zolecarboxy1ic acid methyl-d3-(tetrahydro-furan y1)—amide (140) I H-NMR (DMSO-d6): 5 0 O 8.06-8.00 (m, 1H), 7.92 — N/O/09/51 7.87 (m, 1H), 7.42 _ 7.36 (m, N N_£ D 1H), 7.00 (t, 1H), 6.88 (s, / .5 ads. . 1H), 6.71 (s, 1H), 6.64 (t, 1H), 5.81 (s, 1H), 5.37 (s, 7-Meth0xy(1-methy1-1H— 2H), 5.12-4.86 (m, 1H), 4.46 pyrr01—3-y1)—1—thiophenyl— (s, 1H), .79 (m, 35H), 1,4—dihydro-chromcno[4,3— 3.70-3.50 (m, 4H), 2.47 _ c]pyrazole—3—carboxy1ic acid 2.38 (m, 1H), 2.24 — 1.98 (m, (3-methoxy-d3-cyclobuty1)- 2H). methyl—d3—amide (142) H-NMR (DMSO-d6): 8 O O 8.02-7.97 (m, 1H), 7.81 (dd, D / Dfi‘NxN’ 0 \ 1H), 7.56 (s, 1H), 7.36 (s, N—é MO 1H), 7.17 (s, 1H), 6.79-6.69 S (m, 1H), .55 (m, 1H), / D’éd .58 (s, 1H), 5.42 (s, 2H), 8-(1-methy1, 3-methy1—d3—1H- 5.19 (s, 1H), 3.99 _ 3.92 (m, pyrazolyl)mcth0xy 1H), 3.81-3.53 (m, 4H), 2.26- thiophen—3—y1—1,4—dihydro- 2.14 (m, 1H), 2.03-1.82 (m, chromeno[4,3-c]pyrazole 4H). carboxylic acid methyl-d3— hydro—furan-3—yl)-amide (143) /0 0 /0 0 m/z = 1H—NMR d6): 8 8.03 O O / / O 494 (dd, 1H), 7.89 (dd, 1H), 7.40 / I / WOO / I [M+H]+ (s, 1H), 7.01 (t, 1H), 6.93- N N_ .1 N0 /N ‘N D" 33 (s, 1H), 6.84 (m, 1H), 6.71 _ /N D 53 6.64 (t, 1H), 5.81 D (s, 1H), .60 s, 1H , 5.39 s, 2H , 7-Meth0Xy(1-methy1-1H- 5.19 Es, 1H), 3.99-(3.92811, pyrroly1)—1-thiophenyl- 1H), 3.84 (s, 3H), 3.80 — 3.53 1,4-dihydro-chromen0[4,3- (m, 7H), 2.26 — 2.16 (m, 1H), c]pyrazole-3—carboxylic acid 1.97 (s, 1H). methyl-d3—(tetrahydr0-furan y1)—amide (146) I I m/z = 1H—NMR (DMSO-d6): 5 7.96 O O 0 0 W123 W 504 (dd, 1H), 7.83 (dd, 1H), 7.33 [M+H]+ (dd, 1H), 6.66 (s, 1H), 6.42 , (s, 1H), 5.37 (s, 2H), 4.69 (d, N N‘N N‘N Ago ‘ ”2&0 2H), 4.39 (d, 2H), 3.88 (s, S/j o/KD J; 0 o 2H), 3.76 (s, 3H), 2.14 (d, / D 4 2H), 1.62 (septet, 1H), 0.74 D D o (d, 6H). 8-Isobuty1methoxy thiopheny1—1,4-dihydro- chromeno[4,3-C]pyrazole-3— carboxylic acid (3-methoxy— hy1—oxetan—3-yl)- methyl—d3—amide (162) | | m/z = 1H—NMR (DMSO-d6): 8 7.96 o o O W 471 (dd, 1H), 7.83 (dd, 1H), 7.33 (dd, 1H), 6.66 (s, 1H), 6.42 / (s, 1H), 5.37 (s, 2H), 4.69 (d, N—N N,@O 2H), 4.24 (d, 2H), 3.76 (s, d 07‘ 3H), 2.14 (d, 2H), 1.66 — 1.60 (m, 4H), 0.74 (d, 6H). 8—Isobuty1—7-methoxy thiopheny1—1,4—dihydrochromeno [4,3-C]pyrazole-3— carboxylic acid methyl-d3—(3- methyl-0xetan-3—y1)-amide (163) /O O 1H-NMR (DMSO-d6): 5 8.00-7.93 (m, 1H), 7.85 _ /‘ D / O ,N N—N 7.80 (m, 1H), 7.60 (d, 1H), /N 7.33 (d, 1H), 6.76 (s, 1H), S5 D133.” / D 6.50 (d, 1H), 5.76 (s, 1H), 7-Methoxy(1-methy1-1H- 5.43 (s, 2H), 4.59-4.41 (m, 4H), 3.99 (s, 1H), 3.84 (s, pyrazol—3—yl)thi0phen—3-y1— 3H), 3.80—3.76 (m, 3H), 3.69 1,4—dihydro—chromeno[4,3— (S, 1H)- c]pyrazolecarboxylic acid (3-methoxy—d3-oxetan ylmethy1)-methyl-d3-amide (167) 0% /0 0 m/z = 1H-NMR (DMSO-d6): 5 DD / 527 8.06-7.99 (m, 1H), 7.92 _ N—[\/J “1% [M+H]+ 7.87 (m, 1H), 7.41-7.36 (In, dN‘N D’Di/fiD 1H), 7.00 (s, 1H), 6.94-6.84 0 (m, 1H), 6.71 (s, 1H), 6.63 (t, 1H), 5.80 (s, 1H), 5.40 (s, 2H), 4.58 — 4.40 (m, 5H), 7—Methoxy(1-methy1-lH— 3.99 (S, 1H), 3.84 (8, 3H), y1)—1-thi0phen-3—yl- 359 (s. 3H). 1,4—d1hydr0—chromeno[4,3- c]pyrazole—3-carboxylic acid (3-methoxy—d3-oxetan—3— ylmethy1)-methyl-d3—amide (168) /O 0 H-NMR d6): 5 7.96 / (s, 1H), 7.83 (s, 1H), 7.60 (s, /NJ“ N4 WOW; 1H), 7.51 (d, 1H), 7.34 (s, )0 1H), 6.76 (s, 1H), 6.50 (s, D D 1H), 5.48-5.36 (m, 2H), 5.25 (s, 1H), 4.97 (s, 1H), 3.88— 3.67 (m, 7H), 2.14 (s, 1H), 7-Meth0xy(1-methy1-1H— 1.85—1.49 (m, 5H). l—3—yl)-1—thiophen—3—yl— 1,4-dihydr0-chromen0[4,3- c]pyrazole-3—carboxylic acid ((18,3R)-3—methoxy-d3- cyclopentyl)—methyl-d3—amide (177) /0 0 1H—NMR (DMSO-d6): 5 8.02 / (s, 1H), 7.90 (s, 1H), 7.39 (s, N WOO 1H), 7.01 (s, 1H), 6.94-6.84 /N s5 NH [9% d (m, 1H), 6.71 (s, 1H), 6.64 (3, D 1H), 5.81 (s, 1H), 5.44—5.32 (m. 2H), 5.24 (s, 1H). 4.97 (s, 1H), 3.87 — 3.67 (In, 4H), 7-MethOXy(l-methyl-IH- 359 (S, 3H), 213 (S, 1H), Pyrr01y1)thiOPheny1- 1.87-1.49 (111, 5H). 1,4—dihydr0—chromeno[4,3— c]pyrazole—3—carboxylic acid ((18,3R)methoxy—d3- cyclopentyl)—methyl-d3—amide (178) /o o /O 0 m/Z: 0 O / / 523 / D / N111 N~|\/J N 0’{\ N71‘ N~rx1 60 [M+H]+ / D \ D / \ s 5 / / (2-Meth0xy—d3-methy1—2- methyl-pyrrolidiny1)-[7- methoxy-S-(1-methy1— 1H- pyrazol—3—yl)thiophen—3-y1— 1,4—d1hydro—chromeno[4,3— z01—3-y1] -methan0ne (3%o/ 1H-NMR(DMSO—d6): 5 8.01 (s, 1H), 7.89 (s, 1H), 7.38 (s, WO+DD N; M1 1H,7.) 00(s,1H,)685(s. , / 6 D 1H), 6.71 (s, 1H), 6.63 (s, / 1H), 5.80 (s, 1H), 5.44 (s, 2H ,4.11—4.02 111,1H ,3.90 (Z'Meflloxy'dg‘methyl'z' _ 3381 (m, 5H),(3.62-3?54 (m, methyl'PYrmhdm'1'3’1)'[7' 4H), 2.17—2.07 (m, 1H), 1.88— methOXy-S-(l-methyl-lH- 1.74 (m, 2H), .59 (m, pyrr01y1)thiophenyl- 1H), 1.42 (s, 3H). 1,4—d1hydr0—chromeno[4,3— c]pyrazol-3—y1]-methan0ne (184) /o o 1H-NMR(DMSO-d6): 5 8.23 o (s, 1H), 8.02 (dd, 1H), 7.86 / o I / N (dd, 1H), 7.60 (d, 1H), 7.42 N’N N~N (j (s, 1H), 7.34 (dd, 1H), 6.76 / \ 014 (s, 1H), 6.49 (d, 1H), 5.54 (s, S D / D 2H), 5.18 (s, 1H), 3.84 (s, 7-Meth0xy(1-methy1-1H— 3H), 3.77 (s, 3H), 3.44-3.36 (m, 4H), 1.05 (s, 3H). pyrazol—3-yl)—1-thiophen—3-y1— 1,4—d1hydro-chromeno[4,3— c]pyrazole—3—carboxy11c acid methyl-d3-(3-methy1-azetidin- 3-yl)-amide (193) /0 0 1H—NMR (DMSO-d6): 5 / 8.00-7.90 (m$ 1H) 9 7.83 (dd3 / I / NVO 1H), 7.63—7.46 (m, 2H), 7.32 N” N‘“ 53x D (dd, 1H), 6.76 (s, 1H), 6.50 D D d Dj;DD (d, 1H), 5.50-5.26 (m, 2.5H), 7-Meth0xy(1-methy1-1H— 31?? 5—111),531>.?r11:36.;5).(m, pyrazol—3-yl)—1-thiophen—3-y1— 1,4—d1hydro—chromeno[4,3— c]pyrazole—3—carboxy11c acid ((18,3S)meth0xy-d3- cyclopentyD—methyl—d3—amide (196) /0 o /0 O m/z 1H-NMR(DMSO-d6): 88.00 / / 525 (s, 1H), 7.89 (dd, 1H), 7.37 g I M WORD 11 NW/ WOW} [M+H]+ (d, 1H), 7.00 (d, 1H), 6.89 (d, / 5 0/1 /\\ / ~ 1H), 6.71 (s, 1H), 6.64 (t, / D” D DD 8 / 81(s,1H),5.45-5.24 7-Meth0xy(l-methyl-IH— (m, 25H), 5‘01 (S, 05H), pyrr01—3-y1)—1—thi0phenyl— 3.84 (S, 4H), 336457 (H17 1,4—dihydro-chromeno[4,3— 4H)~ 2-03 — 1‘50 (m 8H)- c]pyrazolecarboxylic acid ((18,3S)methoxy-d3- cyclopentyl)—methyl-d3-amide (197) 0 O /0 O / m/z 1H-NMR(DMSO-d6): 5 8.03 / / 541 (dd, 1H), 7.89 (dd, 1H), 7.38 / O / I / N I (dd, 1H), , 1H), 6.86 (s, N N‘N '1 (t, N 1H), 6.72 (s, 1H), 6.63 \ 0" / DD 1H), 5.80 (dd, 1H), 5.37 (s, 0 D ‘60 2H), 4.09 (d, 1H), 3.85 — 3.72 D (m, 7H), 3.67-3.56 (m, 6H). 7-Meth0xy—8-(1-methy1-1H— y1)—1 -thi0pheny1— 1,4—dihydro—chromeno[4,3— c]pyrazolecarboxylic acid [3-(2—meth0xy-d3-ethy1)— oxetan—3—yl]-methyl-d3-amide (198) lH-NMR (DMSO-d6): 5 7.99 (dd, 1H), 7.85 (dd, 1H), 7.33 (dd, 1H), 7.22 (s, 1H), 6.93 (s, 1H), 5.57 (s, 2H), 4.69 (d, 2H), 4.24 (d, 2H), 3.90 (s, 3H), 3.45 (septet, 1H), 1.62 (s, 3H), 1.08 (d, 6H). 7-Methoxy—8-(pr0pane sulfony1)- 1-thi0phcn—3—y1—1,4— dihydro-chromeno[4,3- c]pyrazole—3—carboxylic acid methyl—d3—(3—methy1—oxetan—3— 1)—amide (199) | | m/z = lH—NMR d6): 5 7.99 0 O 0 O 554 (dd, 1H), 7.85 (dd, 1H), 7.33 o 0 Ct [M+H]+ (dd, 1H), 7.22 (s, 1H), 6.94 Q‘s / O 048 Nfi )\ / 0 N (s, 1H), 5.57 (s, 2H), 4.69 (d, 0% N—Kt N‘N 2H), 4.39 (d, 2H), .85 \ D/fi O (m, 5H), 3.45 (septet, 1H), 3 D 5:; / D /{\ 1.08 (d, 6H).

D D 7-Methoxy(propane sulfony1)thiopheny1—1,4- dihydro—chromeno[4,3— c]pyrazole-3—carboxylic acid (3—methoxy—d3-methyl—oxetan- 3-yl)—methyl—d3-amide (200) Example 9 butylmethoxythiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazol-S-yl)-[4- (tetrahydro-furancarbonyl)-[1,4]diazepanyl]-methanone (21) Step 1: To 8-isobutylmethoxy—1-(3-thienyl)—1,4—dihydrochromeno[4,3—c]pyrazole— 3-carboxylic acid (70.00 mg; 0.18 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 85.68 eq.) was added N,N-Diisopropylethylamine (0.04 ml; 0.22 mmol; 1.20 eq.) 1—boc-hexahydro-1,4— diazepine (0.04 ml; 0.22 mmol; 1.20 eq.) and 2,4,6—tripropyl-l,3,5,2,4,6—trioxatriphosphinane 2,4,6-trioxide (0.08 ml; 0.27 mmol; 1.50 eq.). After stirring at room temperature for 2 h, the reaction mixture washed with water and 1N HCL. The c layer was dried with NaZSO4, filtered, concentrated to afford 4-(8-Isobuty1methoxy-l-thiopheny1-1,4-dihydro- chromeno[4,3-c]pyrazolecarbony1)-[1,4]diazepanecarboxylic acid tert-butyl ester (103.00 mg; 0.18 mmol) as a white foam. To 4—(8—Isobutyl—7—methoxy—1-thiophenyl—1,4—dihydro— chromeno[4,3—c]pyrazolecarbony1)—[1,4]diazepane-l-carboxylic acid tert—butyl ester (103.00 mg; 0.18 mmol) in methanol (1.00 ml; 24,69 mmol; 135.58 eq.) was added hydrogen chloride (0.46 ml; 1.82 mmol; 10.00 eq.) (4M in dioxane). After stirring for 4h the reaction was mixture was concentrated to s and diluted with water. Mixture was lyophilized to afford [1,4]Diazepan—l—yl—(8—isobutyl—7—methoxy—1—thiophen—3—yl—l,4—dihydro—chromeno[4,3— c]pyrazol—3—yl)-methanone as a white solid.

Step 2: To [1,4] diazepan—l—yl—(8—isobutyl—7—methoxy—l—thiophen—3—yl—1,4—dihydro— chromeno[4,3-c]pyrazol—3—yl)-methanone (30.00 mg; 0.06 mmol; 1.00 eq.) in DCM (1.00 ml; .60 mmol; 242.64 eq.) was added isopropylethylamine (0.01 ml; 0.08 mmol; 1.20 eq.), tetrahydro—2—furoic acid (0.01 ml; 0.13 mmol; 2.00 eq.) and 2,4,6-tripropyl—l,3,5,2,4,6— trioxatriphosphinane 2,4,6—trioxide (0.03 ml; 0.10 mmol; 1.50 eq.). After ng for 30 min at room temperature the reaction was concentrated to dryness and purified by flash tography to afford the desired compound (10.7mg, 30%) as a white solid. 1H NMR (400 MHz, CDC13) 5 7.51 — 7.44 (m, 2H), 7.50 — 7.44 (m, 1H), 7.25 — 7.21 (m, 1H), 6.59 (d, J: 7.0 Hz, 1H), 6.56 (d, J: 2.7 Hz, 1H), 5.50 (dd, J: 4.9, 3.5 Hz, 2H), 4.70 — 4.58 (m, 1H), 4.53 — 4.41 (m, 1H), 4.41 — 4.22 (m, 1H), 4.19 — 4.09 (m, 1H), 4.08 — 3.82 (m, 4H), 3.79 (s, 3H), 3.71 — 3.59 (m, 2H), 3.58 — 3.42 (m, 1H), 2.36 — 2.26 (m, 1H), 2.26 — 2.20 (m, 2H), 2.19 — 1.83 (m, 3H), 1.78 — 1.60 (m, 2H), 0.81 (d, J: 6.6 Hz, 6H). m/z: 565 [M+H]+ Example 10 7-Methoxy(1H-pyrazolyl)—1-thiophenyl-1,4-dihydro-chromen0[4,3-c]pyraz0le carboxylic acid methylamide (22) Step 1: To 8—bromo—7—methoxy-1—thiophen—3—yl—l,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid (100.00 mg; 0.25 mmol; 1.00 eq.) in a microwave Vial was added 4— (4,4,5,5—tetramethyl—1,3,2—dioxaborolan—2—yl)—pyrazole—l—carboxylic acid tert—butyl ester (108.35 mg; 0.37 mmol; 1.50 eq.), bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complex with dichloromethane (1:1) (20.05 mg; 0.02 mmol; 0.10 eq.), and cesium carbonate (0.25 ml; 0.49 mmol; 2.00 eq.) (3 Molar solution in water). The vessel was sealed and vaccuumed and backfilled with nitrogen (3 times). Reaction was microwaved at 100°C for 30min. Mixture was diluted with EtOAc and washed with water and 1N HCl. Organic layer was dried (Na2804), filtered, concentrated to afford 8—(1—tert—Butoxycarbonyl—1H—pyrazol—4—yl)—7—methoxy—1— thiophen—3—yl—1,4—dihydro—chromeno[4,3—c]pyrazole—3-carboxylic acid as a crude product.

Step 2: To ert—Butoxycarbonyl—1H—pyrazol—4—yl)—7—methoxy—1—thiophen—3—yl— 1,4—dihydro—chromeno[4,3—c]pyrazole-3—carboxy1ic acid (121.00 mg; 0.24 mmol; 1.00 eq.) in DCM (1.50 ml; 23.40 mmol; 95.64 eq.) was added DIPEA (0.09 ml; 0.49 mmol; 2.00 eq.), 0— (benzotriazol—1—yl)—n,n,n',n'—tetramethyluronium tetrafluoroborate (157.13 mg; 0.49 mmol; 2.00 eq.), and n—tert—butylmethylamine (0.06 ml; 0.49 mmol; 2.00 eq.). After stirring for 30 min at room temperature the mixture was concentrated to dryness and purified by flash chromatography to afford 4-[3-(tert-Butyl-methyl-carbamoyl)methoxythiophenyl-1,4-dihydro- chromeno[4,3—c]pyrazol—8—yl]—pyrazole—1—carboxylic acid utyl ester as a white solid (99 mg, 72%).

Step 3: To 4—[3—(tert—Butyl—methyl—carbamoyl)—7-methoxy—1—thiophen—3—yl—1,4— dihydro—chromeno[4,3—c]pyrazol—8—yl]—pyrazole—1—carboxylic acid tert—butyl ester (99.00 mg; 0.18 mmol) in ol (3.00 ml; 74.06 mmol; 302.68 eq.) was added hydrochloric acid (0.20 ml; 0.80 mmol; 3.27 eq.) (4M in dioxane). After stirring at room temperature for 1h, the mixture was concentrated and purified by flash chromatography to afford the desired product (33.8 mg, 34%) as a white solid. 1H NMR (400 MHz, DMSO) 5 12.83 (s, 1H), 8.33 (dd, J: 9.4, 4.6 Hz, 1H), 8.07 (dd, J: 3.2, 1.4 Hz, 1H), 7.92 (dd, J: 5.1, 3.2 Hz, 1H), 7.77 (s, 1H), 7.41 (dd, J: 5.1, 1.4 Hz, 1H), 7.32 (s, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 5.52 (s, 2H), 3.86 (s, 3H), 2.75 (d, J: 4.7 Hz, 3H). m/z: 408 [M+H]+ e 11 [4-(Azetidinecarbonyl)-azepanyl]-(8-isopropoxymethoxythiophenyl-1,4- dihydro-chromeno[4,3-c]pyrazolyl)-methanone (26) / O A / j/ N S C/N 0 To 1—(8—isopropoxy—7—methoxy—1—(thiophen—3—yl)—1,4—dihydrochromeno[4,3— c]pyrazole—3-carbonyl)azepane—4—carboxylic acid (45.00 mg; 0.09 mmol; 1.00 eq.) in DCM (2.00 ml; 31.20 mmol; 354.72 eq.) was added DIPEA (0.02 ml; 0.13 mmol; 1.50 eq.), Azetidine (0.01 ml; 0.13 mmol; 1.50 eq.) and 2,4,6-tripropy1-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.08 ml; 0.13 mmol; 1.50 eq.). After stirring at room temperature for 30 min the reaction mixture was trated to dryness and purified by flash chromatography to afford the desired t (24.5 mg, 51%) as a white solid. 1H NMR (400 MHz, CDC13) 6 7.54 — 7.45 (m, 2H), 7.24 (t, J: 5.0 Hz, 1H), 6.61 (s, 1H), 6.43 (d, J: 5.8 Hz, 1H), 5.55 — 5.41 (m, 2H), 4.59 (d, J: 14.3 Hz, 1H), 4.23 — 3.86 (m, 4H), 3.83 (s, 3H), 3.77 — 3.49 (m, 1H), 3.35 — 3.27 (m, 1H), 2.42 — 2.07 (m, 4H), 2.03 — 1.68 (m, 6H), 1.27 (t, J: 7.1 Hz, 1H), 1.21 (d, J: 6.1 Hz, 6H). m/z: 551 [M+H]+ e 12 8-Isopropoxymethoxythiophenyl-1,4-dihydro-chr0men0[4,3-c]pyrazole carboxylic acid (3-amino-propyl)-amide (27) / O A N\N/ Cf NM Step 1: To 8—isopropoxy—7—methoxy—1—thiophen—3—y1—1,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid (120.00 mg; 0.31 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 50.24 eq.) was added N,N—Diisopropylethylamine (0.07 ml; 0.37 mmol; 1.20 eq.), n—boc—1,3— diaminopropane (81.16 mg; 0.47 mmol; 1.50 eq.) and 2,4,6—tripropy1—1,3,5,2,4,6— trioxatriphosphinane 2,4,6—trioxide (0.14 ml; 0.47 mmol; 1.50 eq.). After stirring for 30 min at room temperature, the reaction mixture was concentrated to dryness and purified by flash chromatography to afford —Isopropoxy—7—methoxy-1—thiophen—3—yl—1,4—dihydro— no[4,3-c]pyrazole—3—carbonyl)-amino]-propyl}-carbamic acid tert—butyl ester (170 mg, 100 %) as a white solid.

Step 2: To {3—[(8—Isopropoxy—7—methoxy-1—thiophen—3—yl—1,4—dihydro—chromeno[4,3— c]pyrazole—3—carbonyl)—amino]—propyl}—carbamic acid tert—butyl ester (172.70 mg; 0.32 mmol) in methanol (4.00 ml; 98.75 mmol; 317.98 eq.) was added hydrochloric acid in dioxane (0.31 ml; 1.24 mmol; 4.00 eq.). After stirring at room temperature for 18h the reaction mixture was trated to s and purified by flash chromatography to afford the desired compound (71.3 mg, 52%) as a white solid. 1H NMR (400 MHz, CDC13) 8 8.77 — 8.64 (m, 2H), 7.55 (d, J: 7.2 Hz, 2H), 6.62 (s, 1H), 6.36 (s, 1H), 5.51 (s, 2H), 4.13 — 3.94 (m, 2H), 3.85 (s, 3H), 3.65 — 3.59 (m, 2H), 3.23 — 3.07 (m, 2H), 2.21 —2.09 (m, 1H), 1.21 (d, J: 6.0 Hz, 6H). m/z: 443 [M+H]+ Example 13 8-Is0pr0p0xymethoxythiophenyl-1,4-dihydr0-chr0men0[4,3-c]pyrazole carboxylic acid [3-(cyclobutanecarbonyl-amino)-propyl]-amide (28) To 8—isopropoxy-7—methoxy—1—thiophen-3—yl—1,4—dihydro—chromeno[4,3—c]pyrazole— 3—carboxylic acid (3-amino—propyl)—amide (27) (65.00 mg; 0.15 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 106.21 eq.) was added N,N—Diisopropylethylamine (0.03 ml; 0.18 mmol; 1.20 eq.) cyclobutanecarboxylic acid (0.14 ml; 1.50 mmol; 10.21 eq.) and 2,4,6—tripropyl—1,3,5,2,4,6— trioxatriphosphinane 2,4,6—trioxide (0.13 ml; 0.22 mmol; 1.50 eq.). After stirring at room ature for 18 h the reaction mixture was concentrated to dryness and purified by flash chromatography to afford the desired compound (55.8 mg, 72%) as a white solid. 1H NMR (400 MHz, CDC13) 8 7.57 — 7.46 (m, 2H), 7.23 (d, J : 5.0 Hz, 1H), 7.16 (t, J: 6.3 Hz, 1H), 6.59 (s, 1H), 6.35 (m, 2H), 5.54 (s, 2H), 4.02 (dt, J: 12.1, 6.0 Hz, 1H), 3.82 (s, 3H), 3.46 (q, J : 6.2 Hz, 1H), 3.31 (q, J : 6.0 Hz, 2H), 3.03 (p, J : 8.6 Hz, 1H), 2.36 — 2.22 (m, 2H), 2.20 — 2.10 (m, 2H), 2.01 — 1.80 (m, 2H), 1.79 — 1.67 (m, 2H), 1.19 (d, J: 6.1 Hz, 6H). m/z: 525 [M+H]+ Example 14 Cyclobutanecarboxylic acid {1-[7-meth0xy(2-methyl-propenyl)thi0phenyl-1,4- dihydro-chromeno[4,3-c]pyrazolecarbonyl]-azepanyl}-amide (37) N N o: ;N To (4-amino—azepan—1—y1)—[7—methoxy—8—(2—methy1—propeny1)—1—thiophen—3—y1—1,4— dihydro—chromeno[4,3—c]pyrazol—3—yl]—methanone (55.00 mg; 0.11 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 135.76 eq.) was added N,N—Diisopropylethylamine (0.02 ml; 0.14 mmol; 1.20 eq.) cyclobutanecarboxylic acid (0.14 ml; 1.50 mmol; 13.05 eq.) and 2,4,6—tripropy1— 1,3,5,2,4,6—trioxatriphosphinane 2,4,6-trioxide (0.10 ml; 0.17 mmol; 1.50 eq.). After stirring for min at room temperature the reaction mixture was washed with NaHCOg, and extracted with DCM. The c layer was concentrated and purified by flash chromatography to afford the d compound (60.3 mg, 94%) as a white solid. 1H NMR (400 MHz, CDC13) 8 7.53 — 7.44 (m, 2H), 7.23 (dd, J: 5.0, 1.3 Hz, 1H), 6.76 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.60 — 5.45 (m, 3H), 4.61 — 4.49 (m, 1H), 4.43 — 4.30 (m, 1H), 4.18 — 3.99 (m, 2H), 3.82 (s, 3H), 3.60 — 3.48 (m, 1H), 3.45 — 3.34 (m, 1H), 3.26 (t, J = 10.3 Hz, 1H), 3.00 — 2.81 (m, 1H), 2.31 — 2.06 (m, 4H), 2.01 — 1.87 (m, 2H), 1.85 (s, 3H), 1.72 — 1.59 (m, 4H), 1.54 (s, 3H). m/z: 547 [M+H]+ Example 15 8-(1,2-Dihydroxymethyl-propyl)methoxythiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarb0xylic acid tert-butyl-methyl-amide (38) ] To oxy-8—(2—methyl—propenyl)—1—thiophen—3—yl-1,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid tert—butyl—methyl—amide (30.00 mg; 0.07 mmol; 1.00 eq.) in water (0.10 ml), and acetone (0.40 ml) was added 4—methylmorpholine 4—oxide (23.35 mg; 0.20 mmol; 3.00 eq.) and osmium tetroxide (0.51 mg; 0.00 mmol; 0.03 eq.). After stirring for 1 h at room temperature the mixture was quenched with saturated sodium sulfide and extracted with EtOAc.

The organic layer was dried (NaZSO4), filtered, concentrated and purified by flash chromatography to afford the desired compound (22.5 mg, 70%) as a White solid. 1H NMR (400 MHz, 8 7.51 (dd, J: 3.2, 1.3 Hz, 1H), 7.47 (dd, J: 5.1, 3.2 Hz, 1H), 7.21 (dd, J = 5.1, 1.3 Hz, 1H), 6.90 (s, 1H), 6.56 (s, 1H), 5.53 — 5.38 (m, 2H), 4.69 (s, 1H), 3.81 (s, 3H), 3.27 (s, 3H), 2.67 (s, 1H), 1.52 (s, 9H), 1.28 (dd, J: 6.0, 3.0 Hz, 1H), 1.15 (s, 3H), 0.97 (s, 3H). m/z: 486 [M+H]+ Example 16 1-[7-Methoxy(2-methyl-propenyl)thiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarbonyl]-azepanecarb0xylic acid dimethylamide (41) l / O :(N N To l—[7—methoxy—8—(2—methyl—propenyl)—l—thiophen—3—yl—l,4—dihydro—chromeno[4,3— c]pyrazole—3—carbonyl]—azepane—4—carboxylic acid (100.00 mg; 0.20 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 79.19 eq.) was added N,N—Diisopropylethylamine (0.04 ml; 0.24 mmol; 1.20 eq.), dimethylamine hydrochloride (24.10 mg; 0.30 mmol; 1.50 eq.) and 2,4,6—tripropyl— 1,3,5,2,4,6-trioxatriphosphinane trioxide (0.17 ml; 0.30 mmol; 1.50 eq.). After stirring for min at room temperature the reaction mixture was concentrated and purified by flash chromatography to afford the desired compound (92.3 mg, 88%) as a white solid. 1H NMR (500 MHz,cdc13) 6 7.46 — 7.34 (m, 2H), 7.14 (ddd, J: 13.8, 4.9, 1.4 Hz, 1H), 6.67 (d, J = 12.0 Hz, 1H), 6.49 (d, J = 1.8 Hz, 1H), 6.03 (s, 1H), 5.52 — 5.41 (m, 2H), 4.61 — 4.55 (m, 1H), 4.22 — 4.10 (m, 1H), 3.98 — 3.85 (m, 1H), 3.73 (s, 3H), 3.55 — 3.48 (m, 1H), 3.45 — 3.37 (m, 1H), 3.22 — 3.14 (m, 1H), 2.96 (s, 1H), 2.88 (d, J = 8.1 Hz, 3H), 2.83 (s, 1H), 2.71 — 2.60 (m, 1H), 2.14 — 2.04 (m, 1H), 1.95 — 1.83 (m, 2H), 1.76 (s, 3H), 1.70 — 1.53 (m, 2H), 1.45 (d, J: 4.8 Hz, 3H). m/z: 535 [M+H]+ e 17 1-[7-Methoxy(2-methyl-propenyl)thiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarb0nyl]-azepanecarb0xy1ic acid methylamide (42) l / O N N In a similar manner to example 16, 1—[7—methoxy—8—(2—methyl—propenyl)—1—thiophen— 3—yl-1,4—dihydro—chromeno[4,3—c]pyrazole—3—carbonyl]—azepane—4—carboxylic acid methylamide was obtained from 1— hoxy-8—(2—methyl—propenyl)- 1 —thiophen—3—yl— 1 ,4—dihydro— chromeno[4,3-c]pyrazole—3—carbonyl]-azepane-4—carboxylic acid (100.00 mg; 0.20 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 79.19 eq.), and methylamine hydrochloride (13.30 mg; 0.20 mmol; 1.00 eq.). The desired nd was obtained in 52 % yield (53.5 mg) as a white solid. 1H NMR (500 MHz, CdC13) 6 7.49 — 7.43 (m, 2H), 7.21 (d, J: 5.1 Hz, 1H), 6.74 (s, 1H), 6.56 (s, 1H), 6.10 (s, 1H), 5.55 (t, J: 4.9 Hz, 1H), 5.52 (t, J: 4.1 Hz, 2H), 4.49 — 4.43 (m, 1H), 4.18 (dt, J: 14.5, 5.4 Hz, 1H), 4.07 — 4.00 (m, 1H), 3.95 (dt, J = 9.5, 4.4 Hz, 1H), 3.85 — 3.82 (m, 1H), 3.80 (s, 3H), 3.72 — 3.63 (m, 1H), 3.49 — 3.42 (m, 1H), 2.78 (dd, J = 14.0, 4.8 Hz, 3H), 2.34 — 2.12 (m, 1H), 2.05 — 1.91 (m, 1H), 1.84 (d, J: 1.2 Hz, 3H), 1.80 — 1.68 (m, 2H), 1.54 — 1.51 (s, 3H). m/z: 521 [M+H]+ e 18 1-[7-meth0xy(2-methyl-propenyl)thi0phenyl-1,4-dihydr0-chr0meno[4,3-c]pyrazole- 3-carb0nyl]-azepanecarboxylic acid amide (43) l / O N N N 0 To 1—[7—methoxy—8—(2—methyl—propenyl)—1—thiophen—3—yl—1,4—dihydro—chromeno[4,3— c]pyrazolecarbonyl]-azepanecarboxylic acid (75.00 mg; 0.15 mmol; 1.00 eq.) in DMSO (1.00 ml) was added 1,1'—carbonylbis(1H—imidazole) (119.72 mg; 0.74 mmol; 5.00 eq.).

Reaction was stirred at room temperature for 18h, then um acetate (34.17 mg; 0.44 mmol; 3.00 eq.) was added and the reaction was continued to stir at room temperature for 2 h.

After completion, water was added to the mixture and solid formed was filtered, rinsed with water to afford the desired compound (62.5 mg, 84%) as a white solid.

WO 09980 1H NMR (500 MHz, cdclg) 5 7.44 — 7.34 (m, 2H), 7.15 — 7.11 (m, 1H), 6.67 (s, 1H), 6.49 (s, 1H), 6.03 (s, 1H), 5.47 — 5.43 (m, 2H), 5.13 (s, 1H), 4.75 (s, 1H), 4.44 — 4.36 (m, 1H), 4.12 (dt, J = 14.7, 5.3 Hz, 1H), 4.03 — 3.95 (m, 1H), 3.88 (d, J = 14.3 Hz, 1H), 3.83 — 3.74 (m, 1H), 3.73 (s, 3H), 3.66 — 3.56 (m, 1H), 3.43 — 3.37 (m, 1H), 2.36 — 2.25 (m, 1H), 2.23 — 2.11 (m, 1H), 2.03 — 1.87 (m, 2H), 1.76 (d, J: 1.0 Hz, 3H), 1.45 (s, 3H). m/z: 507 [M+H]+ Example 19 7-methoxy-S-(Z-methyl-propenyl)thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazole carboxylic acid [3-(cyclobutanecarbonyl-amino)-propyl]-amide (57) Step 1: In a similar manner to example 12 step 1, (3—{ [7—Methoxy-8—(2—methyl— propenyl)— l —thiophen—3—yl— 1 ,4—dihydro—chromeno [4,3—c]pyrazole—3—carbonyl] —amino } —propyl)— carbamic acid tert—butyl ester was obtained from 7—methoxy—8—(2—methyl—propenyl)—l—thiophen— ,4—dihydro—chromeno[4,3—c]pyrazole-3—carboxylic acid (150mg, 0.39mmol) and N—boc- 1,3—diaminopropane mg, 0.59mmol, 1.5 eq.).

Step 2: In a similar manner to example 12 step 2, 7-methoxy(2-methyl-propeny1)- l—thiophen—3—yl—l,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid (3—amino—propyl)— amide was obtained from (3-{[7—Methoxy—8—(2—methyl—propenyl)—l—thiophen—3—yl-l,4—dihydro— chromeno[4,3—c]pyrazole—3—carbonyl]—amino}—propyl)—carbamic acid tert—butyl ester and HCl (4M in dioxane).

Step 3: In a similar manner to example 12, step 1, oxy-8—(2—methyl—propenyl)— 1—thiophen—3—yl— hydro—chromeno[4,3—c]pyrazole—3—carboxylic acid [3— (cyclobutanecarbonyl-amino)-propyl]-amide was obtained from 7—Methoxy(2-methyl- propenyl)—l—thiophen—3—yl—l,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid (3—amino— propyl)-amide (100mg, 0.23 mmol) and cyclobutanecarboxylic acid (0.14 ml; 1.50 mmol; 6.58 eq.). The desired compound was obtained in 97% yield (115 mg) as a white solid. 1H NMR (400 MHz, CDC13) 5 7.55 (s, 1H), 7.53 — 7.48 (m, 1H), 7.25 (d, J: 4.7 Hz, 1H), 7.11 (t, J = 7.1 Hz, 1H), 6.71 (s, 1H), 6.58 (s, 1H), 6.32 — 6.25 (m, 1H), 6.12 (s, 1H), 5.62 (s, 2H), 3.83 (s, 3H), 3.49 (dd, J = 12.3, 5.9 Hz, 2H), 3.34 (dd, J: 12.1, 6.0 Hz, 2H), 3.12 — 3.00 (m, 1H), 2.32 (dt, J: 19.0, 9.7 Hz, 2H), 2.19 (dd, J: 18.8, 9.9 Hz, 2H), 1.98 (dd, J: 18.7, 8.5 Hz, 2H), 1.85 (s, 3H), 1.79 — 1.71 (m, 2H), 1.52 (s, 3H). m/z: 521 [M+H]+ Scheme 3: TYB()/ I O 0 O O :c'IkNASH X7): // \ EtOH AcOH Suzuki coupling O OH X:C N \‘({N S X kl O NHFi1Fi2 LiOH \ —> ' O / DIPEA,DCM, N‘N ng agent {7; OH Scheme 4: 0:897 O O H2N\N)LS O O HCI X7): // \ \ / EtOH AcOH ON Suzuki coupling N_|< X: C N \\ Pd/C H2 0 LiOH NHR1F§2 // _> \(—N // DIPEA, DCM, \‘x N\ coupling agent U N OH Example 20 oxy(2-methyl-propenyl)thiazolyl-1,4-dihydro-chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methyl-amide (89) Step 1: 2—Hydrazino—1,3—thiazole hydrochloride NH2l HCI To a mixture of 2—aminothiazole (10.0 g, 100 mmol) and conc. hydrochloric acid (80 mL), was added a solution of sodium nitrite (6.90 g, 100 mmol) in water (50 mL) drop wise at —10 °C. The reaction mixture was stirred for 10 min at the same temperature and followed by addition of tin loride (37.9 g, 200 mmol) in conc. hydrochloric acid (20 mL) drop wise carefully so that the temperature of the on did not exceed —10.deg.C. After the addition, the reaction mixture stirred for 30 min at the same temperature. The resulting crystals were ted by filtration.

The crystal was recrystalized from diethylether to afford the desired compound (11.0 g, 97 %) as brown solid. 1H NMR (400 MHz, DMSO-d6) 5 10.74 (bs, 1H), 7.27-7.26 (d, J: 4.0 Hz, 1H), 7.00—6.99 (d, J: 4.0 Hz, 1H), 3.45 (bs, 3H). m/z: 116 [M+H]+ Step 2: Ethyl o—7—methoxy—1—(1,3—thiazol—2—yl)—1, 4—dihydrochromeno [4,3— c]pyrazole—3—carboxylate O O o g H2N\ O O N S HCI H 0 Br OEt Br / EtOH, ACOH OEt O OH NN‘ QN9% To a solution of ethyl-(6-bromomethoxyoxo-2H-chromen-3(4H)-ylidene)(hydroxy)acetate (3.0 g, 0.0084 mol) in a mixture of Ethanol (100 mL) and Acetic acid (100 mL) was added 2— Hydrazino—1,3-thiazole hydrochloride (1.9 g 0.0126 mol) at RT under nitrogen. The reaction mixture was stirred at 100 0C for 4 h. The reaction mixture was concentrated under high .

The residue was dissolved with ethyl acetate (40 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated under vacuum. The crude t was purified by column tography using pet ether/ethyl acetate as eluent to afford the desired compound (1.5g, 41 %) as pale yellow solid. 1H NMR (400 MHz, DMSO—dé) 5 8.61 (s, 1H), .85 (d, J: 1.4 Hz, 2H), 6.86 (s, 1H), 5.45 (s, 2H), 4.37-4.32 (dd, J = 7.0, 14.2, 2H), 3.86 (s, 3H), 1.34-1.31 (t, J = 7.1, 14.2, 3H). m/z: 438 [M+H]+ Step 3: Ethyl 7—methoxy—8—(2—methylprop—1—en—1—yl)—1—(1,3—thiazol—2—yl)—1,4— dihydrochromeno[4,3-c]pyrazole—3—carboxylate fi—«OON~’ fwr N O'\ To a solution of ethyl 8—bromo—7—methoxy—1—(1,3—thiazol—2yl)—1,4—dihydrochromeno[4,3— c]pyrazole—3—carboxylate (2.6 g, 0.0059 mol) in THF (100 mL) was added 2,4,6—Tris—(2—methyl— propenyl)—cyclotriboroxanepyridine complex (2.9 g, 0.0089 mol), bis(triphenylphospine)palladium (II) dichloride (417 mg, 0.0006 mol) and potassium tri phosphate (2.0 g, 0.0149 mol) at RT under nitrogen. The reaction mixture was degassed with nitrogen for 10 min and water (10 mL) was added at RT. The on mixture was stirred at 90 ° C for 12 h. The reaction mixture was filtered through celite and washed with DCM (50 mL). The filtrate was trated under vacuum; crude product was dissolved in DCM (200 mL), washed with water (20 ml), brine (20 mL) and dried over sodium sulphate. The organic solvent was removed under vacuum; crude product was purified by column chromatography over (60—120) mesh silica gel and pet ether: ethyl acetate as eluent to afford the d compound (2.2 g, 90 %) as a pale yellow solid. 1H NMR (400 MHz, DMSO—d6) 8 7.94 (s, 1H), 7.87-7.86 (d, J = 3.5 Hz, 1H), 7.82—7.81 (d, J = 3.5 Hz, 1H), 6.69 (s, 1H), 6.01 (s, 1H), 5.42 (s, 2H), 4.35-4.33 (d, J: 7.1 Hz, 2H), 3.77 (s, 3H), 1.82 (s, 3H), 1.70 (s, 3H), 1.34-1.31 (t, J: 7.1, 14.2 Hz, 3H). m/z: 412 [M+H]+ Step 4: 7—Methoxy—8-(2—methy1prop-l-en—1—yl)—1—(1,3-thiazol-2—yl)—1,4—dihydro— chromeno[4,3—c]pyrazole—3—carboxylic acid 2014/043838 / 0 s N‘N/ 05 OH To a solution of ethyl 7—methoxy—8—(2-methylprop—1—en—l—yl)—1—(l,3—thiazol—2—yl)—1,4— dihydrochromeno[4,3—c]pyrazole—3—carboxylate (1 g, 0.0024 mol) in mixture of THF (35 mL) H20 (10 mL), MeOH (5 mL) was added LiOH.HZO ( 302 mg, 0.0073 mol) at RT. The reaction mixture was stirred at RT for 4 h. The reaction mixture was evaporated and acidified with 1.5N HCl solution. The separated solid was filtered and dried under high vacuum to afford the desired compound (900 mg, 97 %) as an off—white solid. 1H NMR (400 MHz, DMSO-d6) 8 13.57 (bs, 1H), 8.00 (s, 1H), 7.85-7.84 (d, J = 3.5 Hz, 1H), 7.80 (d, J: 3.5 Hz, 1H), 6.69 (s, 1H), 6.11 (s, 1H), 5.41 (s, 2H), 3.77 (s, 3H), 1.83 (s, 3H), 1.71 (s, 3H). m/z: 384 [M+H]+ ] Step 5: 7-Methoxy(2-methyl-propenyl)thiazolyl-1,4-dihydro-chromeno[4,3- c]pyrazole—3—carboxylic acid tert—butyl—methyl—amide I O it.“ M To a solution of 7—Methoxy—8-(2—methylprop-l—en—l—yl)—l—(l,3—thiazol—2—yl)-l,4—dihydro— chromeno[4,3—c]pyrazole—3—carboxylic acid (900 mg, 0.0023 mol) in DCM (50 mL) was added N—tert—butyl methyl amine (225 mg, 0.0028 mol), HATU (1.1 g, 0.0028 mol) and diisopropyl ethyl amine (0.6 mL, 0.0035 mol) at RT under nitrogen. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched to sodium bicarbonate (10 mL, 10%), extracted with DCM (2 x 50 mL). The combined organic layer was washed with NaHC03 solution (1 x 100 mL, 10 % solution), brine (100 mL) and dried over ous sodium te. The solvent was removed under vacuum; the crude product was purified by column chromatography using pet ether and ethyl acetate (9:1) as eluent to afford the desired compound (850 mg, 80%) as an off—white solid. 1H NMR (400 MHz, DMSO—d6) 5 8.14 (s, 1H), 7.79—7.76 (dd, J: 3.5, 6.3 Hz, 2H), 6.70 (s, 1H), 6.12 (s, 1H), 5.25 (s, 2H), 3.77 (s, 3H), 3.12 (s, 3H), 1.84 (s, 3H), 1.74 (s, 3H), 1.44 (s, 9H). m/z: 453 [M+H]+ e 21 7-Methoxy(2-methyl-propenyl)thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methyl-amide (90) Step 1: tert—Butyl 1—(2—thienyl)hydrazinecarboxylate + w.NH.O s To a solution of 2—Bromo thiophene (10 g, 0.0613 mol) in DMSO (200 mL) was added tert—butyl carbazate (16.3 g, 0.1227 mol), cesium ate (40 g, 0.1227 mol ) followed by CuI (1.2 g, 0.0061 mol) and 4—Hydroxy—L—Proline (1.6 g, 0.0123 mol) at RT under nitrogen. The reaction mixture was stirred at 80 °C for 14 h. The reaction mixture was cooled to RT, quenched with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The ed organic layer was washed with water (100 mL x 2), brine (100 mL), dried over sodium sulphate and evaporated under . The crude product was purified by column tography by using pet ether and ethyl acetate (7:3) as eluent to afford the desired compound (3.0 g, 40%) as a brown liquid. 1H NMR (400 MHz, DMSO—d6) 8 6.89-6.87 (dd, J: 1.7, 5.4 Hz, 1H), 6.81—6.79 (dd, J: 3.4, 7.2 Hz, 2H), 5.38 (s, 2H), 1.49 (s, 9H). m/z: 115 [M+H]+ Step 2: 2—Thieny1hydrazine hydrochloride 8 H H—CI To a stirred solution of utyl 1-(2—thieny1)hydrazinecarboxylate (4.3 g, 0.0201 mol) in dichloromethane (20 mL) was added HCl in dioxane (30 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 8 h. The organic solvent was removed under reduced pressure to afford the desired compound (2.9 g, 96 %) as pale brown solid. 1H NMR (400 MHz, DMSO—d6) 5 10.17 (bs, 3H), 8.41 (bs, 1H), 7.07-7.05 (dd, J: 1.4, 5.4 Hz, 1H), 6.85-6.83 (dd, J: 3.6, 5.4 Hz, 1H), 6.72-6.71 (dd, J: 1.4, 3.7 Hz, 1H). m/z: 115 [M+H]+ Step 3: Ethyl o—7—methoxy—1—(2—thienyl)—l, 4—dihydrochromeno [4,3— c]pyrazole—3-carboxylate HCI H EtOH AcOH [(1 UN\\ To a solution of ethyl—(6—bromo—7—methoxy-4—oxo—2H—chromen—3(4H)—ylidene)(hydroxy)acetate (6.0 g, 0.0168 mol) in a mixture of Ethanol (100 mL) and acetic acid (100 mL) was added 2— thienylhydrazine hydrochloride (2.9 g 0.0252 mol) at RT under nitrogen. The reaction mixture was stirred at 100 0C for 4 h. The reaction e was concentrated under high vacuum. The e was dissolved with ethyl acetate (40 mL), washed with water (20 mL), brine (20 mL), dried over sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography using pet ether/ethyl acetate as eluent to afford d compound (4.0 g, 55 %) as a pale yellow solid. 1H NMR (400 MHz, DMSO-dé) 8 7.84—7.82 (dd, J = 1.2, 5.5 Hz, 1H), 7.49—7.47 (dd, J: 1.2, 3.6 Hz, lH),7.24-7.22 (dd, J = 3.8, 5.4 Hz, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 5.51 (s, 2H), 4.33—4.28 (dd, J: 7.1, 14.2 Hz. 2H), 3.82 (s, 3H), 1.32—1.28 (t, J: 7.1, 14.2 Hz, 3H). m/z: 437 [M+H]+ Step 4: 7—Methoxy—8—(2—methyl—propenyl)—l—thiophen—2—y1—l,4—dihydro— chromeno[4,3-c]pyrazole—3—carboxylic acid ethyl ester To a solution of Ethyl 8—bromo—7—methoxy—l—(2—thienyl)—l,4—dihydrochromeno[4,3—c]pyrazole—3— carboxylate (3.8 g, 0.0087 mol) in THE (100 mL) was added 2,4,6—Tris—(2—methyl—propenyl)— cyclotriboroxanepyridine complex ( 4.3 g, 0.0131 mol), bis(triphenylphospine)palladium (II) dichloride (306 mg, 0.0004 mol) and potassium tri phosphate (2.4 g, 0.0174 mol) at RT under 2014/043838 nitrogen. The reaction mixture was degassed with nitrogen for 10 min and water (10 mL) was added at RT. The reaction mixture was stirred 0 C for 12 at 90 h. The reaction mixture was filtered through celite and washed with DCM (50 mL). The filtrate was concentrated under vacuum; the crude product was dissolved in DCM (200 mL), washed with water (20 ml), brine (20 mL) and dried over sodium sulphate. The organic solvent was removed under ; crude product was purified by column chromatography using pet ether: ethyl acetate as eluent to afford the desired compound (2.5 g, 70 %) as pale yellow solid. 1H NMR (400 MHz, 6) 8 7.79-7.77 (dd, J: 1.4, 5.5 Hz, 1H), 7.46-7.45 (dd, J: 1.5, 3.7 Hz, 1H), 7.20—7.18 (dd, J: 3.7, 5.6 Hz, 1H), 6.66 (s, 1H), 6.56 (s, 1H), 6.00 (s, 1H), 5.47 (s, 2H), 4.33-4.27 (dd, J = 71,142 Hz, 2H), 3.74 (s, 3H), 1.73 (d, J = 1.1 Hz, 3H), 1.39 (d, J = 1.2 Hz,3H), 1.32-1.28 (t, J: 71,142 Hz, 3H). m/z: 411 [M+H]+ Step 5: 7—Methoxy—8—(2—methyl—propenyl)-1—thiophen—2—y1—1,4—dihydro— chromeno[4,3-c]pyrazole—3—carboxylic acid To a solution of 7—methoxy-8—(2—methyl—propenyl)—1—thiophen—2—yl—1,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid ethyl ester (1 g, 0.0024 mol) in mixture of THF (35 mL) , H20 (10 mL), MeOH (5 mL) was added LiOH.HZO ( 303 mg, 0.0073 mol) at RT. The reaction mixture was stirred at RT for 4 h. The reaction mixture was evaporated and acidified with 1.5N HCl solution. The separated solid was filtered and dried under high vacuum to afford the d compound (800 mg, 75 %) as an ite solid. 1H NMR (400 MHz, DMSO-dg) 8 13.30 (bs, 1H), 7.78—7.76 (dd, J: 1.4, 5.6 Hz, 1H), .44 (dd, J: 1.4 3.7 Hz, 1H), 7.19—7.17 (dd, J: 3.7, 5.5 Hz, 1H), 6.66 (s, 1H), 6.56 , (s, 1H), 6.00 (s, 1H), 5.46 (s, 2H), 3.73 (s, 3H), 1.73 (s, 3H), 1.39 (s, 3H). m/z: 383 [M+H]+ Step 6: 7—Methoxy—8—(2—methyl—propenyl)—1—thiophen—2—yl—1,4—dihydro— chromeno[4,3-c]pyrazolecarboxylic acid tert-butyl-methyl-amide I O N U N xN7< 159 To a solution of 7—methoxy-8—(2—methyl—propenyl)—1—thiophen—2—yl—1,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid (800 mg, 0.0021 mol) in DCM (50 mL) was added N—tert—butyl methylamine (220 mg, 0.0025 mol), HATU (950 mg, 0.0025 mol) and diisopropylethylamine (0.6 mL, 0.0032 mol) at RT under nitrogen. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched to sodium bicarbonate (10 mL, 10%), ted with DCM (2 x 50 mL). The combined c layer was washed with NaHC03 solution (1 x 100 mL, 10% solution), brine (100 mL) and dried over anhydrous sodium te. The solvent was removed under vacuum; the crude product was purified by column chromatography using pet ether and ethyl acetate (9: 1) as eluent to afford the desired compound (850 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 7.75-7.73 (dd, J = 1.4, 5.5 Hz, 1H), 7.42-7.41 (dd, J: 1.4 3.6 Hz, 1H), 7.18-7.15 (dd, J: 3.8, 5.6 Hz, 1H), 6.66 (s, 1H), 6.59 (s, 1H), 6.01 (s, 1H), 5.33 (s, 2H), 3.73 (s, 3H), 3.12 (s, 3H) 1.73 (s, 3H), 1.41 (s,12 H). m/z: 452 [M+H]+ Example 22 8-Isobutylmethoxythiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazolecarb0xylic acid utyl-methyl-amide (91) Step 1: 8—Isobutyl—7—methoxy—1—thiophen—2—yl—1,4—dihydro—chromeno[4,3—c]pyrazole— 3-carboxylic acid ethyl ester {I O_\ To a solution of 7—methoxy(2—methy1—propenyl)—1-thiophen—2—yl-1,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid ethyl ester (1.2 g, 0.0027 mol) in methanol and ethyl acetate mixture (100 mL) was added palladium on carbon (20 %, 0.24 g). The reaction mixture was hydrogenated under 3 bar of pressure for 8 h at RT. The on mixture was filtered h celite to remove the catalyst and the filtrate was concentrated under vacuum. The residue was purified by column chromatography using pet ether/ ethyl acetate as eluent to afford the desired compound (1.1 g, 90 %) as an off white solid. 1H NMR (400 MHz, DMSO'dé) 8 7.81-7.79 (dd, J: 1.4, 5.5 Hz, 1H), 7.43-7.41 (dd, J: 1.4, 3.7 Hz, 1H), 7.20—7.18 (dd, J: 3.7, 5.5 Hz, 1H), 6.65 (s, 1H), 6.36 (s, 1H), 5.44 (s, 2H), 4.33-4.27 (dd, J: 70,142 Hz, 2H), 3.74 (s, 3H), .10 (d, J: 6.9 Hz, 2H), 1.59-1.56 (m, 1H), 1.32— 1.28 (t, J: 7.1,14.2 Hz, 3H), 0.86-0.85 (d, J: 6.6 Hz, 6H).

Step 2: 8—Isobutyl—7—methoxy—1—thiophen—2—yl—l,4—dihydro—chromeno[4,3—c]pyrazole— 3—carboxylic acid N‘N/ Us OH To a on of 8—isobutyl—7—methoxy—1—thiophen—2—yl—1,4—dihydro—chromeno[4,3-c]pyrazole—3— carboxylic acid ethyl ester (1.1 g, 0.0027 mol) in mixture of THF (35 mL), H20 (10 mL), MeOH (5 mL) was added LiOH.HZO (332 mg, 0.0080 mol) at RT. The reaction mixture was stirred at RT for 4 h. The reaction mixture was ated and acidified with 1.5N HCl solution.

The ted solid out was filtered to afford the desired compound (900 mg, 88 %) as an off— white solid. 1H NMR (400 MHz, DMSO'dfi) 8 13.33 (bs, 1H), 7.79-7.78 (dd, J = 1.4, 5.5 Hz, 1H), 7.41—7.40 (dd, J: 1.4 3.7 Hz, 1H), 7.19-7.17 (dd, J: 3.8, 5.5 Hz, 1H), 6.65 (s, 1H), 6.36 , (s, 1H), 5.43 (s, 2H), 3.73 (s, 3H),2.12-2.10 (d, J: 7.0 Hz, 2H), 1.59-1.56 (m, 1H), .70 (d, J: 6.6 Hz 6H) m/z: 385 [M+H]+ Step 3: 8—Isobutyl-7—methoxy—1—thiophen-2—yl—1,4-dihydro—chromeno[4,3-c]pyrazole— 3—carboxylic acid tert—butyl—methyl—amide s N‘N «J /N7< To a solution of 8—isobuty1—7-methoxy-1—thiophen—2-yl—1,4—dihydro-chromeno[4,3—c]pyrazole—3— carboxylic acid (900 mg, 0.0023 mol) in DCM (50 mL) was added N—tert—butyl methyl amine (245 mg, 0.0028 mol), HATU (1.0 g, 0.0028 mol) and diisopropyl ethyl amine (0.6 mL, 0.0038 mol) at RT under nitrogen. The reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched to sodium bicarbonate (10 mL, 10 %), extracted with DCM (2 x 50 mL). The combined organic layer was washed with NaHC03 on (100 mL, 10 % solution), brine (100 mL) and dried over anhydrous sodium sulphate. The solvent was removed under vacuum; the crude product was purified by column chromatography using pet ether and ethyl acetate (9:1) as eluent to afford the desired compound (800 mg, 75%) as a white solid. 1H NMR (400 MHz, 6) 8 7.76-7.75 (dd, J: 1.4, 5.5 Hz, 1H), 7.38—7.37(dd, J: 1.4 3.7 Hz, 1H), 7.18—7.15 (dd, J: 3.7, 5.6 Hz, 1H), 6.64 (s, 1H), 6.39 (s, 1H), 5.30 (s, 2H), 3.73 (s, 3H), 3.12 (s, 3H),3.12 (s, 3H), 2.12-2.10 (d, J = 7.0 Hz, 2H), .56 (m, 1H), 1.41 (s, 9H) 0.71- 0.70 (d, J: 6.6 Hz 6H). m/z: 454 [M+H]+ Scheme 5: /O /O o ’0 /O O O A/ O NH3/MeOH S / / Cul, CuCN / Br 8 / ‘— / O —> / / OEt O N—N Ra/NiH N‘N (N N4 \ N \ R S/5 S S / / / 33— H202, NaOH 1 0‘ ’0— Example 23 (3,3-Dimethyl-morpholinyl)-(8-isobutylsulfanylmethoxythiophenyl-1,4-dihydro- chromen0[4,3-c]pyrazolyl)-methan0ne (97) Step 1: 8—Isobutylsulfanyl—7—methoxy- l—thiophen—3—yl-1,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid /o o Pd(OAc)2, Kco3 0 To 8—bromo—7—methoxy—1—thiophen—3—yl—1,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid (100.00 mg; 0.25 mmol; 1.00 eq.) suspended in [1,4]Dioxane (3.00 ml) was added 2—Methy1— e—l—thiol (33.22 mg; 0.37 mmol; 1.50 eq.), palladium acetate (2.76 mg; 0.01 mmol; 0.05 eq.), 4,5—Bis—diphenylphosphanyl—9,9-dimethyl—9H—xanthene (14.21 mg; 0.02 mmol; 0.10 eq.), and ium carbonate (101.81 mg; 0.74 mmol; 3.00 eq.). The reaction was heated at 120 0C for 8 days. Mixture was diluted with EtOAc and washed with brine. The organic layer was dried (NaZSO4), filtered, concentrated to afford product 8—Isobutylsulfanyl—7—methoxy—1—thiophen—3—yl— 1,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid as a yellow crude product.

Step 2: (3,3—Dimethy1—morpholin—4—yl)—(8—isobutylsulfanyl—7—methoxy—l—thiophen—3- yl—1,4—dihydro—chromeno[4,3—c]pyrazol—3—yl)—methanone /o o /o o O O / N / s TSP, DIPEA s o + E M M ‘ 0 ~ L0 s S / / To 8—isobutylsulfanyl—7—methoxy—1—thiophen—3—yl—1,4—dihydro—chromeno[4,3—c]pyrazole—3— carboxylic acid (80.00 mg; 0.19 mmol; 1.00 eq.) suspended in DCM (3.00 ml; 46.80 mmol; 243.67 eq.) was added 2,4,6—tripropyl—1,3,5,2,4,6—trioxatriphosphinane trioxide (0.17 ml; 0.29 mmol; 1.50 eq.), 3,3—Dimethyl—morpholine (0.14 ml; 0.29 mmol; 1.50 eq.) and Ethyl— diisopropyl—amine (0.10 ml; 0.58 mmol; 3.00 eq.). The reaction was stirred at RT for 1 h.

Mixture was concentrated and purified by flash chromatography to afford the desired product (40 mg, 40%) as a white solid. 1H—NMR d6): 8 .98 (s, 1H), 7.88—7.83 (m, 1H), 7.35 (dd, 1H), 6.72 (s, 1H), 6.60 (s, 1H), 5.37 (s, 2H), 3.94 (m, 2H), 3.80 (s, 3H), 3.72 (t, 2H), 3.42 (s, 2H), 2.34 (d, 2H), 1.60 (septet, 1H), 1.42 (s, 6H), 0.91 (d, 6H). m/z = 514 [M+H]+ Example 24 8-isopr0pylsulfanylmeth0xythi0phenyl-1,4-dihydro-chromeno[4,3-c]pyrazole carboxylic acid tert-butyl-methyl-amide (52) » O / O or N dN / ] In a smiliar manner to example 23, 8—isopropylsulfanyl—7—methoxy-1—thiophen—3—y1- l,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid utyl-methyl-amide was obtained from 8—Isopropylsulfanyl—7-methoxy- l—thiophen—3-yl— l ,4—dihydro-chromeno[4,3—c]pyrazole—3— ylic acid (170 mg, 0.42 mmol), and n—tert—butylmethylamine (73.63 mg, 0.84 mmol, 2eq.) as a white solid in 15 % yield (29 mg). m/z = 472 [M+H]+ HPLC retention time = 6.45 min.

Example 25 7-methoxy(propanesulfonyl)thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazole-S- carboxylic acid tert—butyl-methyl-amide (79) To 8-isopropylsulfanylmethoxythiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazole—3—carboxylic acid tert—butyl—methyl—amide (24 mg, 0.05 mmol) in DCM ( 2mL) was added 3—chloroperbenzoic acid (11.40 mg; 0.05 mmol; 1.00 eq.). The reaction was stirred at RT for 2 h. The mixture was purified by flash chromatography to afford the desired product (8 mg, 32 %) as a white solid. m/z = 504 [M+H]+, HPLC retention time = 4.40 min.

Example 26 (8-Cyclopropanesulfonylmethoxy-l-thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazol- 3-yl)-(3,3-dimethyl-morpholinyl)-methan0ne (106) WO 09980 /O O O O \\ / o’/S A / 6 Step 1: 8-(cyclopropylsulfonyl)methoxy(thiophenyl)-1,4- dihydrochromeno[4,3—c]pyrazole—3—carboxylic acid /0 O Na_ /N\/\N/ (0 O + O\\ /O s —_> o / To 8—Bromo—7—methoxy— l —thiophen—3—yl- l ,4—dihydro—chromeno[4,3—c]pyrazole-3—carboxylic acid (100.00 mg; 0.25 mmol; 1.00 eq.) suspended in N,N—Dimethyl—formamide (3.00 ml) was added cyclopropanesulfinic acid sodium (47.19 mg; 0.37 mmol; 1.50 eq.), copper iodide (23.38 mg; 0.12 mmol; 0.50 eq.). and N,N'—Dimethyl—ethane—1,2—diamine (0.04 ml; 0.37 mmol; 1.50 eq.). The reaction mixture was heated to 90 0C for 18 h. The mixture was filtered, concentrated and lyophilized to afford lopropylsulfonyl)—7—methoxy—l-(thiophen—3—yl)- 1,4— dihydrochromeno[4,3—c]pyrazole—3—carboxylic acid as a blue crude solid.

Step 2: (8—Cyclopropanesulfonyl—7—methoxy—l—thiophen—3—yl-1,4—dihydro— chromeno[4,3—c]pyrazol—3—yl)—(3,3—dimethyl—morpholin—4—yl)—methanone In a r manner to example 23 above step 2, (8—cyclopropanesulfonyl—7—methoxy—l—thiophen— 3—yl—1,4—dihydro—chromeno[4,3—c]pyrazol—3—yl)—(3,3—dimethyl—morpholin—4—yl)—methanone was obtained from 8—(cyclopropylsulfonyl)—7—methoxy—l—(thiophen—3—yl)—l,4—dihydrochromeno[4,3— c]pyrazolecarboxylic acid (30.00 mg; 0.07 mmol; 1.00 eq.) and 3,3-dimethyl-morpholine (0.05 ml; 0.10 mmol; l.50 eq.). The desired compound was obtained in a yield of 12 mg (33 %) as a blue solid.

LCMS: m/z = 530 [M+H]+ HPLC retention time = 3.24 min.

Example 27 (3,3—Dimethyl-morpholinyl)-[7-meth0xy(propanesulf0nyl)thi0phenyl-1,4- dihydro-chromeno[4,3-c]pyrazolyl]-methanone (112) ] Step 1: 7-methoxy(propanesulfonyl)-l-thiophenyl-1,4-dihydrochromeno [4,3—c]pyrazole—3—carboxylic acid In a similar manner to example 26 (step 1), oxy—8—(propane-2—sulfonyl)—l—thiophen-3—yl— l,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid was obtained from o—7—methoxy— l—thiophen—3—yl—l,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid (100.00 mg; 0.25 mmol; 1.00 eq.) and propane—2—sulfinic acid sodium (47.94 mg; 0.37 mmol; 1.50 eq.) as a crude blue solid.

Step 2: (3,3—Dimethyl—morpholin—4—yl)—[7—methoxy—8—(propane—2—sulfonyl)—1- thiophen—3—yl- l ,4—dihydro—chromeno[4,3—c]pyrazol—3—yl] —methanone In a similar manner to example 26 (step 2), (3,3-Dimethyl—morpholin-4—yl)—[7-methoxy—8— (propane—2—sulfonyl)— l —thiophen—3—yl— l ,4—dihydro—chromeno[4,3—c]pyrazol-3—yl] —methanone was obtained from 7—Methoxy—8—(propane—2—sulfonyl)—l—thiophen—3—yl—l,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid (100.00 mg; 0.23 mmol; 1.00 eq.), and 3,3—Dimethyl—morpholine (0.17 ml; 0.35 mmol; 1.50 eq.) in 8.2% yield (10 mg) as a blue solid. LCMS: m/z = 532 [M+H]+, HPLC retention time = 3.25 min.

Example 28 (3,3-Dimethyl-morpholinyl)-[7-meth0xy(2-methyl-propanesulfonyl)thiophen yl-1,4-dihydro-chr0meno[4,3-c]pyrazolyl]-methan0ne (127) /O O O O \\ / \ L0 ] Step 1: 7—Methoxy—8—(2—methyl—propane—1—sulfonyl)—l—thiophen—3—yl—1,4—dihydro— chromeno[4,3—c]pyrazole—3-carboxylic acid In a similar manner to example 26 (step 1), 7—Methoxy—8—(2—methyl—propane—l—sulfonyl)—1— thiophen—3—yl—1,4—dihydro—chromeno[4,3—c]pyrazole—3-carboxylic acid was obtained from 8— Bromo—7—methoxy—1-thiophen—3—yl— 1,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid (100.00 mg; 0.25 mmol; 1.00 eq.) and 2—Methyl—propane—1—sulfinic acid sodium (53.10 mg; 0.37 mmol; 1.50 eq.) as a blue crude solid.

Step 2: (3,3—Dimethyl—morpholin-4—yl)—[7—methoxy—8—(2—methyl-propane—1—sulfonyl)— 1—thiophen—3—yl—1,4-dihydro—chromeno[4,3—c]pyrazol—3—yl]—methanone In a similar manner to example 26 (step 2), imethyl—morpholin—4—yl)—[7—methoxy—8—(2— methyl-propanesulfony1)thiophenyl- 1,4-dihydro-chromeno[4,3-c]pyrazolyl]- methanone was obtained from 7—Methoxy—8—(2—methyl—propane—1—sulfonyl)—1—thiophen—3—yl—1,4— o—chromeno[4,3-c]pyrazole—3—carboxylic acid (30.00 mg; 0.07 mmol; 1.00 eq.), and 3,3— Dimethyl—morpholine (46.22 mg; 0.40 mmol; 6.00 eq.) as a white solid in 13.7 % yield (5 mg).

LCMS: m/z = 546 [M+H]+, HPLC retention time = 3.56 min.

Example 29 7-Methoxy(propanesulfonyl)—1-thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazole-S- carboxylic acid (3-hydroxymethyl-oxetanyl)-amide (187) In a similar manner to example 27, 7—methoxy—8-(propane—2—sulfonyl)—1—thiophen—3— yl—1,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid (3—hydroxymethyl—oxetan—3—yl)— amide was obtained from 7—Methoxy—8—(propane—2—sulfonyl)—l—thiophen—3—yl—l,4—dihydro— no[4,3—c]pyrazole—3-carboxylic acid (70.00 mg; 0.16 mmol; 1.00 eq.) and (3—Amino— oxetan—3—yl)—methanol (24.92 mg; 0.24 mmol; 1.50 eq.) as white solid in 25 % yield (21 mg). 1H—NMR (DMSO—d6): 5 8.77 (s, 1H), 8.02 (dd, 1H), 7.86 (dd, 1H), 7.34 (dd, 1H), 7.19 (s, 1H), 6.93 (s, 1H), 5.64 (s, 2H), 5.14 (s, 1H), 4.67 (d, 2H), 4.51 (d, 2H), 3.90 (s, 3H), 3.68 (d, 2H), 3.45 (septet, 1H), 1.08 (d, 6H). m/z = 520 [M+H]+ Example 30 7-Meth0xy(propanesulf0nyl)thiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazole- 3-carb0xylic acid (3-methyl-0xetanyl)-amide (188) In a similar manner to example 27, 7—methoxy—8—(propane—2—sulfonyl)—1—thiophen—3— yl—1,4—dihydro-chromeno[4,3-c]pyrazole—3—carboxylic acid (3—methyl—oxetan—3—yl)-amide was obtained from 7—Methoxy—8—(propane—2—sulfonyl)—1—thiophen—3—yl—1,4—dihydro—chromeno[4,3— zole—3—carboxylic acid (70.00 mg; 0.16 mmol; 1.00 eq.) and 3—Methyl—oxetan—3—ylamine hydrochloride (29.87 mg; 0.24 mmol; 1.50 eq.) as a White solid in 34 % yield (28 mg). 1H—NMR (DMSO—d6): 8 8.95 (s, 1H), 8.03 (dd, 1H), 7.85 (dd, 1H), 7.34 (dd, 1H), 7.18 (s, 1H), 6.93 (s, 1H), 5.64 (s, 2H), 4.71 (d, 2H), 4.31 (d, 2H), 3.90 (s, 3H), 3.45 (septet, 1H), 1.59 (s, 3H), 1.07 (d, 6H). m/z = 504 [M+H]+ Example 31 (3,3-Dimethyl-morpholinyl)-[8-(1-hydr0xymethyl-propyl)methoxythi0phenyl- 1,4-dihydro-chromeno[4,3-c]pyrazol-S-yl]-methan0ne (131) WO 09980 ] To imethyl—morpholin—4—yl)—[7—methoxy—8—(2—methyl—propenyl)—l—thiophen—3— yl—1,4—dihydro—chromeno[4,3—c]pyrazol—3-yl]—methanone (70.00 mg; 0.15 mmol; 1.00 eq.) suspended in THF (3.00 ml), was added methylsulfanylmethane; with borane (16.63 mg; 0.22 mmol; 1.50 eq.). The reaction was stirred at RT for 2 h. Then NaOH (2N solution) was added very slowly. The reaction e was purified using reverse phase prep—HPLC (45—60 % CH3CN in 0.1 % NH4OH in H20) to afford the desired product (19 mg, 26 %) as a white solid. 1H-NMR (DMSO-d6): 8 7.86 (dd, 1H), 7.78 (dd, 1H), 7.28 (dd, 1H), 6.92 (s, 1H), 6.65 (s, 1H), .39 (d, 1H), 5.26 (d, 1H), 4.56 (d, 1H), 4.50 (t, 1H), 4.03—3.96 (m, 1H), 3.93—3.85 (m, 1H), 3.77 — 3.70 (m, 5H), 3.42 (s, 2H), 1.61 (sextet, 1H), 1.42 (d, 6H), 0.74 (d, 3H), 0.68 (d, 3H). m/z = 498 [M+H]+ Example 32 (3,3-Dimethyl-morpholinyl)-[7-meth0xythi0phenyl(5-trimethylsilanyl-5H- [1,2,4]triazolyl)-1,4-dihydro-chromeno[4,3-c]pyrazolyl]-methan0ne (139) To diazomethyl—trimethyl-silane (0.17 ml; 0.33 mmol; 3.00 eq.) suspended in Ethoxy— ethane (3.00 ml) at 00 C was added n—butyl lithium (0.09 ml; 0.22 mmol; 2.00 eq.). The reaction mixture was stirred at 00 C for 30 min then 3-(3,3—Dimethyl-morpholine—4—carbonyl)—7—methoxy— l—thiophen—3—yl—l,4—dihydro—chromeno[4,3—c]pyrazole—8—carbonitrile (50.00 mg; 0.11 mmol; 1.00 eq.) was added and the reaction was stirred at 0 0C for another 30 min. The reaction mixture was warmed to RT and stirred at RT for 1 h. The mixture was trated and purified by column chromatography to afford the desired product (18 mg, 29 %) as a white solid. 1H-NMR (DMSO-d6): 8 7.92 (dd, 1H), 7.72 (dd, 1H), 7.28 (dd, 1H), 6.79 (s, 1H), 6.73 (s, 1H), .43 (s, 2H), 3.96 — 3.92 (m, 2H), 3.74 — 3.68 (m, 5H), 3.42 (s, 2H), 3.18 (s, 1H), 1.43 (s, 6H), 0.06 (s, 9H). m/z = 565 [M+H]+ Example 33 imethyl-morpholinyl)-[7-methoxythiophenyl(5H-[1,2,4]triazolyl)-1,4- dihydro-chromeno[4,3-c]pyrazolyl]-methanone (161) To (3 ethyl—morpholin—4—yl)— [7—methoxy— l -thiophen—3—yl—8— (5 —trimethylsilanyl— 5H—[1,2,4]triazol—3—yl)—l,4—dihydro—chromeno[4,3—c]pyrazol—3—yl]—methanone (34.00 mg; 0.06 mmol; 1.00 eq.) dissolved in THF (3.00 ml) was added utyl—ammonium fluoride (1M in THF) (0.30 ml; 0.30 mmol; 5.00 eq.) and the reaction was stirred at RT for 18 h. Reaction mixture was concentrated and purified by reverse phase prep—HPLC (35—40 % CH3CN in 0.1 % NH4OH in H20) to afford the desired product (36 mg, 82 %) as a white solid. 1H—NMR (DMSO—d6) (tetrabutyl ammonium salt): 6 7.89 (dd, 1H), 7.79 (dd, 1H), 7.73 (s, 1H), 7.53 (s, 1H), 7.31 (dd, 1H), 6.70 (s, 1H), 5.31 (s, 2H), 3.96 (t, 2H), 3.83 (s, 3H), 3.73 (t, 2H), 3.43 (s, 2H), 3.20 — 3.13 (m, 9H), 1.64-1.52 (m, 9H), 1.43 (s, 6H), 1.33 (sextet, 9H), 0.94 (t, 12H). m/z = 493 [M+H]+ Example 34 (8-Aminomethylmethoxythiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazolyl)- (3,3-dimethyl-morpholinyl)-methanone (166) O O N N3 N60 Step 1: Ethyl 8—cyano—7—methoxy—1—(3—thienyl)—1, 4—dihydrochromeno [4,3— c]pyrazole—3—carboxylate WO 09980 /0 O /O O O Cul, CuCN 0 Br // —> NC // OEt OEt N_N N—N s? 83 To a solution of ethyl 8—bromo-7—methoxy—1-(3—thienyl)—1, 4-dihydrochromeno ]pyrazole— oxylate (2 g, 0.0459 mol) in NMP (50 mL), was added CuI (90 mg, 0.5 mmol) and ed by CuCN (825 mg, 9.1 mmol) in a sealed tube. The reaction mixture was heated to 160 ° C for 16 h. The reaction mixture was filtered through celite and the filtrate was concentrated.

The crude product was purified by column chromatography by using dichloromethane / methanol (9:1) as eluent. The product was triturated with acetonitrile and filtered, to afford of the desired compound (0.7 g, 83 %) as a white solid. 1H NMR (400 MHz, DMSO ) 5 8.05-8.04 (dd, J: 1.4, 3.1 Hz, 1H), 7.90-7.88 (dd, J: 3.2, 5.1 Hz, 1H), 7.37—7.35 (dd, J: 1.4, 5.1 Hz, 1H), 5.63 (s, 1H), 4.33-4.28 (m, 2H), 3.89 (s, 1H), 1.32— 1.28 (t, J: 12.9 Hz, 3H). m/z = 382 [M+H]+ Step 2: 8—Cyano—7—methoxy—1—thiophen—3—yl—1,4—dihydro—chromeno[4,3—c]pyrazole— 3—carboxylic acid To 8—cyano—7—methoxy—1—thiophen—3—yl—l,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid ethyl ester (300.00 mg; 0.79 mmol; 1.00 eq.) ved in Methanol (6.00 ml; 177.52 mmol; 225.69 eq.) was added potassium hydroxide (66.20 mg; 1.18 mmol; 1.50 eq.) and water (0.60 ml). The reaction mixture was heated to 500 C for 2 h. The reaction was concentrated and lyophilized to afford the crude desired product as a gray solid.

Step 3: 3—(3,3—Dimethyl—morpholine—4—carbonyl)—7—methoxy—l—thiophen—3—yl—l,4— dihydro—chromeno[4,3—c]pyrazole—8—carbonitrile (86) To 8—cyano—7-methoxy—l—thiophen—3-yl—l,4—dihydro-chromeno[4,3—c]pyrazole—3—carboxylic acid 0 mg; 0.76 mmol; 1.00 eq.) suspended in DCM (6.00 ml; 93.60 mmol; 122.50 eq.) was added tripropyl—l,3,5,2,4,6—trioxatriphosphinane 2,4,6—trioxide (1.35 ml; 2.29 mmol; 3.00 eq.), 3,3-Dimethyl—morpholine (176.01 mg; 1.53 mmol; 2.00 eq.) and ethyl—diisopropyl—amine (0.38 ml; 2.29 mmol; 3.00 eq.). The reaction was d at RT for l h. Mixture was concentrated and purified by flash chromatography to afford the desired product (309 mg, 90 %) as a white solid. LCMS: m/z = 451 [M+H]+ Step 4: (8—Aminomethyl—7—methoxy-l—thiophen—3—yl—l,4—dihydro—chromeno[4,3— c]pyrazol—3—y1)—(3,3—dimethy1—morpholin—4—yl)—methanone /o o NH3/MeOH N N‘N N RafNi,H2 O\ x [K a O o 3—(3 ,3—dimethyl—morpholine—4—carbonyl)—7—methoxy— l —thiophen—3—yl— l ,4—dihydro—chromeno [4,3— c]pyrazole—8—carbonitrile (50.00 mg; 0.11 mmol; 1.00 eq.) was dissolved in amonia in methanol (10.00 ml; 20.00 mmol; 180.20 eq.) and the reaction mixture was run through an H—cube under full H2 pressure using Raney nickel cartridge at 70 0C for 2 h. The mixture was concentrated and purified by reverse phase PLC (35—45 % CH3CN in 0.1 % NH4OH in H20) to afford the desired product as white solid (7 mg, 14 %). LCMS: m/z = 455 [M+H]+, HPLC retention time = 2.71 min.

Example 35 N-[3-(3,3-Dimethyl-morpholinecarbonyl)meth0xythi0phenyl-1,4-dihydr0- chromeno[4,3-c]pyrazolylmethyl]-acetamide (175) /O O GYM 5N1 6O To nomethyl—7—methoxy—l-thiophen—3—yl—l,4—dihydro—chromeno[4,3—c]pyrazol— 3—yl)—(3,3—dimethyl-morpholin—4—yl)—methanone (20.00 mg; 0.04 mmol; 1.00 eq.) suspended in DCM (2.00 ml; 31.20 mmol; 709.11 eq.) was added 2,4,6—tripropyl—l,3,5,2,4,6— trioxatriphosphinane trioxide (0.04 ml; 0.07 mmol; 1.50 eq.), acetic acid (3.96 mg; 0.07 mmol; 1.50 eq.) and ethyl—diisopropyl—amine (0.02 ml; 0.13 mmol; 3.00 eq.). The reaction mixture was stirred at RT for l h. The e was concentrated and purified by reverse phase prep-HPLC (32—38 % CH3CN in 0.1 % NH4OH in H20) to afford the desired product (4 mg, 18%) as a white solid. 1H-NMR (DMSO-d6): 5 7.91—7.76 (m, 2H), 7.28-7.22 (m, 1H), 6.74—6.61 (m, 2H), 5.37-5.26 (m, 2H), 4.14 (s, 0.5H), 3.96 (d, 3.5H), 3.84—3.69 (m, 5H), 3.42 (s, 2H), 2.05 (s, 0.5H), 1.91 (s, 0.5H), 1.86 — 1.76 (m, 3H), 1.42 (s, 6H). m/z = 497 [M+H]+ Example 36 8-Cyanomethoxythi0phenyl-1,4-dihydr0-chr0men0[4,3-c]pyrazolecarb0xylic acid tert-butyl-methyl-amide (12) +Cu |—>N/ / O N\N/ sot\ /N7< To 8—bromo—7—methoxy— l —thiophen—3—yl— l ,4—dihydro—chromeno[4,3—c]pyrazole—3— carboxylic acid tert—butyl—methyl—amide (210 mg, 0.44 mmol) in NMP (5 mL) was added CuCN 43.5 mg, 0.48 mmol, l.l eq.) and CuI (8.4 mg, 0.044mmol 0.1 eq.). The reaction ws microwaved at 170° C for 70 min. The mixture was purified by reverse pahse prep HPLC to afford the desired product (10mg, 5 %) as a white solid. 1H NMR (400 MHz, CDClg) 8 7.54 (ddd, J = 4.7, 4.1, 2.4 Hz, 2H), 7.19 (dd, J = 5.0, 1.5 Hz, 1H), 6.97 (s, 1H), 6.62 (s, 1H), 5.58 (s, 2H), 3.92 (s, 3H), 3.28 (s, 3H), 1.53 (s, 9H). m/z = 423 [M+H]+ Example 37 7-meth0xy(1-methyl-1H-pyrrolyl)thi0phenyl-1,4-dihydr0-chromeno[4,3- c]pyrazolecarboxylic acid (2-hydroxyhydroxymethylmethyl-ethyl)-amide (179) To 8—bromo—7-methoxy—1—thiophen—3-yl—1,4—dihydro-chromeno[4,3—c]pyrazole—3— carboxylic acid (3—methyl—oxetan—3—yl)—amide (1.00 g; 2.10 mmol; 1.00 eq.) was added 1— Methyl—3—(4,4,5,5—tetramethyl—[1,3,2]dioxaborolan—2-yl)—1H-pyrrole (652.08 mg; 3.15 mmol; 1.50 eq.), palladium acetate (23.57 mg; 0.10 mmol; 0.05 eq.), dicyclohexyl—(2',6'—dimethoxy- biphenyl—2—yl)—phosphane (86.18 mg; 0.21 mmol; 0.10 eq.), ium carbonate (870.42 mg; 6.30 mmol; 3.00 eq.), dioxane (10.00 ml) and water (1.00 ml). The reaction mixture was heated at 120 °C for 24 h. The mixture was trated, filtered and ed by reverse phase prep— HPLC (35-45 % CH3CN in 0.1 % NH4OH in H20) to afford the hydrolyzed product (14 mg, 1.3 %) as a white solid. 1H—NMR d6): 5 8.06 (s, 1H), 7.90 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 7.00 (s, 1H), 6.79 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 5.77 (s, 1H), 5.49 (s, 2H), 4.95 (s, 2H), 3.83 (s, 3H), 3.65—3.56 (m, 5H), 3.53—3.45 (m, 2H), 1.30 (s, 3H). m/z = 495 [M+H]+ Example 38 7-Methoxy(1-methyl-1H-pyrazolyl)thiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarboxylic acid (2-hydroxyhydroxymethylmethyl-ethyl)-amide (185) Using a procedure similar to example 37, 7—methoxy—8—(l—methyl—lH—pyrazol—3—yl)— 1—thiophen—3—yl—1,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid (2—hydroxy— 1— hydroxymethyl—1—methyl—ethyl)—amide was obtained from 8—Bromo—7—methoxy—1—thiophen—3—yl— 1,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid (3-methyl-oxetan-3—yl)—amide (1.00 g; 2.10 mmol; 1.00 eq.) and l—Methyl—3—(4,4,5,5—tetramethyl—[1,3,2]dioxaborolan—2—yl)—1H— pyrazole (655.19 mg; 3.15 mmol; 1.50 eq.). as a white solid in 2 % yield (20 mg). 1H-NMR (DMSO-d6): 8 8.01 (s, 1H), 7.85 (d, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 7.32 (s, 2H), 6.76 (s, 1H), 6.49 (s, 1H), 5.53 (s, 2H), 4.95 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.66—3.57 (m, 2H), 3.53—3.45 (m, 2H), 1.30 (s, 3H). m/z = 496 [M+H]+ Example 39 7-Meth0xy(tetrahydr0-furanyl)thiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarboxylic acid tert—butyl-methyl-amide (194) To 8-(2,5—dihydro-furan—3-yl)—7—methoxythiophen—3—yl-1,4—dihydro—chromeno[4,3— zole—3—carboxylic acid tert—butyl—methyl—amide (30.00 mg; 0.06 mmol; 1.00 eq.) suspended in acetic acid (3.00 ml) was added palladium on carbon (0.02 ml; 0.32 mmol; 5.00 eq.). The flask was capped with a rubber septum and topped with a hydrogen balloon. The on mixture was stirred at RT for 18 h. Triethylamine was added, the e was filtered through celite and the mixture was purified by reverse phase prep—HPLC (55—63 % CH3CN in 0.1 % NH4OH in H20) to afford the desired product (11 mg, 37 %) as a white solid. 1H-NMR (DMSO-d6): 8 7.95 (dd, 1H), 7.84 (dd, 1H), 7.32 (dd, 1H), 6.69 (s, 1H), 6.60 (s, 1H), .34 (d, 2H), 3.85 (t, 1H), 3.79 (s, 3H), 3.71 — 3.57 (m, 2H), 3.43 (quintet, 1H), 3.21 — 3.15 (m, 4H), 2.10 — 2.00 (m, 1H), .40 (m, 10H). m/z = 468 [M+H]+ Example 40 7-Meth0xy(tetrahydro-furanyl)thiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarb0xylic acid tert-butyl-methyl-amide (201) In a r manner to example 39, 7-methoxy(tetrahydro-furan-Z-yl)thiophen- 3—yl—1,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid utyl—methyl—amide was ed from 8- (4,5—Dihydro—furan—2—yl)—7—methoxy— 1—thiophen—3—yl- 1 ,4—dihydro— chromeno[4,3—c]pyrazole—3—carboxylic acid tert—butyl—methyl—amide (65.00 mg; 0.14 mmol; 1.00 eq.) as a white solid in 9% yield (6 mg). 1H-NMR (DMSO-d6): 8 7.93 (dd, 1H), 7.82 (dd, 1H), 7.30 (dd, 1H), 6.75 (s, 1H), 6.66 (s, 1H), .33 (q, 2H), 4.90 (dd, 1H), 3.77 (s, 3H), 3.65—3.58 (m, 2H), 3.17 (s, 3H), 2.18 — 2.07 (m, 1H), 1.85-1.74 (m, 1H), 1.70 — 1.59 (m, 1H), 1.50-1.40 (m, 10H). m/z = 468 [M+H]+ Example 41 7-Methoxy(1-methyl-1H-pyrazolyl)thiophenyl-1,4-dihydro-chromeno[4,3- c]pyrazolecarboxylic acid (1S,3S)amino-cyclopentyl ester (180) / /O O O O (3| 0 O TBTU, DIPEA / B / r Br Br / O + + Nwho,o / / / N‘N "II'O N‘N .....

N\N 0 ~ ‘ S S S / / Step 1: To 8—bromo—7—methoxy—1—thiophen—3—yl—1,4—dihydro—chromeno[4,3— c]pyrazolecarboxylic acid (500.00 mg; 1.23 mmol; 1.00 eq.) ded in DCM (10.00 ml; 156.01 mmol; 127.06 eq.) was added (1S,3S)—3—amino—cyclopentanol hydrochloride (253.43 mg; 1.84 mmol; 1.50 eq.), [(benzotriazol-1—yloxy)—dimethylamino—methylene]—dimethyl—ammonium tetrafluoroborate (788.43 mg; 2.46 mmol; 2.00 eq.), and ethyl—diisopropyl—amine (0.61 ml; 3.68 mmol; 3.00 eq.). The reaction was stirred at RT for 1 h. The mixture was concentrated and purified by flash chromatography to afford a mixture of 8—bromo—7—methoxy—1-thiophen—3—yl— 1,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid ((1S,3S)—3-hydroxy—cyclopentyl)—amide and 8-bromomethoxythiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazolecarboxylic acid (1S,3S)—3—amino—cyclopentyl ester (total 247 mg, 41 %) as a white solid. o o iwo//B O O °O,.QN INN o / / l C /. , N , 00.

UMN db.N 5N‘N /N’N N-N "N Pd(OAc)2, S- Phos K2COa /N _ Step 2: To a mixture of o—7—methoxy—1—thiophen—3—y1—1,4—dihydro- chromeno[4,3—c]pyrazole—3—carboxylic acid ((lS,3S)—3—hydroxy—cyclopentyl)—amide and 8— 7-methoxythiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazolecarboxylic acid (lS,3S)—3—amino—cyclopentyl ester (120.00 mg; 0.24 mmol; 1.00 eq.) was added l—methyl—3— (4,4,5,5—tetramethyl—[l,3,2]dioxaborolan—2—yl)—1H—pyrazole (76.37 mg; 0.37 mmol; 1.50 eq.), palladium acetate (2.75 mg; 0.01 mmol; 0.05 eq.), dicyclohexyl—(2',6'—dimethoxy—biphenyl—2—yl)— phosphane (10.05 mg; 0.02 mmol; 0.10 eq.), potassium carbonate (101.46 mg; 0.73 mmol; 3.00 eq.), dioxane (4.00 ml) and water (0.40 ml). The reaction mixture was heated at 140 0C for 18 h.

The mixture was concentrated and a portion of it was ed by flash chromatography (KPNH, 80-100 % EtOAc/Hexanes, 0-20 % MeOH/EtOAc) to afford 7-methoxy(1-methyl-1H- l—3—yl)-1—thiophen—3—yl—l,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid ((1S,3S)— 3—hydroxy—cyclopentyl)—amide (78 mg, 65 %) as a white solid. The rest of the crude material was purified by reverse phase prep—HPLC (35—45 % CH3CN in 0.1 % NH4OH in H20) to afford 7— methoxy—8—(l-methyl-lH—pyrazol—3—yl)—l—thiophen—3-yl—1,4—dihydro-chromeno[4,3—c]pyrazole— 3—carboxylic acid (lS,3S)—3-amino—cyclopentyl ester (5 mg, 4.2 %) as a white solid. 1H-NMR (DMSO-d6): 8 7.94 (s, 1H), 7.82 (s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.33 (s, 1H), 6.77 (s, 1H), 6.50 (s, 1H), 5.38 (s, 2H), 4.96 (s, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.63 (s, 1H), 1.32 (d, 12H). m/z = 492 [M+H]+ Example 42 7-Methoxy(1-methyl-1H-pyrrolyl)thiophenyl-1,4-dihydr0-chromeno[4,3- c]pyrazolecarb0xylic acid (1S,3S)amino-cyclopentyl ester (181) o o ] In a similar manner to example 41, 7—methoxy—8—(1—methyl—lH—pyrrol—3-yl)—l— thiophen—3—yl—l,4—dihydro—chromeno[4,3—c]pyrazole—3—carboxylic acid )—3—amino— cyclopentyl ester was obtained from 8—bromo—7—methoxy-1—thiophen—3—yl—l,4—dihydro— chromeno[4,3-c]pyrazole—3—carboxylic acid (lS,3S)—3-amino-cyclopentyl ester, in 3 % yield (3 mg) as a white solid. 1H-NMR (DMSO-d6): 8 8.01 (s, 1H), 7.88 (s, 1H), 7.38 (s, 1H), 7.01 (s, 1H), 6.88 (s, 1H), 6.72 (s, 1H), 6.64 (s, 1H), 5.81 (s, 1H), 5.34 (s, 2H), 4.98 (s, 1H), 4.09 (s, 5H), 3.84 (s, 3H), 3.59 (s, 4H), 1.48 — 1.14 (m, 12H). m/z = 491 [M+H]+ Example 43 7-Methoxythiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazolecarboxylic acid tert- methyl-amide (133) To 8—bromo—7-methoxy—1—thiophen—3-yl—1,4—dihydro-chromeno[4,3—c]pyrazole—3— carboxylic acid tert—butyl—methyl—amide (70.00 mg; 0.15 mmol; 1.00 eq.), was added boronic acid, [1,1'—bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complex with dichloromethane (1:1) (24.00 mg; 0.03 mmol; 0.20 eq.), cesium carbonate (143.63 mg; 0.44 mmol; 3.00 eq.) dioxane (2.00 ml; 23.47 mmol; 159.74 eq.) and water (0.20 ml). The reaction was heated to 120 0C for 18 h. The reaction mixture was concentrated, purified by reverse phase using prep—HPLC (45—55 % CH3CN in 0.1 % NH4OH in H20) to afford 7-methoxy—l—thiophen— 3—yl—l,4-dihydro—chromeno[4,3-c]pyrazole—3-carboxylic acid tert—butyl—methyl—amide as the major t as a white solid (30 mg, 51 %). 1H-NMR (DMSO-d6): 8 7.94 (dd, 1H), 7.81 (dd, 1H), 7.32 (dd, 1H), 6.67 (d, 1H), 6.62 (d, 1H), 6.47 (dd, 1H), 5.33 (s, 2H), 3.73 (s, 3H), 3.17 (s, 3H), 1.44 (s, 9H). m/z = 398 [M+H]+ Example 44 (2-Methoxymethylmethyl-pyrrolidinyl)-(7-methoxythi0phenyl-1,4-dihydrochromeno [4,3-c]pyrazolyl)-methan0ne (183) In a similar manner to example 43, (2—methoxymethyl—2—methyl—pyrrolidin—1—yl)—(7— methoxy-l-thiophenyl-1,4-dihydro-Chromeno[4,3-c]pyrazoly1)-methanone was obtained from (2—Hydroxymethyl—2—methyl—pyrrolidin— (7—methoxy-1—thiophen—3—y1— 1,4—dihydro— chromeno[4,3-c]pyrazol—3—yl)-methanone as a white solid (13 mg, 50 %). 1H-NMR (DMSO-d6): 8 7.95 (s, 1H), 7.82 (s, 1H), 7.32 (s, 1H), 6.69 — 6.60 (m, 2H), 6.49—6.44 (m, 1H), 5.43 (s, 2H), 4.05 (s, 1H), 3.90—3.79 (m, 2H), 3.73 (s, 3H), 3.59—3.52 (m, 1H), 2.16 — 2.07 (m, 1H), 1.88-1.72(m, 2H), 1.68—1.58 (m, 1H), 1.42 (s, 3H). m/z = 443 [M+H]+ Example 45 (3,3-Dimethyl-morpholinyl)-(7-methoxythi0phenyl-1,4-dihydr0-chromen0[4,3- c]pyrazolyl)-methanone (128) ”3%o// N‘N NJ§ S/‘S Lo In a similar manner to example 43, (3,3—Dimethyl—morpholin-4—yl)—(7-methoxy—1— thiophen—3—y1—1,4—dihydro—chromeno[4,3—c]pyrazol—3—yl)—methanone was ed from (8— Bromo-7—methoxy—1—thiophen—3—yl—1,4—dihydro—chromeno[4,3—c]pyrazol—3—yl)—(3,3—dimethyl— morpholin—4—yl)—methanone as a white solid (13 mg, 46 %).

LCMS: m/z = 427 [M+H]+, HPLC retention time = 3.65 min. e 46 7-Methoxythiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazole-3,8-dicarboxylic acid 8- amide 3-(tert-butyl-methyl-amide) (50) Step 1: 8-Carbamoyl—7—methoxy- l—thiophen—3—yl— l ,4—dihydro—chromeno[4,3— c]pyrazole—3—carboxylic acid / O \ O To 8—cyano—7-methoxy—l—thiophen—3-yl—l,4—dihydro-chromeno[4,3—c]pyrazole—3—carboxylic acid (45.00 mg; 0.13 mmol; 1.00 eq.) (example 34) in DMSO (4 mL) was added H202 (0.12 ml; 1.27 mmol; 10.00 eq.) and 2.0M NaOH aq (0.64 ml; 1.27 mmol; 10.00 eq.). The reaction was stirred at RT for 2 h. The mixture was purified by reverse phase HPLC to afford the d product (17 mg, 35 %) as a white solid.

Step 2: 7—Methoxy-l—thiophen—3—yl-l,4—dihydro—chromeno[4,3—c]pyrazole-3,8— dicarboxylic acid 8—amide 3—(tert—butyl—methyl—amide) \\N o To 8-carbamoylmethoxythiophenyl-1,4-dihydro-chromeno[4,3-c]pyrazolecarboxylic acid (17 mg, 0.05 mmol) in DCM (1.00 ml; 46.80 mmol; 1022.39 eq.) was added DIPEA (0.02 ml; 0.09 mmol; 2.00 eq.), o-(benzotriazol—l—yl)—n,n,n',n'—tetramethyluronium tetrafluoroborate (29.40 mg; 0.09 mmol; 2.00 eq.), and N—tert—butylmethylamine (0.01 ml; 0.09 mmol; 2.00 eq.).

Reaction was stirred at RT for 30 min. The e was concentrated and purified by reverse phase prepHPLC to afford the desired product (2.5 mg, 11 %) as a white solid. 1H NMR (400 MHz, MeOD) 8 7.88 (s, 1H), 7.71 (s, 1H), 7.69 — 7.56 (m, 1H), 7.26 (d, J = 4.9 Hz, 1H), 6.79 (s, 1H), 5.46 (s, 2H), 3.98 (s, 3H), 3.23 (s, 3H), 1.54 (s, 9H). m/z = 441 [M+H]+ Example 47 The ing compounds were prepared using procedures ous to those disclosed in Example 1: WO 09980 Compound Boronic acid Amine LC/MS NMR Starting Starting al material XL K m/z: 532 1H NMR (DMSO— I N [M+H]+ B\ d6): 5 8.03 (dd, / O Ng K/o 1H), 7.91 (dd, 1H), 4 7.82 (s, 1H), 7.38 (8-( 1 -Cyc10pr0py1- 1H-pyrazol (d, 1H), 7.21 (s, y1)—7—methoxy—1—(thiophen—3—y1)— 1H), 6.79 (d, 2H), 1,4—dihydrochromen0[4,3— 5.40 (s, 2H), 3.96 c]pyraz01—3—y1)(3,3— (t, 2H), 3.86 (s, dimethylmorpholino)methanone 3H), 3.73 (t, 3H), (215) 3.42 (s, 2H), 1.42 (s, 6H), 1.05 — 0.93 (m, 4H). m/z: 547 H NMR (DMSO- [M+H]+ d6): 5 7.96 (s, 1H), 7.83 (s, 1H), 7.60 (s, 1H), 7.46 (s, 1—(4—(7—methoxy—8—( 1—methy1— 1H— 1H), 7.35 — 7.30 pyrazol—3—y1)—1—(thi0phen—3—y1)— (m, 1H), 6.76 (s, 1,4—dihydr0chromen0 [4,3— 1H), 6.49 (s, 1H), c]pyrazolecarb0ny1)-3 ,3- 5.41 (s, 2H), 4.27 dimethylpiperazin—1—y1)ethan0ne (t, 1H), 4.19 (t, 1H), (216) 3.84 (s, 3H), 3.77 (s, 3H), 3.65 — 3.57 (m, 3H), 3.44 (t, 1H), 2.00 (d, 3H), 1.49 (d, 6H). m m: 492 N [M+H]+ / / I / o\K6 0K/o /N’N N‘N LoN’g 3/0 HPLC SC; retention / \ ,N . time: (7—methoxy—8—(1—methyl— 1H- 4.91 min pyrazol—3—yl)—1—(thiophen—3—yl)— l,4—dihydrochromeno[4,3— c]pyrazolyl) (3- methylmorpholino)methanone (218) Example 48 N-(1,3-dihydroxy-2—methylpropan-Z-yl)meth0xy-N-methyl(1-methyl-1H-pyrazol yl)(thiophenyl)—1,4-dihydrochromeno[4,3-c]pyrazole—3-carboxamide (217) O O / / I / N 83 D Compound 116 01240) (30.00 mg; 0.06 mmol; 1.00 eq.) was dissolved in hydrochloric acid in water (2.00 ml). The reaction mixture was stirred at room temperature overnight. The mixture was applied to a prep—HPLC (32—38 % CH3CN in 0.1 % NH4OH in H20) to afford the desired t 7—Methoxy—8—(1—methy1—1H—pyrazol—3—y1)—1—thiophen—3—yl-1,4—dihydro— chromeno[4,3—c]pyrazole—3—carboxylic acid (2—hydroxy—1—hydroxymethyl— 1—methyl—ethyl)— methyl—amide (19.00 mg; 0.04 mmol) as a white solid (61%). LCMS: m/z = 513 [M+H]+, HPLC retention time: 2.67 min. e 49 EC50 of cyclic AMP production in CHO FSHR cells + EC20 FSH (Assay A) 2500 Cho-FSHR—LUC—1—1—43 cells were plated per well in 5 pl of phenol red free DMEM/F12 + 1% FBS. Cells were plated in 384 well, solid white low volume plates (Greiner 784075) by Multidrop. Cells were assayed by adding 100 pl of 2X ECZO FSH/IBMX in DMEM/F12 + 0.1 % BSA) by Multidrop to 2 pl of test compound d in 384 well plates (compounds are diluted 1:50). The final FSH concentration was 0.265 pM, and the final IBMX concentration was 200 pM. The compound plate map was as follows: Column 1: 2 pl of DMSO; Column 2: 2 pl of DMSO; Columns 3—12 and 13—24: 2 pl of test compound, diluted 1:4 in 100% DMSO, or 2 pl of FSH, diluted 1:4 in DMEM/F12+0.1% BSA. The starting tration for FSH was 50 nM (final concentration was 0.5 nM). Furthermore, Column 23 ned 2 pl of EC100 FSH reference (100X) (diluted in 12 + 0.1% BSA) at a final concentration of 0.5 nM, and Column 24 contained 2 pl of 1 mM AS707664/2 reference compound 2. 5 pl of compound + ECZO FSH mixture were transferred to cell plates (1:2 dilution into 5 pl of cell media) The plates were incubated at 37 °C for 1 h. 10 pl of mixed HTRF (CisBio # EC) reagents were added per well and incubated at room temperature for 1 h. The plates were read on Envision using the cAMP HTRF — low volume 384 well protocol. The readout was the calculated fluorescence ratio (665 nm / 620 nm). Values given in percent (%) indicate the percental effect (response) at a certain concentration of agonist relative to the maximum response of the FSH standard. The results are provided below.

Example 50 Rat granulosa EC50 FSH (Assay B) ] The assay was performed pursuant to the ng of Yanofsky et al. (2006) eric activation of the follicle—stimulating e (FSH) receptor by selective, nonpeptide agonists (JBC 281(19): 13226—13233, which is incorporated by reference in the disclosure of the invention). The results are provided below.

The data is interpreted according to the following: + > 5 pM; ++ >1-5 pM; +++ > 0.1-1 pM; ++++ < 0.1 pM.

WO 09980 Compound number Assay A Assay B ++++ ++++ 3 ++++ ++ 4 +++ 62% @ 6 “M ++++ ++ 6 ++++ ++ ++ 43.5% @ 6 MM 8 + 9 ++ 40.5% @ 30 MM +++ ++ 11 ++ 12 ++++ ++ 13 +++ ++ 14 ++ + 16 + 17 +++ + ++ 30% @ 30 MM +++ +++ 21 +++ + 23 ++++ ++++ 24 ++++ ++ —+ + N\D ++++ WO 09980 +++ 32 +++ 33 +++ ++ 36 +++ 38 ++ 39 ++++ 41 +++ 42 +++ 43 ++++ 44 +++ 45 +++ 46 ++ 47 ++ 48 ++++ 49 +++ 50 ++++ +++ 51 ++++ 52 ++++ +++ 53 ++++ 54 +++ 55 ++++ 56 ++++ 57 ++ 58 ++++ 59 +++ WO 09980 60 +++ 62 +++ 63 ++++ +++ 65 ++++ 66 ++++ 68 ++++ 69 +++ 71 ++++ 72 ++++ 73 ++++ 74 ++++ 75 ++++ 76 ++++ 77 ++++ 78 ++++ 79 ++++ + 80 ++++ 81 ++++ 82 ++++ ++ 83 ++++ +++ 84 + 85 ++++ 86 ++++ 87 +++ 88 ++++ 89 ++++ WO 09980 90 ++++ 92 ++++ 93 ++++ +++ 95 ++++ +++ 96 ++++ +++ 98 ++++ ++ 99 +++ +++ 100 +++ 101 ++++ 102 +++ 103 +++ 104 ++ 105 ++++ ++++ 106 +++ 107 + 108 ++++ ++ 109 +++ 110 ++++ 111 +++ 112 ++ 113 ++++ +++ 114 ++++ ++ 115 ++++ +++ 116 ++++ ++ 117 +++ 118 ++++ 119 ++++ ++ WO 09980 120 ++++ 121 ++++ + 122 ++++ + 123 ++++ 124 ++++ 125 ++++ ++ 126 ++++ +++ 127 + 128 + 129 ++++ 130 ++++ 131 ++++ ++ 132 ++++ +++ 133 ++ 134 +++ 135 ++ 136 + 137 ++ 138 + 139 ++++ ++ 140 ++ 141 ++ 142 + 143 +++ 144 ++++ 145 +++ 146 +++ +++ 147 ++++ +++ 148 ++++ +++ 149 ++++ +++ WO 09980 150 ++++ +++ 152 ++++ 153 ++++ ++++ 154 ++++ ++ 155 + 156 +++ 157 +++ +++ 158 ++ 159 ++++ ++++ 160 ++++ ++++ 161 ++++ ++++ 162 ++++ +++ 163 ++++ +++ 164 ++ 165 + 166 ++ 167 +++ +++ 168 ++++ +++ 169 ++++ +++ 170 ++++ ++ 171 +++ 172 + 173 + 174 +++ 175 +++ + 176 ++++ 177 ++ 178 ++ 179 +++ WO 09980 180 ++++ 181 ++++ 182 ++++ ++++ 183 +++ 184 ++++ ++++ 185 +++ 186 ++++ +++ 187 + 188 + 189 ++++ ++++ 190 ++++ 191 ++++ 192 ++++ 193 + 194 ++++ +++ 195 ++++ 196 + 197 ++ 198 ++++ ++++ 199 ++++ 200 ++++ + 201 +++ ++ 202 +++ +++ 203 +++ 204 ++++ 205 ++++ ++++ 206 +++ 207 ++++ 208 ++++ ++++ 209 ++++ ++++ 210 ++++ + ++++ 218 ++++ +++ e 51 Pharmaceutical preparations (A) Injection Vials: A solution of 100 g of an active ient according to the invention and 5 g of um hydrogen ate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred into injection Vials, is lyophilized under sterile conditions and is sealed under sterile conditions. Each injection Vial contains 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soy lecithin and 1400 g of cocoa , is poured into moulds and is allowed to cool. Each suppository contains 20 mg of active ingredient.

(C) Solution: A solution is prepared from 1 g of an active ingredient according to the invention, 9.38 g of NaH2P04 - 2 H20, 28.48 g of Na2HP04 - 12 H20 and 0.1 g of benzalkonium de in 940 m1 of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilized by irradiation. This solution could be used in the form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the invention is mixed with 99.5 g of ne under aseptic conditions.

] (E) Tablets: A mixture of 1 kg of an active ingredient according to the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to give tablets in a conventional manner in such a way that each tablet contains 10 mg of active ingredient.

(F) Coated tablets: Tablets are pressed analogously to e E and subsequently are coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the ion are introduced into hard n capsules in a tional manner in such a way that each capsule contains 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according to the invention in 60 l of bidistilled water is sterile filtered, transferred into ampoules, is lyophilized under sterile conditions and is sealed under sterile conditions. Each e contains 10 mg of active ingredient.

(I) Inhalation spray: 14 g of an active ingredient according to the invention are dissolved in 10 l of isotonic NaCl solution, and the solution is transferred into commercially available spray containers with a pump mechanism. The solution could be d into the mouth or nose. One spray shot (about 0.1 ml) corresponds to a dose of about 0.14 mg.

While a number of embodiments of this invention are described herein, it is apparent that the basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this ion is to be defined by t ed claims rather than by the specific embodiments that have been represented by way of example.

Claims (6)

We claim :

1. A nd, selected from: O O N N N N N N N S S 1 2 O O N Br N N O N O N N N 3 4 O O O N N N N N N 5 6 N HN S NH O O N HN O N N HN S OH 9 10 O O N HN N O NH N N N N S 11 12 O O N N N HN O O S N O 13 14 O O O O O O N N N N N N S S O O HO O 17 18 O O O O O O N N N N O N N N S S 19 20 O O N N S HN N O NH N N N O S 21 22 O O O O N N N O S N N O S N O O 23 24 O O N N N O O O O O O O O O N N N N N S N S O 29 30 O O O O N N N N N S S O N 31 32 O O O O O O N N N N N O S N O O 33 34 N N O N N O NH 35 36 N O N N S HO O NH N N 37 38 O O N N N N N S OH 39 40 N N N N N N O N O 41 42 O O N O N N N O N N H N O 43 44 O O O O O O N N N N N N S S N O N O 45 46 O O N N N N N S OH 47 48 O O O H N N N O S N O N N D S D D 49 50 O O D S O O N N N N N N S S 51 52 O O O O N F N N N N N N S S 53 54 O O O O N O N N N N O S N S D 55 56 O O N HN N S N N S O D D 57 58 N D N HN D N HN S O D S N D D O 59 60 O O D HN D O N N N O S N D N D N HN O D D S N 61 62 O O O O O O N N N N N N N N N S S 63 64 O O O O O O N N N N N N N N N N S S 65 66 O O O O N N N O N N N S S 67 68 O O O O N N N S D O N N N D D N N 69 70 O O O O O O N N N N N N N O N S S 71 72 O O O O O O S O N N N N N N S S 73 74 O O O O N N S N N N N N S S 75 76 O O O D O O D D N O N N O N N N N N O O S N S D 77 78 O O S N O O O HN N N N N N 79 80 O O O O O N D N N N N D N N D N S S D 81 82 O O N D N D O S D O O HN O N O N N N N S N S D D O 85 86 O O O O S N N N N N S NH D D S 87 88 O O O O N N N N N S S 89 90 O O O O O N N N N S N N N 91 92 O O O O S O N N N N N N N S S O 93 94 O O O N O N N N N N N N D S S O D 95 96 O O O O O O N N N N N N N O O S S 97 98 O O O O O O O O N N N N H N N N N H S S 99 100 O O O O O O N N N N N N N N S O 101 102 O O O O N O N N N N N N N N S S 103 104 O O O O O O O N N S N N N N N S O 105 106 O O N N N N O O O O N N N N N H N N N N S O 109 110 O O O O O O O O S N O N N N N N H N N S S 111 112 O O O O O O O O N N N N N N N N D O D O S D D S D D D D D D D 113 114 O O O O O O O O N N N N N N N N D D S D D S D 115 116 O O O N N N N N D N N S D S D 117 118 O O O O N N N N D O N N N S D D D O 119 120 O O O O N N N N N N N N S O 121 122 O O O O O O N N N N N N N N N S O 123 124 O O O O N N N N N N N N N S O 125 126 O O O O N N N N N N N N N S S 129 130 O O O O HO O N N N O N N S O 131 132 O O O O N N N N N S S 133 134 O O O O O O HN OH N N N N H N N N N H S S 135 137 O O O O O O N O N N N N N N N N N Si D S S D 139 140 O O N N N H O O O O O F N N D N N F D N N N N N N D S S D D O 143 144 O O O O O O N N N N H N N N S S D 145 146 O O O O O O O O N N N N N S S 147 148 O O O O N N N N N N S S 149 150 O O O O O O N N N N N N S O 151 152 O O O O N N N N O N N N N 153 154 N N N N O O N O N N N N N N N O O 157 158 O O O O N N N N N N N N S S N N 159 160 O O O O N O N‐ N N N N N N N D O S D S D D 161 162 O O O O O O O OH N N N N N N N H S D O D S 163 164 O O NH2 N N S O O O O O O O D D O D N O N N N N N D N N N D D D S D O O D S D 167 168 O O N N N N N N N S S NH NH 169 170 O O O O O N N N N N N N N N 171 174 O O O O O O O NH N N N N N N N OH S O 175 176 O O O O N N N N N O N N N N O D D S D D D D S D D D D D D 177 178 O O O O N N H N N O N N NH S S 179 180 O O O O O O O N N N N NH 2 N N N N O S S 181 182 O O O O O O D D N N N N O N N N O D D D D S S 183 184 O O O O O OH O N N N N N N H N N N H S S 185 186 O O N N N N O N N 189 190 O O O O O O N N N N N N N N N O S 191 192 O O O O O N N N N N N S O 194 195 O O O O N N N N N N N O D S D D D O D S D D D D D D D 197 198 O O O O O O O S O S O O N O N N N N N D O D S D S D D D D 199 200 O O O O O O O N N N N N N O 201 202 O O O O N N N N N N N N N S 203 204 O O O O N N N N N N N N O S S N 205 206 O O O O N N N N N N N N S O 207 208 O O O O O O N N N N N N N O N N N S O 209 210 O O O O O O N N N N N N N S O 211 212 O O O O O O N N N N N D N N N O S D 213 214 O O O O O O N N N N N N N O O 215 216 O O O O N N N N N N N N N D OH O S D D S 217 , and 218, or a pharmaceutically acceptable salt f.

2. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 1, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

3. A method for modulating FSHR, or a mutant thereof, in a biological , comprising the step of contacting said biological sample with a compound or pharmaceutically acceptable salt of claim 1.

4. The use of a compound or pharmaceutically acceptable salt of claim 1, in the production of a medicament for modulating FSHR, or a mutant thereof, ty in a patient.

5. The use of a compound or pharmaceutically acceptable salt of claim 1 in the production of a medicament for treating fertility disorders in a subject.

6. Use of a compound or pharmaceutically acceptable salt according to claim 1, for the production of a medicament for the prophylactic or eutic treatment of a FSHR-mediated disorder.