Substituted 4-phenyl pyridine compounds as non-systemic tgr5 agonists

2020, Year of Leona Vicario, Meritorious Mother of the Country

MEXICAN HjriTurO or INDUSTRIAL PROPERTY

Continuation of Classification Symbols

Classification: CPC: A61K31/4433; A61K31/4436; A61K31/4439; A61K31/4545; A61K31/5377;

A61K45/06; A61P1/04; A61P1/08; A61P1/12; A61P1/14; A61P1/16;

A61P3/00; A61P5/16; A61P5/50; A61P7/00; A61P9/00; A61P11/00;

A61P13/12; A61P17/06; A61P19/02; A61P25/00; A61P29/00; A61P37/08; C07B59/002; C07D213/30; C07D213/38; C07D213/80; C07D213/81;

C07D401/12; C07D405/04; C07D405/12; C07D409/12; C07D413/12;

C07D471/04; C07D487/08; C07H15/04; C07H15/18; C07H15/26;

C07H15/234; C07B2200/05

Inventors Continuation

Inventor(s) TAO CHEN; MATTHEW SIEGEL www.gob.mx/impi

Arenal No. 550, Pueblo Santa María Tepepan, Mexico City, CP 16020. CDMX

Creativity for Wellbeing

MX/E/2018/085580

SUBSTITUTED 4-PHENYLPYRIDINE COMPOUNDS AS NON-SYSTEMIC TGR5 AGONISTS

RELATED REQUESTS

This application claims the benefit and priorities of US Provisional Application Nos. of series 62/269,804, filed on December 18, 2015; and 62/419,939, filed November 9, 2016, the contents of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to modulators of the TGR5 receptor useful in the treatment of diseases or disorders mediated by TGR5. Specifically, the invention relates to compounds, and compositions thereof, that activate the TGR5 receptor, methods of treating diseases or disorders associated with TGR5, including chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose , impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis (UC), Crohn's disease (CD), disorders associated with parenteral nutrition especially during short bowel syndrome and irritable bowel syndrome and methods of synthesis of these compounds.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a growing threat to human health. For example, in the United States current estimates hold that approximately 16 million people suffer from diabetes mellitus. Type II diabetes accounts for approximately 90-95% of diabetes cases, which kills approximately 193,000 US residents each year. Type II diabetes is the seventh leading cause of all deaths. In Western societies, type II diabetes currently affects 6% of the adult population and the worldwide incidence is expected to grow by 6% per year. Although there are certain inherited traits that may predispose particular individuals to developing type II diabetes, the driving force behind the current rise in the incidence of the disease is the rise in ω-style

σ>

ω < or

<img file="MX376739B_D0001.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 of sedentary life, diet and obesity currently prevalent in developed countries. Approximately 80% of diabetics with type II diabetes are significantly overweight. In addition, an increasing number of young people are developing the disease. Type II diabetes is now internationally recognized as one of the major threats to human health in the 21st century.

Type II diabetes manifests as an inability to adequately regulate blood glucose levels and can be characterized by a defect in insulin secretion or by insulin resistance. Namely, those who suffer from Type II diabetes have too little insulin or cannot use insulin effectively. Insulin resistance refers to the inability of the body's tissues to respond adequately to endogenous insulin. Insulin resistance develops due to multiple factors, including genetics, obesity, increasing age, and having high blood sugar for long periods of time. Type II diabetes can develop at any age, but most commonly becomes apparent during adulthood. However, the incidence of type II diabetes in children is increasing. In diabetics, glucose levels build up in the blood and urine, causing excessive urination, thirst, hunger, and problems with fat and protein metabolism. If left untreated, diabetes mellitus can cause life-threatening complications, including blindness, kidney failure, and heart disease.

Type II diabetes is currently treated at various levels. A first level of therapy is through diet and/or exercise, either alone or in combination with therapeutic agents. Such agents may include insulin or pharmaceuticals that lower blood glucose levels. Approximately 49% of individuals with type II diabetes require oral medications, approximately 40% require insulin injections or a combination of insulin injections and oral medications, and 10% use diet and exercise alone.

Traditional therapies include: insulin secretagogues, such as sulfonylureas, which increase insulin production from pancreatic β cells; glucose lowering effectors, such as metformin which reduce glucose production from the liver; ω activators

σ>

ω &lt; or

<img file="MX376739B_D0002.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 peroxisome proliferator-activated receptor γ (PPAR γ), such as thiazolidinediones, which increase the action of insulin; and α-glucosidase inhibitors, which interfere with intestinal glucose production. There are, however, shortcomings associated with currently available treatments. For example, sulfonylureas and insulin injections can be associated with hypoglycemic episodes and weight gain. Additionally, patients often lose responsiveness to sulfonylureas over time. Metformin and α-glucosidase inhibitors often lead to gastrointestinal problems, and PPAR γ agonists tend to cause weight gain and edema.

More recently, new agents have been introduced to the market that prolong or mimic the effects of naturally secreted incretin hormones (Neumiller, J. Am Pharm Assoc. 49(suppl. 1): S16-S29, 2009). Incretins are a group of gastrointestinal hormones that are released from specialized intestinal cells when nutrients, especially glucose, are detected in the intestine. The two most important incretin hormones are glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 (released from L cells), which stimulate insulin secretion from the pancreas in a glucose-dependent manner and suppress glucagon secretion. . However, GLP-1 itself is not practical as a clinical treatment for diabetes, since it has a very short half-life in vivo. To address this, incretin-based agents currently available or under regulatory review for the treatment of T2DM are designed to achieve prolonged incretin action. For example, dipeptidyl peptidase-4 inhibitors, such as sitagliptin, inhibit the normally rapid proteolytic breakdown of endogenous incretin hormones. There are also synthetic and human-derived incretin mimetics designed to be more stable and/or have a prolonged serum half-life compared to naturally secreted GLP-1, and include agents such as liraglutide and exenatide. In either approach, the goal is to provide a sustained incretin response and thereby increase glucose-dependent insulin secretion. It is the glucose dependence of the insulin response that provides incretin therapies with low risk of hypoglycemia. Furthermore, GLP-1 ω

σ>

ω &lt; or

<img file="MX376739B_D0003.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 may also delay gastric emptying and otherwise beneficially affect satiety and thus weight loss (Neumiller 2009).

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract that causes segments of the gastrointestinal tract to become inflamed and ulcerated. IBD generally takes one of two forms (CD) and (UC), and is generally considered to be the result of a combination of factors (environmental, genetic, microbiota, and immune dysfunction). These factors are probably all necessary to some degree for clinical disease to occur. Ultimately, dysregulation of the host's immune system, which occurs in response to environmental stimuli or gut bacteria, leaves the host at risk for uncontrolled chronic inflammation directed at the gut. Gut health is compromised by reduced barrier function, which exacerbates the response to antigen loading, creating a vicious cycle of chronic inflammation and disease. The diversity of causal factors makes the treatment of the disease very difficult and many IBD patients are undertreated, resulting in a high proportion of surgical resections (especially in CD).

The worldwide incidence rate of UC varies widely between 0.5-24.5/100,000 people, while that of CD varies between 0.1-16/100,000 people with an IBD prevalence rate reaching up to 396/100,000 people (cdc .gov). In a 2012 review, the highest prevalence values ​​for IBD were in Europe (UC, 505 per 100,000 people, CD, 322 per 100,000 people) and North America (UC, 249 per 100,000 people, CD, 319 per 100,000 people ). In addition, there was evidence of an increasing incidence over time. IBD is one of the most important Gl diseases in the US, requiring a lifetime of care for patients. Each year in the United States, IBD accounts for more than 700,000 physician visits, 100,000 hospitalizations, and 119,000 patients considered disabled (cdc.gov). In the long term, up to 75% of patients with CD and 25% of those with UC will require surgery (Ref: http://www.cdc.gov/ibd/). IBD is more common in European Americans compared to African Americans, and the lowest rates of IBD have been reported in Hispanics

MX/E/2018/085580 and Asian. CD may affect as many as 700,000 Americans. Men and women are probably affected equally, and although the disease can occur at any age, it is most prevalent among adolescents and young adults between the ages of 15 and 35.

Treatment of IBD includes taking prudent measures as well as surgical approaches in those who do not respond to medical treatment. The therapeutic objectives are: to improve the quality of life of the patient, to induce and maintain remission, to prevent complications, to restore nutritional deficits and to modify the course of the disease. The main therapeutic categories for this disease are anti-inflammatory drugs, immunosuppressive therapy, biological agents, antibiotics and drugs for symptom relief. Recent advances in understanding the pathogenesis of IBD have led to numerous new targeted therapies being developed. First-line treatment is usually mesalamine and its derivatives. It is relatively safe and effective, with 30-50% of patients achieving long-term relief. Second-line therapy is steroid therapy, with 30% long-term efficacy. After steroids, immune modulators (thiopurines, cyclosporine) are tried. Recently, TNF inhibitors have been used more widely in IBD. They demonstrate good healing and mucosal recovery, but have a high rate of complications and do not maintain long-term efficacy. Last-line treatment in IBD is surgical removal of diseased tissue. This is highly invasive and decreases the quality of life of these patients.

GLP-2 is of particular importance for GL health The peripheral actions of GLP2 are largely confined to the intestinal mucosa where it acts as a trophic hormone. Most of its effects occur in the small intestine and, to a lesser degree, in the large intestine. Chronic administration of GLP-2 to healthy rodents improves gut weight through increased crypt cell proliferation and decreased villous apoptosis, leading to expansion of villus height and, consequently, less consistent, from the depth of the crypt. As stated above, the trophic effects of GLP-2 are more pronounced in the proximal small intestine and all changes in intestinal morphology are ω

σ>

ω &lt; or

<img file="MX376739B_D0004.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 rapidly revert after cessation of treatment. GLP-2 treatment also increases the digestive and absorptive capacity of the intestine, as indicated by increased expression and activity of brush border enzymes and nutrient absorption, and improves barrier function through a decreased permeability. The positive effects of GLP-2 treatment on intestinal growth and/or function have been demonstrated in rodent models of intestinal damage including resection, colitis (IBD), chemotherapy-induced diarrhea, necrotizing pancreatitis, food allergy, and thermal injury. in patients with short bowel syndrome. Additional effects of GLP-2 in the gut include stimulation of intestinal glucose transport; inhibition of gastrointestinal motility in rodent models [conflicting results in humans]; gastric emptying and acid secretion (infusion of GLP-2 in healthy humans reduces stimulated gastric acid secretion, but has no effect on acid secretion or basal volume).

Intestinal L cells, the source of GLP-1 and GLP-2, co-express TGR5 receptors. Therefore, activation of TGR5 with small molecule agonists or partial agonists has the potential to be a treatment for chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance , insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome and irritable bowel syndrome (IBS) and other disorders. For this reason, there is still a considerable need for potent non-systemic small molecule agonists of TGR5.

Synthesis of the invention

[0001]

A first aspect of the invention refers to compounds of formula (I'):

MX/E/2018/085580

And their pharmaceutically acceptable salts, hydrates, solvates, prodrug isotopes, stereoisomers and tautomers, wherein:

Q is C=(O), -CH₂-, -NR₅- or -O-;

when Q is C=(O) then Qi is -NR₅-, when Q is -NR₅- or -O- so Qi is CH₂- or when Q is -CH₂- then Qi is -O(CH₂)₀-i- or -NR₅-;

Xi is CRe or N;

X₂ is CR? or N;

X3 is CRe or N;

X4 is CRg or N;

Y is CRb or N;

R_a and Rb are each independently H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy or halogen; either

R1 and R_a together with the carbon atoms to which they are attached form a heterocycloalkyl;

R1 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1C4), -OH, -NH_2> -NH(C1-C4)alkyl and -N((C1-C4)alkyl)₂; either

MX/E/2018/085580

Ri and R_a together with the carbon atoms to which they are attached form a heterocycloalkyl; either

Ri and R3, when on adjacent atoms, together with the carbon atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl -C6), haloalkoxy (C1-C6) and halogen;

R2 and Rz are each independently H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, or (C1-C6)haloalkoxy; either

R₂ and Rz together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl;

each R3 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1-C4), -OH, -NH₂, -NH(C1-C4)alkyl and -N((C1C4)alkyl)₂; either

R1 and R3 together with the carbon atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy -C6) and halogen;

R4 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, halogen, cycloalkyl ( C3-C8), heterocycloalkyl, -OH, -NH₂, C-N, -S(O)_m(C1-C6)alkyl, -NH(C1-C4)alkyl or -N((C1-C4)alkyl)₂;

R₅ is H, (C1-C6)alkyl, -C(O)NRi₀Rn, -C(O)(C1-C6)alkyl or -C(O)O(C1-C6)alkyl;

each Re and Rg is independently H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl -C6), halogen, (C3-C8)cycloalkyl, heterocycloalkyl,-OH, -NH₂, C-N, -S(O)_either(C1-C6)-alkyl, -NH(C1-C4)-alkyl or N((C1-C4)-alkyl)₂;

MX/E/2018/085580 each R? and Re is independently H, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, heterocycloalkyl, -OH, -NH₂, -S(O)_whatNH₂, -S(O)_whatOH, CN, or (C1-C18)alkyl, wherein 0 to 7 methylene of the (C1-C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, -NRi₃-, -S(O)_what-, -C(O)-, -C(CH₂)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then two -O-, two -S(O)_what- or two -NR13- and -O- and -NRi₃- are not contiguous, where the alkyl is optionally substituted with one or more Ri₂ and wherein the cycloalkyl and cycloalkenyl are optionally substituted with one or more Ri₃;

Rio and R11 are each independently H or (C1-C6) alkyl optionally substituted with one or more substituents independently selected from -NH₂ and OH;

R12 is D, -OH, halogen, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, -C(O)OH, OC(O)(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl, or R17, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents selected from -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1C6)alkyl)₂, halogen and R14;

Ri₃ is H, -OH, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl, or (C1-C12)alkyl, wherein 0 to 7 methylene of the (C1-C12)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, -NRi₃-, -S(O)r-, -C(O)-, or -C(NH)-, provided that when any two methylenes in the alkyl are replaced, then O and N, are not contiguous and wherein the alkyl is optionally substituted with one or more R15 and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl and N((C1-C6)alkyl)₂;

R14 is (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -O-heterocycloalkyl, (C1-C12)alkyl or (C2-C12)alkenyl, where 0 to 7 methylene of (C1 -C12) and (C2-C12)alkenyl are optionally replaced by a moiety selected from the group consisting of ω

σ>

ω &lt; or

<img file="MX376739B_D0005.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 in -O-, -NR13-, -S(O)_r-, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or various R15 and the cycloalkyl and heterocycloalkyl are optionally substituted with one or more Rie; or when R12 is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form C=(O); or when R12 is cycloalkyl or heterocycloalkyl, two R14 together with the atoms to which they are attached form a (C3-C8)cycloalkyl or heterocycloalkyl optionally substituted with one or more R13; or when R12 is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form a (C3-C8)spirocycloalkyl or a spiroheterocycloalkyl optionally substituted with one or more R13; or when R12 is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form a (C6-C10)aryl or heteroaryl optionally substituted by one or more R13;

Ri₅ is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein (C3-C8)cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from (C1-C6)hydroxyalkyl, (C1-C1)aminoalkyl -C6), -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((01-06)alkyl)2 and oxo;

Rie is -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -Oheterocycloalkyl, (C6-C10)aryl, or heteroaryl, where cycloalkyl (C3-C8) and heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

R17 is (C1-C18)alkyl or (C2-C18)alkenyl, wherein 0 to 8 methylene of (C1-C18)alkyl and (C2-C18)alkenyl are optionally replaced by a moiety selected from the group consisting of - O-, -NR13-, -S(O)r-, -C(O)-, or -C(NH)-, provided that when any two methylenes in the alkyl or alkenyl are replaced, then O and N are not contiguous and in ω

σ>

ω &lt; or

<img file="MX376739B_D0006.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 where the alkyl and alkenyl are optionally substituted with one or more Rie;

Rie is R19, (C6-C10)aryl or heteroaryl optionally substituted by one or more R21;

R19 is (C1-C18)alkyl wherein 0 to 8 methylene of the (C1-C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_r, -C(O) or -C(NH)-, provided that when any two methylenes on the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl is optionally substituted with one or more R20

R20 is (C6-C10)aryl or heteroaryl optionally substituted with one or more R21;

R21 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy or halogen; or two R21 when together on adjacent atoms form a cycloalkyl or heterocycloalkyl optionally substituted with one or more R22;

R22 is -C(O)NH_2> -C(O)NH(C1-C6)alkyl, -C(O)N((C1-C6)alkyl)₂,

-C(O)(C3-C7)cycloalkyl or -C(O)heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from -OH and CN;

each m, o, p, q and r is independently at each occurrence 0, 1 or 2; and n is 0, 1 or 2.

Another aspect of the invention relates to a method of treating or preventing a disease or disorder associated with modulation of TGR5. The method comprises administering to a patient in need of treatment for diseases or disorders associated with TGR5 modulation of an effective amount of a compound of formula (I') or one of its salts, hydrates, solvates, prodrugs, stereoisomers or pharmaceutically acceptable tautomers.

Another aspect of the invention relates to a method of treating a disease or disorder associated with TGR5 activation. The method comprises administering to a patient in need thereof a treatment for diseases or disorders ω

σ>

ω &lt; or

<img file="MX376739B_D0007.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 associated with TGR5 activation of an effective amount of a compound of formula (I') or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers.

Another aspect of the invention refers to a method of treating diarrhea induced by chemotherapy. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention refers to a method of treating type II diabetes mellitus. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention refers to a method for the treatment or prevention of hyperphosphatemia. The method comprises administering to a patient in need thereof, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or one of its salts, hydrates, solvates, prodrugs, stereoisomers or pharmaceutically acceptable tautomers.

Another aspect of the invention relates to a method for the treatment or prevention of kidney disease. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention relates to a method for reducing serum creatinine levels. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention relates to a method for the treatment or prevention of proteinuria. The method comprises administering to a patient

MX/E/2018/085580 requires an effective amount of a compound of formula (I') or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers.

Another aspect of the invention refers to a method to delay the time of renal replacement therapy (RRT). The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention refers to a method to reduce the levels of FGF23. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention refers to a method for reducing the hyperphosphatemic effect of active vitamin D. The method comprises the administration to a patient in need of an effective amount of a compound of formula (I') or one of its salts pharmaceutically acceptable hydrates, solvates, prodrugs, stereoisomers, or tautomers.

Another aspect of the invention relates to a method of attenuating hyperparathyroidism. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention relates to a method of lowering serum parathyroid hormone (PTH). The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention relates to a method of ameliorating endothelial dysfunction. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

ω σ>

ω &lt; or

<img file="MX376739B_D0008.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Another aspect of the invention relates to a method of reducing vascular calcification. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention relates to a method for reducing phosphorus in urine. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention relates to a method for normalizing serum phosphorus levels. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention relates to a method of reducing phosphate load in an elderly patient. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention relates to a method of reducing phosphate uptake. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention refers to a method to reduce renal hypertrophy. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention relates to a method of reducing cardiac hypertrophy. The method comprises administering to a patient in need of an amount ω

σ>

ω &lt; or

<img file="MX376739B_D0009.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 of a compound of formula (I') or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers.

Another aspect of the invention relates to a method for the treatment and/or prevention of a stomach and bowel-related disorder. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention refers to a method for the treatment and/or prevention of a collateral effect of chemotherapy or radiotherapy. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

Another aspect of the invention refers to the use of a compound of formula (I') or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers in the manufacture of a medicament for treating a disease associated with activation of TGR5.

Another aspect of the invention refers to the use of a compound of formula (I') or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers in the treatment of a disease associated with the activation of TGR5.

Another aspect of the invention refers to a prodrug of a compound of formula (I') having a formula (II'):

<img file="MX376739B_D0010.tif" />

ΙΜΡΙ

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580

<img file="MX376739B_D0011.tif" />

where:

P is -O, -CH2OC(O)(C1-C6)alkyl, or -CH₂OC(O)NR_yes (C1-C6)alkyl, wherein the alkyl is optionally substituted with -OC(O)(C1-C3)alkyl; Y

R_s is H or (C1-C6)alkyl; and where P is a cleavable group.

Another aspect of the invention refers to a prodrug of a compound of formula (I') having formula (II):

<img file="MX376739B_D0012.tif" />

where:

P is -O, -CH2OC(O)(C1-C6)alkyl, or -CH₂OC(O)NR_yes (C1-C6)alkyl, wherein the alkyl is optionally substituted with -OC(O)(C1-C3)alkyl; and ω

σ>

ω &lt; or

<img file="MX376739B_D0013.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

R_s is H or (C1-C6)alkyl; and where P is a cleavable group.

The present invention further provides methods of treating a disease or disorder associated with TGR5 modulation including, but not limited to, chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance , insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome and irritable bowel syndrome (IBS), comprising, administering to a patient suffering from at least one of said diseases or disorders a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

The present invention provides TGR5 agonists which are therapeutic agents in the treatment of diseases such as chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity , metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome and irritable bowel syndrome (IBS) and other diseases associated with modulation of TGR5.

The present invention also provides compounds and compositions with an improved efficacy and safety profile relative to known TGR5 agonists. The present description also provides novel mechanisms of action towards the TGR5 receptor in the treatment of various types of diseases including chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, glucose tolerance impaired, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome and irritable bowel syndrome (IBS). Finally, the present invention provides the medical community with a new ω

σ>

ω &lt; or

<img file="MX376739B_D0014.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 pharmacological strategy for the treatment of TGR5-mediated diseases and disorders.

1. Brief description of the drawings

FIG. 1 shows fecal form score (FFS) in mice with 5-fluorouracil (5-FU)-induced diarrhea after treatment with Compound I-388 at 30 mg/kg, teduglutide at 0.4 mg/kg, and vehicle. .

FIG. 2 shows the DAI score in a post-treatment mouse inflammatory bowel disease model when mice were treated with sitagliptin at 3.6 g/L, compound I-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 30 10 mg/kg and vehicle.

FIG. 3 shows the length of the colon in a mouse model of inflammatory bowel disease after treatment when mice were treated with sitagliptin at 3.6 g/L. Compound 1-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound 1-389 at 30 mg/kg, and vehicle.

FIG. 4 shows the colonic cytokine level of KC/Gro in a mouse model of inflammatory bowel disease after treatment when mice were treated with sitagliptin at 3.6 g/L. Compound 1-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound 1-389 at 30 mg/kg, and vehicle.

FIG. 5 shows colonic histological scoring in a mouse inflammatory bowel disease model after treatment when mice were treated with sitagliptin at 3.6 g/L, compound 1-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound 1-389 at 30 mg/kg and vehicle.

FIG. 6 shows the amount of contrast in the length of the small intestine traveled in mice when treated with compound 1-389 at 30 mg/kg and vehicle.

FIG. 7 shows the weight of the small intestine in mice when treated with teduglutide at 0.5 mg/kg, sitagliptin at 3.6 g/L. Compound 1-389 at 30 mg/kg. Compound 1-389 at 100 mg/kg, a ω

σ>

ω &lt; or

<img file="MX376739B_D0015.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 combination of sitagliptin at 3.6 g/L and compound 1-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound 1-389 at 100 mg/kg and vehicle.

FIG. 8 shows the weight of the colon in mice when treated with teduglutide at 0.5 mg/kg, sitagliptin at 3.6 g/L, compound I-389 at 30 mg/kg, compound I-389 at 100 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 100 mg/kg, and vehicle.

FIG. 9 shows the length of the villous crypts of the jejunum in mice when treated with teduglutide at 0.5 mg/kg, sitagliptin at 3.6 g/L, compound I-389 at 30 mg/kg, compound I-389 at 100 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 100 mg/kg, and vehicle.

FIG. 10 shows the length of the villous crypts of the ileum in mice when treated with teduglutide at 0.5 mg/kg, sitagliptin at 3.6 g/L, compound I-389 at 30 mg/kg, compound I-389 at 100 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 100 mg/kg, and vehicle.

FIG. 11 shows the depth of colonic crypts in mice when treated with teduglutide at 0.5 mg/kg, Sitagliptin at 3.6 g/L, compound I-389 at 30 mg/kg. Compound I-389 at 100 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 100 mg/kg and vehicle.

FIG. 12 shows active GLP-1 in mice when treated with teduglutide at 0.5 mg/kg, sitagliptin at 3.6 g/L, compound I-389 at 30 mg/kg, compound I-389 at 100 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 100 mg/kg, and vehicle.

FIG. 13 shows total GLP-2 in mice when treated with teduglutide at 0.5 mg/kg, sitagliptin at 3.6 g/L, compound I-389 at 30 mg/kg, compound I-389 at 100 mg/kg , a combination of sitagliptin at 3.6 g/L and compound I-389 at 30 mg/kg, a combination of sitagliptin at 3.6 g/L and compound I-389 at 100 mg/kg, and vehicle.

MX/E/2018/085580

FIG. 14 shows active GLP-1 in fed WD mice when treated with Liraglutide at 0.4 mg/kg, Linagliptin at 10 mg/kg, Compound I-389 at 30 mg/kg, a combination of Linagliptin at 10 mg/kg, and compound I-389 at 30 mg/kg, lean vehicle and WD vehicle.

FIG. 15 shows total GLP-1 in fed WD mice when treated with Liraglutide at 0.4 mg/kg, Linagliptin at 10 mg/kg, Compound I-389 at 30 mg/kg, a combination of Linagliptin at 10 mg/kg and Compound I-389 at 30 mg/kg, lean vehicle and WD vehicle.

Detailed description of the invention

The present invention relates to compounds and compositions that are capable of activating TGR5. The invention features methods for treating, preventing, or ameliorating a disease or disorder in which TGR5 plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers. The methods of the present invention can be used in the treatment of a variety of TGR5-dependent diseases and disorders through activation of the TGR5 receptor. Activation of TGR5 provides a novel approach for the treatment, prevention, or amelioration of diseases including, but not limited to, chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome and irritable bowel syndrome (IBS).

In a first aspect of the invention, the compounds of formula (I') are described:

MX/E/2018/085580 and its pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers, where Q, Qi, R_a, Ri, R2, Rz, R3, R4, X1, X2, X3, X4, Y, and n are as previously described herein.

The details of the invention are set forth in the following accompanying description. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, illustrative methods and materials will now be described. Other features, objects, and advantages of the invention will be apparent from the description and claims. In the specification and appended claims, singular forms also include the plural, unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention pertains. All patents and publications cited in this specification are incorporated herein by reference in their entirety.

definitions

The articles a nd una are used in this description to refer to one or more than one (ie at least one) of the grammatical object of the article. By way of example, an element means one element or more than one element.

The term and/or is used in this description to mean either and or, unless otherwise indicated.

ω σ>

ω &lt; or

<img file="MX376739B_D0016.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

The term "optionally substituted" is understood to mean that a given chemical moiety (eg, an alkyl group) may (but is not required to) be linked to other substituents (eg, heteroatoms). For example, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (ie, a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents other than hydrogen. For example, it may be attached, at any point along the chain, to a halogen atom, a hydroxyl group, or any other substituentdescribed herein. Thus, the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any other functional groups. Appropriate substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, COOH, -CH₂CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, Ci-Ce alkoxy, (C1-C6)haloalkyl, C1-C6haloalkoxy, -O-(C2-C6)alkenyl, -O-alky (C2-C6)-nyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, OP(O)(OH)₂, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH₂, NH((C1-C6)alkyl), -N((C1-C6)alkyl)₂, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, S(O)₂(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N((C1-C6)alkyl)₂. The substituents themselves may be optionally substituted. "Optionally substituted" as used herein also refers to substituted or unsubstituted, the meaning of which is described below.

As used herein, the term "substituted" means that the specified group or moiety bears one or more appropriate substituents, wherein the substituents may be connected to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl is connected to an aryl atom by a bond or by fusion with the aryl and by sharing two or more common atoms.

As used herein, the term "unsubstituted" means that the specified group bears no substituents.

ω σ>

ω &lt; or

<img file="MX376739B_D0017.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

As used herein, the term "TGR5 activation" means that a compound or group of compounds acts as an agonist or partial agonist of TGR5.

Unless specifically defined otherwise, the term "aryl" refers to cyclic aromatic hydrocarbon groups having 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. When it contains two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be bonded at a single point (eg, biphenyl) or may be fused (eg, naphthyl). The aryl group may be optionally substituted with one or more substituents, eg, 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl C6), (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)_2> -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, NH₂, NH((C1-C6)alkyl), N((C1-C6)alkyl)₂, -S(O)₂-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl and S(O)N((C1-C6)alkyl)₂. The substituents may themselves be optionally substituted. On the other hand, when containing two fused rings, the aryl groups defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

Unless otherwise specifically defined, heteroaryl means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more hetero ring atoms selected from N, O or S, C being the ring atoms. remaining ring. Heteroaryl as defined herein also means a bicyclic heteroaromatic group in which the heteroatom is selected from N, O or S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, I have[3,2ω σ>

ω &lt; or

<img file="MX376739B_D0018.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

b]thiophene, triazolyl, triazinyl, ¡midazo[1,2-b]p¡razol¡lo, furo[2,3-c]pyridin¡lo, ¡midazo[1,2-a]pyridinyl, indazolyl, pyrrolo[ 2,3-c]pindinyl, pyrrolo[3,2-c]pyridinyl, p¡razolo[3,4-c]pyridinyl, thieno[3,2c]pindinyl, thieno[2,3-c] pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanil, thiochromanil, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanil, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a] Pyridinyl, [1,2,4]Triazolo[4,3-a]pyridinyl, Isoindolyl, Pyrrolo[2,3b]pyridinyl, Pyrrolo[3,4-b]pyridinyl, Pyrrolo[3,2-b]pyridinyl, Imidazo [5,4-b]pyridinyl, pyrrolo[1,2a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrim¡din¡l, 3,4-dihydro-2H-1 □²-pyrrolo[2,1-b]pinmidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1 H-pyrido[ 3,4-b][1,4]thiazinyl, Benzooxazolyl, Benzoisoxazolyl, Furo[2,3-b]pyridinyl, Benzothiophenyl, 1,5-naphthyridinyl, Furo[3,2-b]pindine, [1, 2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]tnazolo[4,3-b]pyridazinyl , benzo[c][1,2,5]thiadiazolo, benzo[c][1,2,5]oxadiazole, 1,3-dihydro2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-p¡razolo[1,5-b][1,2]oxazinyl, 4,5,6,7tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]t azolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl and their derivatives. On the other hand, when containing two fused rings, the aryl groups defined herein may have an unsaturated or partially saturated ring fused to a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

Halogen or "halo" refers to fluorine, chlorine, bromine or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

ω σ>

ω &lt; or

<img file="MX376739B_D0019.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms that contains an “O” terminal in the chain, i.e. -O(alkyl). Examples of alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

"Alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group may be unconjugated or may be conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group may be unsubstituted or may be substituted. Alkenyl, as defined herein, can be linear or branched.

"Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group may be unsubstituted or may be substituted.

The term "alkylene" or "alkylenyl" refers to a divalent alkyl radical. Any of the aforementioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As defined herein, alkylene can also be a Ci-Ce alkylene. An alkylene can be a C1-C4 alkylene. Typical alkylene groups include, but are not limited to -CH₂-, -CH(CH₃)-, -C(CH₃)₂-, -CH2CH2-, CH₂CH(CH₃)-, -CH₂C(CH₃)₂-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

The term "aminoalkyl" as used herein refers to an alkyl group, as defined herein, substituted with one or more amino. Examples of aminoalkyl groups include, but are not limited to, aminomethyl, diaminomethyl, aminoethyl, 1,2-aminoethyl, etc.

"Cycloalkyl" means monocyclic or polycyclic saturated carbon rings (eg, fused, bridged, or spiro rings) containing 3-18 carbon atoms (eg, C₃cw). Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, ω

σ>

ω &lt; or

<img file="MX376739B_D0020.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 cyclopentyl, cyclohexyl, cycloheptanil, cyclooctanil, norboranil, norborenil, bicyclo[2,2,2]octane or bicyclo[2,2,2]octene.

"Heterocyclyl" or "heterocycloalkyl" means monocyclic or polycyclic rings (eg, fused, bridged, or spiro rings) containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and in which there are no delocalized π electrons (aromaticity) shared between the ring carbon or heteroatoms. Heterocycloalkyl can be a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents themselves may be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanil, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S -dioxide, piperazinil, azepinil, oxepinil, diazepinil, tropanil, oxazolidinonil and homotropanil. According to the present invention, 3- to 10-membered heterocyclyl refers to saturated or partially saturated non-aromatic ring structures containing between 3 and 10 atoms where there is at least one heteroatom selected from the group N, O or S.

The term "hydroxyalkyl" means an alkyl group as defined above, where the alkyl group is substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HO-CH₂-, HO-CH₂-CH₂- and CH₃-CH(OH)-.

The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

ω σ>

ω &lt; or

<img file="MX376739B_D0021.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

The term "cyano" as used herein means a substituent having a carbon atom bonded to a nitrogen atom via a triple bond, ie, C^N.

The term "amine" as used herein refers to primary (R-NH2, R*H), secondary (R2-NH, R2*H), and tertiary (R3-N, RH) amines. A substituted amine is intended to mean an amine, where at least one of the hydrogen atoms has been replaced by the substituent.

The term "amino" as used herein implies a substituent containing at least one nitrogen atom. Specifically, the NH substituents₂, -NH(alkyl) or alkylamino, -N(alkyl)2 or dialkylamino, amide, carbamide, urea and sulfamide are included in the term "amino".

The term "dialkylamino" as used herein refers to an amino or NH2 group where the two hydrogens have been replaced by alkyl groups, as defined hereinabove, ie, -N(alkyl)2. The alkyl groups in the amino group may be the same or different alkyl groups. Examples of alkylamino groups include, but are not limited to, dimethylamino (i.e. -N(CH3)2), diethylamino, dipropylamino, diiso-propylamino, di-n-butylamino, di-sec-butylamino, di-tert-butylamino, methyl (ethyl)amine, methyl(butylamine), etc.

"Spirocycloalkyl" or "spirocyclyl" means carbonogenic bicyclic ring systems with both rings connected through a single atom. The ring may be different in size and nature or the same in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both rings in a spirocycle may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle may be substituted with a heteroatom (eg, O, N, S, or P). A (C3-C12)spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. One or more carbon atoms may be substituted with a heteroatom.

The term "spiroheterocycloalkyl" or "spiroheterocyclyl" is understood to mean a spirocycle in which at least one of the rings is a heterocycle (eg, at least one of the rings is furanyl, morpholinyl, or piperadinyl).

ω σ>

ω &lt; or

<img file="MX376739B_D0022.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

The term solvate refers to a complex of variable stoichiometry formed by a solute and solvent. These solvents for the purposes of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates in which water is the solvent molecule are normally referred to as hydrates. "Hydrates" include compositions that contain stoichiometric amounts of water, as well as compositions that contain varying amounts of water.

The term isomer refers to compounds that have the same composition and molecular weight, but differ in physical and/or chemical properties. The structural difference can be in the constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). Regarding the stereoisomers, the compounds of the formula (I') may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

The compounds of the invention or their pharmaceutically acceptable salts may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or as (D)- or (L)- for amino acids. The present invention is intended to include all of these possible isomers, as well as their racemic and optically pure forms. The (+) and (-), (R)- and (S)- or optically pure (D)- and (L) isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques, e.g. chromatography and crystallization by fractionation. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis of an appropriate optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry and unless otherwise specified, the compounds are meant to include both the E and Z geometric isomers. Likewise, all forms are also intended to be included. tautomeric.

ω σ>

ω &lt; or

<img file="MX376739B_D0023.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

A "stereoisomer" refers to a compound made of the same atoms held together by the same bonds but having different three-dimensional structures, which are not indistinguishable. The present invention contemplates various stereoisomers and their mixtures and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

A "tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any such compound.

The chemical naming protocol and structural diagrams used herein are a modified form of the IUPAC nomenclature system, using the software program "IUPAC Naming Plugin" (ChemAxon) and/or ChemDraw Struct=Name Pro 11.0 (CambridgeSoft). For complex chemical names used herein, a substituent group is named before the group to which it is bonded. For example, cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent.

The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative pharmaceutically acceptable salts include, for example, water-soluble and water-insoluble salts, such as the acetate salt, amsonate (4,4-diaminostilben-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate , Borate, Bromide, Butyrate, Calcium, Calcium Edetate, Camsylate, Carbonate, Chloride, Citrate, Clavulariate, Dihydrochloride, Edetate, Edisylate, Stolate, Esylate, Fumerate, Fiunarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexafluorophosphate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Magnesium, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-Methylglucaminemonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methen-bis-2hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/d¡phosphate, picrate, polygalacturonate, ω

σ>

ω &lt; or

<img file="MX376739B_D0024.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate.

A patient or subject is a mammal, for example: a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig or non-human primate, such as monkey, chimpanzee, Baboon or rhesus.

An effective amount when used in connection with a compound is an amount effective to treat or prevent a disease in a subject as described herein.

The term carrier, as used in this description, encompasses carriers, excipients, and diluents and means a material, composition, or carrier, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in the carrier or transport of a pharmaceutical agent from one organ or body part to another organ or body part of a subject.

The term "treating", with respect to a subject, refers to ameliorating at least one symptom of the subject's disorder. Treatment includes curing, ameliorating, or at least partially ameliorating the disorder.

The term disorder is used in this description to mean, and is used interchangeably with, the terms disease, condition, or disease, unless otherwise indicated.

The term administer, which administers or administration, as used in this description, refers to the direct administration of a described compound or a pharmaceutically acceptable salt of the described compound or a composition to a subject, or the administration of a prodrug derivative. or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which is capable of forming an equivalent amount of active compound within the body of the subject.

The compounds of the present invention can also be prepared as prodrugs, eg, pharmaceutically acceptable prodrugs. The terms proω σ>

ω &lt; or

<img file="MX376739B_D0025.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 drug and prodrug are used interchangeably herein and refer to any compound that releases an active parent drug in vivo. Because prodrugs are known to improve numerous desirable qualities of pharmaceuticals (eg, solubility, bioavailability, manufacturing, etc.), the compounds of the present invention can be administered in prodrug form. Therefore, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of administering them, and compositions containing them. Prodrugs are understood to include any covalently bound carrier that releases an active parent drug of the present invention in vivo when said prodrug is administered to a subject. The prodrugs in the present invention are prepared by modifying the functional groups present in the compound in such a way that the modifications cleave, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention in which a hydroxy, amino, sulfhydryl, carboxy, or carbonyl group is attached to any group that can be cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl, free carboxy, or carbonyl group. free, respectively.

Examples of prodrugs include, but are not limited to esters (eg, acetate derivatives, dialkylaminoacetates, formates, phosphates, sulfates, N-oxides, and benzoate) and carbamates (eg, Ν,Ν-dimethylaminocarbonyl) of hydroxy functional groups, esters (eg, ethyl esters, morpholinoethanol esters) of carboxyl functional groups, N-acyl derivatives (eg, N-acetyl bases) N-Mannich, Schiff bases, and enaminones of amino functional groups, oximes, acetals, ketals, and enol esters of ketone and aldehyde functional groups in compounds of the invention, and the like, See Bundegaard, H., Design of Prodrugs, p1-92, Elesevier, New York-Oxford (1985).

The present invention relates to pharmaceutically acceptable compounds or salts, hydrates, solvates, prodrugs, stereoisomers or tautomers thereof, capable of activating TGR5, which are useful for the treatment of diseases and disorders associated with modulation of a TGR5 receptor. The invention further relates to the compounds, or salts, hydrates, solvates,

MX/E/2018/085580 pharmaceutically acceptable prodrugs, stereoisomers or tautomers of these, which are useful for activating TGR5.

In one embodiment, the compounds of formula (I') have the structure of formula (I) or (la'):

r₂x and their pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In one embodiment, the compounds of formula (I') have the structure of formula (Ib') or (le¹):

IMPI

<img file="MX376739B_D0026.tif" />

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

<img file="MX376739B_D0027.tif" />

(l).

ω and its pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In another embodiment, the compounds of formula (!') have the structure of formula (la):

<img file="MX376739B_D0028.tif" />

(the),

MX/E/2018/085580 and its pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In another embodiment, the compounds of formula (I') have the structure of formula (Ib):

and their pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In one embodiment, the compounds of formula (I') have the structure of formula (le):

Ri xí

X^ X3 (le), ω

<img file="MX376739B_D0029.tif" />

ΙΜΡΙ

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 and its pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In another embodiment, the compounds of formula (I') have the structure of formula (Id), formula (le), formula (If) or formula (Ig):

<img file="MX376739B_D0030.tif" />

(Go).

<img file="MX376739B_D0031.tif" />

(If) ω

<img file="MX376739B_D0032.tif" />

ΙΜΡΙ

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 and its pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In another embodiment, the compounds of formula (I') have the structure of formula (Ih), formula (Ij), formula (Ik), formula (Im):

<img file="MX376739B_D0033.tif" />

<img file="MX376739B_D0034.tif" />

(lm), ω

σ>

ω &lt; or

<img file="MX376739B_D0035.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 and its pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In another embodiment, the compounds of formula (I') have the structure of formula (lo), formula (Ip), formula (Iq) or formula (Ir):

<img file="MX376739B_D0036.tif" />

and their pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In another embodiment, the compounds of formula (I') have the structure of formula (lu), formula (Iv), formula (Iw) or formula (Ix):

ω

<img file="MX376739B_D0037.tif" />

ΙΜΡΙ

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580

<img file="MX376739B_D0038.tif" />

¢1^ tlwj, Q and its pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In another embodiment, the compounds of formula (I') have the structure of formula (l¡), formula (Iz), formula (laa) or formula (Ibb):

<img file="MX376739B_D0039.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω

EITHER)

GO

MX/E/2018/085580

<img file="MX376739B_D0040.tif" />

and their pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In one embodiment, compounds of the formula (!') have the structure of the formula (read):

<img file="MX376739B_D0041.tif" />

ω

<img file="MX376739B_D0042.tif" />

ΙΜΡΙ

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 and its pharmaceutically acceptable salts, hydrates, solvates, isotopes, prodrugs, stereoisomers and tautomers.

In one embodiment, the compound of formula (I') is a prodrug having

Formula (II') or (II):

<img file="MX376739B_D0043.tif" />

<img file="MX376739B_D0044.tif" />

where:

P is -O, -CH2OC(O)(C1-C6)alkyl, or -CH₂OC(O)NR_yes (C1-C6)alkyl, wherein the alkyl is optionally substituted with -OC(O)(C1-C3)alkyl; and ω

σ>

ω &lt; or

<img file="MX376739B_D0045.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

R_s is H or (C1-C6)alkyl; and where P is a cleavable group.

In one embodiment, P is -O,

<img file="MX376739B_D0046.tif" />

<img file="MX376739B_D0047.tif" />

In some embodiment of the above formulas,

Q is -NR₅- or -O-;

Qi is -CH₂-;

Xi is CRe or N;

X₂ is CR? or N;

X₃ is CRs or N;

X4 is CRg or N;

Yes CH;

R_a it's H;

R1 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1C4), -OH, -NH₂, -NH(C1-C4)alkyl and -N((C1-C4)alkyl)₂;

R₂ is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl or (C1-C6)haloalkoxy;

MX/E/2018/085580

R₂· is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl or (C1-C6)haloalkoxy; either

R₂ and R₂· together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl;

each R3 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1-C4), -OH, -NH₂, -NH(C1-C4)alkyl and -N((C1C4)alkyl)₂;

R4 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, halogen, cycloalkyl ( C3-C8), heterocycloalkyl, -OH, -NH₂, C-N, -S(O)_m(C1-C6)alkyl, -NH(C1-C4)alkyl or -N((C1-C4)alkyl)₂;R₅ is H, (C1-C6)alkyl, -C(0)NRioRn, -C(O)(C1-C6)alkyl or -C(O)O(C1-C6)alkyl;

each Re and Rg is independently H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, C6), halogen, (C3-C8)cycloalkyl, heterocycloalkyl,-OH, -NH₂, C-N, -S(O)_either(C1-C6)alkyl, -NH(C1-C4)alkyl or N((C1-C4)alkyl)₂;

each R7 and Re is independently H, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl C6), (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, heterocycloalkyl, OH, -NH₂, -S(O)_whatNH₂, -S(O)_whatOH, CN or (C1-C18)alkyl, wherein 0 to 7 methylenes of the (C1-C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_what-, -C(O)-, -C(CH₂)- or -C(NH)-, provided that, when any two methylenes are replaced on the alkyl, then two -O-, two -S(O)_what- or two -NR13- and O- and -NR13 are not contiguous, where the alkyl is optionally substituted with one or more Ri₂ and wherein the cycloalkyl and cycloalkenyl are optionally substituted with one or more R13;

ω σ>

ω &lt; or

<img file="MX376739B_D0048.tif" />

ΙΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Rio and R11 are each independently H or (C1-C6)alkyl optionally substituted with one or more substituents independently selected from -NH₂ and OH;

R12 is -OH, halogen, -NH₂, -NH(C1-C6)alkyl, -N((Ci-C6)alkyl₆))₂, -C(O)OH, OC(O)(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1C6)alkyl)₂, halogen and R14;

R13 is H, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl, or (C1-12)alkyl, wherein 0 to 7 methylenes of the (C1-C12)alkyl are optionally replaced by a moiety selected from the group consisting of consists of -O-, -NR13-, -S(O)_r, -C(O)- or -C(NH)-, provided that, when any two methylenes are replaced on the alkyl, then O and N are not contiguous and wherein the alkyl is optionally substituted with one or more R15 and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl and N((C1-C6)alkyl)₂;

R14 is (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -Oheterocycloalkyl, (C1-C12)alkyl or (C2-C12)alkenyl, where 0 to 7 methylenes of the (C1-C12)alkyl ) and (C2-C12)alkenyl are optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_r, -C(O)- or -C(NH)-, provided that, when any two methylenes on the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or various R15 and the cycloalkyl and heterocycloalkyl are optionally substituted with one or more Rw; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two Ru together with the atom to which they are attached form C=(O); or when i laughed₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atoms to which they are attached form a (C3-C8)cycloalkyl or heterocycloalkyl optionally substituted with one or more Ri₃; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form a spirocycloalkyl (C3-C8) or a ω

<img file="MX376739B_D0049.tif" />

ΙΜΡΙ

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 spiroheterocycloalkyl optionally substituted with one or more R13; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form a (C6-C10) aryl or heteroaryl optionally substituted with one or more OH or R13;

Ri₅ is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein (C3-C8)cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from (C1-C6)hydroxyalkyl, (C1-C1)aminoalkyl -C6), -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

R16 is -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -Oheterocycloalkyl, (C6-C10)aryl, or heteroaryl, where cycloalkyl (C3-C8) and heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

each m, o, p, q and r is independently at each occurrence 0, 1 or 2; and n is 0, 1 or 2.

In some embodiments of the above formulas:

Q is -NR₅- or -O-;

X1 is CRe or N;

X₂ is CR? or N;

X3 is CRs or N;

X4 is CR9 or N;

R1 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -Oheterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halogen , alkoxy (C1C4), -OH, -NH₂, -NH(C1-C4)alkyl and N((C1-C4)alkyl)₂;

ω σ>

ω &lt; or

<img file="MX376739B_D0050.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

R₂ and Rz are each independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, or (C1-C6)haloalkoxy; either

R₂ and R₂' together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl;

each R3 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1-C4), -OH, -NH₂, -NH(C1-C4)alkyl and -N((C1C4)alkyl)₂;

R4 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, halogen, cycloalkyl ( C3-C8), heterocycloalkyl, -OH, -NH₂, C-N, -S(O)_m(C1-C6)alkyl, -NH(C1-C4)alkyl or -N((C1-C4)alkyl)₂;

R₅ is H, (C1-C6)alkyl, -C(O)NRi₀Rn, -C(O)(C1-C6)alkyl or -C(O)O(C1-C6)alkyl;

each Re and Rg is independently H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl -C6), halogen, (C3-C8)cycloalkyl, heterocycloalkyl,-OH, -NH₂, C-N, -S(O)_either(C1-C6)alkyl, NH(C1-C4)alkyl, or -N((C1-C4)alkyl)₂;

each R7 and Rs is independently H, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl -C6), (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, heterocycloalkyl, -OH, -NH₂, -S(O)_whatNH₂, -S(O)_whatOH, CN, or (C1-C18)alkyl, wherein 0 to 7 methylene of the (C1-C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_what-, -C(O)-, -C(CH₂)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then two -O-, two -S(O)_what- or two NR13- and -O- and -NR13- are not contiguous, where the alkyl is optionally substituted with one or more Ri₂ and wherein the cycloalkyl and cycloalkenyl are optionally substituted with one ω

σ>

ω &lt; or

<img file="MX376739B_D0051.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 or various R13;

R10 and R11 are each independently H or (C1-C6) alkyl optionally substituted with one or more substituents independently selected from -NH₂ and OH;

Ri₂ is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, -C(O)OH, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂ and R14;

R13 is H, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl or (C1-12)alkyl, wherein 0 to 7 methylene of the (C1-C12)alkyl is optionally replaced by a moiety selected from the group consisting of consists of -O-, -NR13-, -S(O)r-, -C(O)-, or -C(NH)-, provided that when any two methylenes on the alkyl are replaced, then O and N do not are contiguous and wherein alkyl is optionally substituted with one or more R15 and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl and N((C1-C6)alkyl)₂;

R14 is (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -O-heterocycloalkyl, (C1-C12)alkyl or (C2-C12)alkenyl, where 0 to 7 methylene of (C1 -C12) and (C2-C12)alkenyl are optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_r-, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or various R15 and the cycloalkyl and heterocycloalkyl are optionally substituted with one or more Rie; or when R12 is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form C=(O); or two R14 together with the atoms to which they are attached form a (C3-C8)cycloalkyl or heterocycloalkyl optionally substituted with one or more R13; or when R12 is cycloalkyl or heterocycloalkyl, two together with the atom to which they are attached form a spirocycloalkyl (C3-C8) or a spiroheterocycloalkyl optionally substituted with one or ω

<img file="MX376739B_D0052.tif" />

ΙΜΡΙ

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 various R13;

Ri₅ is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein (C3-C8)cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from (C1-C6)hydroxyalkyl, (C1-C1)aminoalkyl -C6), -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

Ri₆ is -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -Oheterocycloalkyl, (C6-C10)aryl, or heteroaryl, where cycloalkyl (C3-C8) and heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

each m, o, p, q and r is independently at each occurrence 0, 1 or 2; and n is 0, 1 or 2

In some embodiments of the above formulas:

Q is -NR₅- or -O-;

X1 is CRe or N;

X₂ is CR7 or N;

X3 is CRs or N;

X4 is CRg or N;

R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -Oheterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halogen , alkoxy (C1C4), -OH, -NH₂, -NH(C1-C4)alkyl and -N((C1-C4)alkyl)₂;

R₂ and R₂are each independently (C1-C6)alkyl, (C1-C6)alkoxy, haloalkyl ω

σ>

ω &lt; or

<img file="MX376739B_D0053.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (C1-C6), or haloalkoxy (C1-C6); either

R₂ and R₂' together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl;

each R3 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1-C4), -OH, -NH₂, -NH(C1-C4)alkyl and -N((C1C4)alkyl)₂;

R4 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, halogen, cycloalkyl ( C3-C8), heterocycloalkyl, -OH, -NH₂, C-N, -S(O)_m(C1-C6)alkyl, -NH(C1-C4)alkyl or -N((C1-C4)alkyl)₂;

R₅ is H, (C1-C6)alkyl, -C(O)NRi₀Rn, -C(O)(C1-C6)alkyl or -C(O)O(C1-C6)alkyl;

each Re and Rg is independently H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl -C6), halogen, (C3-C8)cycloalkyl, heterocycloalkyl,-OH, -NH₂, C-N, -S(O)_either(C1-C6)alkyl, NH(C1-C4)alkyl, or -N((C1-C4)alkyl)₂;

each R7 and Rs is independently H, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl -C6), (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, heterocycloalkyl, -OH, -NH₂, CN, or (C1-C18)alkyl, wherein 0 to 7 methylene of the (C1C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, NR13-, -S(O)q-, -C (O)-, -C(CH₂)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then two -O-, two -S(O)_what- or two -NR13- and -O- and -NR13- are not contiguous, wherein the alkyl is optionally substituted with one or more Ri₂ and wherein the cycloalkyl and cycloalkenyl are optionally substituted with one or more R13;

R10 and R11 are each independently H or (C1-C6)alkyl optionally ω

σ>

ω &lt; or

<img file="MX376739B_D0054.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 substituted with one or more substituents independently selected from -NH₂ and OH;

R12 is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, -C(O)OH, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂ and Ri₄;

R13 is H, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl or (C1-12)alkyl, wherein 0 to 7 methylene of the (C1-C12)alkyl is optionally replaced by a moiety selected from the group consisting of consists of -O-, -NR13-, -S(O)r-, -C(O)-, or -C(NH)-, provided that when any two methylenes on the alkyl are replaced, then O and N do not are contiguous and wherein alkyl is optionally substituted with one or more R15 and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl and N((C1-C6)alkyl)₂;

R14 is (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -O-heterocycloalkyl, (C1-C12)alkyl or (C2-C12)alkenyl, where 0 to 7 methylene of (C1 -C12) and (C2-C12)alkenyl are optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_r-, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or various R15 and the cycloalkyl and heterocycloalkyl are optionally substituted with one or more Rie; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two Ri₄ together with the atom to which they are attached they form C=(O); or two Ri₄ together with the atoms to which they are attached they form a (C3-C8)cycloalkyl or heterocycloalkyl optionally substituted with one or more R13; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two together with the atom to which they are attached form a spirocycloalkyl (C3-C8) or a spiroheterocycloalkyl optionally substituted with one or more R13;

Ri₅ is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C3-C8)cycloalkyl, ω

σ>

ω &lt; or

<img file="MX376739B_D0055.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 heterocycloalkyl, aryl (C6-C10) or heteroaryl, wherein cycloalkyl (C3-C8) and heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxyalkyl (C1-C6), aminoalkyl (C1- C6), -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)2 and oxo;

Ri₆ is -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -Oheterocycloalkyl, (C6-C10)aryl, or heteroaryl, where cycloalkyl (C3-C8) and heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

each m, o, p, q and r is independently at each occurrence 0, 1 or 2; and n is 0, 1 or 2.

In some embodiments of the above formulas:

Q is -NR₅- or -O-;

Ri is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents from (C1-C4)alkoxy or -OH;

R₂ and R₂· are each independently (C1-C4)alkyl; either

R₂ and R₂· together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl;

each R3 is independently, at each occurrence, halogen;

R4 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, halogen, cycloalkyl ( C3-C8), heterocycloalkyl, -OH, -NH₂, C-N, -S(O)_m(C1-C6)alkyl, -NH(C1-C4)alkyl or -N((C1C4)alkyl)₂;

R₅ is H, (C1-C6)alkyl, -C(O)NRi₀Rn, -C(O)(C1-C6)alkyl or -C(O)O(C1-C6)alkyl;

MX/E/2018/085580 each Re and Rg is, independently, H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl -C6), (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, heterocycloalkyl,-OH, -NH₂, C-N, -S(O)_either(C1-C6)alkyl, NH(C1-C4)alkyl, or -N((C1-C4)alkyl)₂;

each R? and Rs is independently H, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl ), (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, heterocycloalkyl, -OH, -NH₂, CN or (C1-C18)alkyl, wherein 0 to 7 methylene of the (C1C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, NR13-, -S(O)_what-, -C(O)-, -C(CH₂)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then two -O-, two -S(O)_what- or two -NR13- and -O- and -NRi₃- are not contiguous, where the alkyl is optionally substituted with one or more Ri₂ and wherein the cycloalkyl and cycloalkenyl are optionally substituted with one or more Ri₃;

Rio and R11 are each independently H or (C1-C6) alkyl optionally substituted with one or more substituents independently selected from -NH₂ and OH;

Ri₂ is -OH, -NH_2> -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, -C(O)OH, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂ and Ri₄;

Ri₃ is H, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl or (C1-12)alkyl, wherein 0 to 7 methylene of the (C1-C12)alkyl is optionally replaced by a moiety selected from the group consisting of in -O-, -NRi₃-, -S(O)_r, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then O and N, are not contiguous and wherein the alkyl is optionally substituted with one or more R15 and in where cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl and N((C1-C6)alkyl)₂;

ω σ>

ω &lt; or

<img file="MX376739B_D0056.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

R14 is (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -O-heterocycloalkyl, (C1-C12)alkyl or (C2-C12)alkenyl, where 0 to 7 methylene of (C1 -C12) and (C2-C12)alkenyl are optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_r-, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or various R15 and the cycloalkyl and heterocycloalkyl are optionally substituted with one or more Rie; or when R12 is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form C=(O); or two R14 together with the atoms to which they are attached form a (C3-C8)cycloalkyl or heterocycloalkyl optionally substituted with one or more R13; or when R12 is cycloalkyl or heterocycloalkyl, two together with the atom to which they are attached form a (C3-C8)spirocycloalkyl or a spiroheterocycloalkyl optionally substituted with one or more R13;

Ri₅ is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein (C3-C8)cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from (C1-C6)hydroxyalkyl, (C1-C1)aminoalkyl -C6), -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((01-06)alkyl)2 and oxo;

Rie is -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -Oheterocycloalkyl, (C6-C10)aryl, or heteroaryl, where cycloalkyl (C3-C8) and heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((01-06)alkyl)2 and oxo;

each m, o, p, q and r is independently at each occurrence 0, 1 or 2; and n is 0 or 1.

In some embodiments of the above formulas:

ω σ>

ω &lt; or

<img file="MX376739B_D0057.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Q is -O-;

Ri is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents from (C1-C4)alkoxy and -OH;

R2 and R2' are each independently (C1-C4)alkyl; either

R₂ and R2' together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl;

each R3 is independently, at each occurrence, halogen;

R4 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, halogen, cycloalkyl ( C3-C8), heterocycloalkyl, -OH, -NH₂, C-N, -S(O)_m(C1-C6)alkyl, -NH(C1-C4)alkyl or -N((C1-C4)alkyl)₂;

each Re and Rg is independently H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl -C6), halogen, (C3-C8)cycloalkyl, heterocycloalkyl,-OH, -NH₂, C-N, -S(O)_either(C1-C6)-alkyl, -NH(C1-C4)-alkyl or N((C1-C4)-alkyl)₂;

each R7 and Rs is independently H, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl -C6), (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, heterocycloalkyl, -OH, -NH₂, CN or (C1-C18)alkyl, wherein 0 to 7 methylene of the (C1C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, NR13-, -S(O)_what-, -C(O)-, -C(CH₂)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then two -O-, two -S(O)_what- or two -NR13- and -O- and -NR13- are not contiguous, where alkyl is optionally substituted with one or more R12 and where cycloalkyl and cycloalkenyl are optionally substituted with one or more R13;

R10 and R11 are each independently H or (C1-C6) alkyl optionally substituted with one or more substituents independently selected from -NH₂ and OH;

ω σ>

ω &lt; or

<img file="MX376739B_D0058.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

R12 is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, -C(O)OH, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂ and Ri₄;

R13 is H, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl or (C1-12)alkyl, wherein 0 to 7 methylene of the (C1-C12)alkyl is optionally replaced by a moiety selected from the group consisting of consists of -O-, -NR13-, -S(O)r-, -C(O)-, or -C(NH)-, provided that when any two methylenes on the alkyl are replaced, then O and N do not are contiguous and wherein alkyl is optionally substituted with one or more R15 and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl and N((C1-C6)alkyl)₂;

R14 is (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -O-heterocycloalkyl, (C1-C12)alkyl or (C2-C12)alkenyl, where 0 to 7 methylene of (C1 -C12) and (C2-C12)alkenyl are optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_r-, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or various R15 and the cycloalkyl and heterocycloalkyl are optionally substituted with one or more Rie; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form C=(O); or two R14 together with the atoms to which they are attached form a (C3-C8)cycloalkyl or heterocycloalkyl optionally substituted with one or more R13; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two together with the atom to which they are attached form a spirocycloalkyl (C3-C8) or a spiroheterocycloalkyl optionally substituted with one or more R13;

Ri₅ is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, or heteroaryl, where (C3-C8)cycloalkyl and ω

σ>

ω &lt; or

<img file="MX376739B_D0059.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxyalkyl (C1-C6), aminoalkyl (C1-C6), -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)2 and oxo;

Ri₆ is -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -Oheterocycloalkyl, (C6-C10)aryl, or heteroaryl, where cycloalkyl (C3-C8) and heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

each m, o, p, q and r is independently at each occurrence 0, 1 or 2; and n is 0 or 1.

In some embodiments of the above formulas, Q is -NR₅-. In another embodiment, Q is -O-. In yet another embodiment, -O-, -N(CH3)-, -N(H)-, or -N(C(O)NH₂). In another embodiment, Q is -NH- or -O-.

In some embodiments of the above formulas, Xi is CRe, X₂ is CR7, X3 is CRe and X4 is CRg. In another embodiment, X1 is N, X₂ it's CR7, X₃ is CRe and X4 is CRg. In yet another embodiment, X1 is CRe, X₂ is N,X₃ is CRs and X4 is CRg. In another embodiment, X1 is CRe, X₂ is CR7, X3 is N and X4 is CRg. In yet another embodiment, X1 is CRe, X₂ it's CR7, X₃ is CRs and X4 is N. In another embodiment, X1 is N, X₂ is CR7, X3 is N and X4 is CRg. In yet another embodiment, X1 is N, X₂ it's CR7, X₃ is CRe and X4 is N. In another embodiment, X1 is CRe, X₂ is N,X₃ is CRs and X4 is N.

In some embodiments of the above formulas, R1 is H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1-C4), -OH, -NH₂, -NH(C1-C4)alkyl and -N((C1-C4)alkyl)₂. In another embodiment, R1 is H, (C1-C4)alkyl, (C1-C4)alkoxy,

MX/E/2018/085580 haloalkyl (C1-C4), haloalkoxy (C1-C4), halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents of halogen, (C1-C4)alkoxy and -OH. In yet another embodiment, Ri is H, CH₃, -CH2CH3, -CH(CH₃)₂, F, Cl, -OCH₃, -OCH₂CH₃, -OCH(CH₃)₂, -OCH₂CH(CH₃)₃, -OCF₃, OCH₂CF₃, -CH₂OCH₃, -SCH₃, -SCH₂CH₃ or -SCH(CH₃)₂, where each is optionally substituted with -OH. In another embodiment, R1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, or -O-cyclohexyl, each optionally substituted with -OH.

In yet another embodiment, R1 is . c^— , where each is optionally substituted with -OH.

In some embodiments of the above formulas, R₂ is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy. In another embodiment, R₂ is (C1-C2)alkyl, (C1-C2)alkoxy, (C1-C2)haloalkyl or (C1-C2)haloalkoxy. In yet another embodiment, R₂ is methyl, ethyl, methoxy, ethoxy, trifluoroalkyl, or trifluoroalkoxy. In another embodiment, R₂ is methyl or ethyl. In yet another embodiment, R₂ it is methyl.

In some embodiments of the above formulas, R₂· is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy. In another embodiment, R₂is alkyl ω

σ>

ω &lt; or

<img file="MX376739B_D0060.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (C1-C2), alkoxy (C1-C2), haloalkyl (C1-C2) or haloalkoxy (C1-C2). In yet another embodiment, R₂· is methyl, ethyl, methoxy, ethoxy, trifluoroalkyl or trifluoroalkoxy. In another embodiment, R₂· is methyl or ethyl. In yet another embodiment, R₂· is methyl.

In another embodiment, R₂ and R₂· together with the carbon atom to which they are attached form a cycloalkyl (C3-C8) or heterocycloalkyl ring. In yet another embodiment, R₂ and R₂· Together with the carbon atom to which they are attached they form a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl or furanyl ring. In another embodiment, R₂ and R₂· Together with the carbon atom to which they are attached, they form a cyclopropyl or oxetanil ring.

In some embodiments of the above formulas, R₃ is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, halogen, -S(O)_p(C1-C4)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1-C4), -OH, -NH₂, -NH(C1-C4)alkyl and N((C1-C4)alkyl)₂. In another embodiment, R₃ is (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl or (C1-C4)haloalkoxy, halogen, wherein the alkyl and alkoxy are optionally substituted with one or more substituents selected from (C1-C4)alkoxy -C4), -OH, -NH₂, -NH(C1-C4)alkyl and -N((C1-C4)alkyl)₂. In yet another embodiment, R₃ is halogen or (C1-C4)alkyl optionally substituted with one or more substituents selected from (C1-C4)alkoxy, -OH, -NH₂, -NH(C1-C4)alkyl and N((C1-C4)alkyl)₂. In another embodiment, R₃ is halogen or (C1-C4)alkyl. In yet another embodiment, R₃ it is halogen.

In some embodiments of the above formulas, R4 is H, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, (C1-C3)hydroxyalkyl, aminoalkyl (C1C3), Halogen, (C3-C8)Cycloalkyl, Heterocycloalkyl,-OH, -NH₂, C-N, -S(O)_m(C1-C3)alkyl, NH(C1-C3)alkyl or -N((C1-C3)alkyl)₂. In another embodiment, R₄ is H, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, (C1-C3)hydroxyalkyl, (C1-C3)aminoalkyl, halogen, -OH, -NH₂, C-N, -S(O)_either(C1-C3)alkyl, -NH(C1-C3)alkyl or -N((C1-C3)alkyl)₂.

ω σ>

ω &lt; or

<img file="MX376739B_D0061.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

In yet another embodiment, R₄ is H, (C1-C3)alkyl, (C1-C3)haloalkyl, halogen, or S(O)_either(C1-C3)alkyl. In another embodiment, R₄ is H, methyl, ethyl, n-propyl, iso-propyl, trifluoromethyl, F, Cl, or -S(O)2CH₃.

In some embodiments of the above formulas, R5 is H, (C1-C3)alkyl, C(O)NRi₀Rii, -C(O)(C1-C3)alkyl or -C(O)O(C1-C3)alkyl. In another embodiment, R₅ is H, (C1-C3)alkyl, or -C(O)NRi₀Rn. In another embodiment, R₅ is H, methyl, ethyl, n-propyl, iso-propyl, or -C(0)NRioRn.

In some embodiments of the above formulas, Re is H, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, (C1-C3)hydroxyalkyl, aminoalkyl (C1C3), halogen, (C3-C8)cycloalkyl, heterocycloalkyl, -OH, -NH₂, C-N, -S(O)_either(C1-C3)alkyl, NH(C1-C3)alkyl or -N((C1-C3)alkyl)₂. In another embodiment, R₆ is H, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, (C1-C3)hydroxyalkyl, (C1-C3)aminoalkyl, halogen, -OH, -NH₂, C-N, -S(O)_either(C1-C3)alkyl, -NH(C1-C3)alkyl or -N((C1-C3)alkyl)₂. In yet another embodiment, Re is H, (C1-C3)alkyl, (C1-C3)haloalkyl, halogen, or S(O)_either(C1-C3)alkyl. In another embodiment, R₆ is H, methyl, ethyl, n-propyl, iso-propyl, trifluoromethyl, F, Cl, or -S(O)₂CH3. In yet another embodiment, Re is H.

In some embodiments of the above formulas, R7 is H, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, hydroxyalkyl (C1-C6), (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, heterocycloalkyl, -OH, -NH₂, CN, or (C1-C18)alkyl, wherein 0 to 7 methylene of the (C1-C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_what-, -C(O)-, -C(CH₂)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then two -O-, two -S(O)_what- or two -NR13- and -O- and -NR13- are not contiguous, wherein the alkyl is optionally substituted with one to eight Ri₂ and wherein the cycloalkyl and cycloalkenyl are optionally substituted with one to eight R13.

In some embodiments of the above formulas, Re is H, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, hydroxyalkyl (C1-C6), ω

σ>

ω &lt; or

<img file="MX376739B_D0062.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, heterocycloalkyl, -OH, -NH2, CN or (C1-C18)alkyl, where 0 (C1-C18)alkyl methylene is optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_what-, -C(O)-, -C(CH₂)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then two -O-, two -S(O)_what- or two -NR13- and -O- and -NR13- are non-contiguous, wherein alkyl is optionally substituted with one to eight R12 and wherein cycloalkyl and cycloalkenyl are optionally substituted with one to eight R13.

In some embodiments of the above formulas, Rg is H, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, (C1-C3)hydroxyalkyl, (C1-C3)aminoalkyl (C1C3), halogen, (C3-C8)cycloalkyl, heterocycloalkyl, -OH, -NH₂, C-N, -S(O)_either(C1-C3)alkyl, NH(C1-C3)alkyl or -N((C1-C3)alkyl)2. In another embodiment, Rg is H, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, (C1-C3)hydroxyalkyl, (C1-C3)aminoalkyl, halogen, -OH, -NH₂, C-N, -S(O)_either(C1-C3)alkyl, -NH(C1-C3)alkyl or -N((C1-C3)alkyl)₂. In yet another embodiment, Rg is H, (C1-C3)alkyl, (C1-C3)haloalkyl, halogen, or S(O)_either(C1-C3)alkyl. In another embodiment, Rg is H, methyl, ethyl, n-propyl, iso-propyl, trifluoromethyl, F, Cl, or -S(O)2CH3. In yet another embodiment, Rg is H or Cl.

In some embodiments of the above formulas, R10 is H or (C1-C6) alkyl optionally substituted with one or more OH. In another embodiment, R10 is H.

[uuuzj In some embodiments of the above formulas, Rn is H or (C1C6)alkyl optionally substituted with one or more OH. In another embodiment, Rn is H.

In some embodiments of the above formulas, R12 is -OH, -NH2, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -C(O)OH, (C3-C8)cycloalkyl ), heterocycloalkyl, (C6-C10)aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to six substituents selected from -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)2 and R14.

In some embodiments of the above formulas, R13 is H, cycloalkyl (OSOS), heterocycloalkyl, (C6-C10)aryl, heteroaryl, or (C1-C12)alkyl, where 0 to 7 methylene ω

σ>

ω &lt; or

<img file="MX376739B_D0063.tif" />

ΙΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (C1-C12)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)r-, -C(O)- or - C(NH)-, provided that when any two methylene in the alkyl are replaced, then O and N, are not contiguous and wherein alkyl is optionally substituted with one to eight R15 and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one to eight substituents selected from -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl and -N((C1-C6)alkyl)₂.

In some embodiments of the above formulas, Ru is (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -O-heterocycloalkyl, (C1-C12)alkyl, or (C2-C12)alkenyl, wherein 0 to 7 methylene of (C1-C12)alkyl and (C2-C12)alkenyl are optionally replaced by a moiety selected from the group consisting of -O-, -NRi₃-, S(O)r, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one to eight R15 and cycloalkyl and heterocycloalkyl are optionally substituted with one to eight Rw In some embodiments of the above formulas, when Ri₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form C=(O). In another embodiment, two R14 together with the atoms to which they are attached form a (C3C8)cycloalkyl or heterocycloalkyl optionally substituted with one or six Ri₃. In yet another embodiment, when Ri₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form a spirocycloalkyl (C3-C8) or a spiroheterocycloalkyl optionally substituted with one or six Ri₃.

In some embodiments of the above formulas, R15 is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein (C3-C8)cycloalkyl and heterocycloalkyl are optionally substituted with one to eight substituents selected from (C1-C6)hydroxyalkyl, (C1-C1)aminoalkyl -C6), C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂ and oxo.

ω σ>

ω &lt; or

<img file="MX376739B_D0064.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

In some embodiments of the above formulas, Rw is -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -O-heterocycloalkyl, (C6-C10)aryl, or heteroaryl, where cycloalkyl (C3-C8) and heterocycloalkyl are optionally substituted with one to eight substituents selected from hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂ and oxo.

In some embodiments of the above formulas, m is 0 or 1. In yet another embodiment, m is 1 or 2. In another embodiment, m is 0. In yet another embodiment, m is 1. In another embodiment, m is 2.

In some embodiments of the above formulas, o is 0 or 1. In yet another embodiment, o is 1 or 2. In another embodiment, o is 0. In yet another embodiment, o is 1. In another embodiment, o is 2.

In some embodiments of the above formulas, p is 0 or 1. In yet another embodiment, p is 1 or 2. In yet another embodiment, p is 0. In yet another embodiment, p is 1. In another embodiment, p is 2.

In some embodiments of the above formulas, q is 0 or 1. In yet another embodiment, q is 1 or 2. In another embodiment, q is 0. In yet another embodiment, q is 1. In another embodiment, q is 2.

In some embodiments of the above formulas, r is 0 or 1. In yet another embodiment, r is 1 or 2. In another embodiment, r is 0. In yet another embodiment, r is 1. In another embodiment, r is 2.

In some embodiments of the above formulas, n is 0 or 1. In yet another embodiment, n is 1 or 2. In another embodiment, n is 0. In yet another embodiment, n is 1. In another embodiment, n is 2.

In some embodiments of the above formulas, Xi is CRe and Re is H or halogen.

ω σ>

ω &lt; or

<img file="MX376739B_D0065.tif" />

ΙΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

In some embodiments of the above formulas, X₂ is CRg and Rg is H or halogen.

In some embodiments of the above formulas, X₂ is n

In some embodiments of the above formulas, X3 is CR7.

In some embodiments of the above formulas, X4 is N.

In some embodiments of the above formulas, X4 is CRs.

In some embodiments of the above formulas, Q is -NH- or -O-.

In some embodiments of the above formulas, Q is -NH- or -O- and Q1 is CH₂-.

In some embodiments of the above formulas, Q is C=(O) and Q1 is -NR₅·-.

In some embodiments of the above formulas, Q is CH₂- and Q1 is -O(CH₂)₀. 1- or -NR₅-.

In some embodiments of the above formulas, Q is CH₂- and Q1 is -O(CH₂)₀. 1-. In another embodiment, Q is CH₂- and Q1 is -O(CH₂)-. In another embodiment, Q is CH₂- and Q1 is -O(CH₂)-.

In some embodiments of the above formulas, Q is CH₂- and Q1 is -NR₅-.

In some embodiments of the above formulas, R₂ and R₂· together with the carbon atom to which they are attached form cycloalkyl (C3-C8) or heterocycloalkyl.

In some embodiments of the above formulas, R₂ it is methyl.

In some embodiments of the above formulas, R₂· is methyl.

In some embodiments of the above formulas, Rs is halogen.

In some embodiments of the above formulas, X1 is CRe and Re is H or halogen.

In some embodiments of the above formulas, X₂ is CRg and Rg is H or halogen.

In some embodiments of the above formulas, X₂ is n

In some embodiments of the above formulas, X3 is CR7.

ω σ>

ω &lt; or

<img file="MX376739B_D0066.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

In some embodiments of the above formulas, X4 is N.

In some embodiments of the above formulas, X4 is CRs.

In some embodiments of the above formulas, n is 1.

In some embodiments of the above formulas, n is 0.

In some embodiments of the above formulas, R2 is H and R2 is H.

In some embodiments of the above formulas, R2 is H and R2' is (C1C6)alkyl.

In some embodiments of the above formulas, R2 is H and R2· is methyl.

In some embodiments of the above formulas, R2 is (C1-C6)alkyl and R2' is H.

In some embodiments of the above formulas, R2 is methyl and R2' is H.

In some embodiments of the above formulas, R2 is (C1-C6)alkyl and R2' is (C1-C6)alkyl.

In some embodiments of the above formulas, R2 is (C1-C3)alkyl and R2· is (C1-C3)alkyl.

In some embodiments of the above formulas, R2 is methyl and R2' is methyl.

In some embodiments of the above formulas, Y is CRt>. In another embodiment, Y is N. In another embodiment, Y is CH or N. In another embodiment, Y is CH. In another embodiment, Y is N.

In some embodiments of the above formulas, R_a is H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy or halogen. In another embodiment, R_a is H, (C1-C4)alkyl or (C1-C4)alkoxy. In another embodiment, R_a is H, (C1-C3)alkyl or (C1-C3)alkoxy. In another embodiment, R_a is (C1-C3)alkyl or (C1-C3)alkoxy. In another embodiment, R_a is (C1-C3)alkyl. In another embodiment, R_a is H or (C1C3)alkyl. In another embodiment, R_a it's H.

In some embodiments of the above formulas, Rb is H, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy, or halogen. In another embodiment,

MX/E/2018/085580

Rb is H, (C1-C4)alkyl or (C1-C4)alkoxy. In another embodiment, R_b is H, (C1-C3)alkyl or (C1-C3)alkoxy. In another embodiment, R_b is (C1-C3)alkyl or (C1-C3)alkoxy. In another embodiment, R_b is alkoxy (C1-C3). In another embodiment, R_b is H or alkoxy (C1C3). In another embodiment, R_b it's H.

In some embodiments of the above formulas, Ri and R_a together with the carbon atoms to which they are attached form a heterocycloalkyl. In another embodiment, Ri and R_a together with the carbon atoms to which they are attached form a 5 to 7 membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O or S.

In some embodiments of the above formulas, Ri and R3 together with the carbon atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy and halogen. In another embodiment, R1 and R3, when on an adjacent carbon atom, together with the carbon atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents selected from (C1-C6)alkyl, alkoxy ( C1-C6), (C1-C6)haloalkyl, (C1-C6)haloalkoxy and halogen. In another embodiment, R1 and R₃, when at an adjacent carbon atom, together with the carbon atoms to which they are attached form a 5- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S and optionally substituted with one or more selected substituents of (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy and halogen. In another embodiment, R1 and R3, when on an adjacent carbon atom, together with the carbon atoms to which they are attached form a 5 to 7 membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O or S and optionally substituted with halogen.

In some embodiments of the above formulas, R12 is D, -OH, halogen, NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, -C(O)OH, -OC(O)(C1-C6)alkyl, (C3C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl or R17, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more ω

σ>

ω &lt; or

<img file="MX376739B_D0067.tif" />

ΙΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 substituents selected from -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, halogen, and Rl4In some embodiments of the above formulas, R13 is H, -OH, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl, or (C1-C12)alkyl, where 0 to 7 (C1-C12)alkyl methylene is optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)r-, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then O and N, are non-contiguous and wherein alkyl is optionally substituted by one or more R15 and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted by one or more substituents selected from -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl and N((C1-C6)alkyl)₂.

In some embodiments of the above formulas, when Ri₂ is cycloalkyl or heterocycloalkyl, two together with the atom to which they are attached form a (C6-C10)aryl or heteroaryl optionally substituted with one or more R13. In another embodiment, when Ri₂ is cycloalkyl or heterocycloalkyl, two together with the atom to which they are attached form an aryl (Ce-Cio) optionally substituted with one or more R13. In another embodiment, when Ri₂ is cycloalkyl or heterocycloalkyl, two together with the atom to which they are attached form a 5 to 12 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O or S optionally substituted with one or more R13. In another embodiment, when Ri₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form a 5 to 7 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O or S optionally substituted with one or more R13. In another embodiment, when Ri₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form a 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O or S optionally substituted with one or more R13.

In some embodiments of the above formulas, R17 is (C1-C18)alkyl or (C2-C18)alkenyl, wherein 0 to 8 methylene of the (C1-C18)alkyl and (C2-C18)alkenyl are optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, ω σ>

ω &lt; or

<img file="MX376739B_D0068.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

S(O)r, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally Substituted with one or more RieIn some embodiments of the above formulas, Rie is R19, (C6-C10)aryl, or heteroaryl optionally substituted with one or more R21.

In some embodiments of the above formulas, R19 is (C1-C18)alkyl wherein 0 to 8 methylene of the (C1-C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, -NR13- , -S(O)_r, -C(O)- or -C(NH)-, provided that when any two methylenes on the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl is optionally substituted with one or more R20.

In some embodiments of the above formulas, R20 is (C6-C10)aryl or heteroaryl optionally substituted with one or more R21.

In some embodiments of the above formulas, R21 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen; or two R21 when together on adjacent atoms form a cycloalkyl or heterocycloalkyl optionally substituted with one or more R22. In another embodiment, R21 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen; or two R21 when together on adjacent atoms form a 5 to 8 membered (C5-C8) cycloalkyl or heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or various R22. In another embodiment, R21 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or halogen. In another embodiment, two R21 when together on adjacent atoms form a 5- to 8-membered (C5-C8) cycloalkyl or heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R22. In another embodiment, two R21 when together on adjacent atoms form a (C5-C8)cycloalkyl optionally substituted with one or more R22. In another embodiment, two R21 when together on ω atoms

σ>

ω &lt; or

<img file="MX376739B_D0069.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 form a 5 to 8 membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N or S, optionally substituted with one or more R₂₂.

In some embodiments of the above formulas, R22 is -C(O)NH2, C(O)NH(C1-C6)alkyl, -C(O)N((C1-C6)alkyl)₂, -C(O)(C3-C7)cycloalkyl or C(O)heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from -OH and CN. In another embodiment, R₂₂ is -C(O)N((C1-C6)alkyl)₂, -C(O)(C3-C7)cycloalkyl or C(O)heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from -OH and CN. In another embodiment, R₂₂ is -C(O)heterocycloalkyl optionally substituted with one or more substituents independently selected from -OH and CN.

In some embodiments of the above formulas,

Q is-NR₅- or -O-;

Q1 is -CH₂-;

X1 is CRe or N;

X₂ is CR7 or N;

X3 is CRe or N;

X4 is CRg or N;

Yes CH;

R_a it's H;

R1 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1C4), -OH, -NH₂, -NH(C1-C4)alkyl and N((C1-C4)alkyl)₂;

R₂ and R₂· are each independently (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, or (C1-C6)haloalkoxy; or ω

σ>

w&lt;o

<img file="MX376739B_D0070.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

R₂ and R₂' together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl;

each R₃ is, independently, at each occurrence, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1-C4), -OH, -NH₂, -NH(C1-C4)alkyl and -N((C1C4)alkyl)₂;

R₄ is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, halogen, (C3)cycloalkyl -C8), heterocycloalkyl, -OH, -NH₂, C-N, -S(O)_m(C1-C6)alkyl, -NH(C1-C4)alkyl or -N((C1-C4)alkyl)₂;

R₅ is H, (C1-C6)alkyl, -C(O)NRi₀Rn, -C(O)(C1-C6)alkyl or -C(O)O(C1-C6)alkyl;

each Re and Rg is independently H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl -C6), halogen, (C3-C8)cycloalkyl, heterocycloalkyl,-OH, -NH₂, C-N, -S(O)_either(C1-C6)alkyl, NH(C1-C4)alkyl, or -N((C1-C4)alkyl)₂;

each R? and Rs is independently H, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl ), (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, heterocycloalkyl, -OH, -NH₂, -S(O)_whatNH₂, -S(O)_whatOH, CN, or (C1-C18)alkyl, wherein 0 to 7 methylene of the (C1-C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, -NRi₃-, -S(O)_what-, -C(O)-, -C(CH₂)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then two -O-, two -S(O)_what- or two NR13- and -O- and -NR13- are not contiguous, where the alkyl is optionally substituted with one or more Ri₂ and wherein the cycloalkyl and cycloalkenyl are optionally substituted with one or more Ri₃;

Rio and R11 are each independently H or (C1-C6)alkyl optionally

MX/E/2018/085580 substituted with one or more substituents independently selected from -NH₂ and OH;

R12 is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, -C(O)OH, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from -OH, - NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂ and R14;

R13 is H, (Cs-Cs)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl, or (C1-C12)alkyl, wherein 0 to 7 methylene of the (C1-C12)alkyl is optionally replaced by a moiety selected from the group consisting of consists of -O-, -NR13-, -S(O)_r, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then O and N, are not contiguous and wherein the alkyl is optionally substituted with one or more R15 and in where cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl and N((C1-C6)alkyl)₂;

R14 is (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -O-heterocycloalkyl, (C1-C12)alkyl or (C2-C12)alkenyl, where 0 to 7 methylene of (C1 -C12) and (C2-C12)alkenyl are optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_r-, -C(O)- or -C(NH)-, provided that when any two methylene in the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or various R15 and the cycloalkyl and heterocycloalkyl are optionally substituted with one or more Rw; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form C=(O); or when i laughed₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atoms to which they are attached form a (C3-C8)cycloalkyl or heterocycloalkyl optionally substituted with one or more R13; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form a spirocycloalkyl (C3-C8) or a spiroheterocycloalkyl optionally substituted with one or more R13;

Ri₅ is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C3-C8)cycloalkyl, ω

<img file="MX376739B_D0071.tif" />

ΙΜΡΙ

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 heterocycloalkyl, aryl (C6-C10) or heteroaryl, wherein cycloalkyl (C3-C8) and heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxyalkyl (C1-C6), aminoalkyl (C1- C6), -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

Ri₆ is -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -Oheterocycloalkyl, (C6-C10)aryl, or heteroaryl, where cycloalkyl (C3-C8) and heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

each m, o, p, q and r is independently at each occurrence 0, 1 or 2; and n is 0, 1 or 2.

<img file="MX376739B_D0072.tif" />

<img file="MX376739B_D0073.tif" />

ω σ>

ω &lt; or

<img file="MX376739B_D0074.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

In some embodiments of the above formulas, Q is O. In another embodiment, Q is O and Xi is CRe. In yet another embodiment, Q is O, Xi is CRe, and X₂ is CR? In another embodiment, Q is O, Xi is CRe, X₂ is CR? and X₃ it's CR's. In yet another embodiment, Q is O, Xi is CRe, X₂ is CR?, X₃ is CRs and X4 is CRg. In another embodiment, Q is O, X1 is CRe, X₂ is CR?, X₃ is CRs, X4 is CRg, and R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or

-O-heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH. In yet another embodiment, Q is O, X1 is CRe, X₂ is CR?, X₃ is CRs, X4 is CRg, R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH and R₂ and R₂· are each independently (C1-C6)alkyl. In another embodiment, Q is O, X1 is CRe, X₂ is CR?, X₃ is CRs, X4 is CRg, R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH , R₂ and R₂are each independently (C1-C6)alkyl and Re is H.

In another embodiment, Q is O, X1 is CRe, X₂ is CR?, X₃ is CRs, X4 is CRg, R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH , R₂ and R₂· are each independently (C1-C6)alkyl, Re is H and Rg is H or halogen. In yet another embodiment, Q is O, X1 is CRe, X₂ is CR?, X₃ is CRs, X4 is CRg, R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH , R₂ and R₂are ω

σ>

ω &lt; or

<img file="MX376739B_D0075.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 each independently (C1-C6)alkyl, Re is H, Rg is H or halogen, and n is 0. In another embodiment, Q is O, Xi is CRe, X₂ is CR?, X3 is CRe, X4 is CRg, R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH , R₂ and R₂· are each independently (C1-C6)alkyl, Re is H, Rg is H or halogen, n is 1, and R3 is halogen.

In some embodiments of the above formulas, Q is O. In another embodiment, Q is O and X1 is CRe. In yet another embodiment, Q is O, X1 is CRe, and X₂ it's CR7. In another embodiment, Q is O, X1 is CRe, X₂ is CR7 and X3 is CRs. In yet another embodiment, Q is O, X1 is CRe, X₂ is CR7, X3 is CRs and X4 is CRg. In another embodiment, Q is O, X1 is CRe, X₂ is CR7, X3 is CRs, X4 is CRg, and R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH . In yet another embodiment, Q is O, X1 is CRe, X₂ is CR7, X3 is CRs, X4 is CRg, R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH and R₂ and R₂· together with the carbon atom to which they are attached form cycloalkyl (C3-C8) or heterocycloalkyl. In another embodiment, Q is O, X1 is CRs, X₂ is CR7, X3 is CRs, X4 is CRg, R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH , R₂ and R₂together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl and Re is H.

In another embodiment, Q is O, X1 is CRs, X₂ is CR7, X3 is CRs, X4 is CRg, R1 is ω

σ>

ω &lt; or

<img file="MX376739B_D0076.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (C1-C6)-alkyl, (C1-C6)-alkoxy, (C1-C6)-haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH , R₂ and R₂· together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl, Re is H and Rg is H or halogen. In yet another embodiment, Q is O, Xi is CRe, X₂ is CR7, X3 is CRe, X4 is CRg, R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH, R₂ and R₂together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl, Re is H, Rg is H or halogen, and n is 0. In another embodiment, Q is O, X1 is CRe, X₂ is CR7, X3 is CRe, X4 is CRg, R1 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH , R₂ and R₂together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl, Re is H, Rg is H or halogen, n is 1 and R₃ it is halogen.

In some embodiments of the above formulas, Q is O. In another embodiment, Q is O and X1 is CRe. In yet another embodiment, Q is O, X1 is CRe, and X₂ it's CR7. In another embodiment, Q is O, X1 is CRe, X₂ is CR7 and X3 is CRs. In yet another embodiment, Q is O, X1 is CRe, X₂ it's CR7, X₃ is CRs and X4 is CRg. In another embodiment, Q is O, X1 is CRe, X₂ it's CR7, X₃ is CRs, X4 is CRg, and R1 is -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH. In yet another embodiment, Q is O, X1 is CRe, X₂ is CR7, X3 is CRs, X4 is CRg, R1 is -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH and R₂ and R₂· are each independently (C1-C6)alkyl. In another embodiment, Q is O, X1 is CRe, X₂ it's CR7, X₃ is CRs, X4 is CRg, R1 is -O-(C3-C8)cycloalkyl or ω

σ>

ω &lt; or

<img file="MX376739B_D0077.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

-O-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH, R₂ and R₂are each independently (C1-C6)alkyl and Re is H.

In another embodiment, Q is O, Xi is CRe, X₂ is CR7, X3 is CRe, X₄ is CRg, R1 is -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH, R₂ and R₂· are each independently (C1-C6)alkyl, Re is H and Rg is H or halogen. In yet another embodiment, Q is O, X1 is CRe, X₂ it's CR7, X₃ is CRe, X4 is CRg, R1 is -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH, R₂and R₂are each independently (C1-C6)alkyl, Re is H, Rg is H or halogen, and n is 0. In another embodiment, Q is O, X1 is CRe, X₂ is CR7, X3 is CRe, X₄ is CRg, R1 is -OC3-C8-cycloalkyl or -O-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH, R₂ and R₂· are each independently (C1-C6)alkyl, Re is H, Rg is H or halogen, n is 1, and R3 is halogen.

In some embodiments of the above formulas, Q is O. In another embodiment, Q is O and X1 is CRe. In yet another embodiment, Q is O, X1 is CRe, and X₂ it's CR7. In another embodiment, Q is O, X1 is CRe, X₂ is CR7 and X3 is CRs. In yet another embodiment, Q is O, X1 is CRe, X₂ it's CR7, X₃ is CRs and X₄ is CRg. In another embodiment, Q is O, X1 is CRe, X₂ it's CR7, X₃ is CRs, X4 is CRg, and R1 is -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH. In yet another embodiment, Q is O, X1 is CRe, X₂ is CR7, X3 is CRs, X4 is CRg, R1 is -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH and R₂ and R₂· together with the carbon atom to which they are attached form cycloalkyl (C3-C8) or heterocycloalkyl. In another embodiment, Q is O, X1 is CRe, X₂ it's CR7, X₃ is CRe, X4 is CRg, R1 is -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, where cycloalkyl and ω

<img file="MX376739B_D0078.tif" />

IMPI σ>

ω &lt; or

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 heterocycloalkyl are optionally substituted with one to three -OH, R₂ and R₂together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl and Re is H.

In another embodiment, Q is O, Xi is CRe, X₂ is CR?, X₃ is CRs, X₄ is CRg, Ri is -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH, R₂ and R₂· together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl, Re is H and Rg is H or halogen. In yet another embodiment, Q is O, Xi is CRe, X₂ is CR?, X₃ is CRs, X₄ is CRg, Ri is -O(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH, R₂ and R₂together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl, Re is H, Rg is H or halogen, and n is 0. In another embodiment, Q is O, Xi is CRe, X₂ is CR?, X₃ is CRe, X₄ is CRg, Ri is O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one to three -OH, R₂ and R₂together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl, Re is H, Rg is H or halogen, n is 1 and R₃ it is halogen.

In an embodiment of formula (I') or formula (I):

Q is -NR₅- or -O-;

Xi is CRe or N;

X₂ is CR? or N;

X₃ is CRs or N;

X₄ is CRg or N;

Ri is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -Oheterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from halogen , alkoxy (C1C4), -OH, -NH₂, -NH(C1-C4)alkyl and N((C1-C4)alkyl)₂;

R₂ and R₂are each independently (C1-C6)alkyl, (C1-C6)alkoxy, ω

σ>

ω &lt; or

<img file="MX376739B_D0079.tif" />

ΙΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (C1-C6)haloalkyl, or (C1-C6)haloalkoxy; either

R₂ and R₂' together with the carbon atom to which they are attached form (C3-C8)cycloalkyl or heterocycloalkyl;

each R3 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, -S(O)_p(C1-C6)alkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl or -O-heterocycloalkyl, wherein alkyl, alkoxy, cycloalkyl and heterocycloalkyl are optionally substituted with one or more selected substituents halogen, alkoxy (C1-C4), -OH, -NH₂, -NH(C1-C4)alkyl and -N((C1C4)alkyl)₂;

R4 is H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, halogen, cycloalkyl ( C3-C8), heterocycloalkyl, -OH, -NH₂, C-N, -S(O)_m(C1-C6)alkyl, -NH(C1-C4)alkyl or -N((C1-C4)alkyl)₂;

R₅ is H, (C1-C6)alkyl, -C(O)NRi₀Rn, -C(O)(C1-C6)alkyl or -C(O)O(C1-C6)alkyl;

each Re and Rg is independently H, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl -C6), halogen, (C3-C8)cycloalkyl, heterocycloalkyl,-OH, -NH₂, C-N, -S(O)_either(C1-C6)alkyl, NH(C1-C4)alkyl, or -N((C1-C4)alkyl)₂;

each R7 and Rs is independently H, (C1-C8)alkenyl, (C1-C8)alkynyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)hydroxyalkyl -C6), (C1-C6)aminoalkyl, halogen, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, heterocycloalkyl, -OH, -NH₂, -S(O)_whatNH₂, -S(O)_whatOH, CN, or (C1-C18)alkyl, wherein 0 to 7 methylene of the (C1-C18)alkyl is optionally replaced by a moiety selected from the group consisting of -O-, -NR13-, -S(O)_what-, -C(O)-, -C(CH₂)- or -C(NH)-, provided that when any two methylene in the alkyl are replaced, then two -O-, two -S(O)_what- or two NR13- and -O- and -NR13- are not contiguous, where the alkyl is optionally substituted with one or more Ri₂ and wherein the cycloalkyl and cycloalkenyl are optionally substituted with one or more R13;

ω σ>

ω &lt; or

<img file="MX376739B_D0080.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Rio and R11 are each independently H or (C1-C6) alkyl optionally substituted with one or more substituents independently selected from -NH₂ and OH;

R12 is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, -C(O)OH, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂ and Ri₄;

R13 is H, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl, heteroaryl or (C1-12)alkyl, wherein 0 to 7 methylene of the (C1-C12)alkyl is optionally replaced by a moiety selected from the group consisting of consists of -O-, -NR13-, -S(O)r-, -C(O)-, or -C(NH)-, provided that when any two methylenes on the alkyl are replaced, then O and N do not are contiguous and wherein alkyl is optionally substituted with one or more R15 and wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl and N((C1-C6)alkyl)₂;

R14 is (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -O-heterocycloalkyl, (C1-C12)alkyl or (C2-C12)alkenyl, where 0 to 7 methylene of (C1-C1 -C12) and (C2-C12)alkenyl are optionally replaced by a moiety selected from the group consisting of -O-,

-NR13-, -S(O)_r, -C(O)- or -C(NH)-, provided that when any two methylenes on the alkyl or alkenyl are replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or more R15 and cycloalkyl and heterocycloalkyl are optionally substituted with one or more Rw; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two R14 together with the atom to which they are attached form C=(O); or two R14 together with the atoms to which they are attached form a (C3-C8)cycloalkyl or heterocycloalkyl optionally substituted with one or more R13; or when i laughed₂ is cycloalkyl or heterocycloalkyl, two Together with the atom to which they are attached form a spirocycloalkyl (C3-C8) or a spiroheterocycloalkyl optionally substituted with one or ω

σ>

ω &lt; or

<img file="MX376739B_D0081.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 various R13;

Ri₅ is -OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C3-C8)cycloalkyl, heterocycloalkyl, (C6-C10)aryl or heteroaryl, wherein (C3-C8)cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents selected from (C1-C6)hydroxyalkyl, (C1-C1)aminoalkyl -C6), -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

Rie is -OH, -C(O)OH, -NH₂, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)₂, (C1-C6)alkoxy, (C1-C6)hydroxyalkyl, (C3-C8)cycloalkyl, heterocycloalkyl, -O-(C3-C8)cycloalkyl, -Oheterocycloalkyl, (C6-C10)aryl or heteroaryl, where (C3 -C8) and heterocycloalkyl are optionally substituted with one or more substituents selected from hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl, -C(O)OH, -OH, -NH₂, -NH(C1-C6)alkyl, N((C1-C6)alkyl)₂ and oxo;

each m, o, p, q and r is independently at each occurrence 0, 1 or 2; and n is 0, 1 or 2.

Illustrative non-limiting compounds of the invention include: 1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]-N-[(2,5-dichlorophenyl)methyl]c¡ clopropan-1-amine (1-1); N-[(2,5-d¡chlorophenyl)methyl]-1-{4-[2-(propan-2-¡lox¡)phenyl]p¡rdin-3-¡l }cyclopropan-1-amine (I-2); 1-[4-(2-cyclopropoxy-5-fluorophenyl)p¡rdan-3-¡l]-N-[(2,5-dichlorophenyl)methyl ]cyclopropan-1-amine (I-3); N-[(2,5-d¡chlorophenyl)methyl]-1-[4-(2-methoxyphenyl)p¡rdin-3-¡l]cyclopropan-1- amine (I-4);

1-[4-(2-cyclobutoxyphenyl)p¡r¡d¡n-3-¡l]-N-[(2,5-dichlorophenyl)methyl]cyclopropan- 1-amine (I-5);

N-[(2,5-dichlorophenyl)methyl]-1-[4-(2-methylphenyl)pyridin-3-¡l]cyclopropan-1-amine (I-6);

N-[(2,5-dichlorophenyl)methyl]-1-{4-[2-(methylsulfan¡l)phenyl]p¡rdin-3-yl}c¡clopropan-1-amine (I- 7); N-[(2,5-d¡chlorophenyl)methyl]-1-{4-[2-(2,2,2-trifluoroethoxy)phenyl]p¡r¡d¡n -3-¡l}c¡clopropan-1-am¡na (I-8); N-[(2,5-dichlorophenyl)methyl]-1-[4-(2-ethylphenyl)pyridin-3-l]cyclopropan-1-amine (I-9);

-[4-(2-cyclopropylphenyl)pyridin-3-yl]-N-[(2,5-dichlorophenyl)methyl]cyclopropan-1-amine (1-10) ; N-[(2,5-d¡chlorophenyl)methyl]-1-{4-[2-(trifluoromethoxy)phenyl]p¡r¡d¡n-3-¡l} cyclopropan-1-amine (1-11);

N-[(2,5-d¡chlorophenyl)methyl]-1-{4-[2-(methoxymethyl)phenyl]p¡r¡din-3-¡l}c clopropan-1-amine (1-12);

ω σ>

ω &lt; or

<img file="MX376739B_D0082.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

1-(4-{2-[(tert-butox¡)methyl]phenyl}p¡ndin-3-¡l)-N-[(2,5-dichlorophenyl)methyl ]cyclopropan-1-amine (1-13);

N-[(2,5-dichlorophenyl)methyl]-1-(4-phenylpyridin-3-yl)cyclopropan-1-amine (1-14);

N-[(2,5-d¡chlorophenyl)methyl]-1-[4-(2-ethoxy¡-4,5-d¡fluorophenyl)p¡ndin-3-¡l]c clopropan-1-amine (1-15); 1-[4-(2-chlorophenyl)p¡nd¡n-3-yl]-N-[(2,5-dichlorophenyl)methyl]cyclopropan-1-amine (1 -16);

N-[(2,5-d¡chlorophenyl)methyl]-1-[4-(2-fluorophenyl)p¡ndin-3-¡l]c¡clopropan-1-amine (1- 17);

-[4-(2-cyclopropoxy-4-fluorophenyl)p¡r¡d¡n-3-¡l]-N-[(2,5-dichlorophenyl)methyl]c¡ clopropan-1-amine (1-18); N-[(2,5-d¡chlorophenyl)methyl]-1-{4-[2-(oxetan-3-¡lox¡)phenyl]pyridin-3-¡l }cyclopropan-1-amine (1-19);

2-{2-[3-(1-{[(2,5-d¡chlorophenyl)methyl]amno}cycloprop¡l)pyr¡d¡n-4-¡l]fenox ¡}propan-1-ol (I-20);

N-[(2,5-d¡chlorophenyl)methyl]-1-{4-[2-(oxolan-3-¡lox¡)phenyl]p¡ndin-3-¡l}c clopropan-1-amine (1-21);

(3R,4R)-4-{2-[3-(1-{[(2,5-d¡chlorophenyl)methyl]am¡no}c¡cloprop¡l)p¡r¡din- 4-¡l]phenoxy¡}oxolan-3-ol (I-22);

N-{[2-chloro-5-(methylsulfan¡l)phenyl]methyl}-1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l ]cyclopropan-1-amine (I23);

1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-yl]-N-[(2,5-d¡methylphenyl)methyl]c clopropan-1-amine (I-24);

-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]-N-{[3-methyl-6-(methylsulfan¡l)pyridin-2-¡l ]methyl}cyclopropan-1 amine (I-25);

1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-yl]-N-[(2,3-dichlorophenyl)methyl]cyclopropan -1-amine (I-26);

1-[4-(2-c¡clopropoxyphenyl)p¡nd¡n-3-¡l]-N-[(tnmet¡lp¡raz¡n-2-¡l)met¡l]c clopropan-1-amine (I-27);

1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-yl]-N-[(2,4-dichlorophenyl)methyl]cyclopropan -1-amine (I-28);

1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l]-N-[(4-methoxy-2,5-d¡methylphenyl) methyl]cyclopropan-1-amine (I-29);

N-{[5-chloro-2-(tnfluoromethyl)phenyl]methyl}-1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l ]cyclopropan-1-amine (I30);

N-[(2-chloro-5-cyclopropylphenyl)methyl]-1-[4-(2-cyclopropoxyphenyl)pyridin-3-1] cyclopropan-1-amine (I31);

N-{[2-chloro-5-(tnfluoromethyl)phenyl]methyl}-1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l ]cyclopropan-1-amine (I32);

N-[(2-chloro-5-methylphenyl)methyl]-1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]c¡ clopropan-1-amine (I-33);

IMPI

<img file="MX376739B_D0083.tif" />

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω

MX/E/2018/085580

N-[(5-chloro-2-methylpyridin-4-yl)methyl]-1-[4-(2-cyclopropoxyphenyl)pyridin-3-yl]cyclopropan-1-amine (I34);

N-[(3-chloro-6-methylpyridin-2-yl)methyl]-1 -[4-(2-cyclopropoxyphenyl)p¡hd¡n-3-¡l]cyclopropan-1-amine ( I35);

N-[(3-chloro-5-fluoro-4-methoxy¡-2-methylphenyl)methyl]-1-[4-(2-cyclopropoxyphenyl)p¡ndin- 3-¡l]cyclopropan-1amine (I-36);

1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]-N-{[2-methyl-5-(tnfluoromethyl)phenyl]met ¡l} cyclopropan-1-amine (I-37);

1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-yl]-N-{[4-methoxy-2-methyl-5-(propan-2 -¡l)phenyl]methyl}cyclopropan-1amine (I-38);

-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]-N-{[3-methyl-5-(methylsulfan¡l)pyridin-2-¡l ]methyl}cyclopropan-1 amine (I-39);

N-[(5-chloro-2-methylphenyl)methyl]-1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]c¡ clopropan-1-amine (I-40);

-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]-N-{[2-methyl-5-(methylsulfan¡l)pyridin-4-¡l ]methyl}cyclopropan-1 amine (I-42);

N-[(5-chloro-2-methanesulfonylphenyl)methyl]-1-[4-(2-cyclopropoxyphenyl)pyridin-3-l]c clopropan-1-amine (I43);

1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-yl]-N-[(3,5-dichlorophenyl)methyl]cyclopropan -1-amine (I-44);

3-{1-[(2,5-dichlorophenyl)methoxy]cyclopropyl}-4-(2-methoxyphenyl)pandine (I-45);

4-(2-cyclopropoxyphenyl)-3-{1-[(2,5-dichlorophenyl)methoxy]cyclopropyl}pandin (I-46);

4-(2-cyclopropoxyphenyl)-3-{1-[(2,3-dichlorophenyl)methoxy]cyclopropyl}pandin (I-47);

4-(2-cyclopropoxyphenyl)-3-{1-[(2,4-dichlorophenyl)methoxy]cyclopropyl}pandin (I-48);

4-(2-cyclobutoxyphenyl)-3-{1-[(2,5-dichlorophenyl)methoxy]cyclopropyl}pandin (I-49);

3-{1-[(2,5-dichlorophenyl)methoxy]cyclopropyl}-4-(2-fluorophenyl)pandine (I-50);

3-(1-{[5-chloro-2-(trifluoromethyl)phenyl]methoxy}cyclopropyl)-4-(2-cyclopropoxyphenyl)pindine (1-51);

3-(1-{[2-chloro-5 -(trifluoromethyl)phenyl]methoxy}cyclopropyl)-4-(2-cyclopropoxyphenyl)pindina (I-52);

3-{1-[(2-chloro-5-cyclopropylphenyl)methoxy]cyclopropyl}-4-(2-cyclopropoxyphenyl)p¡nd 53);

MX/E/2018/085580

3-{1-[(2-chloro-5-methylphenyl)methoxy]cyclopropyl}-4-(2-cyclopropoxyphenyl)pandine (I-54) ;

3-{1-[(5-chloro-2-methylphenyl)methoxy]cyclopropyl}-4-(2-cyclopropoxyphenyl)pandine (I-55) ;

4-(2-c¡clopropoxyphenyl)-3-{1-[(3,5-dichlorophenyl)methoxy]cyclopropyl}p¡rdina (I-56) ;

-{1-[4-(2-cyclopropoxyphenyl)pandin-3-yl]cyclopropyl}-1-[(2,5-dichlorophenyl)methyl]urea (I-57 );

1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]-N-[(2,5-dichlorophenyl)methyl]-N -methylcyclopropan-1-amine (I-58);

4-(2-cyclopropoxyphenyl)-3-{3-[(2,5-dichlorophenyl)methoxy]oxethan-3-yl}pandin (I-59) ;

1-(5-{2,5-d¡chloro-4-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cycloprop¡l }amino)methyl]phenyl}pentyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-60);

5-{2,5-d¡chloro-4-[({1-[4-(2-c¡clopropoxyphenyl)pyridin-3-¡l]c¡cloprop¡l} amino)methyl]phenyl}pentanoic acid (1-61);

5-{2,5-d¡chloro-4-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-yl]cyclopropyl} amino)methyl]phenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (I-62);

4-[(4-{2,5-d¡chloro-4-[({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]c¡ cloprop¡l}am¡no)methyl]phenyl}but¡l)[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]carbamo¡l ]butano¡co (I-63);

-{4-[4-chloro-3-({1 -[4-(2-cyclopropoxyphen ¡I )p¡ rid i n-3-¡ l]cyclopropox¡}met¡l )phen¡ I] butyl}- 3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-64);

-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)-2-methylphenyl]butyl}- 3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-65);

(2R,3R,4R,5S)-6-({4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)pind¡n-3 l]cyclopropoxy}methyl)phenyl]butyl}amno)hexan-1,2,3,4,5-pentol (I-66);

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-yl]c¡clopropox¡}met l)phenyl]butyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]oxane-4-carboxamide (I-67);

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-yl]c¡clopropox¡}met l)phenyl]butyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]acetamide (I-68);

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-yl]c¡clopropox¡}met ¡l)phenyl]butyl}-2-methyl-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexíl]propanamide (I-69);

ω σ>

ω &lt; or

<img file="MX376739B_D0084.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

3-(benzenesulfonyl)-N-{4-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)pyridin-3- ¡l]cyclopropox¡}methyl)phenyl]but¡l}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l] propanamide (I-70);

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-2-hydroxyN-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]acetamide (1- 71);

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-2-methox¡N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]acetamide (I- 72);

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-N

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]propanamide (I-73);

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-N

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]butanamide (I-74);

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-3-methoxyN-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]propanamide (I-75) ;

1-{4-[2,5-dichloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-3-(2-methoxyethyl)-1-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]urea (I-76);

(5S)-3-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]c ¡clopropox¡}methyl)phenyl]but¡l}-5[(1 S,2R,3R)-1,2,3,4-tetrahydroxybutyI]-1,3-oxazolidin-2-one (I -77);

(2S)-4-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]c ¡clopropox¡}methyl)phenyl]but¡l}-2[(1 S,2R,3R)-1,2,3,4-tetrahydroxybutyl]-1,4-oxazepan-5-one (I -78);

1-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-3-methyl-1

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-79);

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rdin-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]formamide (I-80);

(2R,3S,4R,5R)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropox¡}methyl)phenyl]but¡l}-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox¡but¡l) hexanamide (1-81);

(2S,3S,4R,5S)-N-(carbamoylmethyl)-N-{4-[2,5-dichloro-4-({1-[4-(2-c¡clopropox¡ phenyl)p¡r¡d¡n-3 ¡l]c¡clopropox¡}methyl)phenyl]but¡l}-2,3,4,5,6-pentah¡drox¡hexanam¡da (I- 82);

ω σ>

ω &lt; or

<img file="MX376739B_D0085.tif" />

ΙΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2R,3S,4R,5R)-N-{4-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p ¡r¡d¡n-3¡l]c¡clopropox¡}methyl)phenyl]but¡l}-2,3,4,5,6-pentah¡drox¡-N-(6-h¡drox hexyl)hexanamid (I-83);

(2R,3S,4R,5R)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropoxy}methyl)phenyl]but¡l}-2,3,4,5,6-pentah¡drox¡-N-(2-sulfamo¡let¡l)hexanam¡da (I-84);

(2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropox¡}methyl)phenyl]but¡l}-2,3,4,5,6-pentah¡drox¡-N-[2-(2-h¡drox¡etox ¡)ethyl]hexanamide (I-85); 1-{4-[2,5-dichloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-1-[2-(2-hydroxyethoxy)ethyl]-3-[(2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl]urea (I-86);

2-{5-[2,5-dichloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}met ¡l)phenyl]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanamido}acetic (I-87);

2-(4-{5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡l]c¡ acid clopropox¡}methyl)phenyl]pentano¡l}pperaz¡n-1-¡l)acetic (I-88);

2-(4-{5-[2,5-dichloro-4-({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3¡l]c¡clopropox ¡}methyl)phenyl]pentano¡l}p¡peraz¡n-1-¡l)-N-methylN-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl ] acetamide (I-89);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N-(2-{2-[2-(2-{5[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r d¡n-3¡l]c¡clopropox¡}met¡l)phen¡l]pentanam¡do}ethox¡)ethox¡]ethox¡}et¡l)pentanam¡da (I-90);

2-[4-(2-{5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡l acid ]cyclopropox¡}methyl)phenyl]pentanamido}et¡l)p¡peraz¡n-1-¡l]acet¡c (1-91);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-1-{4[(2S,3R,4S,5R)-2,3,4,5,6-pentahydroxy¡hex¡l]p¡peraz¡n-1-¡l}pentan-1- one (I-92);

acid (2S,3S,4R,5R,6S)-6-({5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡ d¡n-3-¡l]cyclopropox¡}met¡l)phen¡l]pentanam¡do}met¡l)-3,4,5-tr¡h¡drox¡oxan-2-carboxyl¡co (I -93);

1-{4-[5-chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-¡l]c¡clopropox¡}methyl) -2-methylphenyl]butyl}-3-ethyl-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-94) ;

MX/E/2018/085580

-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)-2-methylphenyl]butyl}- 3[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l]urea (I-95);

-{4-[5-chloro-4-({1 -[4-(2-cyclopropoxyphenyl)p¡ndin-3-yl]cyclopropoxy}methyl)-2-meth ¡phenyl]but¡l}-1-ethyl-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]urea (I-96);

1-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]cyclopropoxy}methyl)-2 -methylphenyl]butyl}-1-(2hydroxyethyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl ]urea (I-97);

2-(4-{5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡l]cyclopiOpox¡} meth¡l)phenyl]pentano¡l}p¡peraz¡n-1-¡l)-N-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhex¡l]acetam Give (I-98);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N-{2-[4({[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l]carbamo¡l}methyl)p¡ perazn-1-¡l]ethyl}pentanamide (I99);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N-{2-[4({methyl[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]carbamo¡l}methyl )p¡peraz¡n-1-¡l]et¡l}pentanam¡da (1-100);

5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l]cyclopropoxy}methyl )phenyl]-N-{3-[4-(3-{5-[2,5dichloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d ¡n-3¡l]c¡clopropox¡}met¡l)phen¡l]pentanam¡do}prop¡l)p¡peraz¡n-1-¡l]prop¡l}pentanam¡da (1-101 );

4-(2-carboxyethyl)-4-{5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)pyrid acid ¡n-3-¡l]cyclopropoxy}methyl)phen¡l]pentanam¡do}heptane¡co (1-102);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl)phen ¡l]-1-{4[(2S,3R,4R,5R)-2,3,5,6-tetrah¡drox¡-4-{[(2S,3R,4S,5R,6R)-3, 4,5-tr¡h¡drox¡-6-(h¡drox¡methyl)oxan-2yl]ox¡}hex¡l]p¡perazin-1-¡l}pentan-1-one (1-103) ;

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N-{[(3R,4R,5S,6R)3,4,5-tnh¡droxy-6-(h¡drox¡methyl)oxan-2-¡l]methyl}pentanam give(1-104);

5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl) phenyl]-N-(2-h¡drox¡ethyl)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanam¡de (1 -105);

ω σ>

ω &lt; or

<img file="MX376739B_D0086.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 acid (2R,3R,4S,5R)-2-[({4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl) p¡ndin-3-¡l]c¡clopropox¡}methyl)-2-methylphenyl]but¡l}carbamo¡l)am¡no]-3,4,5,6-tetrah¡drox¡hexane¡ co(1-106);

1-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)- 2-methylphenyl]but¡l}-3-(2hydroxyethyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy hexyl]urea (1-107);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-¡l]cyclopropox¡}methyl)phen ¡l]-N-ethylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanamide (1-108);

3-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)- 2-methylphenyl]butyl}-1{[(2S,3R,4R,5S,6R)-3,4,5-trih¡drox¡-6-(h¡drox¡methyl) oxan-2-¡l]methyl urea (1-109);

acid (2S,3S,4R,5R,6S)-6-{[({4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)pyr¡d¡ n-3-¡l] c¡clopropox¡}met¡l)-2-met¡lfen¡l]but¡l}carbamo¡l)am¡no]met¡l}-3,4,5-trih¡ drox¡oxan-2-carboxyl¡co (I110);

2-(2-{2-[({4-[5-chloiO-4-({1-[4-(2-c¡clopiOpox¡fen¡l)p¡ndin-3-¡l]c¡ acid clopiOpox¡}methyl)-2-methylphenyl]but¡l}carbamo¡l)am¡no]acetamido}acetamido)acetic (1-111);

(2S)-2-[(2S)-2-[(2S)-2-[({4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡ l] cyclopropox¡}methyl)-2-methylphenyl]but¡l}carbamoic)am¡no]propanam¡do]propanann¡do] propanoic (I112);

acid (2S)-5-carbam¡dam¡do-2-[({4-[5-chloro-4-({1-[4-(2-c¡clopropox¡fen¡l)p¡r d¡n-3¡l]cyclopropoxy}methyl)-2-methylphenyl]but¡l}carbamo¡l)am¡no]pentano¡c (1-113);

N-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)- 2-methylphenyl]butyl}-4[(2S,3R,4S,5R)-2,3,4,5,6-pentahydroxyhexyl]pperazn-1-carboxam give(1-114);

1-{4-[5-chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-¡l]c¡clopropox¡}methyl) -2-methylphenyl]butyl}-1-methyl3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-115);

1-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)- 2-methylphenyl]butyl}-1-(2-methoxyethyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl] urea (1-116);

1-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)- 2-methylphenyl]butyl}-1-[2-(2-hydroxyethoxy)ethyl]-3-[(2S,3R,4R,5R)-2,3,4,5, 6-pentahydroxyhexyl]urea (1-117);

ω σ>

ω &lt; or

<img file="MX376739B_D0087.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

1-{4-[5-chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡ l)-2-methylphenyl]butyl}-1-(5hydroxypentyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy hexy]urea (1-118);

(2R)-6-am¡no-2-[({4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n acid -3-¡l]cyclopropoxy}methyl)-2-methylphenyl]but¡carbamoyl)am¡no]hexano¡c (1-119);

N-benzyl-5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l] cyclopropoxy}methyl)phenyl]-N[(2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-120);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met ¡l)phenyl]-N-methyl-N-(2{[(2R,3R,4S,5S,6R)-3,4,5-tnhidrox¡-6-(h¡drox¡methyl) oxan-2-¡l]ox¡}ethyl)pentanamide (1-121); 5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rd¡n-3-¡l]c¡clopropox¡}methyl )phenyl]-N-(2,3dih¡drox¡prop¡l)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l ]pentanam¡da (1-122);

5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l]cyclopropoxy}methyl )phenyl]-N-[(2R)-2-hydroxy-but-yl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox-hexyl]pentanam give(1-123);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]-N-[(2R)-2-h¡drox¡-3methoxypropyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡ hex¡l]pentanamide (1-124);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]-N-[(2S)-2-h¡drox¡-3methoxypropyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡ hex¡l]pentanamide (1-125);

N-benzyl-5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l]c¡ clopropoxy}methyl)phenyl]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-126);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]-N-(2-methoxyethyl)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1- 127);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rd¡n-3-¡l]c¡clopropox¡}methyl )phen¡l]-N-[(2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhex¡l]-N-(propan-2-¡l)pentanam¡de (1-128 );

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rd¡n-3-¡l]c¡clopropox¡}methyl )phenyl]-N-[(2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhexyl]-N-propylpentanamide (1-129);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rd¡n-3-¡l]c¡clopropox¡}methyl )phenyl]-N-(2methanesulfonyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanam (1-130 );

MX/E/2018/085580

5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rdin-3-¡l]cyclopropoxy}methyl)phenyl]-N-( oxan-4-¡l)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanamide (1-131);

(2S,3S,4R,5S)-N-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l ]cyclopropox¡}methyl)-2-methylphenyl]but¡l}-2,3,4,5,6-pentahydrox¡-N-methylhexanam¡de (1-132);

5-{2,5-d¡chloro-4-[({1-[4-(2-methoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am ¡no)methyl]phenyl}-N-[(2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-133);

5-{2,5-d¡chloro-4-[({1-[4-(2-methoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am ¡no)methyl]phenyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-134) ;

5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l]cyclopropoxy}methyl )phenyl]-N-[(2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-135);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met l)phenyl]-N-methyl-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-136);

5-{2,5-d¡chloro-4-[({1-[4-(2-c¡clopropoxyphenyl)p¡rd¡n-3-¡l]c¡cloprop¡l }amino)methyl]phenyl}-N-methyl-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-137) ;

1-(4-{2,5-d¡chloro-4-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡ clopropyl}amino)methyl]phenyl}butyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-138);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met l)phenyl]-2-methyl-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-139);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N,2-dimethylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexíl]pentanamide (1-140);

1-{4-[2,5-dichloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-141);

5-{5-chloro-4-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]-2-methylphenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-142);

5-{5-chloro-4-[({1-[4-(2-c¡clopropoxyphenyl)p¡rdin-3-¡l]c¡cloprop¡l}am¡no)met ¡l]-2-methylphenyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanam¡de (1-143 );

MX/E/2018/085580

5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-yl]cyclopropoxy}methyl)phenyl]-2, 2-dimethylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-144);

5-[5-chloro-4-({1-[4-(2-c¡clopropox¡fen¡l)p¡r¡d¡n-3-¡l]c¡clopiOpox¡}met¡l)- 2-methylphenyl]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-145);

5-[5-chloro-4-({1-[4-(2-c¡clopropox¡fen¡l)p¡r¡d¡n-3-¡l]c¡clopiOpox¡}met¡l)- 2-methylphenyl]-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-146);

1-(4-{4-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡no) methyl]-2,5-dimethylphenyl}butyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea ( 1-147);

5-{4-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cycloprop¡l}am¡no)methyl]-2 ,5-dimethylphenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-148);

5-{4-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡no)methyl ]-2,5-d¡methylphenyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanam¡de (1 -149);

1-{4-[4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropoxy}methyl)-2,5- dimethylphenyl]butyl}-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-150);

1-(4-{5-chloro-4-[({1-[4-(2-c¡clopropoxyphenyl)p¡rdin-3-¡l]c¡cloprop¡l}am¡ no)methyl]-2-methylphenyl}butyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1- 151);

2-{2-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]ethoxy}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]propanamide (1-152);

(2R,3R,4S,5R)-2-{5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n acid -3¡l]cyclopropoxy}methyl)phenyl]pentanam¡do}-3,4,5,6-tetrahydrox¡hexano¡co (1-153);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N[(2R,3R,4R,5S,6R)-2,4,5-t¡hydroxy¡-6-(h¡drox¡methyl)oxan-3-¡l]pentanam¡de (1-154);

2-{2-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡} methyl)phenyl]ethoxy}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]propanamide (1-155 );

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N-[(2S,3R,4S,5R)1,3,4,5,6-pentahydroxy¡hexan-2-¡l]pentanam¡de (1-156);

ω σ>

ω &lt; or

<img file="MX376739B_D0088.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l] acid cyclopropoxy}methyl)phenyl]pentanoic acid (1-157);

1-(1-{5-[2,5-dichloro-4-({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3¡l]c¡clopiOpox ¡}methyl)phenyl]pentanoyl}ppend¡n-4-¡l)-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhex¡l]urea (1-158);

1-(1-{5-[2,5-dichloro-4-({1-[4-(2-c¡clopropox¡fen¡l)p¡rdin-3yl]c¡clopiOpox¡}met¡ l)phen¡l]pentano¡l}p¡per¡n-4-¡l)-3-methyl-3-[(2S,3R,4R,5R)-2,3,4,5 ,6-pentahydroxyhexyl]urea (1-159);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N-[(2S,3R,4S,5R)3,4,5,6-tetrahydrox¡-1-(morpholin-4-¡l)hexan-2-¡l]pentanamide (1- 160);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N-[(2S,3R,4R,5R)2,3,4,5,6-pentahydroxy hex¡l]hexanamide (1-161);

5-[2,5-dichloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rd¡n-3-yl]c¡clopropox¡}met¡ l)phenyl]-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (1-162);

1-(5-{2,5-d¡chloro-4-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡ cloprop¡l}am¡no)methyl]phenyl}pentyl)-3methyl-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]urea ( 1-163);

2-{[(2S,3R,4S,5R)-2-{5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r acid ¡d¡n-3-¡l]cyclopropox¡}met¡l)phen¡l]pentanam¡do}-3,4,5,6-tetrah¡drox¡hex¡l](met¡l)am¡no }acetic (1-164);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N-[(2S,3R,4S,5R)1-(dimet¡lam¡no)-3,4,5,6-tetrah¡drox¡hexan-2-¡l]pentanam¡da (1 -165);

4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)-2-meth yphenyl]butan-1-amine (1-166);

1-{4-[5-chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡ l)-2-methylphenyl]butyl}-3-methyl3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-167 );

5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)phenyl]-/V,/Vb ¡s(2{[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhexl]carbamoyl}ethyl)pentanamide (1-168);

ω σ>

ω &lt; or

<img file="MX376739B_D0089.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)phenyl]-/V, /V-bis(2{methyl[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]carbamo¡l}et¡l)pentanam¡da (1 -169);

5-{2,5-d¡chloro-4-[({1-[4-(2-c¡clopropoxyphenyl)p¡rd¡n-3-¡l]c¡cloprop¡l }am¡no)methyl]phenyl}-A/,A/-b¡s(2{[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]carbamo ¡l}ethyl)pentanamide (1-170);

5-{2,5-d¡chloro-4-[({1-[4-(2-c¡clopropoxyphenyl)p¡rd¡n-3-¡l]c¡cloprop¡l }am¡no)methyl]phenyl}-A/,A/-b¡s(2{methyl[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡ hexyl]carbamo(l}ethyl)pentanamide (1-171);

(2S,3S,4R,5S)-N-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]c clopropoxy}methyl)-2-methylphenyl]butyl}-2,3,4,5,6-pentahydroxyhexaneamide (1-172);

acid (2S,3S,4R,5S)-6-[(1-{5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p ¡rid¡n-3-¡l] c¡clopropox¡}met¡l)phen¡l]pentano¡l}p¡pendin-4-¡l)am¡no]-2,3,4,5-tetrah ¡droxy¡hexano¡c (1-173);

1-[4-(2,5-d¡chloro-4-{[(1-{4-[2-(oxetan-3-¡lox¡)phenyl]p¡r¡d¡n-3-¡l }c¡cloprop¡l)am¡no]methyl}phenyl)but¡l]-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]urea (1- 174);

1-[4-(2,5-d¡chloro-4-{[(1-{4-[2-(oxetan-3-¡lox¡)phenyl]p¡r¡d¡n-3-¡l }c¡cloprop¡l)am¡no]methyl}phenyl)but¡l]-3methyl-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡droxyhex ¡l]urea (1-175);

(2S,3S,4R,5S)-N-{4-[5-chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]c ¡clopropox¡}methyl)-2methylphenyl]butyl}-2,3,4,5-tetrah¡drox¡-6-(morphol¡n-4-¡l)hexanam¡da (1-176 );

5-(2,5-d¡chloro-4-{[(1-{4-[2-(oxetan-3-¡lox¡)phenyl]p¡r¡d¡n-3-yl}c ( 1-177);

3-(5-{2,5-d¡chloro-4-[({1-[4-(2-cyclopropoxyphenyl)p¡rdin-3-¡l]cycloprop acid ¡l}am¡no)methyl]phenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanam¡do)propano¡co (1- 178);

(2S,3S,4R,5S)-N-{4-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡ l]cyclopropox¡}methyl)phenyl]butyl}-2,3,4,5-tetrah¡drox¡-6-(morphol¡n-4-¡l)hexanam¡da (1-179 );

acid (2S,3S,4R,5S)-6-[(3-{5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p ¡rid¡n-3-¡l]c¡clopropox¡}methyl)phenyl]-N-methylpentanam¡do}prop¡l)am¡no]-2,3,4,5-tetrah¡drox ¡-hexano¡co (I180);

ω σ>

ω &lt; or

<img file="MX376739B_D0090.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

N-{[(2R,3S,4S,5R,6R)-6-{[(1R,2R,3S,4R,6S)-4,6-diam¡no-3-{[(2S,3R,4S ,5S,6R)-4-am¡no-3,5d¡hdrox¡-6-(h¡drox¡methyl)oxan-2-¡l]ox¡}-2-h¡drox¡cyclohex ¡l]ox¡}-3,4,5-t¡drox¡oxan-2-¡l]met¡l}-5[2,5-d¡chloro-4-({1-[4- (2-cyclopropoxyphenyl)pyrdn-3-I]cyclopropoxymethyl)phenyl]pentanamide (1-181); 4-({4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)pyr¡n-3-¡l]cyclopropox ¡}methyl)phenyl]butyl}[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]carbamo¡l)butanoic (1-182 );

3-{5-[2,5-dichloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}met ¡l)phenyl]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanam¡do}propano¡co (1-183);

(2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]cyclopropoxy}methyl)phenyl]but¡l}-2,3,4,5,6-pentahydrox¡-N-methylhexanam¡de (1-184); (2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]cyclopropoxy}methyl)phenyl]but¡l}-2,3,4,5,6-pentahydrox¡hexanam¡de (1-185);

2-[({4-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropox¡} methyl)phenyl]butyl}[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]carbamoyl)methoxy]acetic (1-186) ;

3-({4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropoxyphenyl)pyr¡n-3-¡l]c¡clopropox ¡}methyl)phenyl]butyl}[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]carbamo¡l)propanoic (1-187 );

2-({2-[(carbox¡methyl)[({4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)pyr¡ d¡n-3-¡l] cyclopropox¡}methyl)phenyl]but¡l}(methyl)carbamo¡l)met¡l]am¡no]et¡l}[({4- [2,5-dichloro-4-({1-[4-acid (2-cyclopropoxyphenyl)pyridin-3-¡l]cyclopropoxy}methyl)phenyl]but¡l} (methyl)carbamoyl)methyl]amno)acetic (I188);

(2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropox¡}methyl)phenyl]butyl}-2,3,4,5-tetrah¡drox¡-N-methyl-6-(morphol¡n-4-¡l hexanamide (1-189); 1-(4-{5-chloro-2-methyl-4-[(1-{4-[2-(oxetan-3-¡lox¡)phenyl]p¡nd¡n-3-¡ l}cyclopropox¡)methyl]phenyl}but¡l)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]urea (1-190) ;

1-(4-{5-chloro-2-methyl-4-[(1-{4-[2-(oxetan-3-¡lox¡)phenyl]p¡nd¡n-3-¡ l}cyclopropoxy¡)methyl]phenyl}but¡l)-3methyl-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]urea (1-191);

ω σ>

ω &lt; or

<img file="MX376739B_D0091.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

5-{2,5-d¡chloro-4-[(1-{4-[2-(oxetan-3-¡lox¡)phenyl]p¡r¡d¡n-3-¡l}c ¡clopropox¡)methyl]phenyl}-N-methyl-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanam¡de (1-192 );

1-(4-{2,5-d¡chloro-4-[(1-{4-[2-(oxetan-3-¡lox¡)phenyl]p¡r¡d¡n-3-¡ l}cyclopropoxy)methyl]phenyl}butyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-193);

1-({4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)pyr¡d¡n-3-¡l]cyclopropox¡ }methyl)phenyl]butyl}sulfamoyl)3-methyl-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhexl]urea ( 1-194);

2-{[({4-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropox¡ }methyl)phenyl]butyl}[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]carbamoyl)methyl](methyl )am¡no}acetic acid (1-195);

4-({4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)pyr¡n-3-¡l]cyclopropox ¡}methyl)phenyl]but¡l}[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l]carbamo¡l)-3,3- dimethylbutanol (1-196);

2-[({4-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropox¡} methyl)phenyl]butyl}[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]carbamoyl)amno]acetic (1 -197);

3-[({4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropox¡} met¡l)phenyl]but¡l}[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxy¡hex¡l]carbamo¡l)am¡no]propano¡co (1 -198);

4-[({4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropox¡} met¡l)phenyl]but¡l}[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxy¡hex¡l]carbamo¡l)am¡no]butano¡co (1 -199);

2-({[(4-{2,5-dichloro-4-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cycloprop ¡l}am¡no)met¡l]phenyl}but¡l)[(2S,3R,4R,5R)-2,3,4,5,6pentah¡drox¡hex¡l]carbamo¡l] methyl}(methyl)amino)acetic acid (I-200);

4-[(4-{2,5-d¡chloro-4-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cycloprop ¡l}am¡no)methyl]phenyl}but¡l)[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]carbamo¡l] -3,3-dimethylbutanoic acid (1-201);

ω σ>

ω &lt; or

<img file="MX376739B_D0092.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-2methanesulfonyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]acetamide (I-202) ;

N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} met¡l)phenyl]butyl}-2(d¡met¡lam¡no)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex I]acetamide (I-203);

1-{4-[2,5-dichloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]butyl}-1-methyl-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-204);

(2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡fen¡l)p¡r¡d¡ n-3-¡l]cyclopropoxy}methyl)phenyl]butyl}-2,3,4,5,6-pentahydrox¡-N-propylhexanam¡da (I-205);

(2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropox¡}met¡l)phen¡l]but¡l}-2,3,4,5,6-pentah¡drox¡-N-(2-methox¡et¡l)hexanam¡ da (I-206);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopiOpox¡}met ¡l)phenyl]-N-[2(dimet¡lam¡no)et¡l]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox hexyl]pentanamide (I-207);

N-(carbamoylmethyl)-5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-¡ l]cyclopropoxy}methyl)phenyl]N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (I-208);

(2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]cyclopropox¡}methyl)phenyl]but¡l}-N-ethyl-2,3,4,5,6-pentahydrox¡hexanam¡de (I-209);

(2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropox¡}met¡l)phen¡l]but¡l}-2,3,4,5,6-pentah¡drox¡-N-(propan-2-¡l)hexanam¡da (1-210); (2S,3S,4R,5S)-N-(c¡cloprop¡lmethyl)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-c¡ clopropoxyfen¡l)p¡r¡d¡n-3¡l]ciclopropox¡}met¡l)fen¡l]but¡l}-2,3,4,5,6-pentah¡drox¡hexanam¡da ( 1-211);

(2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropoxy}methyl)phenyl]but¡l}-2,3,4,5,6-pentah¡drox¡-N-(3-methox¡prop¡l)hexanam¡da (1-212); (2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropox¡}met¡l)phen¡l]but¡l}-2,3,4,5,6-pentah¡drox¡-N-(2-h¡drox¡et¡l) hexanamide (1-213);

(2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropox¡}methyl)phenyl]but¡l}-2,3,4,5,6-pentah¡drox¡-N-[(2R)-2-h¡drox¡ propyl]hexanamid (1-214);

ω σ>

ω &lt; or

<img file="MX376739B_D0093.tif" />

ΙΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-{4-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p ¡r¡d¡n-3¡l]c¡clopropox¡}methyl)phenyl]but¡l}-2,3,4,5,6-pentah¡drox¡-N-[(2S)-2 -h¡drox¡prop¡l]hexanam¡da (1-215); (2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]cyclopropox¡}met¡l)phen¡l]but¡l}-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡l)hexanam¡da (1 -216);

(2S,3S,4R,5S)-N-{4-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropox¡}methyl)phenyl]but¡l}-2,3,4,5,6-pentah¡drox¡-N-(3-h¡drox¡prop¡l)hexanam¡ gives (1-217);

5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropoxy}methyl) phenyl]-N-(3-h¡drox¡prop¡l)N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]pentanam¡de (1-218);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopiOpox¡}met ¡l)phenyl]-N[(methylcarbamo¡l)methyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l ]pentanam¡da (1-219);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N-(3-methoxy¡prop¡l)N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l]pentanam¡de (I- 220);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopiOpox¡}met ¡l)phenyl]-N[(dimethylcarbamo¡l)methyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex ¡l]pentanamide (1-221);

5-[2,5-d¡chloro-4-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopiOpox¡}met ¡l)phenyl]-N-[2(dimethylcarbamo¡l)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox hexyl]pentanamide (I-222);

N-(2-carbamoylethyl)-5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3 -¡l]cyclopropoxy}methyl)phenyl]N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]pentanam¡de (I-223 );

(2S,3S,4R,5S)-N-{5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropox¡}methyl)phenyl]pent¡l}-2,3,4,5,6-pentah¡drox¡-N-[2-(2-h¡drox¡ethox¡) ethyl]hexanamid (I224);

1-{5-[2,5-dichloro-4-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)phenyl]pentyl}-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-225);

(2S,3S,4R,5S)-N-{5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡clopropox¡}methyl)phenyl]pent¡l}-2,3,4,5,6-pentah¡drox¡-N-(2-methanesulfon¡let¡l)hexanam¡ gives (I226);

ω

<img file="MX376739B_D0094.tif" />

ΙΜΡΙ

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 (2S,3S,4R,5S)-N-{5-[2,5-dichloro-4-({1-[4-(2-cyclopropoxyphenyl)p ¡r¡d¡n-3¡l]c¡clopropox¡}methyl)phenyl]pent¡l}-N-[2-(ethansulfon¡l)et¡l]-2,3,4, 5,6-pentahydrox¡hexanam¡de (I-227); (2S,3S,4R,5S)-N-{5-[2,5-d¡chloro-4-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]cyclopropoxy}methyl)phenyl]pent¡l}-2,3,4,5,6-pentahydrox¡-N-methylhexanam¡de (I-228);

5-[4-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}met¡l)-2,5-d¡met¡ lfen¡l]-N-[(2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhex¡l]pentanamide (I-229);

5-[4-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropoxy}methyl)-2,5-d¡met yphenyl]-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (I-230);

5-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l]cyclopropoxy}methyl)phenyl ]-N-[(2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhexyl]pentanamide (1-231);

5-[4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}methyl)phen ¡l]-N-methyl-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanamide (I-232);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡clopiOp¡l}amino)met ¡l]phenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanamide (I-233);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met l]phenyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (I-234);

5-[3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡l)-4-met¡ lphenyl]-N-[(2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhexyl]pentanamide (I-235);

5-[3-({1-[4-(2-c¡clopropox¡fen¡l)p¡r¡d¡n-3-¡l]c¡clopiOpox¡}met¡l)-4-met¡ lphenyl]-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (I-236);

5-{3-[({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡cloprop¡l}am¡no)met¡l]-4- methylphenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (I-237);

5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cycloprop¡l}am¡no)methyl]-4 -methylphenyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (I-238);

1-{4-[3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}methyl)-4 -methylphenyl][(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-239);

butyl}-3ω σ>

ω &lt; or

<img file="MX376739B_D0095.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

1-(4-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡no) methyl]-4-methylphenylbutyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-240);

1-(4-{4-chloro-3-[({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡cloprop¡l}am¡no) methyl]phenyl}butyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-241);

N-{[5-(6-am¡nohexan-2-¡l)-2-chlorophenyl]methyl}-1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡ n-3-¡l]cyclopropan-1amine (I-242);

N-({5-[(2S)-6-am¡nohexan-2-¡l]-2-chlorophenyl}methyl)-1-[4-(2-cyclopropoxyphenyl) pndin-3-µl]cyclopropan-1-amine (I-243);

N-({5-[(2R)-6-am¡nohexan-2-¡l]-2-chlorophenyl}methyl)-1-[4-(2-cyclopropoxyphenyl)p¡ nd¡n-3yl]cyclopropan-1-amine (I-244);

(5S)-5-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}methyl)phen ¡l] hexan-1-amine (I245);

(5R)-5-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]hexan-1-amine (I-246);

(5S)-5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropyl}am acid ¡no)methyl]phenyl}hexanoic acid (I-247);

(5R)-5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropyl}am acid ¡no)methyl]phenyl}hexanoic acid (I-248); 6-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cycloprop¡l}am¡no)meth l]phenyl heptanoic acid (I-249);

N-({5-[(2S)-5-am¡nopentan-2-¡l]-2-chlorophenyl}methyl)-1-[4-(2-cyclopropoxyphenyl)p¡ nd¡n-3yl]cyclopropan-1-amine (I-250);

N-({5-[(2R)-5-am¡nopentan-2-¡l]-2-chlorophenyl}methyl)-1-[4-(2-cyclopropoxyphenyl) pindn-3yl]cyclopropan-1-amine (1-251);

N-{[5-(5-am¡nopentan-2-¡l)-2-chlorophenyl]methyl}-1-[4-(2-c¡clopropox¡phenyl)p¡ndin- 3-¡l]cyclopropan-1amine (I-252);

ω

<img file="MX376739B_D0096.tif" />

ΙΜΡΙ

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 acid (5S)-5-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡ndin-3-¡l]c¡cloprop¡l }amino)methyl]-4-methylphenyl}hexano(I-253);

(5R)-5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]cycloprop¡l}am¡no)met ¡l]-4-methylphenyl}hexano¡c (I254);

1-[(5S)-5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡ clopropyl}amino)methyl]phenyl}hexyl]-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-255);

1-[(5R)-5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡ clopropyl}amino)methyl]phenyl}hexyl]-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-256);

5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropyl}am¡no)methyl]-4- methylphenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (I-257);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡cloprop¡l}am¡no)met¡l]phenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-met¡lhexanam¡da (I-258 );

N-benzyl-5-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am ¡no)methyl]-4-methylphenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]hexanam¡de (I-259 );

5-{2,5-d¡chloro-4-[({1-[4-(2-c¡clopropoxyphenyl)p¡rd¡n-3-¡l]c¡cloprop¡l }amino)methyl]phenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (I-260); 5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rdin-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-(5hydroxypent¡l)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]hexanamide (1-261);

5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]cycloprop¡l}am¡no)met ¡l]phenyl}-N-[2-(morpholine-4sulfonyl)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡ drox¡hex¡l]hexanamide (I-262);

1-[(5S)-5-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡}met¡ l)phenyl]hexyl]-3[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-y]urea (I-263);

1-[(5R)-5-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡} methyl)phenyl]hexyl]-3[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-y]urea (I-264);

1-(4-{4-chloro-3-[({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡ no)methyl]phenyl}pentyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-265);

MX/E/2018/085580

-(5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]cyclopropyl}amno)methyl ]

[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l]urea (I-266);

1-(5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡ non)methyl]phenyl}hexyl)-3phenyl}hexyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-267);

1-(6-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡ non)methyl]phenyl}heptyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-268);

1-(5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡ non)methyl]phenyl}hexyl)-1-methyl3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-269);

1-(5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡ no)methyl]phenyl}hexyl)-1-[2-(2-hydroxyethoxy)ethyl]-3-[(2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl] urea (I-270);

1-(4-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}amino)met¡ l]-4-methylphenyl}pentyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-271);

1-(5-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡no) methyl]-4-methylphenyl}hexyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-272) ;

1-[(5R)-5-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡} methyl)phenyl]hexyl]-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-273);

1-[(5S)-5-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox }methyl)phenyl]hexyl]-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-274);

-{5-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡ridin-3-¡l]cyclopropoxy}methyl)phen¡I]hexyl}-3-

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-275);

1-{5-[3-({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡clopropox¡}met¡l)-4-met¡lfen ¡l]hexyl}-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]urea (I-276);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡cloprop¡l}am¡no)methyl]phenyl}pentyl)-2,3,4,5,6-pentah¡drox¡-N-[2-(2-oxo¡m¡dazol ¡dn-1-¡l)ethyl]hexanamide (I-277);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]cycloprop¡l}am¡no)methyl]phenyl}pent¡l)-2,3,4,5,6-pentahydrox¡hexanam¡da (I-278);

ω σ>

ω &lt; or

<img file="MX376739B_D0097.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-(5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡ d¡n-3¡l]cycloprop¡l}am¡no)met¡l]phenyl}hex¡l)-2,3,4,5,6-pentahydrox¡hexanam¡da (I-279 );

(2S,3S,4R,5S)-N-(6-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]cycloprop¡l}am¡no)methyl]phenyl}hept¡l)-2,3,4,5,6-pentahydrox¡hexanam¡da (I-280);

(2S,3S,4R,5S)-N-(5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡l ]cyclopropyl}am¡no)methyl]phenyl}hex¡l)-2,3,4,5,6-pentahydrox¡-N-methylhexanam¡de (1-281);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡cloprop¡l}am¡no)met¡l]phenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(2-methox¡et¡l) hexanamide (I-282); (2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡cloprop¡l}am¡no)met¡l]fen¡l}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox¡but¡ l) hexanamide (I-283); (2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡cloprop¡l}am¡no)met¡l]fen¡l}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(3-methox¡prop¡l) hexanamide (I284);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡clopropyl}am¡no)methyl]phenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡l)hexanam¡da (I-285);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡cloprop¡l}am¡no)met¡l]fen¡l}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-[2-(2-h¡drox ¡ethoxy¡)et¡l]hexanam¡da (I-286);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡cloprop¡l}amino)methyl]phenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡lmet¡l)hexanam gives (I287);

(2S,3S,4R,5S)-N-(5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡l ]c¡cloprop¡l}am¡no)met¡l]fen¡l}hex¡l)-2,3,4,5,6-pentah¡drox¡-N-[2-(2-h¡drox ¡ethoxy¡)et¡l]hexanam¡da (I-288);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡cloprop¡l}amino)methyl]phenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(2-methanesulfon¡let¡l)hexanam¡ da (I-289);

ω σ>

ω &lt; or

<img file="MX376739B_D0098.tif" />

IMPI

100

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pind¡ n-3¡l]c¡cloprop¡l}am¡no)methyl]phenyl}pent¡l)-N-(4-acetam¡dobut¡l)-2,3,4,5,6 -pentahydrox¡hexanam¡de (I290);

(2S,3S,4R,5S)-N-(5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l]c ¡cloprop¡l}amino)methyl]phenyl}hex¡l)-2,3,4,5,6-pentah¡drox¡-N-(2-methanesulfon¡let¡l)hexanam¡da ( I291);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l]c cloprop(l}amino)methyl]phenyl}pentyl)-2,3,4,5,6-pentahydroxy-N-(3-methanesulfonylpropyl)hexanamide (I-292);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l]c ¡cloprop¡l}am¡no)met¡l]phenyl}pent¡l)-N-[2-(ethanesulfon¡l)et¡l]-2,3,4,5,6-pentah¡drox hexanamide (I293);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l]c ¡cloprop¡l}amino)methyl]phenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-[3-(2-oxop¡rrol¡d¡n -1¡l)propyl]hexanamide (I-294);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l]c ¡chloropropyl}am¡no)methyl]phenyl}pent¡l)-N-(1,1-dioxo-1 A⁶-thian-4-yl)-2,3,4,5,6-pentahydroxyhexanamide (I-295);

(2S,3S,4R,5S)-N-(5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rdin-3-¡ l]c¡cloprop¡l }amino)methyl]phenyl}hex¡l)-N-[2-(ethansulfon¡l)et¡l]-2,3,4,5,6-pentah¡ droxyhexanamid (I-296);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l]c ¡chloropropyl}am¡no)methyl]phenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(4-methanesulfonam¡dobut¡l) hexanamide (I- 297);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pind¡n-3yl]c¡cloprop ¡l}am¡no)methyl]phenyl}pent¡l)-N-[2-(1,1-dioxo-1 A⁶,4-thiomorpholin-4-¡l)ethyl]-2,3,4,5,6-pentahydroxyhexanamide (I-298);

ω

<img file="MX376739B_D0099.tif" />

IMPI

101 σ>

ω &lt; or

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-(4-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡ (I -299);

(2S,3S,4R,5S)-N-(5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l] cycloprop¡l}am¡no)methyl]-4methylphenyl}hex¡l)-2,3,4,5,6-pentahydrox¡hexanam¡da (I-300);

(2S,3S,4R,5S)-N-(4-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l] c¡cloprop¡l}am¡no)methyl]-4methylphenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-methylhexanam¡da (1-301 );

(2S,3S,4R,5S)-N-(4-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l] c¡cloprop¡l}am¡no)methyl]-4methylphenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(2-methox¡et¡l) hexanamide (I-302);

(2S,3S,4R,5S)-N-(4-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l] c¡cloprop¡l}am¡no)methyl]-4methylphenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(3-methoxy¡prop¡l) hexanamide (I-303);

(2S,3S,4R,5S)-N-(4-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l] c¡cloprop¡l}am¡no)methyl]-4methylphenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡l)hexanam give (I-304);

(2S,3S,4R,5S)-N-(4-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l] c¡cloprop¡l}am¡no)methyl]-4methylphenyl}pent¡l)-2,3,4,5,6-pentah¡drox¡-N-(2-methanesulfonyleth¡l)hexanamide ( I-305);

(2S,3S,4R,5S)-N-(4-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l] c¡cloprop¡l}am¡no)met¡l]-4met¡lfen¡l}pent¡l)-N-(1,1-d¡oxo-1A⁶-t¡an-4-¡l)-2,3,4,5,6-pentahydrox¡hexanam¡da (I-306);

(2S,3S,4R,5S)-N-(4-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l] cycloprop¡l}am¡no)methyl]-4methylphenyl}pent¡l)-N-[2-(ethansulfon¡l)ethyl]-2,3,4,5,6-pentah ¡drox¡hexanam¡de (I-307);

(2S,3S,4R,5S)-N-{5-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l ]cyclopropoxy}methyl)phenyl]hexyl}2,3,4,5,6-pentahydroxyhexanamide (I-308);

(2S,3S,4R,5S)-N-{4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l]c¡ clopropox¡}methyl)phenyl]pentyl}-2,3,4,5,6-pentahydrox¡-N-(2-methanesulfon¡lethyl)hexanam¡de (I309); (2S,3S,4R,5S)-N-{4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l]c¡ clopropox¡}met¡l)fen¡l]pent¡l}-N-[2-(ethansulfon¡l)et¡l]-2,3,4,5,6-pentah¡drox¡hexanam¡da (1 -310);

ω σ>

ω &lt; or

<img file="MX376739B_D0100.tif" />

IMPI

102

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-{4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd ¡n-3¡l]c¡clopropox¡}met¡l)phen¡l]pent¡l}-N-(1,1-d¡oxo-1A⁶-t¡an-4-¡l)-2,3,4,5,6-pentahydrox¡hexanam¡da (I311);

(2S,3S,4R,5S)-N-{5-[3-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡} methyl)-4-methylphenyl]hexyl}2,3,4,5,6-pentahydroxyhexanamide (1-312);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡clopiOp¡l}amino)met ¡l]phenyl}-N[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxy¡hexan-2-¡l]hexanamide (1-313);

(5S)-5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am ¡no)methyl]phenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (1-314);

(5R)-5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l]cycloprop¡l }amino)methyl]phenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (1-315);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡clopiOp¡l}amino)met ¡l]phenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]hexanamide (1-316);

6-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡clopiOp¡l}amino)met ¡l]phenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]heptanamide (1-317);

acid (2S,3S,4R,5S)-6-{[1-(5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡ n-3¡l]c¡cloprop¡l}am¡no)met¡l]phen¡l}hexano¡l)p¡per¡d¡n-4-¡l]am¡no}-2,3, 4,5-tetrahydrox¡hexano¡co (I318);

4-(5-{4-chloro-3-[({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡ (1 -319);

1-[1-(5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡ndin-3-¡l]c¡cloprop¡l}am ¡no)methyl]phenyl}hexane¡l)p¡peridin-4-¡l]-3-[(2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl]urea (I-320);

2-[4-(5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡ndin-3-¡l]c¡cloprop¡l}am ¡no)methyl]phenyl}hexanoyl)p¡peraz¡n-1-¡l]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡ droxyhexil]acetamide (1-321); 4-[2-(5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡ndin-3-¡l]c¡cloprop¡l}am ¡no)methyl]phenyl}hexanam¡do)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l ]pperazin-1-carboxamide (I322);

MX/E/2018/085580

-{2-[4-(5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyridin-3-¡l]c¡clopropyl}amino)met ¡l]phenyl}hexane¡l)p¡peraz¡n-1-¡l]ethyl}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡ drox¡hex¡l]urea (I-323); 5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-{2-[4({[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l]carbamo¡l}met¡ l) perazin-1-yl]ethyl}hexanamid (I324);

(5S)-5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am ¡no)methyl]phenyl}-N-methyl-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamide (I-325);

(5R)-5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l]cycloprop¡l }am¡no)methyl]phenyl}-N-methyl-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]hexanam¡de (I-326) ;

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]hexanamide (I-327);

(6S)-6-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am ¡no)methyl]phenyl}-N-methyl-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]heptanamide (I-328);

(6R)-6-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l]cycloprop¡l }am¡no)methyl]phenyl}-N-methyl-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]heptanamide (I-329) ;

6-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met l]phenyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]heptanamide (I-330);

5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-yl]cyclopropyl}amno) methyl]phenyl}-N-(2-hydroxyethyl)N-[(2R,3S,4S,5S)-2,3,4,5,6-pentahydroxyhexyl ]hexanamid (1-331);

N-(carbamoylmethyl)-5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cycloprop¡ l}am¡no)met¡l]fen¡l}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]hexanam¡da ( I332);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rdin-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-(2-methoxyethyl)N-[(2R,3S,4S,5S)-2,3,4,5,6-pentahydroxy¡hex¡l]hexanam¡ gives (I-333);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-(3hydroxy¡prop¡l)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]hexanam give (I-334);

ω σ>

ω &lt; or

<img file="MX376739B_D0101.tif" />

104

ΙΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

N-(2-carbamoylethyl)-5-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l] cycloprop¡l}am¡no)met¡l]phenyl}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]hexanam¡ gives (I335);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡clopiOp¡l}amino)met ¡l]phenyl}-N[(methylcarbamo¡l)methyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l ]hexanamid (I-336);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-[2(d¡met¡lam¡no)et¡l]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah ¡drox¡hex¡l]hexanam¡de (I-337); 5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-(3methoxypropyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]hexanam¡da (I-338);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-(oxan-4-¡l)-N[(2R,3S,4S,5S)-2,3,4,5,6-pentahydroxy¡hex¡l]hexanam¡da (I-339);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡clopiOp¡l}amino)met ¡l]phenyl}-N[(dimethylcarbamo¡l)methyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex ¡l]hexanamide (I-340);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rdin-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-(3-h¡drox¡-2,2dimet¡lprop¡l)-N-[(2R,3S,4S,5S)-2,3,4,5,6- pentahydroxyhexyl]hexanamid (1-341);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-[2-(2-hydroxyethoxy¡)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox ¡hex¡l]hexanamide (I-342);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡clopiOp¡l}amino)met ¡l]phenyl}-N[(2R,3S,4S,5S)-2,3,4,5,6-pentahydroxy¡hex¡l]-N-[(1s,4s)-4-h¡ droxycyclohexyl]hexanamide (I-343);

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-[2(ethylcarbamo¡l)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex l]hexanamid (I-344); 5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-[2(dimethylcarbamo¡l)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox ¡hex¡l]hexanamide (I-345); 5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-(2methanesulfonyleth¡l)-N-[(2R,3S,4S,5S)-2,3,4,5,6-pentah¡drox¡hex¡l]hexanam¡da (I-346); 5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-(3methanesulfonylpropyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]hexanam¡da (I-347);

<img file="MX376739B_D0102.tif" />

105

IMPIa

MEXICAN INSTITUTE OF PROPERTY w

INDUSTRIAL &lt;0

MX/E/2018/085580

5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]phenyl}-N-[2(dimethylsulfamo¡l)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox hexyl]hexanamid (I-348); 5-{3-[({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡cloprop¡l}am¡no)met¡l]-4- ethylphenyl}-N-[(2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhexyl]hexanamid (I-349);

(5S)-5-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡nd¡n-3-yl]c¡cloprop¡l}am¡no)met¡ l]-4-methylphenyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamide (I-350) ;

(5R)-5-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rdin-3-¡l]c¡cloprop¡l}am¡no)met ¡l]-4-methylphenyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]hexanam¡de (1-351 );

5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cycloprop¡l}am¡no)methyl]-4 -methylphenyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (I-352);

5-{3-[({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡cloprop¡l}am¡no)met¡l]-4- methylphenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]-N-(propan-2-¡l)hexanam¡de ( I-353);

5-{3-[({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡cloprop¡l}am¡no)met¡l]-4- methylphenyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]-N-propylhexanamid (I-354);

5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropyl}am¡no)methyl]-4- methylphenyl}-N-(2-h¡drox¡ethyl)N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]hexanam¡da (I-355);

N-(carbamoylmethyl)-5-{3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l }am¡no)met¡l]-4methylphenyl}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]hexanam¡da ( I-356);

5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cycloprop¡l}am¡no)methyl]-4- methylphenyl}-N-(2-methoxyethyl)N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanam¡de (I -357);

5-{3-[({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡cloprop¡l}am¡no)met¡l]-4- methylphenyl}-N-(3-hydroxy-propyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox-hex-l]hexanam da (I-358);

N-(2-carbamoyl)-5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]c ¡cloprop¡l}amino)methyl]-4methylphenyl}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]hexanam¡ da (I-359);

5-{3-[({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡cloprop¡l}am¡no)met¡l]-4- methylphenyl}-N[(methylcarbamoyl)methyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl] hexanamide (I-360);

ω

<img file="MX376739B_D0103.tif" />

IMPI

106 σ>

w&lt;o

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

5-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡no)methyl ]-4-methylphenyl}-N-[2(dimethyllamino)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl]hexanamid (1-361);

5-{3-[({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡cloprop¡l}am¡no)met¡l]-4- met¡lfen¡l}-N-(3methoxiprop¡l)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]hexanam¡da ( I-362);

5-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡no)methyl ]-4-methylphenyl}-N-(oxan-4-¡l)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]hexanam¡ gives (I-363);

5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropyl}am¡no)methyl]-4- methylphenyl}-N[(dimethylcarbamoyl)methyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox hex l]hexanamide (I-364);

5-{3-[({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡cloprop¡l}am¡no)met¡l]-4- methylphenyl}-N-[2(ethylcarbamoyl)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox hex l]hexanamid (I-365);

5-{3-[({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡cloprop¡l}am¡no)met¡l]-4- methylphenyl}-N-[2(dimethylcarbamoyl)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahdrox¡ hex¡l]hexanamide (I-366);

(5S)-5-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡ndin-3-¡l]c¡cloprop¡l}am¡no)methyl ]-4-methylphenyl}-N-(2methanesulfonylethyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]hexanamide ( I-367);

(5R)-5-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rid¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l]-4-methylphenyl}-N-(2methanesulfonylethyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l] hexanamide (I-368);

5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropyl}am¡no)methyl]-4- met¡lfen¡l}-N-(2methanesulfonyleth¡l)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]hexanam¡da ( I-369);

5-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropyl}am¡no)methyl]-4- met¡lfen¡l}-N-(3methanesulfonilprop¡l)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]hexanam¡da ( I-370);

2-[4-(5-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡clopiOp¡l}am ¡no)methyl]-4methylphenyl}hexanoyl)p¡peraz¡n-1-¡l]-N-[(2S,3R,4R,5R)-2,3,4,5,6 -pentahydroxyhexyl]acetamide (I371);

4-[2-(5-{4-chloro-3-[(1-{1-[4-(2-c¡clopropoxyphenyl)pyridin-3-¡l]c¡cloprop ¡l} {[(2S,3R,4R,5R)-2,3,4,5,6pentah¡droxyhex¡l]carbamo¡l}am¡no)met¡l]phen¡l}hexanam¡do) ethyl ]-N-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhex]piperazin-1-carboxamide (I-372);

ω σ>

ω &lt; or

<img file="MX376739B_D0104.tif" />

IMPI

107

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

5-[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡r¡d¡n-3-¡l]c¡clopiOpox¡}met¡l)fen ¡l]-N-et¡lN

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (I-373);

5-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pandn-3-yl]cyclopropoxy}methyl)phenyl] -N-(2-h¡drox¡et¡l)-N

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (I-374);

5-[3-({1-[4-(2-c¡clopropox¡fen¡l)p¡r¡d¡n-3-¡l]c¡clopiOpox¡}met¡l)-4-met¡ lfen¡l]-N-et¡lN

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (I-375);

5-[3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)-4-methylphenyl] -N-(2-h¡drox¡et¡l)-N

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (I-376);

N-(4-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡ no)methyl]phenyl}pentyl)-N

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]acetamide (I-377);

N-(5-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡ no)methyl]phenyl}hexyl)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl ]acetamide (I-378);

5-{2,5-d¡chloro-4-[({1-[4-(2-c¡clopropoxyphenyl)p¡rd¡n-3-¡l]c¡cloprop¡l }am¡no)methyl]phenyl}-N-methyl-N

[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (I-379);

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡cloprop¡l}amino)methyl]phenyl}-5-h¡drox¡pent¡l)-2,3,4,5,6-pentah¡drox¡hexanam¡da (I-380 );

(2S,3S,4R,5S)-N-(4-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡cloprop¡l}am¡no)met¡l]fen¡l}pent-4-en-1-¡l)-2,3,4,5,6-pentah¡drox¡hexanam¡da (1 -381);

(2S,3S,4R,5S)-N-[3-(1-{4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3¡l]c¡cloprop¡l}am¡no)met¡l]phen¡l}c¡cloprop¡l)prop¡l]-2,3,4,5,6-pentah¡drox¡hexanam¡da (I-382);

1-(4-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡ no)methyl]phenyl}pent-4-en-1-yl)3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-383 );

1-(4-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡ no)methyl]phenyl}-5-hydroxypentyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I- 384);

1-[3-(1-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop ¡l}amino)methyl]phenyl}cycloprop¡l)prop¡l]-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l ]urea (I-385);

ω σ>

ω &lt; or

<img file="MX376739B_D0105.tif" />

IMPI

108

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-(4-{3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡ n-3-¡l]c¡cloprop¡l}am¡no)methyl]-4methylphenyl}-5-h¡drox¡pent¡l)-2,3,4,5,6-pentah¡ droxyhexanamid (I-386);

1-(4-{3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡no) methyl]-4-methylphenyl}-5hydroxypentyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl] urea (I-387);

(2S,3S,4R,5S)-N-{4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3yl]c¡clopropox¡ }methyl)benzenesulfonamido]butyl}-2,3,4,5,6-pentahydroxyhexananida (I-388);

1-{4-[N-methyl4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3yl]cyclopropoxy}methyl)benzenesulfonam ¡do]but¡l}-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2yl]urea (I-389);

1-{4-[N-ethyl4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3yl]cyclopropoxy}methyl )benzenesulfonamido]but¡l}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]urea (I-390);

3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]-1-{4-[N-(propan-2-¡l)4-chloro-3- ({1-[4-(2c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}methyl)benzenesulfonamido]but¡l}urea (1- 391);

1-(4-{N-methyl2,4-d¡chloro-5-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]c ¡cloprop¡l}am¡no)methyl]benzenesulfonamido}but¡l)-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhex¡l]urea (I -392);

4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]cyclopropox¡}methyl)-/\/,/ /-dimethylbenzene-1sulfonamide (I-393);

4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]cyclopropoxy}methyl)-N-met Ibenzene-1-sulfonamide (I-394);

3-(1-{[2-chloro-5-(p¡rrol¡n-1-sulfon¡l)phenyl]methoxy¡}c¡cloprop¡l)-4-(2-c¡clopropoxyphen l) p¡r¡d¡na (I-395); 3-(1-{[2-chloro-5-(p¡per¡n-1-sulfon¡l)phenyl]methoxy¡}c¡cloprop¡l)-4-(2-c¡clopropoxyphen ¡l) p¡r¡d¡na (I-396); (2S,3R,4R,5R)-S-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyr¡d¡n-3-¡l]c¡ clopropox¡}methyl)phenyl]2,3,4,5,6-pentahydrox¡hexane-1-sulfonamido (I-397);

(2S,3R,4R,5R)-S-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyr¡d¡n-3-¡l]c¡ clopropox¡}methyl)phenyl]2,3,4,5,6-pentahydrox¡-N-methylhexane-1-sulfonamido (I-398);

ω σ>

ω &lt; or

<img file="MX376739B_D0106.tif" />

IMPI

109

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

N-[2-(2-am¡noethox¡)et¡l]-4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)pyr¡n-3- ¡l]cyclopropoxy}methyl)benzene-1-sulfonamide (I-399);

N-[2-(2-am¡noethoxy)ethyl]-4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3- ¡l]cyclopropoxy}methyl)-N-methylbenzene-1-sulfonamide (I-400);

1-{4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l]cyclopropoxy}methyl) benzenesulfonamido]butyl}3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-401);

1-{4-[N-methyl4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropoxy}met¡ l) benzenesulfonamido]butyl}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-402);

1-(2-{2-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]cyclopropoxy}methyl)benzenesulfonam¡ do]ethoxy}ethyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]urea (I-403);

1-(2-{2-[N-methyl4-chloro-3-({1-[4-(2-cyclopropox¡phenyl)p¡nd¡n-3¡l]cyclopropox¡}met¡ l)benzenesulfonamido]ethoxy}ethyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]urea (I-404);

1-{5-[N-methyl4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropoxy}methyl )benzenesulfonamido]pentyl}-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2yl]urea (I-405);

1-(2-{2-[N-methyl4-chloro-3-({1-[4-(2-cyclopropox¡phenyl)p¡nd¡n-3¡l]cyclopropox¡}met¡ l)benzenesulfonamido]ethoxy}ethyl)-3-[(2S,3R,4S,5R)-1,3,4,5,6pentahydroxyhexan-2-¡l]urea (I-406);

1-{4-[N-(2-methoxyethyl)4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropoxy}methyl)benzenesulfonamido]but¡l}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]urea (I -407);

1-(2-{2-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]cyclopropoxy}methyl)benzenesulfonam¡ do]ethoxy¡}ethyl)-3-[(2S,3R,4S,5R)-1,3,4,5,6pentahydroxyhexan-2-¡l]urea (I-408);

ω σ>

ω &lt; or

<img file="MX376739B_D0107.tif" />

IMPI

110

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

-{5-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3yl]cyclopropoxy}methyl)benzenesulfonamido] pent¡l}-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydrox¡hexan-2yl]urea (I-409);

1-{4-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡ l)benzenesulfonamido]butyl}3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-y]urea (1-410);

1-(2-{2-[N-ethyl4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3yl]c¡clopropox¡}met¡ l)benzenesulfonamido]ethoxy}ethyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]urea (1-411);

1-{5-[N-(2-methoxyethyl)4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3yl]c clopropoxy}methyl)benzenesulfonamido]pentyl}-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]urea (1-412);

1-{5-[N-(2-methoxyethyl)4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3yl]c ¡clopropox¡}methyl)benzenesulfonamido]pent¡l}-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentah¡drox¡hexan-2yl]urea ( 1-413);

1-{4-[N-(2-hydroxyethyl)4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3yl ]c¡clopropox¡}methyl)benzenesulfonamido]but¡l}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l] urea (1-414);

1-(2-{2-[N-ethyl4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3¡l]c¡clopropox¡} methyl)benzenesulfonamido]ethoxy}ethyl)-3-[(2S,3R,4S,5R)-1,3,4,5,6pentahydroxyhexan-2-¡l]urea (1-415) ;

1-{4-[N-(2-methoxyethyl)4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3yl]c ¡clopropox¡}methyl)benzenesulfonamido]but¡l}-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2yl]urea (1-416) ;

1-(2-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3yl]c¡clopiOpox¡}methyl)benzenesulfon¡ l]p¡per¡d¡n-4-¡l}ethyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhex¡l]urea (1-417 );

ω σ>

ω &lt; or

<img file="MX376739B_D0108.tif" />

IMPI

111

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]-1-[(1r,4r)-4-[4-chloro-3-({1- [4-(2c¡clopropox¡fen¡l)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡l)benzenesulfonamido]c¡clohex¡l]urea (1-418) ;

3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]-1-[(1s,4s)-4-[4-chloro-3-({1- [4-(2c¡clopropox¡fen¡l)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡l)benzenesulfonamido]c¡clohex¡l]urea (1-419) ;

1-({1-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rdin-3-¡l]c¡clopropox¡}methyl )benzenesulfon¡l]p¡rrol¡d¡n3-¡l}methyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l] urea (I-420);

1-(2-{1-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}met ¡l)benzenesulfon¡l]azet¡d¡n3-¡l}ethyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l] urea (1-421);

1-(4-{2-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3yl]cyclopropoxy}methyl)benzenesulfonam do]ethyl}cyclohexyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]urea (I-422);

1-(3-{4-[4-chloro-3-({1-[4-(2-cyclopropox¡phenyl)pyridin-3¡l]cyclopropox¡}methyl)benzenesulfon¡ l]p¡perazin-1-¡l}propyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexl]urea (I-423);

1-({1-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rd¡n-3-yl]c¡clopropox¡}met¡ l)benzenesulfon¡l]p¡per¡d¡n4-¡l}methyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l ]urea (I-424);

1-(2-{4-[4-chloro-3-({1-[4-(2-cyclopropox¡phenyl)pyridin-3¡l]cyclopropox¡}methyl)benzenesulfon¡ l]pperazin-1-l}ethyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]urea(l-425);

1-({1-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rd¡n-3-yl]c¡clopropox¡}met¡ l)benzenesulfon¡l]p¡per¡d¡n3-¡l}methyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l ]urea (I-426);

1-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]cyclopropoxy}methyl)benzenesulfon¡ l]azet¡d¡n-3¡l}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-427);

1-{7-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l]cyclopropoxy}methyl) benzenesulfon¡l]-7azaspiro[3.5]nonan-2-yl}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l] urea (I-428);

1-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropoxy}methyl)benzenesulfon¡ l]pyrroliden-3¡l}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-429);

ω σ>

ω &lt; or

<img file="MX376739B_D0109.tif" />

ΙΜΡΙ

112

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

1-{2-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l]cyclopropoxy}methyl) benzenesulfon¡l]-2azaspiro[3.3]heptan-6-yl}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l] urea (I-430); 6-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]cyclopropoxy}methyl)benzenesulfonam do]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]hexanamid (1-431);

7-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]cyclopropoxy}methyl)benzenesulfonam do]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]heptanamide (I-432);

5-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]cyclopropoxy}methyl)benzenesulfonam do]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (I-433);

3-[N-methyl4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡}methyl )benzenesulfonamido]N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]propanamide (I-434);

(1R,5S,6S)-3-[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡ }methyl)benzenesulfon¡l]N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]-3-azab¡c¡clo[3,1,0 ]hexane-6-carboxamide (I-435); (1 r,4r)-4-[4-chloro-3-({1 -[4-(2-cyclopropoxyphenyl)pyridin-3yl]cyclopropoxy}methyl)benzenesulfonam domethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]cyclohexane-1-carboxamide (I-436);

1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l]cyclopropoxy}methyl)benzenesulfonyl ]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]p¡per¡d¡n-4-carboxamide (I-437) ;

2-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropoxy}methyl)benzenesulfon I]azet¡d¡n-3yl}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhexíl]acetamide (I-438);

3-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]cyclopropoxy}methyl)benzenesulfonam ¡do]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]cyclopentane-1-carboxamide (I-439);

2-{4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropoxy}methyl)benzenesulfon ¡l]p¡peraz¡n1-yl}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhexíl]acetamide (I-440);

2-{1-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-¡l]c¡clopropox¡}methyl) benzenesulfon¡l]piper¡n-4yl}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex¡l]acetamide (1-441) ;

(1r,4r)-4-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡}met ¡l)benzenesulfonamido]N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]cyclohexane-1-carboxamide (I-442) ;

ω σ>

w&lt;o

<img file="MX376739B_D0110.tif" />

IMPI

113

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

3-{4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]cyclopropoxy}methyl)benzenesulfon¡ l]p¡peraz¡n1-¡l}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]propanam¡da (I-443 );

2-({1-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rd¡n-3-yl]c¡clopropox¡}met¡ l)benzenesulfon¡l]p¡per¡d¡n4-¡l}ox¡)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡ l]acetamide (I-444);

4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]cyclopropoxy}methyl)benzenesulfonam ¡do]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l]bic¡clo[2,2,2]octan-1-carboxam¡da ( I-445);

(2E)-3-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3yl]cyclopropoxy}methyl)benzenesulfon ¡l]azet¡d¡n-3-yl}-N-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxy¡hex¡l]prop-2-enam¡de (I -446);

2-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]cyclopropoxy}methyl)benzenesulfon¡ l]azet¡d¡n-3yl}-N-methyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]acetamide (I- 447);

3-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]cyclopropoxy}methyl)benzenesulfon¡ l]azet¡d¡n-3yl}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]propanam¡da (I-448) ;

3-{1-[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡ l)benzenesulfon¡l]p¡per¡d¡n-4il}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]propanam¡ da (I-449);

(2E)-3-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l]cyclopropoxy}methyl)benzenesulfon ¡l]p¡rrol¡d¡n-3-¡l}-N-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxy¡hex¡l]prop-2-enam¡ da (I-450);

3-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropoxy}methyl)benzenesulfon ¡l]p¡rrol¡d¡n-3il}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]propanam¡da (1 -451);

(2E)-4-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3yl]cyclopropoxy}methyl)benzenesulfon ¡l]azet¡d¡n-3-yl}-N-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhex¡l]but-2-enam¡de (I-452 );

4-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]cyclopropoxy}methyl)benzenesulfon¡ l]azet¡d¡n-3yl}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexíl]butanamide (I-453);

2-({1-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )benzenesulfon¡l]azet¡d¡n-3yl}ox¡)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡droxyhex¡l]acetam¡da ( I-454);

ω σ>

w&lt;o

<img file="MX376739B_D0111.tif" />

IMPI

114

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

2-({1-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met ¡l)benzenesulfonyl]p¡rrol¡d¡n3-¡l}methoxy)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l] acetamide (I-455);

2-({1-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )benzenesulfon¡l]azet¡d¡n-3yl}methoxy)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l] acetamide (I -456);

(2S,3S,4R,5S)-N-{4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c¡ clopropox¡}methyl)benzenesulfonamido]but¡l}-2,3,4,5,6-pentahydrox¡-N-(2-methanesulfon¡lethyl)hexanamide (I-457);

(2S,3S,4R,5S)-2,3,4,5,6-pentah¡drox¡-N-{4-[N-methyl4-chloro-3-({1-[4-(2 -cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropox¡}methyl)benzenesulfonamido]but¡l}hexanam¡de (I-458);

(2S,3S,4R,5S)-2,3,4,5,6-pentahydroxy¡-N-(2-methanesulfonylethyl)-N-{4-[N-methyl4-chloro-3-( {1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]cyclopropoxy}methyl)benzenesulfonamido]but¡l}hexanamide (I-459); (2S,3S,4R,5S)-N-{4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c¡ clopropox¡}methyl)benzenesulfonamido]but¡l}-2,3,4,5,6-pentahydrox¡-N-methylhexanam¡de (I-460); (2S,3S,4R,5S)-2,3,4,5,6-pentahydroxy¡-N-methylN-{4-[N-methyl4-chloro-3-({1-[4-(2c clopropoxyphenyl)pandin-3-yl]cyclopropoxymethyl)benzenesulfonamido]butyl}hexanamid (1-461); (2S,3S,4R,5S)-N-(2-{1-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l ]c¡clopropox¡}met¡l)benzenesulfon¡l]piper¡n-4-¡l}et¡l)-2,3,4,5,6-pentah¡drox¡hexanam¡da (I- 462); N-(4-am¡nobut¡l)-4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)p¡nd¡n-3-yl]c¡clopropox¡ }methyl)-N-ethylbenzene-1-sulfonamide (I-463);

1-(4-{N-methyl4-chloro-3-[(1-{4-[2-(oxetan-3-¡lox¡)phenyl]p¡r¡d¡n-3¡l}cyclopropox ¡)methyl]benzenesulfonamido}but¡l)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]urea (I- 464);

1-{4-[N-ethyl4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropoxy}methyl )benzenesulfonamido]butyl}-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2yl]urea (I-465);

1-{4-[N-methyl4-chloro-5-({1-[4-(2-c¡clopropox¡phenyl)pyr¡d¡n-3-¡l]c¡clopropox¡} methyl)-2-fluorobenzenesulfonamido]butyl}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-466);

ω σ>

ω &lt; or

<img file="MX376739B_D0112.tif" />

IMPI

115

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

1-{4-[N-methyl2,4-dichloro-5-({1-[4-(2-cyclopropoxyphenyl)pyridn-3yl]cyclopropoxy }methyl)benzenesulfonamido]but¡l}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]urea (I-467 );

1-(4-{N-methyl3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡ non)methyl]-4(trifluoromethyl)benzenesulfonamido}but¡l)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex ¡l] urea (I468);

1-{4-[N-methyl3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-¡l]cyclopropoxy}methyl) -4(trifluoromethyl)benzenesulfonamido]but¡l}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l] urea (I469 );

-(4-{N-methyl3-[({1-[4-(2-cyclopropoxyphenyl)p¡hd¡n-3-¡l]cyclopropyl}amino)methyl]-4(trifluoromethyl) benzenesulfonamido}butl)-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxlhexan-2-l]urea (I-470);

1-(4-{N-methyl4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3yl]cycloprop¡l}am ¡no)methyl]benzenesulfonamido}but¡l)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-471);

1-(4-{N-methyl4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3yl]cycloprop¡l}am ¡no)methyl]benzenesulfonamido}but¡l)-3-[(2S,3R,4S,5R)-1,3,4,5,6pentahydroxyhexan-2-¡l]urea (I-472) ;

1-(4-{N-ethyl4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3yl]cycloprop¡l}am ¡no)methyl]benzenesulfonamido}but¡l)-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]urea (I-473);

1-(4-{N-methyl4-chloro-5-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡ cloprop¡l}am¡no)methyl]-2-fluorobenzenesulfonamido}but¡l)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l ] urea (I-474); 1-(4-{N-methyl4-chloro-5-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡ cloprop¡l}amino)methyl]-2-fluorobenzenesulfonamido}but¡l)-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l] urea (I-475);

ω σ>

ω &lt; or

<img file="MX376739B_D0113.tif" />

IMPI

116

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

1-(4-{N-methyl2,4-d¡chloro-5-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]cycloprop ¡l}am¡no)methyl]benzenesulfonamido}but¡l)-3-[(2S,3R,4S,5R)-1,3,4,5,6pentahydroxyhexan-2-¡l]urea ( I-476);

1-(4-{N-methyl3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropyl}amno )methyl]-4methylbenzenesulfonamido}but¡l)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]urea (I- 477); 1-(4-{N-methyl3-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropyl}amno )methyl]-4methylbenzenesulfonamido}but¡l)-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydrox¡hexan-2-¡l]urea (I-478); 1-{4-[N-methyl3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl) -4methylbenzenesulfonamido]but¡l}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]urea (I-479);

(2S)-5-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropoxy}methyl)benzenesulfonam acid ¡do]-2-{[(2,3,4,5,6pentahydroxy¡hex¡l)carbamo¡l]amino}pentano¡co (I-480);

(2R)-2-am¡no-6-[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)pind¡n-3il]c¡clopropox¡}met¡ l)benzenesulfonamido]-N-ethylhexanannida (1-481);

(2R)-6-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met ¡l)benzenesulfonamido]-Netil-2-({[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]carbamo¡l}amno )hexanannida (I-482);

(2S)-2-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropoxy}methyl)benzenesulfonam acid ¡do]-6-({[(2S,3R,4R,5R)-2,3,4,5,6pentahydrox¡hex¡l]carbamo¡m¡no)hexanoic acid (I-483);

(2S)-2-am¡no-6-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3yl]c¡clopropox¡}met acid ¡l) benzenesulfonamido]hexano¡c (I-484);

(2S)-6-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l]cyclopropoxy}methyl)benzenesulfonam acid ¡do]-2-({[(2S,3R,4R,5R)-2,3,4,5,6pentahydrox¡hex¡l]carbamo¡m¡no)hexanoic acid (I-485); (2S)-2-am¡no-6-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3¡l]c¡clopropox¡} methyl)benzenesulfonamido]-N-ethylhexanamid (I-486);

ω σ>

ω &lt; or

<img file="MX376739B_D0114.tif" />

IMPI

117

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S)-6-[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l]c¡clopropox ¡}methyl)benzenesulfonamido]-Netyl-2-({[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]carbamo¡l} amino)hexanamid (I-487);

1-(5-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]sulfanyl}pentyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-488);

(2S,3S,4R,5S)-N-(5-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropoxy}methyl)phenyl]sulfanyl}pentyl)-2,3,4,5,6-pentah¡drox¡-N-[2-(2-h¡droxyethox¡)ethyl]hexanamide (I- 489);

-[2-(2-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3-yl]cyclopropoxy}methyl)phen ¡l]sulfan¡l}ethoxy¡)ethyl]3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]urea (I-490);

1-(2-{2-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]cyclopropoxy}methyl)benzenesulf ¡n¡l]ethoxy¡}et¡l)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]urea (1-491) ;

1-(2-{2-[4-chloro-3-({1-[4-(2-cyclopropox¡phenyl)pyridin-3¡l]cyclopropox¡}methyl)benzenesulfon¡ l]ethoxy¡}ethyl)-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]urea (I-492);

1-{2-[2-({4-chloro-3-[(1-{4-[2-(oxetan-3-¡lox¡)phenyl]p¡r¡d¡n-3-¡ l}cyclopropoxy¡)methyl]phenyl}sulfan¡l)ethoxy¡]ethyl}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡ l]urea (I-493);

1-[5-({4-chloro-3-[({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡cloprop¡l}am¡no )methyl]phenyl}sulfanyl)pentyl]3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-494);

5-({6-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropyl}am¡no)methyl]-5 -met¡lp¡r¡n-2-¡l}sulfan¡l)-Nmethyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡ hexyl]pentanamide (I-495);

1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]-N-{[5-methyl-2-(methylsulfan¡l)p¡r ¡m¡n-4-¡l]methyl}cyclopropan-1amine (I-496);

4-{[3-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]cyclopropoxy}methyl)-4-ethylphenyl ]sulfan¡l}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]butanamide (I-497);

4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]cyclopropoxy}methyl)phenyl] sulfanil}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]butanamide (I-498);

ω σ>

w&lt;o

<img file="MX376739B_D0115.tif" />

ΙΜΡΙ

118

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

N-[5-({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l }am¡no)methyl]phenyl}sulfanyl)pentyl]N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex¡l]acetamide ( I-499);

N-(3-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]sulfan¡l}prop¡l)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]acetamide (I-500) ;

N-(4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]sulfanyl}butyl)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]acetamide (1-501) ;

N-[3-({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l }am¡no)methyl]phenyl}sulfan¡l)propyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hexyl]acetam Give (I-502); N-[4-({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l }am¡no)methyl]phenyl}sulfanyl)but¡l]N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l]acetamide ( I-503);

N-[2-({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l }am¡no)methyl]phenyl}sulfanyl)ethyl]-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex¡l]acetamide ( I-504);

N-(2-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phen¡l]sulfan¡l}ethyl)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]acetamide (I-505) ;

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l] c¡cloprop¡l}am¡no)met¡l]fen¡l}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox¡-N-met¡lhexanam¡da ( I-506); (2S,3S,4R,5S)-N-[5-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l] c¡cloprop¡l}am¡no)met¡l]fen¡l}sulfan¡l)pent¡l]-2,3,4,5,6-pentah¡drox¡-N-met¡lhexanam¡da ( I-507); (2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l]c clopropox¡}methyl)phenyl]sulfan¡l}prop¡l)-2,3,4,5,6-pentahydrox¡-N-methylhexanam¡de (I-508);

(2S,3S,4R,5S)-N-(5-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l]c clopropoxy}methyl)phenyl]sulfanyl}pentyl)-2,3,4,5,6-pentahydroxy-N-methylhexanamid (I-509); (2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l]c clopropoxy}methyl)phenyl]sulfanyl}butyl)-2,3,4,5,6-pentahydroxy-N-methylhexanamid (1-510);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l] c¡cloprop¡l}amino)methyl]phenyl}sulfan¡l)prop¡l]-2,3,4,5,6-pentah¡drox¡-N-met¡lhexanam¡da (1- 511);

<img file="MX376739B_D0116.tif" />

119

IMPI §

MEXICAN INSTITUTE OF PROPERTY w

INDUSTRIAL &lt;0

MX/E/2018/085580 (2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)p¡nd¡ n-3¡l]cyclopropoxy}methyl)phenyl]sulfanyl}but¡l)-2,3,4,5,6-pentahydroxy-N-[2-(2-hydroxyethox¡) ethyl] hexanamide (1-512);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox¡but¡l)hexanam give (I513);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropoxy}methyl)phenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡l)hexanam¡de (1 -514); (2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡-N-[3-(2-oxop¡rrol¡d¡n- 1-yl)propyl]hexanamide (1-515);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}butyl)-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡lmethyl)hexanam¡de ( I516);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}butyl)-2,3,4,5,6-pentah¡drox¡-N-[2-(2-oxo¡m¡dazol¡d¡ n-1-yl)ethyl]hexanamide (1-517);

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropoxy}methyl)phenyl]sulfanyl}propyl)-2,3,4,5,6-pentahydroxy¡-N-[2-(2-h¡drox¡ethoxy¡)ethyl]hexanamide ( 1-518);

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}propyl)-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox¡but¡l)hexanam¡da (I519);

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropoxy}methyl)phenyl]sulfanyl}propyl)-2,3,4,5,6-pentahydroxy¡-N-[3-(2-oxop¡rrolid¡n-1-yl)propyl]hexanamide (I-520);

ω σ>

ω &lt; or

<img file="MX376739B_D0117.tif" />

IMPI

120

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡ n-3yl]cyclopropoxy}methyl)phenyl]sulfanyl}propyl)-N-[2-(1,1-dioxo-1 A⁶,4-thiomorpholin-4-yl)ethyl]-2,3,4,5,6-pentahydroxyhexanamide (1-521);

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}met¡l)phenyl]sulfan¡l}prop¡l)-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡lmet¡l)hexanam¡ gives (I522);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡ l]c¡clopropox¡} methyl)phenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡-N-(3-methanesulfon¡lprop¡l) hexanamide (I-523);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropoxy}methyl)phenyl]sulfanyl}but¡l)-N-[2-(1,1-dioxo-1 A⁶,4-thiomorpholin-4-¡l)ethyl]-2,3,4,5,6-pentahydroxyhexanamide (I-524);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)propyl]-2,3,4,5,6-pentah¡drox¡-N-(3-methanesulfon¡lprop¡l ) hexanamide (I-525);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] c¡cloprop¡l}am¡no)met¡l]phenyl}sulfanil)prop¡l]-2,3,4,5,6-pentah¡drox¡-N-[2-(2-h¡ droxyethoxy)ethyl]hexanamide (I-526);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)propyl]-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox¡but l) hexanamide (I-527);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] c¡cloprop¡l}am¡no)methyl]phenyl}sulfan¡l)prop¡l]-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡l) hexanamide (I528);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] c¡cloprop¡l}am¡no)met¡l]phenyl}sulfanil)prop¡l]-2,3,4,5,6-pentah¡drox¡-N-[3-(2-oxop¡ rrollin-1l)propyl]hexanamide (I-529);

ω σ>

ω &lt; or

<img file="MX376739B_D0118.tif" />

ΙΜΡΙ

121

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind ¡n-3yl]c¡cloprop¡l}am¡no)methyl]phenyl}sulfan¡l)propyl]-N-[2-(1,1-dioxo-1 A⁶,4-thiomorpholin-4-yl)ethyl]-2,3,4,5,6-pentahydroxyhexanamide (I-530);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)prop¡l]-2,3,4,5,6-pentah¡drox¡-N-[2-(2-oxo¡ mdazolin-1l)ethyl]hexanamid (1-531);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}amino)methyl]phenyl}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox¡-N-(3-methanesulfon¡lprop¡l ) hexanamide (I-532);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)but¡l]-2,3,4,5,6-pentahydroxy¡-N-[2-(2-h¡drox¡ ethoxy)ethyl]hexanamide (I-533);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)butyl]-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox¡but l) hexanamide (I-534);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡l) hexanamide (I535);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] c¡cloprop¡l}am¡no)met¡l]phenyl}sulfanil)but¡l]-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡lmet¡ l) hexanamide (I-536);

(2S,3S,4R,5S)-N-(3-{[3-({1-[4-(2-cyclopropoxyphenyl)p¡rdin-3-¡l]c¡ (I -537); (2S,3S,4R,5S)-N-(3-{[3-({1-[4-(2-cyclopropoxyphenyl)p¡rdin-3-¡l]c¡ clopropox¡}methyl)-4methylphenyl]sulfan¡l}propyl)-2,3,4,5,6-pentah¡drox¡-N-[2-(2-h¡drox¡ethox¡ )ethyl]hexanamide (I-538);

(2S,3S,4R,5S)-N-(3-{[3-({1-[4-(2-cyclopropoxyphenyl)p¡rdin-3-¡l]c¡ clopropox¡}methyl)-4methylphenyl]sulfan¡l}propyl)-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox¡but¡l)hexanam Give (I-539);

<img file="MX376739B_D0119.tif" />

122

IMPI §

MEXICAN INSTITUTE OF PROPERTY w

INDUSTRIAL &lt;0

MX/E/2018/085580 (2S,3S,4R,5S)-N-(3-{[3-({1-[4-(2-cyclopropoxyphenyl)pyridin- 3-¡l]c¡clopropox¡}methyl)-4methylphenyl]sulfan¡l}prop¡l)-2,3,4,5,6-pentah¡drox¡-N-(oxan-4- l) hexanamide (I-540);

(2S,3S,4R,5S)-N-(4-{[3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]c¡ clopropox¡}met¡l)-4methylphenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox¡but¡l )hexanamid (1-541);

(2S,3S,4R,5S)-N-[2-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] c¡cloprop¡l}amino)methyl]phenyl}sulfan¡l)et¡l]-2,3,4,5,6-pentah¡drox¡-N-met¡lhexanam¡da (I- 542);

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}prop¡l)-2,3,4,5,6-pentah¡drox¡-N-[2-(2-oxo¡m¡dazol¡ dn-1l)ethyl]hexanamid (I-543);

(2S,3S,4R,5S)-N-[3-({3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l ]c¡cloprop¡l}amino)methyl]-4methylphenyl}sulfan¡l)prop¡l]-2,3,4,5,6-pentah¡drox¡-N-(3-methanesulfon¡lpropyl ) hexanamide (I-544); (2S,3S,4R,5S)-N-[3-({3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l ]c¡cloprop¡l}amino)methyl]-4methylphenyl}sulfan¡l)prop¡l]-2,3,4,5,6-pentahydrox¡-N-[2-(2- hydroxyethoxy)ethyl]hexanamide (I-545); (2S,3S,4R,5S)-N-[3-({3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l ]c¡clopiOp¡l}am¡no)methyl]-4methylphenyl}sulfan¡l)prop¡l]-2,3,4,5,6-pentah¡drox¡-N-(4-h¡droxybutyl ) hexanamide (I-546); (2S,3S,4R,5S)-N-[3-({3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l ]c¡clopiOp¡l}am¡no)methyl]-4methylphenyl}sulfan¡l)prop¡l]-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡ l) hexanamide (I-547);

(2S,3S,4R,5S)-N-[4-({3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l ]c¡clopiOp¡l}am¡no)methyl]-4methylphenyl}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox¡-N-(3-methanesulfon¡lprop l) hexanamide (I-548); (2S,3S,4R,5S)-N-[4-({3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l ]c¡clopiOp¡l}am¡no)methyl]-4methylphenyl}sulfan¡l)butyl]-2,3,4,5,6-pentah¡drox¡-N-[2-(2- hydroxyethoxy)ethyl]hexanamide (I-549); (2S,3S,4R,5S)-N-[4-({3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l ]c¡clopiOp¡l}am¡no)methyl]-4methylphenyl}sulfanyl)but¡l]-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox butl)hexanamid (I-550);

(2S,3S,4R,5S)-N-(4-{[3-({1-[4-(2-cyclopropoxyphenyl)p¡rdin-3-¡l]c¡ clopropox¡}methyl)-4methylphenyl]sulfan¡l}butyl)-2,3,4,5,6-pentah¡drox¡-N-[2-(2-h¡drox¡ethox¡ )ethyl]hexanamid (1-551);

ω σ>

ω &lt; or

<img file="MX376739B_D0120.tif" />

IMPI

123

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r ¡d¡n-3yl]c¡cloprop¡l}am¡no)methyl]phenyl}sulfan¡l)propyl]-N-(1,1-dioxo-1 A⁶-thian-4-yl)-2,3,4,5,6-pentahydroxyhexanamide (I-552);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡ l]cyclopropyl}am¡no)methyl]phenyl}sulfan¡l)prop¡l]-2,3,4,5,6-pentahydroxy-N-(oxan-4¡lmethyl)hexanam¡ da (I-553);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡ l]cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox¡-N-[3-(2- oxoproldan-1l)propyl]hexanamide (I-554);

(2S,3S,4R,5S)-N-(2-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡clopropox¡}methyl)phenyl]sulfan¡l}et¡l)-2,3,4,5,6-pentah¡drox¡-N-methylhexanam¡de (I-555) ; (2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡clopropoxy}methyl)phenyl]sulfan¡l}prop¡l)-N-(1,1-dioxo-1 A⁶-thian-4-yl)-2,3,4,5,6-pentahydroxyhexanamide (I-556);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡ l]c¡cloprop¡l}am¡no)methyl]phenyl}sulfan¡l)but¡l]-N-[2-(1,1-dioxo-1 λ⁶,4-thiomorpholin-4-yl)ethyl]-2,3,4,5,6-pentahydroxyhexanamide (I-557);

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡clopropox¡}methyl)phenyl]sulfan¡l}propyl)-2,3,4,5,6-pentah¡drox¡-N-(3-methanesulfon¡lprop¡l)hexanamide (I -558);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]c¡clopropox¡}methyl)phenyl]sulfan¡l}butyl)-2,3,4,5,6-pentah¡drox¡-N-(2-methanesulfon¡let¡l)hexanam¡da (I-559);

(2S,3S,4R,5S)-N-[4-({3-[({1-[4-(2-c¡clopropoxyphenyl)p¡ndin-3-¡l]c¡cloprop ¡l}am¡no)met¡l]-4met¡lfen¡l}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡ l) hexanamide (I-560);

(2S,3S,4R,5S)-N-(4-{[3-({1-[4-(2-c¡clopropox¡phenyl)p¡ndin-3-¡l]c¡clopropox¡ }met¡l)-4methylphenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡-N-(3-methanesulfon¡lprop¡l)hexanam¡da (1-561);

ω σ>

ω &lt; or

<img file="MX376739B_D0121.tif" />

IMPI

124

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-(4-{[3-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3- ¡l]c¡clopropox¡}methyl)-4methylphenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡l hexanamide (I-562);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cyclopropyl}amino)methyl]phenyl}sulfanyl)butyl]-N-(2-acetamidoethyl)-2,3,4,5,6-pentahydroxyhexanamide (I-563);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}but¡l)-N-(2-acetamidoethyl)-2,3,4,5,6-pentahydrox¡hexanam¡de (I564 );

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropoxy}methyl)phenyl]sulfan¡l}prop¡l)-2,3,4,5,6-pentah¡drox¡-N-(oxan-4-¡l)hexanam¡de (I -565); (2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}but¡l)-N-(3-acetam¡doprop¡l)-2,3,4,5,6-pentah¡drox¡hexanam¡da (I-566);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cyclopropyl}amino)methyl]phenyl}sulfanyl)butyl]-N-(4-acetamidobutyl)-2,3,4,5,6-pentahydroxyhexanamide (I-567);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfanyl}but¡l)-N-(4-acetamidobut¡l)-2,3,4,5,6-pentahydrox¡hexanam¡de (I568 );

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropoxy}methyl)phenyl]sulfanyl}but¡l)-N-(1,1-dioxo-1 A⁶-thian-4-yl)-2,3,4,5,6-pentahydroxyhexanamide (I-569);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfanyl}but¡l)-2,3,4,5,6-pentah¡drox¡-N-(4-methanesulfonamidobut¡l)hexanamide (I-570 );

ω σ>

ω &lt; or

<img file="MX376739B_D0122.tif" />

IMPI

125

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind ¡n-3¡l]c¡cloprop¡l}am¡no)met¡l]phenyl}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox¡-N -(2-methanesulfonamidoethyl)hexanamide (1-571);

ethyl N-{2-[(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r ¡d¡n-3-¡l] c¡cloprop¡l}am¡no)met¡l]phenyl}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox ¡hexanam¡do]ethyl}carbamate (I572);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)but¡l]-N-(3-acetam¡dopiOp¡l)-2,3,4,5,6pentahydroxyhexanamide (I -573);

ethyl N-{3-[(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pyr ¡d¡n-3-¡l] c¡cloprop¡l}am¡no)met¡l]phenyl}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox ¡hexanam¡do]prop¡l} carbamate (I-574);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡-N-(2-methanesulfonam¡doethyl)hexanamide (I-575 );

ethyl N-{2-[(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)pind¡ n-3-¡l]c¡clopropox¡}methyl)phenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡hexanam¡do]et¡l} carbamate (I-576);

(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡-N-(3-methanesulfonamidoprop¡l)hexanamide (1-577 );

ethyl N-{3-[(2S,3S,4R,5S)-N-(4-{[4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)pind¡ n-3-¡l]c¡clopropox¡}methyl)phenyl]sulfan¡l}but¡l)-2,3,4,5,6-pentah¡drox¡hexanam¡do]prop¡l} carbamate (I578);

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfanyl}propyl)-N-(4-acetam¡dobut¡l)-2,3,4,5,6-pentah¡drox¡hexanam¡da (I -579);

ω σ>

ω &lt; or

<img file="MX376739B_D0123.tif" />

IMPI

126

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡ n-3¡l]c¡clopropoxy}methyl)phenyl]sulfan¡l}prop¡l)-2,3,4,5,6-pentah¡drox¡-N-(4-methanesulfonam¡dobut l) hexanamide (I-580);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}amino)methyl]phenyl}sulfan¡l)but¡l]-N-(1,1-dioxo-1 A⁶-thian-4-yl)-2,3,4,5,6-pentahydroxyhexanamide (1-581);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] c¡cloprop¡l}am¡no)met¡l]phenyl}sulfanil)but¡l]-2,3,4,5,6-pentah¡drox¡-N-(4-methanesulfonam¡dobut¡l ) hexanamide (I-582);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)propyl]-2,3,4,5,6-pentah¡drox¡-N-(2-methanesulfon¡let¡l ) hexanamide (I-583);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox¡-N-(2-methanesulfon¡let¡l ) hexanamide (I-584);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] c¡cloprop¡l}am¡no)met¡l]phenyl}sulfanil)prop¡l]-2,3,4,5,6-pentah¡drox¡-N-(2-methanesulfonam¡doet¡l ) hexanamide (I-585);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)piOp¡l]-N-(2-acetam¡doethyl)-2,3,4,5,6pentahydroxyhexanamide (I -586);

ethyl N-{2-[(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p ¡ndin-3-¡l] c¡cloprop¡l}am¡no)met¡l]phenyl}sulfanil)prop¡l]-2,3,4,5,6-pentah¡drox¡hexanam¡do ]et¡l} carbamate (I587);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cyclopropyl}amino)methyl]phenyl}sulfanyl)propyl]-2,3,4,5,6-pentahydroxy-N-(3-methanesulfonamidopropyl)hexanamide (I-588);

ω σ>

ω &lt; or

<img file="MX376739B_D0124.tif" />

IMPI

127

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l]c ¡cloprop¡l}amino)methyl]phenyl}sulfan¡l)prop¡l]-N-(3-acetamidoprop¡l)-2,3,4,5,6-pentah¡drox¡ hexanamide (I-589);

ethyl N-{3-[(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pyridin-3 -¡l] c¡cloprop¡l}amino)methyl]phenyl}sulfan¡l)prop¡l]-2,3,4,5,6-pentah¡drox¡hexanam¡do]prop¡l } carbamate (I-590);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l]c¡cloprop¡l}am¡ no)methyl]phenyl}sulfan¡l)but¡l]-2,3,4,5,6-pentah¡drox¡-N-(3-methanesulfonamidoprop¡l)hexanamide (1-591 );

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)pyridin-3¡l]c¡clopropox }methyl)phenyl]sulfanyl}propyl)-2,3,4,5,6-pentahydroxy-N-(3-methanesulfonamidopropyl)hexanamide (I-592);

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)pyridin-3¡l]c¡clopropox }methyl)phenyl]sulfanyl}propyl)-2,3,4,5,6-pentahydroxy-N-(2-methanesulfonamidoethyl)hexanamide (I-593);

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3yl]cyclopropoxy}methyl )phenyl]sulfanyl}propyl)-N-(3-acetamidopropyl)-2,3,4,5,6-pentahydroxyhexanamide (I-594);

(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)pyridin-3¡l]c¡clopropox ¡}methyl)phenyl]sulfan¡l}propyl)-N-(2-acetam¡doethyl)-2,3,4,5,6-pentahydrox¡hexanam¡de (I-595 );

ethyl N-{3-[(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3- yl]cyclopropoxy}methyl)phenyl]sulfanyl}propyl)-2,3,4,5,6-pentahydroxyhexanamdo]propl}carbamate (I596);

ethyl N-{2-[(2S,3S,4R,5S)-N-(3-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3- yl]cyclopropoxy}methyl)phenyl]sulfanyl}propyl)-2,3,4,5,6-pentahydroxyhexanamdo]ethyl}carbamate (I-597);

ω σ>

ω &lt; or

<img file="MX376739B_D0125.tif" />

IMPI

128

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-[5-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind ¡n-3¡l]c¡cloprop¡l}am¡no)methyl]phenyl}sulfan¡l)pent¡l]-2,3,4,5,6-pentahydroxy-N-[2 -(2-hydroxyethoxy)ethyl]hexanamide (I-598);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] c¡cloprop¡l}amino)methyl]phenyl}sulfan¡l)prop¡l]-2,3,4,5,6-pentah¡drox¡-N-(4-methanesulfonam¡dobut¡l ) hexanamide (I-599);

(2S,3S,4R,5S)-N-[5-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] c¡cloprop¡l}am¡no)met¡l]phenyl}sulfan¡l)pentyl]-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox¡but l) hexanamide (I-600);

(2S,3S,4R,5S)-N-[5-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfan¡l)pentyl]-2,3,4,5,6-pentahydroxy-N-(5hydroxypent¡l)hexanam¡de (1- 601);

(2S,3S,4R,5S)-N-[3-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pind¡n-3¡l] cycloprop¡l}amino)methyl]phenyl}sulfan¡l)prop¡l]-N-(4-acetamidobut¡l)-2,3,4,5,6-pentahydroxyhexanamide (I -602);

(2S,3S,4R,5S)-N-(5-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c clopropoxy}methyl)phenyl]sulfanyl}pentyl)-2,3,4,5,6-pentahydroxy-N-(2-methanesulfonylethyl)hexanamid (I-603);

(2S,3S,4R,5S)-N-(5-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}pentyl)-N-[2-(ethansulfon¡l)et¡l]-2,3,4,5,6-pentah¡drox¡hexanam¡ da (I-604);

(2S,3S,4R,5S)-N-(5-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}pentyl)-2,3,4,5,6-pentah¡drox¡-N-(4-h¡drox¡but¡l)hexanam¡da (I605);

(2S,3S,4R,5S)-N-(5-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3¡l]c ¡clopropox¡}methyl)phenyl]sulfan¡l}pentyl)-2,3,4,5,6-pentah¡drox¡-N-(5-h¡drox¡pent¡l)hexanam¡da (I606);

ω σ>

ω &lt; or

<img file="MX376739B_D0126.tif" />

129

ΙΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (2S,3S,4R,5S)-N-{5-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd ¡n-3¡l]c¡clopropox¡}methyl)benzenesulfin¡l]pent¡l}-2,3,4,5,6-pentahydrox¡hexanam¡da (I-607);

(2S,3S,4R,5S)-N-{5-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l] cyclopropox¡}methyl)benzenesulfon¡l]pent¡l}-2,3,4,5,6-pentahydrox¡hexanam¡de (I-608); (2S,3S,4R,5S)-N-(carbamoylmethyl)-N-(5-{[4-chloiO-3-({1-[4-(2-c¡clopiOpoxyphenyl)p ¡r¡d¡n-3¡l]ciclopropox¡}met¡l)fen¡l]sulfan¡l}pent¡l)-2,3,4,5,6-pentah¡drox¡hexanam¡da (I -609);

(2S,3S,4R,5S)-N-(carbamoylmethyl)-N-[5-({4-chloiO-3-[({1-[4-(2-c¡clopiOpoxyphenyl) p¡r¡d¡n-3¡l]c¡clopropyl}am¡no)methyl]phenyl}sulfan¡l)pent¡l]-2,3,4,5,6-pentah¡drox hexanamide (1-610);

(2S,3S,4R,5S)-N-(5-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l ]cyclopropox¡}methyl)phenyl]sulfan¡l}pent¡l)-2,3,4,5,6-pentahydrox¡hexanam¡de (1-611);

2-({2-[(carbox¡methyl)({[2-(2-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r ¡d¡n-3-¡l] c¡clopropox¡}met¡l)phen¡l]sulfan¡l}ethoxy)et¡l]carbamo¡l}met¡l)am¡no]et¡l}( {[2-(2-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]cyclopropoxy}methyl)phenyl]sulfan ¡l}ethoxy)ethyl]carbamo¡l}methyl)amino)acetic (1-612);

(2R,3R,4R,5S)-6-[(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡ l]cyclopropox¡}methyl)phenyl]sulfan¡l}butyl)(2-methanesulfon¡let¡l)am¡no]hexan-1,2,3,4,5-pentol (1- 613); (2R,3R,4R,5S)-6-[(3-{[3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]c ¡clopropox¡}met¡l)-4met¡lfen¡l]sulfan¡l}prop¡l)(2-methanesulfon¡let¡l)am¡no]hexan-1,2,3,4,5-pentol ( 1-614);

(2R,3R,4R,5S)-6-[(4-{[3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]c ¡clopropox¡}methyl)-4methylphenyl]sulfanyl}but¡l)(2-methanesulfon¡let¡l)am¡no]hexan-1,2,3,4,5-pentol (1- 615);

3-(1-{[2-chloro-5-(methylsulfan¡l)phenyl]methoxy}c¡cloprop¡l)-4-(2-cyclopropox¡phenyl)p¡r¡d na (1-617);

[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]-N-{[5-methyl-2-(methylsulfan¡l)pyridin-4-¡l] methyl} cyclopropan-1-amine (1-619);

4-{[3-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-¡l]c¡clopropox¡}methyl)-4-(propan- 2-yl)phenyl]sulfan¡l}-N-methylN-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]butanam¡de (I- 620);

-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡hd¡n-3-¡l]cyclopropoxy}methyl)phenyl] sulfanyl}butyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (1-621);

ω σ>

w&lt;o

<img file="MX376739B_D0127.tif" />

IMPI

130

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

1-[3-({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡rd¡n-3-¡l]c¡cloprop¡l }amino)methyl]phenyl}sulfanyl)propyl]3-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-622) ;

-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡hdin-3-yl]cyclopropyl}amno)methyl]phenyl }sulfan¡l)butyl]-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea I-623);

(2S,3S,4R,5S)-N-[4-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l] cycloprop¡l}am¡no)methyl]phenyl}sulfanyl)but¡l]-2,3,4,5,6-pentah¡drox¡-N-[2-(2-oxo¡ m¡dazolin-1-¡l)ethyl]hexanamide (I-624);

1-(3-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]sulfanyl}propyl)-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-625);

1-{2-[2-({4-chloro-3-[({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡ cloprop¡l}am¡no)methyl]phenyl}sulfan¡l)ethoxy]ethyl}-3-[(2S,3R,4R,5R)-2,3,4,5,6-pentah [droxyhex]urea (I-626); 1-(4-{[(5-{[4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3¡l]c¡clopropox¡ }methyl)phenyl]sulfan¡l}pent¡l)carbamo¡l]am¡no}but¡l)-3-[(2S,3R,4R,5R)-2,3,4,5 ,6-pentahydroxyhexyl]urea (I-627);

1-(4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]sulfanyl}butyl)-3[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-y]urea (I-628);

1-(4-{[(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡l]cyclopropox¡}met ¡l)phenyl]sulfan¡l}but¡l)carbamo¡l]am¡no}but¡l)-3-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl ] urea (I-629);

1-(5-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]sulfan¡l}pent¡l)-3[(1r,4r)-4-({[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex ¡l]carbamo¡l}amno)cyclohexyl]urea (I-630); 2-(4-{[(5-{[4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3¡l]c¡clopropox¡ }met¡l)phenyl]sulfan¡l}pent¡l)carbamo¡l]am¡no}p¡per¡n-1-¡l)-N-[(2S,3R,4R,5R )2,3,4,5,6-pentahydroxyhexl]acetamide (1-631);

1-(4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]sulfan¡l}but¡l)-3[(1r,4r)-4-({[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex ¡l]carbamo¡l}amno)cyclohexyl]urea (I-632);

ω σ>

w&lt;o

<img file="MX376739B_D0128.tif" />

IMPI

131

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

2-(4-{[(4-{[4-chloro-3-({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3¡l]c¡clopropox¡ }methyl)phenyl]sulfanyl}but¡l)carbamo¡l]am¡no}p¡per¡n-1-¡l)-N-[(2S,3R,4R,5R)2 ,3,4,5,6-pentahydroxyhexyl]acetamide (I-633);

1-(5-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]sulfan¡l}pentyl)-3[(1s,4s)-4-({[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l ]carbamo(l}amno)cyclohexyl]urea (I-634);

-(4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡hd¡n-3-¡l]cyclopropoxy}methyl)phenyl] sulfan¡l}but¡l)-3[(1s,4s)-4-({[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]carbamo¡l} amino)cyclohexyl]urea (I-635);

1-(5-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]sulfanyl}pentyl)-3[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-y]urea (I-636);

1-[2-(2-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-yl]c¡clopropox¡}met ¡l)phenyl]sulfan¡l}ethoxy¡)ethyl]3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l]urea ( I-637);

3-[2-(2-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-yl]c¡clopropox¡}met ¡l)phenyl]sulfan¡l}ethoxy¡)ethyl]1-[4-({[2-(2-{[4-chloro-3-({1-[4-(2-c ¡clopropoxyfen¡l)p¡r¡d¡n-3¡l]c¡clopropox¡}met¡l)fen¡l]sulfan¡l}ethox¡)et¡l]carbamo¡l}am¡no)but ¡l]urea (I-638);

1-{5-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡ l)benzenesulfinl]pentyl}-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-639);

1-{5-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡ l)benzenesulfonyl]pentyl}-3[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]urea (I-640);

1-(2-{2-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3yl]cyclopropoxy}methyl)benzenesulfon¡ l]ethoxy}ethyl)-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2yl]urea (1-641);

1-{5-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡ l) benzenesulfin¡l]pentyl}-3[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l]urea (I-642);

1-{5-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡ l)benzenesulfon¡l]pentyl}-3[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l]urea (I-643);

ω σ>

ω &lt; or

<img file="MX376739B_D0129.tif" />

IMPI

132

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

1-(2-{2-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3¡l]cyclopropoxy}methyl)benzenesulf¡ n¡l]ethoxy¡}ethyl)-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydrox¡hexan-2yl]urea (I-644);

5-({6-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropyl}am¡no)methyl]-5 -met¡lp¡r¡n-2-¡l}sulfan¡l)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]pentanam¡de (I-645);

4-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡no)met ¡l] benzenesulfonyl}-Nmethyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]butanam¡de (I-646);

4-{4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l}am¡no)met l]benzenesulfinyl}-N-methylN-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]butanamide (I-647);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfanil}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]butanamide (I-648);

4-({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡ no)methyl]phenyl}sulfanyl)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]butanamide (I-649);

4-({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡ no)methyl]phenyl}sulfan¡l)-N-methylN-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]butanam¡de ( I-650);

4-{[3-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l]cyclopropoxy}methyl)-4-methylphenyl ]sulfan¡l}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]butanamide (1-651);

4-{[3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡l)-4-met lfphenyl]sulfanyl}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]butanamide (I-652);

4-({6-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropyl}am¡no)methyl]-5 -methylpyridin-2-¡l}sulfan¡l)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]butanam¡de (I-653);

4-({6-[({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]cyclopropyl}am¡no)methyl]-5 -met¡lp¡r¡n-2-¡l}sulfan¡l)-Nmethyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡ hexyl]butanamide (I-654);

4-({4-[({1-[4-(2-c¡clopropox¡fen¡l)p¡nd¡n-3-¡l]c¡cloprop¡l}am¡no)met¡l] -5-methylp¡r¡m¡d¡n-2-¡l}sulfan¡l)N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]butanam Give (I-655);

4-({4-[({1-[4-(2-c¡clopropox¡fen¡l)p¡nd¡n-3-¡l]c¡cloprop¡l}am¡no)met¡l] -5-methylp¡r¡m¡d¡n-2-¡l}sulfan¡l)N-methyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox hexyl]butanamide (I-656);

ω σ>

w&lt;o

<img file="MX376739B_D0130.tif" />

IMPI

133

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

5-{[6-({1-[4-(2-c¡clopropox¡fen¡l)p¡nd¡n-3-¡l]c¡clopropox¡}met¡l)-5-met¡lp ¡r¡n-2-¡l]sulfanyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexíl]pentanamide (I-657);

5-{[6-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox¡}met¡l)-5-met ¡lp¡r¡n-2-¡l]sulfan¡l}-N-methylN-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡ l]pentanamide (I-658);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfanil}-N-ethylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]butanamide (I-659);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-(2hydroxyethyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]butanam¡ da (I-660);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-(3hydroxypropyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]butanam¡ gives (1-661);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-[2(dimethylam¡no)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡ hexyl]butanamide (I-662);

N-(carbamoylmethyl)-4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3¡l]c¡ clopropox¡}methyl)phenyl]sulfan¡l}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]butanam¡da (I663);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-(2methoxyethyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]butanam¡da ( I-664);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-(2methanesulfonyleth¡l)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]butanam¡da ( I-665);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]-N-propilbutanam (I-666);

N-benzyl-4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-3-¡l]c¡clopropox }methyl)phenyl]sulfanyl}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]butanamide (I-667);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]-N-(propan-2-¡l)butanam¡de (I- 668);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-(oxan-4-¡l)N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l]butanam¡de (I- 669);

ω σ>

ω &lt; or

<img file="MX376739B_D0131.tif" />

IMPI

134

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N[(methylcarbamo¡l)methyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l] butanamide (I-670);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-[2(dimethylcarbamo¡l)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡ hex¡l]butanamide (1-671);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-[2(ethylcarbamo¡l)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hexyl] butanamide (I-672);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-(3methoxypropyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]butanam¡da ( I-673);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N[(dimethylcarbamol)methyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡ l]butanamide (I-674);

N-(2-carbamoylethyl)-4-{[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rd¡n-3¡l] cyclopropox¡}methyl)phenyl]sulfan¡l}-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]butanam gives (I675);

3-({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡ no)methyl]phenyl}sulfanyl)-N-methylN-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]propanamide (I-676) ;

3-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexíl]propanamide (I-677);

5-({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡ no)methyl]phenylsulfanyl)-N-methylN-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (I- 678);

2-[1-({[4-chloro-3-({1-[4-(2-cyclopropox¡phenyl)p¡rid¡n-3¡l]c¡clopropox¡}methyl)phen ¡l]sulfan¡l}methyl)c¡clopiOp¡l]-N-methylN-[(2S,3R,4R,5R)-2,3,4,5,6pentahydroxyhexyl]acetamide (I-679 );

4-[({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am ¡no)methyl]phenyl}sulfanyl)methyl]-N-methyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]benzam Give (I-680);

2-{1-[({4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l]c¡cloprop¡l} am¡no)methyl]phenyl}sulfan¡l)methyl]cyclopropyl}-N-methylN-[(2S,3R,4R,5R)-2,3,4, 5,6-pentahydroxyhexyl]acetamide (1-681);

<img file="MX376739B_D0132.tif" />

135

IMPI §

MEXICAN INSTITUTE OF PROPERTY w

INDUSTRIAL &lt;0

MX/E/2018/085580

5-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rdin-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfanil}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pentanamide (I-682);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-[2-(2-hydroxyethoxy)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡ hexyl]butanamide (I-683);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-(5hydroxypent¡l)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]butanam¡ da (I-684);

4-({[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rdin-3-¡l]c¡clopropox¡}methyl)phen ¡l]sulfan¡l}methyl)-N-methylN-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]benzam¡de (I -685);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-[2(morpholine-4-sulfon¡l)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡ droxyhexyl]butanamide (I-686); 4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rdin-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-(3-h¡drox¡2,2-dimethylpropyl)-N-[(2R,3S,4S,5S)-2,3,4,5,6- pentahydroxyhexyl]butanamide (I-687);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N[(2R,3S,4S,5S)-2,3,4,5,6-pentahydroxy¡hex¡l]-N-[(1s,4s)-4-h¡drox cyclohexyl]butanamide (I-688); 4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rdin-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfanyl}-N,2-dimethylN[(2S,3R,4R,5R)-2,3,4,5,6 -pentahydroxyhexyl]butanamide (I-689);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfanil}-2-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]butanamide (I-690);

4-{[3-({1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl]cyclopropoxy}methyl)-4-ethylphenyl l]sulfan¡l}-N-methylN[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexíl]butanamide (1-691);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-(4hydroxybut¡l)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]butanam¡ da (I-692);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-[2(dimethylsulfamo¡l)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡ hex¡l]butanamide (I-693);

4-{[4-chloro-3-({1-[4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l]c¡clopropox¡}met¡l)fen¡ l]sulfan¡l}-N-[2(methylsulfamo¡l)ethyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡ l]butanamide (I-694);

ω σ>

w&lt;o

<img file="MX376739B_D0133.tif" />

IMPI

136

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

N-(5-{[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rdin-3-¡l]c¡clopropox¡}methyl )phenyl]sulfan¡l}pent¡l)-N[(2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l]acetamide (I-695) ;

1-(4-{N-ethyl4-chloro-3-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3¡l]c¡cloprop¡l }am¡no)methyl]benzenesulfonamido}but¡l)-3-[(2S,3R,4S,5R)-1,3,4,5,6pentahydroxyhexan-2-¡l]urea (I- 696); 3-{1-[(2-chloro-5-{methyl[4-({[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2¡l]carbamo¡l }am¡no)but¡l]sulfamo¡l}phenyl)methoxy¡]c¡cloprop¡l}-4-(2-c¡clopropox¡phenyl)p¡rd¡n-1-¡o -1-olate (I-697);

3-[1-({2-chloro-5-[(2S)-6-({[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2¡l]carbamo ¡l}am¡no)hexan-2-¡l]phenyl}methoxy¡)c¡clopropyl]-4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-1-¡ o-1-olate (I698);

3-{1-[(2-chloro-5-{ethyl[4-({[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]carbamo ¡l}am¡no)but¡l]sulfamo¡l}phenyl)methoxy¡]c¡clopropyl}-4-(2-c¡clopropox¡phenyl)p¡r¡d¡n-1- ¡o-1-olate (I-699);

2,5-d¡chloro-4-[({1-[4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l]c¡cloprop¡l}am¡ non)methyl]phenol (I-700); 3-{1-[(2-chloro-5-{ethyl[4-({[(2S,3R,4R,5R)-2,3,4,5,6-pentah¡drox¡hex¡l]carbamo ¡l}am¡no)butyl]sulfamo¡l}phenyl)methoxy¡]cycloprop¡l}-4-(2-cyclopropox¡phenyl)-1-{[(2,2dimethylpropanoil) oxy]methyl}pyridin-1-io (1-701);

1-[({[2-(acetyloxy)ethyl](methyl)carbamoyl}ox)methyl]-3-{1-[(2-chloro-5-{ethyl[4 -({[(2S,3R,4R,5R)-2,3,4,5,6pentahydrox¡hex¡l]carbamo¡l}amno)but¡l]sulfamo¡l}phenyl)methoxy] cyclopropyl}-4-(2-cyclopropoxyphenyl)p¡rdan-1-io (I-702) 3-(1-{[2-chloro-5-(ethylsulfamo¡l) phenyl]methoxy cyclopropyl)-4-(2-cyclopropoxyphenyl)p¡rdn-1-¡o-1-olato (I703); 3-(1-{[2-chloro-5-(methylsulfamoyl)phenyl]methoxy}cyclopropyl)-4-(2-cyclopropoxyphenyl)pd ¡n-1-¡o-1-olato (I-704);

4-chloiO-3-({1-[4-(2-c¡clopiOpox¡fen¡l)p¡r¡d¡n-3-¡l]c¡clopiOpox¡}met¡l)-A/, A/-diethylbenzene-1sulfonamide (I-705);

ω σ>

ω &lt; or

<img file="MX376739B_D0134.tif" />

IMPI

137

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

1,3-b¡s[(5S)-5-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡ l]cyclopropoxy}methyl)phenyl]hexyl]urea (I-706);

2-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pindin-3yl]cyclopropoxy}methyl)benzenesulfonamido]ethane-1-sulfonic acid (I-707);

3-{1-[(2-chloro-5-sulfamoylphenyl)methoxy]cyclopropyl}-4-(2-cyclopropoxyphenyl)pyridin-1-¡o-1-olato (I-708); 4-Chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdin-3-yl]cyclopropoxy}methyl)benzene-1-sulfonamide (I- 709); 1-{2-[2-({4-chloro-3-[(1-{4-[2-(oxetan-3-ylox¡)phenyl]pyridin-3-¡l}c ¡clopropoxy)methyl]phenyl}sulfanyl)ethoxy¡]ethyl}-3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l]urea (1-710);

4-Chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdin-3-yl]cyclopropoxy}methyl)-N-methyl-N-(propan-2- ¡l) benzene-1-sulfonamide (1-711);

4-Chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡ndin-3-yl]cyclopropoxy}methyl)-N-(propan-2-¡l)benzene-1sulfonamide (1-712);

4-Chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-yl]cyclopropoxy}methyl)-N-methyl-N-propylbenzene-1sulfonamide (1-713);

4-Chloro-Nc¡clopent¡l-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rdin-3-¡l]c¡clopropox¡}methyl) -N-methylbenzene-1sulfonamide (1-714);

4-[4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡rdin-3-yl]cyclopropoxy}methyl)benzenesulfonyl]-3,3dimethylmorpholine (1- 715);

3-{1-[(2-chloro-5-{[4-({[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l]carbamo¡l} am¡no)but¡l](propan2-¡l)sulfamoyl}phenyl)methoxy]cyclopropyl}-4-(2-cyclopropoxyphenyl)pyridin-1-¡o-1-olato (1-716);

3-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxy-hexan-2-yl]-1-{4-[N-(propan-2-yl)4-chloro -3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-¡l]cyclopropoxy}methyl)benzenesulfonamido]butyl}urea (1-717);

(2S,3S,4R,5S)-2,3,4,5,6-pentahydroxy-N-{4-[N-(propan-2-¡l)4-chloro-3-({1-[4 -(2-cyclopropoxyphenyl)pyridin-3-¡l]cyclopropoxy}methyl)benzenesulfonamido]but¡l}hexanamide (1-718); N-tert-butyl-4-chloro-3-({1-[4-(2-cyclopropoxyphenyl)pyridin-3-yl]cyclopropoxy}methyl)benzene-1sulfonamide (1-719);

ω σ>

ω &lt; or

<img file="MX376739B_D0135.tif" />

IMPI

138

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

4-Chloro-3-({1-[4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l]cyclopropoxy}methyl)-N-(oxan- 4-¡l)benzene-1sulfonamide (I-720);

(2S)-S-[4-chloro-3-({1-[4-(2-c¡clopropox¡phenyl)p¡rid¡n-3-¡l]c¡clopropox¡}methyl )phenyl]-1-hydroxypropane-2-sulfonamido (1-721);

(2R)-S-[4-chloro-3-({1-[4-(2-cyclopropox¡phenyl)p¡rd¡n-3-¡l]cyclopropox¡}methyl )phenyl]-1-hydroxypropane-2-sulfonamido (I-722);

2-(4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l)-N-(2,5-d¡chlorobenzil)propan-2-amine (I-723 );

4-(4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l)cyclopropoxy)methyl)phenethyl)- N-((2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhexyl)benzamide (I-724);

4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l)cyclopropoxy)methyl)-A/, A/-dimethylbenzamide (I-725); 1-(5-(4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)pandan-3-yl)cyclopropoxy)methyl)phenox ¡)pentyl)-3((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)urea (I-726);

3-((4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)p¡rdin-3-¡l)c¡clopropox¡)methyl)benz¡ l)ox¡)-N((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l)benzamide (I-727);

4-chloro-5-((1-(4-(2-cyclopropoxyphenyl)p¡rdan-3-yl)cyclopropoxy)methyl)-2-fluoro- N-¡soprop¡lN-(4-(3((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l)ure¡do)butyl) benzenesulfonamide (I-728 );

N-((4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l)cyclopropoxy)methyl)phen l)sulfon l)acetamide (I729);

4-ChloiO-5-((1-(4-(2-c¡clopiOpox¡phenyl)p¡r¡d¡n-3-¡l)c¡clopiOpox¡)methyl)-2-methoxy¡- A/,A/dimethylbenzenesulfonamide (I-730);

4-chloiO-5-((1-(4-(2-c¡clopiOpox¡phenyl)p¡r¡d¡n-3-¡l)c¡clopiOpox¡)met¡l)-2-h ¡diOxy-A/,A/dimethylbenzenesulfonamide (1-731);

1-(4-((4-chloiO-3-((1-(4-(2-c¡clopiOpox¡phenyl)p¡nd¡n-3-¡l)c¡clopropox¡)methyl )phenyl)sulfonyl)-1,4-diazepan-1-yl)ethan-1-one (I-732);

6-((4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l)cyclopropox¡)methyl)phen¡ l)sulfonyl)-2-methoxy5,6,7,8-tetrahydro-1,6-naphthyridino (I-733);

ω σ>

ω &lt; or

<img file="MX376739B_D0136.tif" />

IMPI

139

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

6-((4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l)c¡clopropox¡)methyl) phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol (I-734);

4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l)cyclopropoxy)methyl)-N-methylN -(4-(3((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l)ure¡do)but¡l-1,1,2,2, 3,3,4,4d8)benzenesulfonamide (I-735);

(2R,3S,4R,5S)-5-(3-(4-((4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡r¡d¡n- 3-¡l)cyclopropoxy)methyl)-N-methylphenyl)sulfonamido)butyl)uredo)hexan-1,2,3,4,6-pentayl pentapropionate (I-738);

3-(1-((2,5-dichlorobenzyl)ox¡)cyclopropyl)-4-(2-(methylthio)phenyl)p¡rdina (I -739);

4-(2-cyclopropoxyphenyl)-3-(2-((2,5-dichlorobenzyl)oxy)propan-2-¡l)p¡rdina (I- 740);

4-(2-cyclopropoxyphenyl)-3-(1-((2,5-dichlorobenzyl)ox¡)cyclobut¡l)p¡rdina (1-741) ;

4-(2-cyclopropoxyphenyl)-3-(1-((2,5-dichlorobenzyl)ox)cyclopentyl)pyridine (I-742) ;

4-(2-cyclopropoxyphenyl)-3-(3-((2,5-dichlorobenzyl)ox)tetrahydrofuran-3-l)p -743);

4-chloro-3-(((1-(4-(2-c¡clopropoxyphenyl)pyridin-3-¡l)c¡cloprop¡l)am¡no)methyl) -N-¡soprop¡lN-(4-(3((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxy¡hexan-2-¡l)ureido)but¡l)benzenesulfonam Give (I-744);

4-(2-cyclopropoxyphenyl)-3-(1-((2,5-dichlorobenzyl)oxy)ethyl)pyridine (I-745);

4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l)cyclobutox¡)methyl)-N-¡ sopropyl-N-(4-(3((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxy¡hexan-2-¡l)ureido)but¡l)benzenesulfonamide (I -746); 4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l)cyclobutox¡)methyl)-N-¡ sopropyl-N-(4-(3((2S,3R,4R,5R)-2,3,4,5,6-pentahydrox¡hex¡l)ure¡do)but¡l)benzenesulfonamide (I- 747);

5-(4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)pyr¡d¡n-3-¡l)cyclopropoxy)methyl)phenethyl )-N-((2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhexyl)picolinamide (I-748);

4-chloro-3-(((3-(4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l)tetrah¡drofuran-3-¡l)ox¡)met¡ l)-N-¡soprop¡lN-(4-(3((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxy¡hexan-2-¡l)ureido)but¡l )benzenesulfonamide (I-749);

4-chloro-3-(((3-(4-(2-c¡clopropox¡fen¡l)p¡rid¡n-3-¡l)tetrah¡drofuran-3-¡l)ox¡)met¡ l)-N-isoprop¡lN-(4-(3((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhex¡l)ure¡do)but¡l) benzenesulfonamide ( I-750);

4-chloro-3-(((1-(4-(2-c¡clopropoxyphenyl)pyridin-3-¡l)c¡cloprop¡l)am¡no)methyl) -N-¡soprop¡lN-(4-(3((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l)ure¡do)but¡l)benzenesulfonam¡ gives (1-751);

ω σ>

ω &lt; or

<img file="MX376739B_D0137.tif" />

IMPI

140

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)pyridin-3-¡l)ethoxy)methyl)-N-¡soprop¡lN- (4-(3-((2S,3R,4S,5R)1,3,4,5,6-pentahydroxylhexan-2-l)ureido)butyl)benzenesulfonamide (I-752);

4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l)ethoxy)methyl)-N-isoprop¡lN -(4-(3-((2S,3R,4R,5R)2,3,4,5,6-pentahydroxyhexyl)ureido)butyl)benzenesulfonamide (I-753);

4-chloro-3-(((2-(4-(2-cyclopropoxyphenyl)pyridin-3-¡l)propan-2-¡l)am¡no)methyl )-N-¡soprop¡lN-(4-(3((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l)ure¡do)but¡l) benzenesulfonamide (I-754);

1-(4-(4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l)cyclopropoxy)methyl)phenoxy) butyl)-3((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)urea (I-755);

3-((4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l)c¡clopiOpox¡)met¡l) benzyl)oxy)-N((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl)benzamide (I-756);

6-((4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l)c¡clopiOpox¡)met¡l) benzyl)oxy)-N((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl)nicotinamide (I-757);

2-((4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l)c¡clopropox¡)methyl) benzyl)thio)-1-methylN((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-1H-mdazol-5 -carboxamide (I-758);

2-((4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l)c¡clopropox¡)methyl) benzyl)thio)-1-methylN((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l)-1 H-imidazole-5- carboxamide (I-759);

1-(5-(4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)pyr¡d¡n-3-¡l)c¡clopropox¡)methyl) phenoxy¡)pentyl)-3((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l)urea (I-760);

4-chloro-3-((1-(4-(2-c¡clopropox¡fen¡l)p¡r¡d¡n-3-¡l)c¡clopiOpox¡)met¡l)-N-¡ sobut¡lN-(4-(3((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxy¡hexan-2-¡l)ureido)but¡l)benzenesulfonamide (1 -761) 4-chloro-3-((1-(4-(2-c¡clopropox¡fen¡l)p¡r¡d¡n-3-¡l)c¡clopiOpox¡)met¡l)- N-¡sobut¡lN-(4-(3((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l)ure¡do)but¡l)benzenesulfonamide (I-762);

4-chloro-5-((1-(4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l)cyclopropoxy)methyl)-2-fluoro -N-¡sopropyl-N-(4-(3((2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-¡l)ure¡do)but¡l) benzenesulfonamide (I-763);

4-chloro-5-((1-(4-(2-cyclopropoxyphenyl)pyridin-3-¡l)cyclopropoxy)methyl)-2-fluoro-N -¡soprop¡lN-(4-(3((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy¡hex¡l)ure¡do)butyl) benzenesulfonamide (I-764) ;

4-(2-chloro-6-methoxyphenyl)-3-(1-((2,5-dichlorobenzyl)ox¡)cyclopropyl)pyridine I-765 );

ω σ>

w&lt;o

<img file="MX376739B_D0138.tif" />

ΙΜΡΙ

141

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

N-(4-((4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l)cyclopropoxy)methyl)- N-methylphenyl)sulfonamido)butyl)acetamide (I-766);

4-(2-chlorophenyl)-3-(1-((2,5-dichlorobenzyl)oxy)cyclopropyl)pyridine (I-768);

1-((4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡ndin-3-¡l)cyclopropoxy)methyl)phenyl) sulfonyl)-4-methyl-1,4-diazepane (I-769);

4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l)cyclopiOpox¡)methyl)-N-( tazol-2¡l)benzenesulfonamide (I-770);

4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l)cyclopropoxy)methyl)-N-phen ¡benzenesulfonamide (I771);

4-Chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l)cyclopiOpox¡)methyl)-N-(2,2, 2-trifluoroethyl)benzenesulfonamide (I-772);

3-(1-((2,5-dichlorobenzyl)ox)cyclopropyl)-4-(o-tolyl)pyridine (I-773);

3-(1-((2,5-dichlorobenzyl)ox¡)cyclopropyl)-4-(2-methoxy-4-methylphenyl)pyridine I- 774);

3-(1-((2-chloro-5-(N-(4-((2S,3S,4R,5S)-2,3,4,5,6-pentahydroxy¡hexanam¡do)but¡l) sulfamoyl)benzyl)oxy)cyclopropyl)-4-(2-cyclopropoxyphenyl)pyridine 1-oxide (I-775);

4-chloro-3-((1-(4-(2-c¡clopropox¡fen¡l)p¡ndin-3-¡l)c¡clopropox¡)methyl)-N-met¡lN-( 4-(3((2S,3R,4R,5R)-1,3,4,5,6-pentahydrox¡hexan-2-¡l)ure¡do)but¡l)benzenesulfonamide I-776);

(1S,4S)-2-((4-chloro-3-((1-(4-(2-c¡clopropox¡phenyl)p¡nd¡n-3-¡l)cyclopropox¡)met¡ l)phenyl)sulfonyl)-5-methyl-2,5-diazabic¡clo[2.2.1]heptane (I-777);

4-(2-cyclopropoxyphenyl)-3-(1-((2,5-dichlorobenzyl)oxy)propyl)pyridine (I-779);

1-((1 S,4S)-5-((4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡nd¡n-3-yl)c¡ clopropox¡)methyl)phenyl)sulfon¡l)2,5-diazabic¡clo[2.2.1]heptan-2-¡l)ethan-1-one (I-780);

4-Chloro-N-(1-(((S)-3-((S)-2-cyanopyrrolidine-1-carbon¡l)-1,2,3,4-tetrahydroisoquinol ¡n-7-¡l)ox¡)-10,21d ioxo-3,6,14,17-tetraoxa-9,11,20,22-tetraazahexacosan-26-yl)-3-((1-(4 -(2-cyclopropoxyphenyl)pyridin-3-1)cyclopropoxy)methyl)-N-methylbenzenesulfonamide (1-781);

4-Chloro-N-(1-(((S)-3-((S)-2-cyanopyrrolidine-1-carbon¡l)-1,2,3,4-tetrahydroisoquinol ¡n-7-¡l)ox¡)10,21,28,39-tetraoxo-3,6,14,17,32,35-hexaoxa-9,11,20,22,27,29,38,40 -octaazatetratetracontanω σ>

ω &lt; or

<img file="MX376739B_D0139.tif" />

IMPI

142

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

44-¡l)-3-((1-(4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l)c¡clopropox¡)methyl)-N -methylbenzenesulfonamide (I782)

4-(2-cyclopropoxyphenyl)-3-(1-((2,5-dichlorobenzyl)ox¡)cyclopropyl)p¡rdazine (I-783)

1-(4-(2-cyclopropoxyphenyl)p¡ndazin-3-¡l)-N-(2,5-dichlorobenzyl)cyclopropan-1-amine (I-784 );

4-chloro-3-((1-(4-(2-c¡clopropox¡fen¡l)-6-et¡lp¡ndin-3-¡l)c¡clopropox¡)methyl)-N- methylN-(4-(3((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)uredo)butyl)benzenesulfonamide I-785);

4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)-6-eth¡lp¡nd¡n-3-¡l)cyclopropox¡)methyl)-N- methylN-(4-(3-methyl-3((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)ureido)butyl)benzenesulfonamide ( I-786);

4-(2-cyclopropoxyphenyl)-5-(1-((2,5-dichlorobenzyl)ox)cyclopropyl)-2-ethylpindine (I -787);

-(1-((2,5-dichlorobenzyl)oxy)cyclopropyl)-5H-chromene[3,4-c]pyridine (I-788);

3-(1-((2,5-dichlorobenzyl)ox)cyclopropyl)-5-ethoxy-4-phenylpindine (I-789);

3-(1-((2,5-dichlorobenzyl)oxy)cyclopropyl)-5-methoxy-4-phenylpandine (I-790);

1-(4-(2-c¡clopropoxyphenyl)p¡nd¡n-3-yl)-N-(2,5-d¡chlorophenyl)c¡clopropan-1-carboxamide ( 1-791);

4-(2-cyclopropoxyphenyl)-3-(1-((2,5-dichlorophenoxy)methyl)cyclopropyl)pandin (I-792);

6-((4-chloro-3-((1-(4-(2-c¡clopiOpox¡fen¡l)p¡nd¡n-3-¡l)c¡clopiOpox¡)met¡l)fenox¡ )methyl)-N((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)nicotinamide (I-793);

4-(2-cyclopropoxyphenyl)-3-(1-(((2,5-dichlorobenzyl)ox)methyl)cyclopropyl)pindine -794);

4-(2-cyclopropoxyphenyl)-3-(((2,5-dichlorobenzyl)ox)methyl)pindina (I-795);

6-((4-chloro-3-((1-(4-(2-c¡clopropoxyphenyl)p¡r¡d¡n-3-¡l)c¡clopiOpox¡)met¡l) benzyl)oxy)-N((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)nicotinamide (I-796);

3-(1-((2,5-dichlorobenzyl)ox¡)cyclopropyl)-4-(2-methoxy-6-methylphenyl)p¡nd¡ne (I-797 );

3-(1-((2,5-dichlorobenzyl)ox¡)cyclopropyl)-4-(2-methoxy-3-methylphenyl)p¡nd¡ne (I-798 );

4-Chloro-3-((1-(4-(2-cyclopropoxyphenyl)p¡r¡d¡n-3-¡l)cyclopiOpox¡)methyl)-N-methyl -N-(4-(3((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)uredo)butyl)benzamide (I-799); 3-(1-((2,5-dichlorobenzyl)ox!)cyclopropyl)-4-(2-methoxy!-5-(tnfluoromethoxy!)phenyl)pyridine (I-800); 3-(1-((2,5-dichlorobenzyl)ox)cyclopropyl)-4-(2-methoxy-5-(tnfluoromethyl)phenyl)pindina ( 1-801) 4-(3-chloro-2-methoxyphenyl)-3-(1-((2,5-dichlorobenzyl)ox¡)cyclopropyl)p¡nd¡na ( I-802);

ω σ>

ω &lt; or

<img file="MX376739B_D0140.tif" />

IMPI

143

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

3-(1-((2,5-dichlorobenzyl)ox)cyclopropyl)-4-phenylpindine (I-803);

3-(1-((2,5-dichlorobenzyl)ox¡)cyclopropyl)-4-(2-methoxy-5-methylphenyl)pindina (I-804 );

3-(1-((2,5-dichlorobenzyl)ox¡)cyclopropyl)-4-(2,2-difluorobenzo[d][1,3]d¡oxol-4 -I) pindina (I-805);

3-(1-((2,5-dichlorobenzyl)oxy)cyclopropyl)-4-(3-methoxyphenyl)pyridine (I-806);

4-(3-chlorophenyl)-3-(1-((2,5-dichlorobenzyl)oxy)cyclopropyl)pyridine (I-807);

3-(1-((2,5-dichlorobenzyl)oxy)cyclopropyl)-4-(4-methoxyphenyl)pyridine (I-808);

3-(1 -((2,5-dichlorobenzyl)oxy)cyclopropyl)-4-(2-(methylsulfonyl)phenyl)pandine (I-809 ); Y

4-(4-chlorophenyl)-3-(1-((2,5-dichlorobenzyl)oxy)cyclopropyl)pyridine (1-810).

In another embodiment, the compounds of the invention include:

3-(4-[/V-methyl[4-chloro-3-([1-[4-(2-cyclopropoxyphenyl)pindn-3yl]cyclopropoxy]methyl)benzene ]sulfonamido]butyl)-1-[2-(2-[2-[([4-[([2-[2-(2-[[(4-[A/-methyl[4-chloro- 3-([1[4-(2-cyclopropoxyphenyl)p¡rdan-3yl]cyclopropoxy]methyl)benzene]sulfonamido]butyl)carbamoyl]amino]ethoxy)ethoxy]ethyl ]carbamoyl)amino]b-util]carbamoyl)amino]ethoxy]ethoxy)ethyl]urea (I-736);

3-(4-[/V-methyl[4-chloro-3-([1-[4-(2-cyclopropoxyphenyl)pindn-3yl]cyclopropoxy]methyl)benzene ]sulfonamido]butyl)-1-[2-(2-[2-[([2-[2-(2-[[(4-[A/-methyl[4-chloro-3-([1 -[4(2-cyclopropoxyphenyl)pandan-3yl]cyclopropoxy]methyl)benzene]sulfonamido]butyl)carbamoyl]amino]ethoxy)ethoxy]ethyl]carbamoyl)amno] e toxy]ethoxy)ethyl]urea (I-737);

A/,A/'-((carbon¡lbis(azaned¡yl))bis(butan-4,1-d¡yl))bis(4-chloro-3-((1-(4-(2-c clopropoxyphenyl)pindin-3yl)cyclopropoxy)methyl)-N-methylbenzenesulfonamide)(1-767);

A/,A/'-(piperazin-1,4-diylbis(propan-3,1-d¡¡l))b¡s(5-(2,5-dichloro-4-((1-(4- (2-cyclopropoxyphenyl)pindin3-1)cyclopropoxy)methyl)phenyl)pentanamide) (1-811);

A/,/V'-(((oxybis(ethan-2,1-diyl))bis(oxy))bis(ethan-2,1-diyl))bis(5-(2,5-dichloro-4- ((1-(4-(2-cyclopropoxyphenyl)pyridin-3-¡l)cyclopropoxy)methyl)phenyl)pentanamide) (1-812);

2,2'-(1,18-b¡s(2,5-dichloro-4-((1-(4-(2-cyclopropoxyphenyl)p¡r¡d¡n acid acetic (1-813);

ω σ>

ω &lt; or

<img file="MX376739B_D0141.tif" />

IMPI

144

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

1,1 '-(butan-1,4-di yl )bis(3-(2-(2-((4-chloro-3-(( 1 -(4-(2-cyclopropoxyphenyl)p indn-3-yl)cyclopropoxy)methyl)phenyl)thio)ethoxy)ethyl)urea) (1-814); and 6-(carbox¡methyl)-14-((4-chloro-3-((1-(4-(2-cyclopropoxyphenyl)pind¡n-3¡l)c¡ acid clopropox¡)methyl)phenyl)thio)-3-(2-((2-(2-((4-chloro-3-((1-(4-(2-cyclopropox¡phen) l)p¡r¡d¡n-3¡l)c¡clopropox¡)met¡l)phenyl)th¡o)ethox¡)et¡l)am¡no)-2-oxoet¡l)- 8-oxo-12-oxa-3,6,9-triazatetradecanoic (1-815).

In another embodiment of the invention, the compounds of the formula (I') are enantiomers. In some embodiments the compounds are the (S)-enantiomer. In other embodiments the compounds are the (R)-enantiomer. In yet other embodiments, the compounds of formula (I') may be (+) or (-) enantiomers.

It is to be understood that all isomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in a cis- or trans-configuration. It is also intended to include all tautomeric forms.

Compounds of the invention, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and prodrugs thereof may exist in their tautomeric form (eg, as amide or imino ether). All of these tautomeric forms are contemplated herein as part of the present invention.

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, as well as their mixtures, including racemic mixtures, are considered to form part of the present invention. Furthermore, the present invention encompasses all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both cis and trans forms, as well as mixtures, are included within the scope of the invention. Each compound described herein includes all enantiomers that fit the general structure of the ω

σ>

ω &lt; or

<img file="MX376739B_D0142.tif" />

IMPI

145

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 Composite. The compounds may be in racemic or enantiomerically pure form, or any other form in terms of stereochemistry. Assay results may reflect data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by conversion of the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (eg, a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separation of the diastereoisomers, and conversion. (eg hydrolysis) of the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the invention may be atropisomers (eg, substituted biaryls) and are considered to be part of this invention. Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the invention may exist in different tautomeric forms and all such forms are included within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (eg, geometric isomers, optical isomers, and the like) of the present compounds (including those of salts, solvates, esters, and prodrugs of the compounds as well as salts, solvates, and esters of prodrugs), such as that can exist due to asymmetric carbons on various substituents, including enantiomeric forms (which can exist even in the absence of asymmetric carbons), rotameric forms, atropisomers and diastereomeric forms are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of formula (I') incorporates a double bond ω

σ>

ω &lt; or

<img file="MX376739B_D0143.tif" />

ΙΜΡΙ

146

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 or a fused ring, both cis and trans forms, as well as mixtures, are included within the scope of the invention. Also, for example, all keto-enol and imineenamine forms of the compounds are included in the invention). The individual stereoisomers of the compounds of the invention may be substantially free of other isomers, or may be mixed, for example, as racemates or with all or other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined in the 1974 IUPAC Recommendations. The use of the terms salt, solvate, ester, prodrug, and the like, is intended to apply equally to salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the compounds of the invention.

Compounds of formula I can form salts which are also within the scope of this invention. Reference to a compound of the Formula herein is understood to include reference to its salts, unless otherwise indicated.

The present invention relates to compounds that are modulators of TGR5. In one embodiment, the compounds of the present invention are TGR5 agonists.

The invention relates to the compounds described herein and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers or tautomers, and pharmaceutical compositions comprising one or more compounds described herein or their salts, hydrates, solvates, prodrugs. pharmaceutically acceptable , stereoisomers or tautomers.

Method for the preparation of the compounds

The compounds of the present invention can be prepared by a variety of methods including standard chemistry. Appropriate synthetic pathways are depicted in the schemes given below.

Compounds of formula (I') may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that the groups ω

σ>

ω &lt; or

<img file="MX376739B_D0144.tif" />

ΙΜΡΙ

147

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 protectors for sensitive or reactive groups are used when necessary according to general principles or chemistry. Protecting groups are handled according to standard methods of organic synthesis (TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage in the synthesis of the compounds using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and the order of their execution must be consistent with the preparation of compounds of formula (I') ·

Those of ordinary skill in the art will recognize whether a stereocenter exists in the compounds of formula (I'). Accordingly, the present invention includes both possible stereoisomers (unless otherwise specified in the synthesis) and includes not only racemic compounds, but also the individual enantiomers and/or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. The resolution of the final product, an intermediate or a starting material can be affected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by EL Eliel, SH Wilen, and LN Mander (Wiley-lnterscience, 1994).

The compounds described herein can be prepared from commercially available starting materials or can be synthesized using known organic, inorganic, and/or enzymatic processes.

The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present invention can be synthesized using the methods described below, in conjunction with synthetic methods known in the art of synthetic organic chemistry or variations thereof, as will be appreciated by those skilled in the art. Preferred methods include, but are not limited to those methods described below. The compounds of the present invention can be synthesized by means of the following steps highlighted in general schemes 1 to 5 ω

<img file="MX376739B_D0145.tif" />

IMPI

148

EITHER)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 that comprise different assembly sequences of intermediates B-1 to B-20. The starting materials are commercially available or can be prepared by procedures known in the informed literature or as illustrated.

General outline 1

<img file="MX376739B_D0146.tif" />

where R_a, Ri, R2, R2', R3, R4, X1-X4, Y and n are defined as in formula (I').

The general way of preparing the compounds of formula (I') using intermediates B-1, B-2, B-3, B-4, B-4, B-5, B-6 and B-7 is highlighted in General Scheme 1. The alkylation of nitrite B-1 using an alkyl lithium or Grignard reagent in a solvent i.e. tetrahydrofuran (THF) or diethyl ether and optionally in the presence of a Lewis acid i.e. cerium(III) or titanium(IV) isopropoxide provides amine B-2. Alternatively, alkylation of nitrite B-1 using an alkyl zinc or Grignard reagent in a solvent, i.e. tetrahydrofuran (THF), diethyl ether or toluene, in the presence of boron trifluoride etherate and a Lewis acid i.e. , titanium (IV) isopropoxide or ω dichloride

<img file="MX376739B_D0147.tif" />

ΙΜΡΙ

149

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 bis(c¡clopentadien¡l) zirconium (IV), provides amine B-2 where R₂ and R₂· form a cyclopropane ring. Boc protection of the primary amine B-2 using known protection methods (i.e. treatment of B-2 with di-tert-butyl dicarbonate using a base, i.e. NaHCOa, in a solvent, i.e. water and /o tetrahydrofuran (THF)) provides B-3. Arylation of B-3 with an arylboronic acid or ester in the presence of a metal catalyst, i.e., palladium(II) acetate (Pd(OAc)₂), tris(d¡benzylideneacetone)d¡palladium (Pd₂(dba)3) etc. and a base, i.e. potassium carbonate (K₂COs), cesium carbonate (Cs₂CO3), in a solvent, ie dichloromethane, toluene, etc., provides B-4.

Alkylation of B-4 with an aryl halide, aryl sulfonate, or aryl sulfate in the presence of base, i.e. K₂CO3,Cs₂CO3, KOH or NaH, in a solvent, ie acetonitrile or acetone and optionally at elevated temperature provides B-5. Alternatively, B-5 ​​can be obtained by alkylating B-4 with a phenol using a Mitsunobu reagent (i.e., diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD)) and triphenylphosphine in a solvent, i.e., tetrahydrofuran (THF), dichloromethane (DCM). Deprotection of B-4 in the presence of an acid, ie, hydrochloric acid (HCI), and in a solvent, ie, dioxane and/or tetrahydrofuran (THF), provides free amine B-6. Alkylation of B-6 with aryl or heteroaryl halide B-7 using a base, i.e. potassium carbonate (K₂COs) or cesium carbonate (Cs₂CO3), in a solvent, ie A/,A/-dimethylformamide (DMF) or tetrahydrofuran (THF) provides the desired compound of formula (I').

General scheme 2

<img file="MX376739B_D0148.tif" />

<img file="MX376739B_D0149.tif" />

stage e

<img file="MX376739B_D0150.tif" />

ω σ>

ω &lt; or

<img file="MX376739B_D0151.tif" />

IMPI

150

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 where R_a, Ri, R₂, R₂·, R3, R4, X1-X4, Y and n are defined as in formula (I').

Alternatively, compounds of formula (I') may be obtained by reductive amination of amine B-6 using aldehyde B-7a in the presence of a reducing agent, i.e. sodium triacetoxyborohydride, sodium cyanoborohydride or sodium borohydride. sodium, in a solvent, i.e. tetrahydrofuran (THF).

General scheme 3

<img file="MX376739B_D0152.tif" />

where R_a, R1, R₂, R₂·, R3, R4, X1-X4, Y and n are defined as in formula (I').

Alternatively, compounds of formula (I') can be prepared using intermediates B-7, B-8, B-9, B-10, B-11 and B-12 as outlined in General Scheme 3 Esterification of B-8 using trimethylsilylmethyldiacene in a solvent, ie dichloromethane or methanol, gives B-9. Alternatively, B-9 can be obtained by treating B-8 with oxalyl chloride in a solvent, ie, methanol. The coupling of B-9 and aryl- or heteroarylboronic acid or aryl- or heteroarylboronate ester B-10 in the presence of a metal catalyst, i.e., ω

<img file="MX376739B_D0153.tif" />

ΙΜΡΙ

151

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 palladium(II) acetate (Pd(OAc)2), tr¡s(d¡benzylideneacetone)d¡palladium (Pd₂(dba)₃) etc. and a base, ie, potassium phosphate, in a solvent, ie, 1,4-dioxane, THF, and/or water, provides B11. Alkylation of ester B-11 using an alkyl lithium or Grignard reagent in a solvent i.e. tetrahydrofuran (THF) or diethyl ether and optionally in the presence of a Lewis acid i.e. cerium(III) chloride or cerium(III) isopropoxide titanium (IV) provides alcohol B-12. For compounds in which R2 and R₂form a cyclopropane ring, intermediate B-11 is treated with a Grignard reagent and bis(cyclopentadenil)zirconium dichloride (IV) in a solvent, i.e. tetrahydrofuran (THF), ether diethyl or toluene, to provide the desired product. Alkylation of B-12 with aryl or heteroaryl halide B-7 in the presence of a strong base, i.e. sodium hydride (NaH), potassium bis(tnmethylsilyl)amide (KHMDS ) or potassium tert-butoxide and in a solvent, i.e., A/,A/-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or tetrahydrofuran (THF), provides the desired compound of the formula (I').

General outline 4

<img file="MX376739B_D0154.tif" />

<img file="MX376739B_D0155.tif" />

<img file="MX376739B_D0156.tif" />

ω σ>

ω &lt; or

<img file="MX376739B_D0157.tif" />

IMPI

152

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 where R_a, Ri, R2, R2', R3, R4, X1-X4, Y and n are defined as in formula (I).

The general route of preparation of the target molecules of formula (I') using intermediates B-7, B-10, B-12, B-13, B-14 and B-15 is highlighted in General Scheme 4. The coupling of B-12 and aryl- or heteroarylboronic acid or aryl- or heteroarylboronate ester B10 in the presence of a metal catalyst, i.e., palladium(II) acetate (Pd(OAc)2), tns(dibenzyl¡ denacetone)d¡palladium (Pd2(dba)s) etc. and a base, ie, potassium phosphate, in a solvent, ie, 1,4-dioxane, THF, and/or water, provides B-11. Treatment of B-11 with an alkyl lithium or alkyl magnesium halide (i.e., butyl lithium and iso-propyl magnesium bromide) followed by addition of ketone B-14 in a solvent, i.e., tetrahydrofuran (THF) or diethyl ether, provides alcohol B-15. Alkylation of B-15 with aryl or heteroaryl halide B7 in the presence of a strong base, i.e. sodium hydride (NaH), potassium bis(tnmethylsilyl)amide (KHMDS), or potassium tert-butoxide and in a solvent, i.e., A/,A/-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or tetrahydrofuran (THF), provides the desired compound of the formula ( YO').

General scheme 5 x_4u nhr₁₂r₁₃^χ3 B-17. A 9------*^Χ1 ,δηη. stage i

OO

HO

<img file="MX376739B_D0158.tif" />

HO^XA/ *1

B-15^Ria not... AA/ ---OOI B-18^R13

<img file="MX376739B_D0159.tif" />

where R_a, R1, R2, R2', R3, R4, X1-X4, Y and n are defined as in formula (I').

ω σ>

ω &lt; or

<img file="MX376739B_D0160.tif" />

ΙΜΡΙ

153

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Alternatively, compounds of formula (I') can be prepared using intermediates B-15, B-16, B-17, B-18, B-19 and B-20 as outlined in General Scheme 5 Treatment of sulfonyl chloride B-13 with amine B-17 in the presence of a base, i.e., pyridine, triethylamine, or NaHCO₃ and in a solvent, ie, tetrahydrofuran (THF), dichloromethane (DCM), or water, provides sulfonylamide B-18. Reduction of carboxylic acid B-18 using isobutylchloroformate in the presence of a base, ie, N-methylmorpholine or trimethylamine, in a solvent, ie, tetrahydrofuran (THF), followed by the addition of sodium borohydride provides B-19. Halomethylene B-20 is obtained by reacting B-19 with dibromotriphenylphosphorane in a solvent, ie, acetonitrile. Alkylation of B-15 with aryl or heteroaryl halide B-20 in the presence of a strong base, i.e. sodium hydride (NaH), potassium bis(thmethylsilyl)amide (KHMDS ), KHMDS, or potassium tert-butoxide and in a solvent, ie, /V,A/-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), or tetrahydrofuran (THF), provides the desired compound of formula (I').

A mixture of enantiomers, diastereomers, cis/trans isomers resulting from the process described above can be separated into their individual components by chiral salt technique, chromatography using normal phase, reverse phase column or chiral, depending on the nature of separation.

It is to be understood that in the description and formula shown above, the various R groups_a, Ri, R₂, R2', R3, R4, X1-X4, Y, and n are defined as in formula (I') and other variables are as previously defined, except where otherwise indicated. On the other hand, for synthetic purposes, the compounds of general schemes 1 to 5 are merely representative with radicals selected to illustrate the general synthetic methodology of the compounds of formula (I') as defined herein.

Methods of use of the compounds

Another aspect of the invention relates to a method of treating or preventing a disease or disorder associated with modulation of TGR5. The method comprises administering to a patient in need of treatment for diseases or disorders associated with ω

σ>

ω &lt; or

<img file="MX376739B_D0161.tif" />

IMPI

154

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 modulation of TGR5 an effective amount of the compositions and compounds of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers. In some embodiments, the disease or disorder associated with modulation of TGR5 activity is selected from chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, resistance to insulin, hyperglycemia, obesity, metabolic syndrome, ischemia, myocardial infarction, retinopathy, vascular restenosis, hypercholesterolemia, hypertriglycedemia, dyslipidemia or hyperlipidemia, lipid disorders such as low HDL cholesterol or high LDL cholesterol, high blood pressure, angina pectoris, coronary artery disease, atherosclerosis, cardiac hypertrophy, hyperphosphatemia, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), psoriasis, ulcerative colitis, Crohn's, disorders associated with parenteral nutrition especially during small intestine syndrome, irritable bowel syndrome (IBS), allergic diseases, fatty liver, non-alcoholic fatty liver disease (NAFLD) liver fibrosis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, primary biliary cirrhosis (PBC), renal fibrosis, anorexia nervosa, intestinal motility, bulimia nervosa and neurological disorders such as Alzheimer's disease, multiple sclerosis, schizophrenia, and cognitive impairment.

In another aspect, the present invention relates to a method of treating or preventing a disease or disorder associated with TGR5 activation. The method comprises administering to a patient in need of treatment for diseases or disorders associated with TGR5 activation an effective amount of the compositions and compounds of formula (I'), or one of their salts, hydrates, solvates, prodrugs, stereoisomers , or pharmaceutically acceptable tautomers. In some embodiments, the disease or disorder associated with activation of TGR5 activity is selected from chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, resistance to insulin, hyperglycemia, obesity, ω syndrome

σ>

ω &lt; or

<img file="MX376739B_D0162.tif" />

IMPI

155

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 metabolic, ischemia, myocardial infarction, retinopathy, vascular restenosis, hypercholesterolemia, hypertriglyceridemia, dyslipidemia or hyperlipidemia, lipid disorders such as low HDL cholesterol or high LDL cholesterol, high blood pressure, angina pectoris, arterial disease coronary artery disease, atherosclerosis, cardiac hypertrophy, hyperphosphatemia, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), psoriasis, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during small bowel syndrome, irritable bowel syndrome (IBS), allergic diseases, fatty liver, non-alcoholic fatty liver disease (NAFLD) liver fibrosis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis ( PSC), liver cirrhosis, primary biliary cirrhosis (PBC), renal fibrosis, intestinal motility, anorexia nervosa, bulimia nervosa and neurological disorders such as Alzheimer's disease, multiple sclerosis, schizophrenia and cognitive impairment.

Another aspect of the invention relates to a method of treating or preventing chemotherapy-induced diarrhea in a patient in need thereof. The method comprises administering to a patient in need of treatment for chemotherapy-induced diarrhea an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to a method of treating or preventing Type II diabetes mellitus. The method comprises administering to a patient in need of treatment for Type II diabetes mellitus an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating or preventing hyperphosphatemia. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the hyperphosphatemia is postprandial hyperphosphatemia.

ω σ>

ω &lt; or

<img file="MX376739B_D0163.tif" />

IMPI

156

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

In another aspect, the present invention relates to a method of treating or preventing kidney disease. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the kidney disease is chronic kidney disease (CKD) or end-stage renal disease (ESRD).

Another aspect of the invention relates to a method for reducing serum creatinine levels. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to a method of treating or preventing proteinuria. The method comprises administering to a patient in need of treatment for chemotherapy-induced diarrhea an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of delaying the time to renal replacement therapy (RRT). The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to a method of reducing FGF23 levels. The method comprises administering to a patient in need of treatment for chemotherapy-induced diarrhea an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention refers to a method to reduce the hyperphosphatemic effect of active vitamin D. The method comprises administering to a patient who ω

σ>

ω &lt; or

<img file="MX376739B_D0164.tif" />

IMPI

157

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 requires an effective amount of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers.

In another aspect, the present invention relates to a method of attenuating hyperparathyroidism. The method comprises administering to a patient in need of treatment for chemotherapy-induced diarrhea an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the hyperparathyroidism is secondary hyperparathyroidism.

Another aspect of the invention relates to a method of lowering serum parathyroid hormone (PTH). The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to a method of ameliorating endothelial dysfunction. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the endothelial dysfunction is induced by postprandial serum phosphorus.

Another aspect of the invention relates to a method of reducing vascular calcification. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the calcification is localized intimal vascular calcification.

In another aspect, the present invention relates to a method of reducing urinary phosphorus. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

ω σ>

ω &lt; or

<img file="MX376739B_D0165.tif" />

IMPI

158

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Another aspect of the invention relates to a method of normalizing serum phosphorus levels. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to a method of reducing phosphate load in an elderly patient. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of decreasing dietary phosphate uptake. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to a method of reducing renal hypertrophy. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of reducing cardiac hypertrophy. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to a method of treating and/or preventing a stomach and intestine related disorder. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the stomach and intestine related disorder is ulcers, digestive disorders, malabsorption syndromes, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue (eg, arising from ω

σ>

ω &lt; or

<img file="MX376739B_D0166.tif" />

IMPI

159

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 gluten-induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, regional enteritis (Crohn's disease), ulcerative colitis, damage to the small intestine or short bowel syndrome. In another embodiment, the stomach and intestine related disorder is radiation enteritis, infectious or postinfectious enteritis, bone marrow transplant induced enteritis, or small intestinal damage due to toxic or other chemotherapeutic agents.

Another aspect of the invention relates to a method of treating and/or preventing a side effect of chemotherapy or radiation treatment. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the side effect of chemotherapy is diarrhea, abdominal cramps, vomiting, or structural and functional damage to the intestinal epithelium resulting from the chemotherapy treatment. In one embodiment, the diarrhea is induced by an immune checkpoint inhibitor.

In another aspect, the present invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in the treatment or prevention of a disease associated with the activation of TGR5. In some embodiments, the disease or disorder associated with activation of TGR5 activity is selected from chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, resistance to insulin, hyperglycemia, obesity, metabolic syndrome, ischemia, myocardial infarction, retinopathy, vascular restenosis, hypercholesterolemia, hyperglyceridemia, dyslipidemia or hyperlipidemia, lipid disorders such as low HDL cholesterol or high LDL cholesterol, high blood pressure, angina pectoris, coronary artery disease, atherosclerosis, cardiac hypertrophy, hyperphosphatemia, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), psoriasis, ulcerative colitis, Crohn's, disorders associated with parenteral nutrition especially during ω-gut syndrome

σ>

ω &lt; or

<img file="MX376739B_D0167.tif" />

IMPI

160

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 thin, irritable bowel syndrome (IBS), allergic diseases, fatty liver, non-alcoholic fatty liver disease (NAFLD), during small bowel syndrome, irritable bowel syndrome, liver fibrosis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, primary biliary cirrhosis (PBC), renal fibrosis, intestinal motility, anorexia nervosa, bulimia nervosa and neurological disorders such as Alzheimer's disease, multiple sclerosis, schizophrenia and cognitive impairment.

In some embodiments, the disease or disorder associated with activation of TGR5 activity is selected from chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, resistance to insulin, hyperglycemia, obesity, metabolic syndrome, ischemia, myocardial infarction, retinopathy, vascular restenosis, hypercholesterolemia, hypertriglyceridemia, dyslipidemia or hyperlipidemia, lipid disorders such as low HDL cholesterol or high LDL cholesterol, high blood pressure, angina pectoris, coronary artery disease, atherosclerosis, cardiac hypertrophy, hyperphosphatemia, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), psoriasis, ulcerative colitis, Crohn's, disorders associated with parenteral nutrition especially during small intestine syndrome, irritable bowel syndrome (IBS), allergic diseases, fatty liver, non-alcoholic fatty liver disease (NAFLD), during small bowel syndrome, irritable bowel syndrome, liver fibrosis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, primary biliary cirrhosis (PBC) , renal fibrosis, anorexia nervosa, bulimia nervosa and neurological disorders such as Alzheimer's disease, multiple sclerosis, schizophrenia, impaired cognition, dysmotility, Parkinson's intestine (GOD), cystic fibrosis intestine, intestinal motility and gastroparesis.

In another embodiment, the disease or disorder associated with the activation of TGR5 activity is intestinal motility, gastrointestinal motility disorder, irritable bowel syndrome, chronic constipation, chronic idiopathic constipation, chronic constipation occurring in cystic fibrosis. , opioid-induced constipation, pseudo-obstruction ω

σ>

ω &lt; or

<img file="MX376739B_D0168.tif" />

IMPI

161

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 chronic intestinal obstruction, colonic pseudo-obstruction, ulcerative colitis, inflammatory bowel disease, gastrointestinal tract disorder associated with chronic kidney disease (stage 4 or 5), calcium supplement-induced constipation, constipation associated with the use of a therapeutic agent, constipation associated with a neuropathic disorder, postsurgical constipation (postoperative ileus), idiopathic constipation (functional constipation or slow transit constipation), constipation associated with a neuropathic, metabolic or endocrine disorder, constipation due to the use of drugs selected from analgesics (eg opioids), antihypertensives, anticonvulsants, antidepressants, antispasmodics and antipsychotics, ulcers gastric disorders, infectious diarrhoea, leaky gut syndrome, cystic fibrosis, gastrointestinal disease, microscopic colitis, necrotizing enterocolitis, atopy, food allergy, acute inflammation, chronic inflammation, obesity-induced metabolic diseases, kidney disease, chronic kidney disease, diabetic kidney disease, heart disease, kidney failure, congestive heart failure, liver disease, cirrhosis, nonalcoholic steatohepatitis non-hepatic fatty liver disease, steatosis, primary sclerosing cholangitis, primary biliary cholangitis, portal hypertension, type 1 diabetes, celiac disease, multiple sclerosis, ankylosing spondylitis, rheumatoid arthritis, lupus, alopecia areata, polymyalgia rheumatica, multiple sclerosis, fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, Crohn's disease, colitis ulcerative, urticaria, Raynaud's syndrome, schizophrenia, autism spectrum disorders, multiple sclerosis, hepatic encephalopathy, bacterial overgrowth of the small intestine and chronic alcoholism.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a drug to treat or prevent induced diarrhea for chemotherapy in a patient who needs it. The compound is administered to a patient in need of treatment for chemotherapy-induced diarrhea.

In another aspect, the present invention relates to the use of a compound of formula (I'), or one of its salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers ω

σ>

ω &lt; or

<img file="MX376739B_D0169.tif" />

162

ΙΜΡΙ

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 pharmaceutically acceptable, in the treatment or prevention of diabetes mellitus Type II. The use comprises administering to a patient in need of treatment for Type II diabetes mellitus an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in the treatment or prevention of hyperphosphatemia. The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the hyperphosphatemia is postprandial hyperphosphatemia.

In another aspect, the present invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in the treatment or prevention of kidney disease . The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the kidney disease is chronic kidney disease (CKD) or end-stage renal disease (ESRD).

Another aspect of the invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in reducing serum creatinine levels. The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment or prevention of proteinuria. The use comprises administering to a patient in need of treatment for diarrhea induced by ω

σ>

ω &lt; or

<img file="MX376739B_D0170.tif" />

IMPI

163

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 chemotherapy an effective amount of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers.

Another aspect of the invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, to delay the time to renal replacement therapy ( RRT). The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in reducing FGF23 levels. The use comprises administering to a patient in need of treatment for chemotherapy-induced diarrhea an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in reducing the hyperphosphatemic effect of active vitamin D . The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the attenuation of hyperparathyroidism. The use comprises administering to a patient in need of treatment for chemotherapy-induced diarrhea an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the hyperparathyroidism is secondary hyperparathyroidism.

ω σ>

ω &lt; or

<img file="MX376739B_D0171.tif" />

IMPI

164

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Another aspect of the invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in the reduction of serum parathyroid hormone (PTH) . The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in ameliorating endothelial dysfunction. The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the endothelial dysfunction is induced by postprandial serum phosphorus.

Another aspect of the invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in reducing vascular calcification. The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the calcification is localized intimal vascular calcification.

In another aspect, the present invention relates to the use of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the reduction of urinary phosphorus. The method comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

ω σ>

ω &lt; or

<img file="MX376739B_D0172.tif" />

IMPI

165

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Another aspect of the invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, to normalize serum phosphorus levels. The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in reducing the phosphate load in an elderly patient. The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, to decrease dietary phosphate uptake. The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present invention relates to the use of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in reducing renal hypertrophy. The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in reducing cardiac hypertrophy. The use comprises administering to a patient ω

σ>

ω &lt; or

<img file="MX376739B_D0173.tif" />

IMPI

166

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 that requires an effective amount of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers.

In another aspect, the present invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in the treatment or prevention of a related disorder with stomach and intestine. The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In one embodiment, the stomach and bowel related disorder is ulcers, digestive disorders, malabsorption syndromes, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue (eg, arising from gluten-induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, regional enteritis (Crohn's disease), ulcerative colitis, damage to the small intestine, or short bowel syndrome. In another embodiment, the stomach and intestine-related disorder is radiation enteritis, infectious or post-infectious enteritis, bone marrow transplant-induced enteritis, or damage to the small intestine due to toxic or other chemotherapeutic agents.

Another aspect of the invention relates to the use of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, in the treatment or prevention of a secondary effect of chemotherapy or radiation treatment. The use comprises administering to a patient in need thereof an effective amount of a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In some embodiments, the side effect of chemotherapy is diarrhea, abdominal cramps, vomiting, or structural and functional damage to the intestinal epithelium resulting from the chemotherapy treatment. In one embodiment, the diarrhea is induced by an immune checkpoint inhibitor.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, ω

σ>

ω &lt; or

<img file="MX376739B_D0174.tif" />

IMPI

167

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 to use the manufacture of a drug to treat or prevent hyperphosphatemia. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof. In one embodiment, the hyperphosphatemia is postprandial hyperphosphatemia.

In another aspect, the present invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for treating or preventing to kidney disease. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof. In one embodiment, the kidney disease is chronic kidney disease (CKD) or end-stage renal disease (ESRD).

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for reducing creatinine levels serum. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof.

In another aspect, the present invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for treating or preventing to proteinuria. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need of treatment for chemotherapy-induced diarrhea.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for delaying the time to renal replacement therapy (RRT). The compound of formula (I'), or one of its salts, hydrates, solvates, ω

σ>

ω &lt; or

<img file="MX376739B_D0175.tif" />

IMPI

168

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 pharmaceutically acceptable prodrugs, stereoisomers, or tautomers is administered in an effective amount to a patient in need.

In another aspect, the present invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for reducing levels of FGF23. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a drug to reduce the hyperphosphatemic effect of active vitamin D. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof.

In another aspect, the present invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for attenuating hyperparathyroidism . The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need of treatment for chemotherapy-induced diarrhea. In one embodiment, the hyperparathyroidism is secondary hyperparathyroidism.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for reducing serum parathyroid hormone (PTH). The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof.

ω σ>

ω &lt; or

<img file="MX376739B_D0176.tif" />

IMPI

169

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

In another aspect, the present invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for the improvement of endothelial dysfunction. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof. In one embodiment, the endothelial dysfunction is induced by postprandial serum phosphorus.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for reducing vascular calcification. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof. In one embodiment, the calcification is localized intimal vascular calcification.

In another aspect, the present invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for reducing phosphorus urinary. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a drug to normalize phosphorus levels be rich. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof.

ω σ>

ω &lt; or

<img file="MX376739B_D0177.tif" />

ΙΜΡΙ

170

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

In another aspect, the present invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for reducing the load of phosphate in an elderly patient. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a drug to decrease phosphate uptake dietary. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof.

In another aspect, the present invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for reducing hypertrophy renal. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for reducing cardiac hypertrophy. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof.

In another aspect, the present invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament for treating and/ or prevent a ω disorder

σ>

ω &lt; or

<img file="MX376739B_D0178.tif" />

IMPI

171

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 related to stomach and intestine. The compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof is administered in an effective amount to a patient in need thereof. In one embodiment, the stomach and bowel related disorder is ulcers, digestive disorders, malabsorption syndromes, short bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue (eg, arising from gluten-induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, regional enteritis (Crohn's disease), ulcerative colitis, damage to the small intestine, or short bowel syndrome. In another embodiment, the stomach and intestine related disorder is radiation enteritis, infectious or post-infectious enteritis, bone marrow transplant induced enteritis, or small intestinal damage due to toxic or other chemotherapeutic agents.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament to treat and/or prevent a side effect of chemotherapy or radiation treatment.The method comprises administering to a patient in need an effective amount of a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers . In some embodiments, the side effect of chemotherapy is diarrhea, abdominal cramps, vomiting, or structural and functional damage to the intestinal epithelium resulting from the chemotherapy treatment. In one embodiment, the diarrhea is induced by an immune checkpoint inhibitor.

Another aspect of the invention relates to a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, for use in the manufacture of a medicament to treat or prevent a disease associated with the activation of TGR5. In some embodiments, the disease or disorder associated with activation of TGR5 activity is selected from chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, ω

σ>

ω &lt; or

<img file="MX376739B_D0179.tif" />

ΙΜΡΙ

172

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ischemia, myocardial infarction, retinopathy, vascular restenosis, hypercholesterolemia, hypertriglyceridemia, dyslipidemia or hyperlipidemia, lipid disorders such as low HDL cholesterol o high LDL cholesterol, high blood pressure, angina pectoris, coronary artery disease, atherosclerosis, cardiac hypertrophy, hyperphosphatemia, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), psoriasis, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during small intestine syndrome, irritable bowel syndrome (IBS), allergic diseases, fatty liver, nonalcoholic fatty liver disease (NAFLD), during small intestine syndrome, irritable bowel syndrome, liver fibrosis, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, primary biliary cirrhosis (PBC), renal fibrosis, intestinal motility, anorexia nervosa, bulimia nervosa, and neurological disorders such as Alzheimer's disease, multiple sclerosis, schizophrenia, and cognitive impairment.

Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula (I'), or one of its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may also include an excipient, diluent, or surfactant.

In one embodiment, methods of treating a disease or disorder associated with TGR5 modulation including, chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ischemia, myocardial infarction, retinopathy, vascular restenosis, hypercholesterolemia, hypertriglyceridemia, dyslipidemia or hyperlipidemia, lipid disorders such as low HDL cholesterol or high LDL cholesterol, high blood pressure, angina pectoris, coronary artery disease, atherosclerosis, cardiac hypertrophy, hyperphosphatemia, rheumatoid arthritis, asthma, obstructive pulmonary disease ω

σ>

ω &lt; or

<img file="MX376739B_D0180.tif" />

IMPI

173

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 chronic (COPD), psoriasis, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during small intestine syndrome, irritable bowel syndrome (IBS), allergic diseases, fatty liver, disease non-alcoholic fatty liver disease (NAFLD), during small bowel syndrome, irritable bowel syndrome, liver fibrosis, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, primary biliary cirrhosis (PBC), renal fibrosis, intestinal motility, anorexia nervosa, bulimia nervosa, and neurological disorders such as Alzheimer's disease, multiple sclerosis, schizophrenia, and cognitive impairment comprises administering to a patient suffering from at least one of said diseases or disorder of a compound of formula (I'). In other embodiments, the disease or disorder associated with the modulation of TGR5 activity is intestinal motility.

One therapeutic use of the compounds or compositions of the present invention that activate TGR5 is to provide treatment to patients or subjects suffering from one or more diseases or disorders selected from chemotherapy-induced diarrhea, diabetes, type II diabetes, gestational diabetes, glucose impaired fasting, impaired glucose tolerance, insulin resistance, hyperglycaemia, obesity, metabolic syndrome, ischemia, myocardial infarction, retinopathy, vascular restenosis, hypercholesterolemia, hypertriglycedemia, dyslipidemia or hyperlipidemia, lipid disorders such as low HDL cholesterol or high LDL cholesterol, high blood pressure, angina pectoris, coronary artery disease, atherosclerosis, cardiac hypertrophy, hyperphosphatemia, rheumatoid arthritis, asthma, obstructive pulmonary disease (COPD), psoriasis, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during small bowel syndrome, irritable bowel syndrome (IBS), allergic diseases, fatty liver, non-alcoholic fatty liver disease (NAFLD), during small bowel syndrome, irritable bowel syndrome, fibrosis non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, primary biliary cirrhosis (PBC), renal fibrosis, anorexia nervosa, bulimia nervosa ω

σ>

ω &lt; or

<img file="MX376739B_D0181.tif" />

IMPI

174

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 and neurological disorders such as Alzheimer's disease, multiple sclerosis, schizophrenia and cognitive impairment.

The disclosed compounds of the invention can be administered in amounts effective to treat or prevent a disorder and/or prevent its development in subjects.

The compounds of the invention may be administered in therapeutically effective amounts in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, eg, non-drug therapies. For example, synergistic effects may occur with other antidiabetic, antidiarrheal, antiobesity or anti-inflammatory substances. When the compounds of the invention are administered in conjunction with other therapies, the doses of the co-administered compounds will obviously vary according to the type of co-drug used, the specific drug used, the condition being treated, and so on.

Combination therapy includes the administration of the present compounds in additional combination with other biologically active ingredients (such as an antidiabetic agent (i.e., DPP-IV inhibitor, insulin, etc.), an antidiarrheal agent, or an antidiarrheal agent or an anti-obesity agent) and non-pharmacological therapies (such as, but not limited to, surgery). For example, the compounds of the invention can be used in combination with other pharmaceutically active compounds, preferably compounds that are capable of enhancing the effect of the compounds of the invention. The compounds of the invention can be administered simultaneously (as a single preparation or a separate preparation) or sequentially to the other drug therapy or treatment modality. In general, a combination therapy provides for the administration of two or more drugs during a single cycle or course of therapy.

In some embodiments, the disclosure provides a pharmaceutical composition comprising any of the above compounds (ie, a compound of formula (I')), a pharmaceutically acceptable carrier or adjuvant, and at least one additional biologically active agent. In some embodiments, the pharmaceutical composition ω

σ>

ω &lt; or

<img file="MX376739B_D0182.tif" />

IMPI

175

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 comprises one or more additional biologically active agents. In some embodiments, the at least one additional biologically active agent is selected from dipeptidyl peptidase (DPP-4) inhibitors, biguanidines, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, incretin mimetics, CB1 antagonists, VPAC2 agonists. , glucokinase activators, glucagon receptor antagonists, PEPCK inhibitors, SGLT1 inhibitors, SGLT2 inhibitors, IL-1 receptor antagonists, SIRT1 activators, inhibitors of SPPARMs or 11 pHSD1.

In other embodiments, at least one additional biologically active agent prolongs the GLP-1 or GLP-2 signal mediated by TGR5. In other embodiments, the at least one additional biologically active agent is a DPP-4 inhibitor. In yet other embodiments, the at least one additional biologically active agent is a DPP-4 inhibitor selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, gemigliptin, omañgliptin, or dutogliptin.

In other embodiments, at least one additional biologically active agent is selected from metformin or another biguanidine, glyburide or another sulfonylurea; acarbose or other α-glucosidase inhibitor; rosiglitazone or another thiazolidinedione and exenatide, liraglutide or another incretin mimetic; mesalazine and its prodrugs olsalazine, sulfasalazine, or balsalazide; agents useful in the treatment of chemotherapy-induced diarrhea including, but not limited to, loperamide, tincture of opium, lomotil, octreotide, elsiglutide, teduglutide, or other GLP-2 mimetics; corticosteroids including, but not limited to, cortisone, prednisone, hydrocortisone, methylprednisolone, or budesonide; immunosuppressants including, but not limited to, mercaptopurine, azathioprine, methotrexate, cyclosponin, or tacrolimus; JAK kinase inhibitors including, but not limited to, tofacitinib or filgotinib; biological immunomodulators including, but not limited to, infliximab, adalimumab, certolizumab, or natalizumab; FXR (Farnesoid X receptor) agonists including, but not limited to, obeticholic acid, INT-767, Px-104, or LJN-452; agents useful in the treatment of NASH (non-alcoholic steatohepatitis) including, but not limited to eicosapentaenoic acid ethyl ester, ω mesylate

σ>

ω &lt; or

<img file="MX376739B_D0183.tif" />

IMPI

176

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 of cenicriviroc, aramchol, emricasan or tipelukast; and agents used to treat hyperphosphatemia including, but not limited to, sevelamer, tenapanor, ferric oxyhydroxide, ferric citrate, bixalomer, lanthanum carbonate, calcium acetate, niacin, fermagate, or cholestilane.

The administration of the described compounds can be carried out by any mode of administration of therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal, or topical modes of administration.

According to the desired mode of administration, the compositions described may be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, lozenges, time-release capsules, elixirs, tinctures, emulsions. , syrups, powders, liquids, suspensions or the like, sometimes in unit doses and compatible with conventional pharmaceutical practices. Similarly, they can also be administered intravenously (both bolus and infusion), intraperitoneal, subcutaneous, or intramuscular, all using forms well known to those skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a Compound of the Invention and a pharmaceutically acceptable carrier, such as a) a diluent, for example, purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures of these, corn oil, olive oil, sunflower oil, safflower oil, fish oils such as EPA or DHA, or their esters or triglycerides or mixtures of these, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, for example silica, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for compressed tablets; c) a binder, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, ω sweeteners

σ>

ω &lt; or

<img file="MX376739B_D0184.tif" />

IMPI

177

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 corn, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, for example, starches, agar, methylcellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavoring and sweetener; F) an emulsifying or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproil 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS, or other acceptable emulsifier ; and/or g) an agent that improves the absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400 and PEG200.

Liquid compositions, particularly injectables, can be prepared, for example, by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. . Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the described compounds.

The disclosed compounds can also be formulated as a suppository which can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as carrier.

Parenteral injectable administration is generally used for subcutaneous, intramuscular, or intravenous injections and infusions. Injectables may be prepared in conventional forms, either as liquid solutions or suspensions, or solid forms suitable for dissolution in liquid prior to injection.

Another aspect of the invention relates to pharmaceutical compositions comprising a compound of formula (I') and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may also include an excipient, diluent, or surfactant.

The dosage regimen utilizing the described compound is selected according to a variety of factors including type, species, age, weight, sex, and medical condition of the ω

σ>

ω &lt; or

<img file="MX376739B_D0185.tif" />

IMPI

178

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 patient; the severity of the condition to be treated; the route of administration; the patient's kidney or liver function; and the particular described compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counteract, or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the described compound, or in a range from one amount to another amount on the dosage list. In one embodiment, the compositions are in the form of a scored tablet.

examples

The description is further illustrated by the following examples and synthetic schemes, which are not to be construed as limiting this description in scope or spirit to the specific procedures described herein. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation on the scope of the description is intended. It is to be further understood that various other embodiments, modifications, and equivalents thereof may be resorted to as may be suggested to those skilled in the art without departing from the spirit of the present description and/or scope of the appended claims.

Analytical methods, materials and instrumentation

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained with a Varian spectrometer at 400 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) or the solvent peak was used as an internal standard. Purity and low resolution mass spectral data were measured using a Thermo Finnigan Surveyor HPLC system with matrix detection of

IMPI

<img file="MX376739B_D0186.tif" />

179

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω

MX/E/2018/085580 photodiodes (PDA) and a Thermo LCQ Fleet™ ion trap mass spectrometer. Column: Synergy 4 micron, hydro-RP80A, 30x2.0 mm, flow rate: 0.500 mL/min; solvent A (water + 0.1% formic acid), solvent B (acetonitrile + 0.1% formic acid); Gradient: 2% B at t=0 to 95% B at 3 min to 95% B at 3.3 min.

Abbreviations used in the following examples and elsewhere herein are:

<td>AcDH</td><td>acetic acid</td>

<td>AC2O</td><td>Beatic anhydride</td>

<td>ac</td><td>aqueous</td>

<td></td><td>bia(di-ter r-butyl{4-dimethylam inoienyl )fasfin a ) d ¡chloro palladium(l I)</td>

<td>IDB</td><td>twice a day</td>

<td>BOC2O</td><td>di-far-butyl dicarbonate</td>

<td>CbzCI</td><td>olonofcrm benzyl ate</td>

IMPIa

<td></td><td>MEXICAN INSTITUTE^F OF PROPERTY W INDUSTRIAL ¢0 1 80</td>

<td>IDC</td><td>1,1 '-carboni Idiim idazcl</td>

<td>CpíZrGh</td><td>his(cyalopentadienylJzirconium dichloride (l·/}</td>

<td>ChiCOí</td><td>cesium carbonate</td>

<td>DCC</td><td>ú^-fií-metan diilidend icicloh axa nam ¡na</td>

<td>DCM</td><td>say chlorom ataño</td>

<td>DEA</td><td>say wave mine</td>

MX/E/2018/085580 Dess-Martin periodinane 1,1.l-Trisfacetyloxyj-l .l-dihydro-IS-benziodoxol-^lífl-cna

<td>DEAD</td><td>dieti lazodica rbcxylalo</td>

<td>DAY D</td><td>drisopropylazod icarboxylate</td>

<td>DIBAL-H</td><td>diishufflalu minium hydride</td>

<td>DIEA</td><td>IV, Wd iisopropyleti la mine</td>

<td>WFD</td><td>dimethyl acelamide</td>

<td>WMD</td><td>4-dimeli Ib mi nopyrid in a</td>

<td>FMD</td><td>N^-d imeti Ifn rm amide</td>

<td>DMED</td><td>dimethylsulfoxide</td>

<td>dppf</td><td>bis(diíen ilfo5fino}íerroaen£i</td>

<td>DSC</td><td>bis(2,5-dioxopyrrolidi n-1 -i^ carbon ate</td>

<td>EDC-HCI</td><td>N^fethyliminoJ-methyleneJ-N^M^-dimethylethane-l.^-diamine hydrochloride</td>

<td>equiv.</td><td>equivalents</td>

<td>ESI</td><td>electro-spray ionization</td>

<td>etc</td><td>ethyl iodide-</td>

<td>EbO</td><td>dietary eler</td>

<td>EtOAc</td><td>ethyl acetate</td>

<td>EtOH</td><td>elanol</td>

<td>h</td><td>hours</td>

<td>HEY YOU</td><td>1 -[bis(dimatilaminojmelilane]-1 W-1.2.S-triazolo^.5h]pyridinium 3-oxide hexafluorophosphate</td>

<td>HCl</td><td>hydrogen chloride</td>

<td>HOAt</td><td>3H-[ 1,2,3]ίπΒζο lo[4.5-b ]pyridin-3-ol</td>

<td>HPCD</td><td>2-h id rcxipropi kp-cyakidextrin a</td>

<td>HPLC</td><td>high performance liquid chromatography</td>

<td>IBCF</td><td>isobutyl chloroformate</td>

<td>APrDH</td><td>isopropyl alcohol</td>

<td>p.</td><td>intraperitoneal injection</td>

<td>KOAc</td><td>potassium acetate</td>

<img file="MX376739B_D0187.tif" />

ΙΜΡΙ

181

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω

EITHER)

GO

<td colspan="2">LGMS</td><td rowspan="2">liquid chromatography-mass spectrometry m-clcropercxybenzoiic acid methanol minutes mass spectrametry methanesulfophyl chloride sodium cold ethoxychlorhydride</td>

<td></td><td>m-CPBA MeOHmin ΜΞ MSQI NaBH{OAD}i</td>

<td> 5 10</td><td>NaCNBH₃NaOMe NaOH NBS NCS NKdpppJCh MY Pd{CAch P.S₂(dba)₃PdídppOChCHzGh</td><td>sodium cyanoborohydride sodium methoxy sodium hydroxide iV-bro mosuaci nimida iV-olorosuacinimide [1,3-bis(d iphenylphosphino ipropanc]dichloron íquel(l I) iV-iodosuacinimide paladin acetate {II) go is{d ¡be ndliden acetone Jdipalad io [1_r1 '-bis(d ifen ilphosphinoiterroca no]d ¡aloro palladiofl I), com μ far with</td>

<td> 15 20</td><td>Pd{PPh₃)4 PPH₃Q.D. Ri Salt S.Q. TBAF TBDPSCI TEA TEMPO THF TFA TfiO TMSOTf FTA XPhos Xanthos</td><td>say olorom yesteryear dioloropalladium bis(lrifE nilfosfin a) friten iliosfina once a day retention factor crowded subcutaneous tetrabulammonium fluoride fer-butilokiradifeni Isil anus friethylamine N-2 oxide₁2.&amp;_Yoe-taframemethylpiperidiny tetrahydrofuran IrrfluoroaDetiD acid carbon dioxide frifluorom atansulion frim ethylsilyl ate thin-layer chromatography di cyclohexiltS¹, ^.e'-triiscpro-pilbiíen il-2-il Ífc^fiiiH 4.5-bis(diphenylfbsfinoJ-SB-diimethylxa ntenc</td>

MX/E/2018/085580 ω

σ>

ω &lt; or

<img file="MX376739B_D0188.tif" />

IMPI

182

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Example 1: Intermediary A-1. 1-[4-(2-cyclopropoxyphenyl)pyridin-3-yl]cyclopropan-1-amine

<img file="MX376739B_D0189.tif" />

Step 1. 4-(2-cyclopropoxyphenyl)pyridine-3-carbonitrile (A-1 a):

To a 100 mL round-bottomed flask, purged and maintained under an inert atmosphere of nitrogen, charged with 4-chloropdin-3-carbonyl (997.5 mg, 7.20 mmol, 1.00 equiv). ), toluene (50 mL), (2-cyclopropoxyphenyl)boronic acid (1.2 g, 6.74 mmol, 0.95 equiv), Pd(OAc)2 (16.14 mg, 0.07 mmol, 0.01 equiv), K3PO4 (3.11 g, 14.65 mmol, 2.00 equiv), and butyldi-1adamantylphosphine (358.5 mg, 0.144 mmol, 0.02 equiv). The resulting solution was stirred for 2 h at 100 °C in an oil bath. The resulting mixture was concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 1.6 g (94%) of 4-(2-cyclopropoxyphenyl)pignan-3-carbonyl (A-1a) as a yellow oil Sure.

Step 2. 1-[4-(2-cyclopropoxyphenyl)pyridin-3-yl]cyclopropan-1-amine (A-1):

To a 250 mL 3-necked round-bottomed vessel purged and maintained under an inert nitrogen atmosphere, charged with 4-(2-cyclopropoxyphenyl)pandan-3-carbonite (1, 7 g, 7.20 mmol, 1.00 equiv) and ether (200 mL). This was followed by the addition of Ti(O/Pr)4 (3.4 mL, 1.66 equiv) at -78 °C. To that was added 3M EtMgBr (7.86 mL, 3.32 equiv) at -78 °C. BF was added to the mixture.₃-Et2O (3.4 mL, 3.03 equiv). The resulting solution was stirred for 5 min at -78 °C in a N2/EtOH bath. The resulting solution was reacted, with stirring, for an additional 2 hours at room temperature. The resulting solution was reacted, with stirring, for an additional 1 h at room temperature. The pH value of the solution was adjusted to 1-2 with 1M HCl. The resulting solution was extracted with 100 mL of ethyl acetate, and the aqueous layers were combined. Sodium hydroxide (1 mol/L) was used to adjust the pH to 10. The resulting solution was extracted

<img file="MX376739B_D0190.tif" />

ΙΜΡΙ

183

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 with 100 mL of ethyl acetate, and the organic layers were combined and concentrated in vacuo. The residue was applied on a silica gel column with dichloromethane/methanol (10:1). This resulted in 580 mg (30%) of intermediate (A-1) as a pale yellow oil.

The above general method for the synthesis of intermediate A1 in Example 1 can be used to prepare intermediates (Int.) A-2-A-18 in Table 1 below from 4-chloropyridine-3-carbontinyl and the appropriate boronate.

<img file="MX376739B_D0191.tif" />

<img file="MX376739B_D0192.tif" />

<td>InL ΝΛ</td><td>Structure</td>

<td>ACE</td><td>|lJ-</td>

<td>A-6</td><td>H/J.. ^-i H Ja ^00</td>

<td>Int. #:</td><td>Structure</td>

<td>A-7</td><td></td>

<td>A-8</td><td>hja</td>

<td>A-9</td><td></td>

<td>A-10</td><td>YZ^</td>

<td>Int. ΝΛ</td><td>Structure</td>

<td>A11</td><td>•hN. ,,1 '^ ΓΙΙ</td>

<td></td><td>YO]</td>

<td>Α1Ϊ</td><td>|lJ</td>

<td></td><td></td>

<td>A13</td><td>η Ί γθυ</td>

<td>A14</td><td>ΛΑ Δ</td>

<td>InL ΝΛ</td><td>Structure</td>

<td>A15</td><td>_Λ ττ</td>

<td>A16</td><td>^ΗεΜχ1 (i Ί</td>

<td>A17</td><td>Π 7~\^z</td>

<td>A18</td><td>A</td>

ω σ>

ω &lt; or

<img file="MX376739B_D0193.tif" />

IMPI

184

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Example 2 Intermediate A-19 1-[4-[2-(oxetan-3-yloxy)phenyl]pyridin-3-yl]cyclopropan-1-amine

Scheme 2:

<img file="MX376739B_D0194.tif" />

Step 1. 1-(4-chloropyridin-3-yl)cyclopropan-1-amine (A-19a):

To a purged 500-mL round-bottomed flask maintained under an inert nitrogen atmosphere, charged with 4-chloropandin-3-carbonite (5.75 g, 41.50 mmol, 1.00 equiv) and ether (150mL). This was followed by the addition of T¡(O¡Pr)₄ (17.7 g, 1.50 equiv) dropwise with stirring at -78 °C in 30 min. To that was added EtMgBr (34.6 mL, 2.50 equiv, 3M in Et₂O) dropwise with stirring at -78 °C in 30 min and stirred for 2 h at room temperature. BF was added to the mixture.₃-et₂OR (23.56 g, 4.00 equiv). The resulting solution was stirred for 2h at room temperature. The reaction was then quenched by the addition of 1M hydrogen chloride. The pH value of the solution was adjusted to 10 with sodium hydroxide (4 mol/L). The resulting solution was extracted with 3 x 80 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with dichloromethane/methanol (0-10%). The collected fractions are ω

σ>

ω &lt; or

<img file="MX376739B_D0195.tif" />

IMPI

185

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 were combined and concentrated in vacuo. This resulted in 2 g (29%) of intermediate A19a as a yellow oil.

Step 2. tert-Butyl N-[1-(4-chloropyridin-3-yl)cyclopropyl]carbamate (A-19b):

To a 250 mL round bottom flask, charged with 1-(4-chloropyridin-3-yl)cyclopropan-1-amine (1.9 g, 11.27 mmol, 1.00 equiv), tetrahydrofuran (30 mL) , water (30 mL), sodium carbonate (4.78 g, 45.10 mmol, 4.00 equiv), BOC2O (3.688 g, 16.90 mmol, 1.50 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x50 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (0-30%). The collected fractions were combined and concentrated in vacuo. This resulted in 1.2 g (40%) of intermediate A-19b as a pale yellow solid.

Step 3. tert-Butyl N-[1-[4-(2-hydroxyphenyl)pyridin-3-yl]cyclopropyl]carbamate (A-19c):

To a purged 8 mL round bottom flask kept under an inert nitrogen atmosphere, charged with tert-butyl N-[1-(4-chlorop¡r¡d¡n-3-¡l)cycloprop¡l] carbamate (100 mg, 0.37 mmol, 1.00 equiv), (2-hydroxyphenyl)boronic acid (77 mg, 0.56 mmol, 1.50 equiv), K3PO4 (158 mg, 0.74 mmol, 2.00 equiv), Pd(OAc)2 (4 mg, 0.02 mmol, 0.05 equiv), butyldi-1adamantylphosphine (13 mg, 0.10 equiv), and toluene (1 mL). The resulting solution was stirred for 3h at 100°C. The resulting mixture was concentrated in vacuo. The resulting solution was extracted with 3x30 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with dichloromethane/methanol (0-5%). The collected fractions were combined and concentrated in vacuo. This resulted in 30 mg (25%) of intermediate A-19c as a pale yellow solid.

Step 4. tert-Butyl N-(1-[4-[2-(oxetan-3-yloxy)phenyl]pyridin-3-yl]cyclopropyl)carbamate (A-19d):

ω σ>

ω &lt; or

<img file="MX376739B_D0196.tif" />

IMPI

186

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

To a 25 mL round bottom flask, charged with fer-butyl N-[1-[4-(2-hydroxyphenyl)pyridin-3-yl]cyclopropyl]carbamate (50 mg, 0.15 mmol, 1.00 equiv), 3-iodooxetane (34 mg, 0.18 mmol, 1.20 equiv), potassium carbonate (42 mg, 0.30 mmol, 2.00 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at 90°C in an oil bath. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3x20 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (0-50%). The collected fractions were combined and concentrated in vacuo. This resulted in 50 mg (85%) of intermediate A-19d as a pale yellow oil.

Step 5. 1-[4-[2-(oxetan-3-yloxy)phenyl]pyridin-3-yl]cyclopropan-1-amine (A-19):

To a 25 mL round bottom flask, charged with tert-butyl N-(1-[4-[2-(oxetan-3-yloxy)phenyl]pyridin-3-yl]cyclopropyl)carbamate (50 mg, 0.13 mmol , 1.00 equiv), dichloromethane (4 mL), trifluoroacetic acid (4 mL). The resulting solution was stirred for 1h at room temperature. The resulting mixture was concentrated in vacuo. This resulted in 36 mg (crude) of intermediate A-19 as a yellow oil.

Intermediates A-20, A-21 and A-22 shown in Table 2 below were prepared using the route shown above in Example 2 to prepare intermediate A-19. Alkylation of the phenol intermediate A19c with the appropriate halide, epoxide or other electrophilic reagent and removal of the Boc protecting group using the general synthetic method described hereinabove provides Intermediates A-20, A-21 and A-22. Substitution of appropriate reagents and conditions in Step 4 of Example 2 is generally known to those skilled in the art.

Table 2:

<img file="MX376739B_D0197.tif" />

IMPIa

MEXICAN INSTITUTE OF PROPERTY w

INDUSTRIAL &lt;0

MX/E/2018/085580

<img file="MX376739B_D0198.tif" />

<img file="MX376739B_D0199.tif" />

<img file="MX376739B_D0200.tif" />

METHOD A:

Example 3: 1-[4-(2-cyclopropoxyphenyl)pyridin-3-yl]-N-[(2,5-dichlorophenyl)methyl]cyclopropan-1-amine (1-1)

<img file="MX376739B_D0201.tif" />

<img file="MX376739B_D0202.tif" />

To a purged 50 mL round-bottomed vessel maintained under an inert nitrogen atmosphere, charged with 1-[4-(2-cyclopropoxyphenyl)pyr¡d¡n-3-¡l]c ¡clopropan-1amine (200 mg, 0.75 mmol, 1.00 equiv), dichloromethane (20 mL), 2,5-dichlorobenzaldehyde ω

σ>

ω &lt; or

<img file="MX376739B_D0203.tif" />

ΙΜΡΙ

188

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (183 mg, 1.05 mmol, 1.00 equiv) and NaBH(OAc)3 (1.34 g, 6.32 mmol, 6.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 100 mg (31%) of compound 1-1 as a pale yellow solid. MS (ES, m/z): 425.05 [M+H]⁺; ¹H NMR (400 MHz, CDCI₃): δ ppm 8.63 (s, 1H), 8.54 - 8.52 (d, 1H), 7.43 - 7.34 (m, 2H), 7.26 - 7.20 (m, 2H ), 7.14 - 7.03 (m, 4H), 3.67 - 3.59 (m, 3H), 2.12 (brs, 1H), 0.84 (s, 4H), 0.73 - 0.64 (m, 2H), 0.62-0.52 (m, 2H).

The compounds in Table 1, compounds I-2 through I-40 and I-42 through I-44, were prepared using Method A described hereinabove in Example 1 and methods generally known to those skilled in the art. of known or commercial starting materials and amine intermediates A2-A22 from charts 1 and 2 above.

Table 1: Compounds 1-1 to I-40 and I-42 to I-44

<img file="MX376739B_D0204.tif" />

IMPI to

MEXICAN INSTITUTE OF PROPERTY w

INDUSTRIAL &lt;0

MX/E/2018/085580

<td>Comp #:</td><td>Amine</td><td>Compound Structure</td><td>Obs mass [M+H]⁺</td>

<td> 1-1</td><td>A-1</td><td>Cl^ι;Λ ClΗΝ^ί A</td><td> 425</td>

<td>I-2</td><td>A-2</td><td></td><td> 427</td>

<td>Comp ΝΛ</td><td>Amine</td><td>Compound Structure</td><td>Obs mass [Μ+ΗΓ</td>

<td>I-3</td><td>A-3</td><td>Y</td><td> 443</td>

<td></td><td>A-4</td><td>Cl e ClHN_vEC</td><td> 399</td>

<img file="MX376739B_D0205.tif" />

ΙΜΡΙ

190

Ο)

7** MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY w &lt;0

MX/E/2018/085580

<td>ccmp #:</td><td>Amine</td><td>Compound Structure</td><td>Mass otes [M+H]⁺</td>

<td>I-5</td><td>TO 5</td><td>Cl Cl u_^</td><td> 339</td>

<td>I-6</td><td>A-6</td><td>Cl ql</td><td> 333</td>

<td>I-7</td><td>A-7</td><td></td><td> 415</td>

<td>LB</td><td>A-8</td><td>Cl ClHN-^i</td><td> 467</td>

<td>Comp ΝΛ</td><td>Amine</td><td>Structure of the compound</td><td>Obs mass [Μ+ΗΓ</td>

<td>lS</td><td>A-9</td><td>Cl</td><td> 397</td>

<td> 1-10</td><td>A-10</td><td>YO *0^-</td><td> 409</td>

<td> 1-11</td><td>A-11</td><td>C! HN^i 11x1^ W'^Ξ</td><td> 453</td>

<td> 1-12</td><td>A-12</td><td>Cl CL</td><td> 412</td>

<img file="MX376739B_D0206.tif" />

191

IMPI §

MEXICAN INSTITUTE OF PROPERTY w

INDUSTRIAL &lt;0

MX/E/2018/085580

<td>ccmp #:</td><td>Amine</td><td>Compound stiuctm</td><td>Mass cbs [M+H]⁺</td>

<td></td><td></td><td>laugh ΙΪΊ</td><td></td>

<td> 1-13</td><td>A-13</td><td>|i YO</td><td> 455</td>

<td>II 4</td><td>A14</td><td>Cl HM^i</td><td> 369</td>

<td></td><td></td><td>iiJ</td><td></td>

<td></td><td></td><td>Cl</td><td></td>

<td> 145</td><td>A-16</td><td></td><td> 449</td>

<td></td><td></td><td>n'VJ</td><td></td>

<td></td><td></td><td></td><td></td>

<td></td><td></td><td>Cl</td><td></td>

<td> 146</td><td>A-16</td><td>ClHN^ |lJ</td><td> 403</td>

<td></td><td></td><td>Cl^</td><td></td>

<td>Comp ΝΛ</td><td>Amine</td><td>Structure of the compound</td><td>Obs mass [Μ+ΗΓ</td>

<td>r-17</td><td>A47</td><td>y yy Fj—Z —□ 2=^</td><td> 387</td>

<td>r-ie</td><td>A4B</td><td>Cl ci π A</td><td> 443</td>

<td>r-19</td><td>Α49</td><td>A Γ</td><td> 441</td>

<td>r-20</td><td>TO 20</td><td>A</td><td> 443</td>

<img file="MX376739B_D0207.tif" />

192

IMPI to

MEXICAN INSTITUTE OF PROPERTY w

INDUSTRIAL &lt;0

MX/E/2018/085580

<td>Comp #:</td><td>Amine</td><td>Compound Structure</td><td>Mass ote [M+H]⁺</td>

<td> 1-21</td><td>A-21</td><td>Cl I HEARD ό</td><td> 455</td>

<td> 1-22</td><td>A22</td><td>ClK LlJ,. Xí ।</td><td> 471</td>

<td> 1-23</td><td>A1</td><td>to the θ 'A</td><td> 437</td>

<td> 1-24</td><td>A1</td><td>Ci^hr^w1 u JL Γ</td><td> 365</td>

<td>Comp ΝΛ</td><td>Amine</td><td>Structure of the compound</td><td>Obs mass [Μ+ΗΓ</td>

<td>I-25</td><td>A-1</td><td>A</td><td> 418</td>

<td>I-26</td><td>A-1</td><td>eleven C! Il&lt; IV A</td><td> 425</td>

<td>I-27</td><td>A-1</td><td>Ψ,^HM&gt; η Ί r</td><td>4Ώ1</td>

<td>I-26</td><td>A-1</td><td>ΐΧ Cl HM . Ν'⁵-γ ·· A</td><td> 425</td>

<img file="MX376739B_D0208.tif" />

193

<td>Comp #:</td><td>Amine</td><td>Compound stiuctm</td><td>Mass ote [M+H]⁺</td>

<td></td><td></td><td></td><td></td>

<td> 1-29</td><td>A-1</td><td>ΤΪ Γ</td><td> 415</td>

<td></td><td></td><td>Cl</td><td></td>

<td> 1-30</td><td>A-1</td><td>v</td><td> 459</td>

<td> 1-31</td><td>A-1</td><td>Os Cl HN-.^ cc^</td><td> 431</td>

<td></td><td></td><td>A</td><td></td>

<td></td><td></td><td> ¿1</td><td></td>

<td> 1-32</td><td>A-1</td><td></td><td> 459</td>

<td></td><td></td><td>0^A</td><td></td>

<td>Comp N?:</td><td>Amine</td><td>Structure of the compound</td><td>Obs mass [Η+ΗΓ</td>

<td>Ϊ-33</td><td>A-1</td><td>Cl [i 1 r</td><td>4Ü5</td>

<td>F-34</td><td>A-1</td><td>1 Cl |l Ί A</td><td>4Ü6</td>

<td>F-35</td><td>A-1</td><td>N Cl A</td><td>4Ü6</td>

<td>F-36</td><td>A-1</td><td>1 JTL^llrK.-· A</td><td> 453</td>

IMPI §

MEXICAN INSTITUTE OF PROPERTY w

INDUSTRIAL &lt;0

MX/E/2018/085580

<img file="MX376739B_D0209.tif" />

IMPI

194

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω

EITHER)

GO

MX/E/2018/085580

<td>Comp #:</td><td>Amine</td><td>structure of the compound</td><td>Mass ote [W+H]*</td>

<td>I-37</td><td>A1</td><td>CF's A</td><td> 439</td>

<td>I-3C</td><td>A-1</td><td>^ΙΙΓΙ&gt;· 1(^1. Γ</td><td> 443</td>

<td>I-3S</td><td>A-1</td><td>Yi Γ</td><td> 416</td>

<td></td><td>A-1</td><td>A CT^ A</td><td> 405</td>

<td>Comp ΝΛ</td><td>Amine</td><td>Compound Structure</td><td>Obs mass [M+HT</td>

<td>I-42</td><td>A-1</td><td>and w</td><td> 418</td>

<td>I-43</td><td>A-1</td><td>A</td><td> 439</td>

<td>I-44</td><td>A-1</td><td>Cl XX A IIΎ oA</td><td> 425</td>

Example 4: 3-[1-[(2,5-dichlorophenyl)methoxy]cyclopropyl]-4-(2-methoxyphenyl)pyridine (I-45) ω

σ>

ω &lt; or

<img file="MX376739B_D0210.tif" />

IMPI

195

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

<img file="MX376739B_D0211.tif" />

Step 1. Methyl 4-chloropyridine-3-carboxylate (Intermediate 45a)

A 100 mL 3 neck round bottom flask was charged with 4-chloropyridine-3-carboxylic acid (1 g, 6.35 mmol, 1.00 equiv), dichloromethane (15 mL), methanol (6 mL). This was followed by the addition of 2.0 M TMS-diazomethane in Et₂O (4.76 mL, 1.50 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 1h at 0°C. The resulting mixture was concentrated in vacuo. This resulted in 1.4 g of methyl 4-chloropindion-3-carboxylate (Intermediate 45a) as a white oil, which was used in the next experiment without further purification.

Step 2. Methyl 4-(2-methoxyphenyl)pyridine-3-carboxylate (Intermediate 45b)

A 100 mL round bottom flask was charged with methyl 4-chloropyridine-3-carboxylate (900 mg, 5.25 mmol, 1.00 equiv), (2-methoxyphenyl)boronic acid (1.2 g, 7 0.90 mmol, 1.50 equiv), Pd(OAc)₂ (11.7 mg, 0.05 mmol, 0.01 equiv), K3PO4 (2.22 g, 10.46 mmol, 2.00 equiv), Butyl di-1-adamantylphosphine (37.5 mg, 0.02 equiv), toluene (50 mL). The resulting solution was stirred for 1.5h at 100°C. The solids were filtered. The resulting mixture was concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (14.6:100). This resulted in 0.2 g (16%) of methyl 4-(2-methoxyphenyl)pindin-3-carboxylate (Intermediate 45b) as a yellow oil.

Step 3. 1-[4-(2-methoxyphenyl)pyridin-3-yl]cyclopropan-1-ol (Intermediate 45c) ω

σ>

ω &lt; or

<img file="MX376739B_D0212.tif" />

ΙΜΡΙ

196

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

A 50 mL 3-neck round bottom flask purged and maintained under an inert nitrogen atmosphere was charged with a solution of Cp2ZrCl2 (1.20 g, 4.11 mmol, 2.00 equiv) in toluene (10 mL). . This was followed by the addition of bromo(ethyl)magnesium (2.74 mL, 4.00 equiv) dropwise with stirring at 0 °C. The mixture was stirred for 1h at 0°C. To that was added to a solution of methyl 4-(2-methoxyphenyl)pyridine-3-carboxylate (500 mg, 2.06 mmol, 1.00 equiv) in toluene (5 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 3h at 0°C. The reaction was then quenched by the addition of 10 mL of NH4Cl (aq). The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers were combined and dried over sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with PE:EA (1:1). This resulted in 150 mg (30%) of 1[4-(2-methoxyphenyl)p¡r¡d¡n-3-¡l]cyclopropan-1-ol (Intermediate 45c) as a yellow oil. Sure.

Step 4. 3-[1-[(2,5-dichlorophenyl)methoxy]cyclopropyl]-4-(2-methoxyphenyl)pyridine (I-45)

A 50 mL round bottom flask was charged with a solution of 1-[4-(2-methoxyphenyl)p¡r¡d¡n-3-¡l]cyclopropan-1-ol (150 mg, 0.62 mmol , 1.00 equiv) in N,N-dimethylformamide (5 mL), 2-(bromomethyl)-1,4-dichlorobenzene (179 mg, 0.75 mmol, 1.20 equiv). This was followed by the addition of sodium hydride (37 mg, 1.54 mmol, 1.50 equiv) in several batches at 0 °C. The resulting solution was stirred for 2h at 0°C. The resulting solution was diluted with 10 mL of ethyl acetate. The reaction was then quenched by the addition of 10 mL. The resulting solution was extracted with 3x30 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 121.5 mg (49%) of I-45 as a pale yellow solid. MS (ES, m/z): 400 [M+H]⁺; ¹H-NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.49 (d, J =5.1 Hz, 1H), 7.38-7.44 (m, 1H), 7, 19-7.30 (m, 4H), 6.97-7.02 (m, 3H), 4.35 (s, 2H), 3.51 (s, 3H), 1.03 (s, 4H) .

ω

<img file="MX376739B_D0213.tif" />

IMPI

197

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580

<img file="MX376739B_D0214.tif" />

Step 1. 1-Cyclopropoxy-2-iodobenzene (Intermediate A-23a)

A 2000 mL round bottom flask was charged with 2-iodophenol (50 g, 227.26 mmol, 1.00 equiv), DMA (750 mL), CS2CO3 (185.1 g, 566.35 mmol, 2, 49 equiv), bromocyclopropane (55 g, 454.64 mmol, 2.00 equiv). The resulting solution was stirred for 3 days at 120°C. The resulting solution was diluted with 2000 mL of H2O. The resulting solution was extracted with 3 x 500 mL of ethyl acetate, and the organic layers were combined and concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether. This resulted in 38 g (64%) of 1-cyclopropoxy-2-iodobenzene (A-23a) as an off-white oil.

Step 2. (2-cyclopropoxyphenyl)boronic acid (Intermediate A-23b)

A 1000 mL 3-neck round bottom flask purged and maintained under an inert nitrogen atmosphere was charged with 1-cyclopropoxy-2-iodobenzene (75 g, 288.38 mmol, 1.00 equiv), THF (600 mL ). This was followed by the addition of butyllithium (138 mL) dropwise with stirring at -78 °C. The above mixture was stirred for 1h at -78°C. To that was added trimethylborate (61.2 g, 588.95 mmol, 2.04 equiv) dropwise with stirring at -78 °C. The above mixture was stirred for 1h at -78°C. The resulting solution was stirred for 1h at 15-25°C. The reaction was then quenched by the addition of 150 mL of MeOH. The resulting mixture was concentrated in vacuo. The crude product is ω

σ>

ω &lt; or

<img file="MX376739B_D0215.tif" />

IMPI

198

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 washed with hexane. The solids were collected by filtration. This resulted in 55 g of dimethyl (2-cyclopropoxyphenyl) (A-23b) boronate as a white solid. A 1000 mL round bottom flask was charged with dimethyl(2-cyclopropoxyphenyl)boronate (55 g, 266.9 mmol, 1.00 equiv), water (500 mL), conc. (30mL). The resulting solution was stirred for 1h at 15-25°C. The solids were collected by filtration and dried. This resulted in 41 g of (2-cyclopropoxyphenyl)boronic acid as a white solid. It was then purified by recrystallization from hexane (150-200 mL) and resulted in 35 g (68%) of product as a white solid.

Step 2. Methyl 4-chloronicotinate hydrochloride (Intermediate A23c)

4-Chloronicotinic acid (3.00 g, 19 mmol) was suspended in DCM (25 mL) and a solution of oxalyl chloride (4.1 mL, 6.1 g, 48 mmol) in DCM (25 mL) was added. dropwise for 15 min. After the addition, DMF was added (7 x 100 pL aliquots over 1 hour). The suspension was stirred for 30 min after the last addition. The reaction mixture was cooled on ice and MeOH (15 mL) was added slowly. The resulting solution was stirred at 0°C for 15 minutes and then at RT for an additional 30 minutes. Toluene (10 mL) was added and the solvents were removed under reduced pressure to give the crude product as a brown solid. The solid was triturated with 50% EtOAc/heptane (15 mL) and collected on a Buchner funnel. The solids were rinsed with 50% EtOAc/heptane (2x10 mL) and then dried in vacuo to give the title compound HCl salt (A-23c) as a brown powder (3.93 g, 99% ).

Step 3. Methyl 4-(2-cyclopropoxyphenyl)pyridine-3-carboxylate (Intermediate A23d)

A 250 mL 3-neck round bottom flask purged and maintained under an inert nitrogen atmosphere was charged with (2-cyclopropoxyphenyl)boronic acid (940 mg, 5.28 mmol, 1.10 equiv), K3PO4 (4.08 g, 19.2 mmol, 4.00 equiv), methyl 4-chloropinedin-3-carboxylate hydrochloride (1.0 g, 4.81 mmol, 1.00 equiv), Pd(OAc)2 (22 mg , ω

σ>

ω &lt; or

<img file="MX376739B_D0216.tif" />

IMPI

199

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

0.10 mmol, 0.02 equiv), XPhos (138 mg, 0.29 mmol, 0.06 equiv), tetrahydrofuran (14 mL), water (0.35 mL, 4.00 equiv). The resulting solution was stirred for 1 h at 75 °C in an oil bath. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 40 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 3 x 50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (2.2 g) was purified by preparative Flash HPLC with the following conditions (CombiFlash-1): Column, silica gel; mobile phase, ethyl acetate/petroleum ether 0% increasing to 25.7% over 30 min; detector, UV 254nm. This resulted in 951 mg (73%) of methyl 4-(2-cyclopropoxyphenyl)pindin-3-carboxylate (A-23d) as a yellow oil.

Step 4.1-[4-(2-cyclopropoxyphenyl)pyridin-3-yl]cyclopropan-1-ol (Intermediate A-23)

A 500-mL 3-necked round-bottomed flask was charged with a solution of Cp₂ZrCl₂ (14.77 g, 50.64 mmol, 2.10 equiv) in freshly distilled toluene (400 mL). The vessel was evacuated and flushed three times with N₂. This was followed by the addition of EtMgBr (3M in ether) (33.7 mL, 101.3 mmol, 4.2 equiv) dropwise with stirring at 0 °C over 20 min and stirred for 40 min. To that was added a solution of A-23d (6.5 g, 24.14 mmol, 1.00 equiv) in toluene (60 mL) dropwise with stirring at 0 °C in 20 min. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL sat. NH4Cl. The resulting mixture was concentrated in vacuo. The resulting solution was diluted with 300 mL of water. The resulting solution was extracted with 5x500 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2x500 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered. The resulting mixture was concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (1:3 to 1:1). The crude product was recrystallized in

MX/E/2018/085580

DCM/hexane in the ratio of 1:10. This resulted in 2.5 g (39%) of 1-[4-(2-cyclopropoxyphenyl)p¡rdan-3-¡l]cyclopropan-1-ol (A-23) as of a light yellow solid. Example 6: 1-(4-(2-fluorophenyl)pyridin-3-yl)cyclopropan-1-ol (Intermediate A-24); 1(4-(2-cyclobutoxyphenyl)pyridin-3-1)cyclopropan-1-ol (Intermediate A-25); 1-(4-(2(oxetan-3-yloxy)phenyl)pyridin-3-¡l)cyclopropan-1-ol (Intermediate A-26) hk N

Intermediates A24-A26 were prepared from known or commercial starting materials according to the procedure used for the preparation of intermediate 45c in Example 4.

The compounds in Table 2 below, compounds I-46 through I-56, were prepared from known or commercial starting materials according to the procedure used for the preparation of compound I-45 in Example 4 and generally known methods. by experts in the art.

Table 2. Compounds I-46 to I-56.

ω

<img file="MX376739B_D0217.tif" />

IMPI

201

EITHER)

7** MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY w &lt;0

MX/E/2018/085580

<td>Comp N.^D:</td><td colspan="2">structure of the compound</td><td>obs mass [M+Hf</td>

<td></td><td>Cl</td><td></td><td></td>

<td>I-46</td><td>ClN</td><td>OA</td><td> 426</td>

<td></td><td> 7</td><td>^r4</td><td></td>

<td>I-47</td><td></td><td></td><td> 426</td>

<td></td><td></td><td>or j A</td><td></td>

<td>Ι-4Ξ</td><td></td><td>A</td><td> 426</td>

<td></td><td>a</td><td></td><td></td>

<td>I-4S</td><td>N' 0</td><td>ό</td><td> 446</td>

<td>Comp N.^D:</td><td>structure of the compound</td><td>obs mass [M&lt;-H]⁺</td>

<td>I-5D</td><td></td><td>38S</td>

<td> 1-51</td><td>Cl A</td><td> 460</td>

<td> 1-52</td><td>|i X A</td><td> 460</td>

<td> 1-53</td><td>K i JL XJ) A</td><td> 432</td>

ω

<img file="MX376739B_D0218.tif" />

IMPI

202

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580

<img file="MX376739B_D0219.tif" />

<img file="MX376739B_D0220.tif" />

Example 7: 1-[1-[4-(2-cyclopropoxyphenyl)pyridin-3-yl]cyclopropyl]-1-[(2,5-dichlorophenyl)methyl]urea (I-57)

<img file="MX376739B_D0221.tif" />

<img file="MX376739B_D0222.tif" />

A 50 mL round-bottomed flask filled with 1-[4-(2-cyclopropoxyphenyl)p-ndin-3-yl]-N-[(2,5-dichlorophenyl)methyl]cyclopropan-1 -amine (1-1, 50 mg, 0.12 mmol, 1.00 equiv), DCM (10 mL), and chlorosulfonylisocyanate (50 mg, 0.35 mmol, 3.00 equiv). This was followed by the addition of water (10 mL) after 2 hr. The resulting solution was stirred for 3h at room temperature. The resulting solution was extracted ω

σ>

ω &lt; or

<img file="MX376739B_D0223.tif" />

IMPI

203

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 with 3 x 25 mL of dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: Column, Atlantis Prep T3 OBD Column, 19 x 150mm 5pm 10nm; mobile phase, water with 10 mmol of NH4HCO3 and MeCN (20.0% MeCN to 50.0% in 8 min); detector, 254nm. This resulted in 5.3 mg (10%) of I-57 as a white solid. MS (ES, m/z): 468 [M+H]⁺; ¹H-NMR (400 MHz, CD3OD) δ 8.85 (s, 1H), 8.42 (d, J = 4.9 Hz, 1H), 7.60-7.47 (m, 2H), 7, 27 (d, J = 8.5 Hz, 1H), 7.22-7.12 (m, 3H), 7.10 (d, J = 5.0 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 3.87-3.74 (m, 3H), 1.81-1.22 (m, 2H), 1.11 (s, 1H), 0.99 (s, 1H), 0.78-0.69 (m, 2H), 0.64 (s, 2H).

Example 8: 1-[4-(2-cyclopropoxyphenyl)pyridin-3-yl]-N-[(2,5-dichlorophenyl)methyl]-N-methylcyclopropan-1-amine (I-58)

<img file="MX376739B_D0224.tif" />

A 50 mL round bottom flask was charged with 1-[4-(2-cyclopropoxyphenyl)p¡nd¡n-3-¡l]-N-[(2,5-dichlorophenyl)met ¡l]cyclopropan-1-am¡na (100 mg, 0.24 mmol, 1.00 equiv), formalin (40%) (0.7 mL, 23.45 mmol, 10.00 equiv), methanol (20 mL) and AcOH (1 mg, 0.02 mmol, 0.10 equiv). This was followed by the addition of NaBH(OAc)3 (300 mg, 1.42 mmol, 6.00 equiv), in portions at 0 °C. The resulting solution was stirred for 3h at room temperature. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 4 x 60 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3 x 30 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by preparative HPLC under the following conditions: Column, Gemini-NX C18, 21.2 x 150mm 5pm; mobile phase, 10 mM aqueous NH4HCO3 ω

<img file="MX376739B_D0225.tif" />

ΙΜΡΙ

204

Ο)

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY ω &lt;ο

MX/E/2018/085580 and MeCN (40.0% MeCN to 70.0% in 10 min); detector, 254nm. This resulted in 68.8 mg (67%) of compound I-58 as a white solid. MS (ES, m/z): 439 [M+H]⁺; ¹H-NMR (400 MHz, CD₃OD) δ 8.66 (s, 1H), 8.42 (d, J = 5.1 Hz, 1H), 7.48-7.38 (m, 2H), 7.36-7.25 (m , 2H), 7.26-7.17 (m, 2H), 7.13 (d, J = 5.2 Hz, 1H), 7,077.03 (m, 1H), 3.77 (tt, J = 6.0, 2.9Hz, 1H), 3.51 (s, 2H), 1.98 (s, 3H), 1.04-0.94 (m, 4H), 0.81-0.71 (m, 2H), 0.55 (h, J=2.8 Hz, 2H).

Example 9: 4-(2-cyclopropoxyphenyl)-3-[3-[(2,5-dichlorophenyl)methoxy]oxetan-3¡l]pyridine (I-59)

<img file="MX376739B_D0226.tif" />

Step 1. 3-bromo-4-(2-cyclopropoxyphenyl)pyridine (Intermediate 59a)

A 100-mL round-bottomed vessel, purged and maintained under an inert nitrogen atmosphere, charged with 3-bromo-4-iodopyridine (568 mg, 2.00 mmol, 1.00 equiv), acid (2-cyclopropoxyphene ¡l)boron¡c (430 mg, 2.42 mmol, 2.00 equiv), sodium carbonate (640 mg, 6.04 mmol, 3.00 equiv), potassium hydroxide (112 mg, 2.00 mmol , 1.00 equiv). The above compounds were dissolved by tetrahydrofuran (40 mL), water (20 mL). This was followed by the addition of Pd(PPh₃)₄ (230 mg, 0.20 mmol, 0.10 equiv) portionwise with stirring at room temperature. The resulting solution was heated to reflux for 20hr. The resulting mixture was concentrated in vacuo. The resulting solution was extracted with 3 x 40 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2 x 100 mL of water and 1 x 100 mL of sat. sodium chloride. The mixture was dried over anhydrous sodium sulfate. The remainder is ω

σ>

ω &lt; or

<img file="MX376739B_D0227.tif" />

IMPI

205

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 applied on a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 500 mg (86%) of 3-bromo-4-(2-cyclopropoxyphenyl)pyridine (59a) as a brown oil.

Step 2. 3-[4-(2-cyclopropoxyphenyl)pyridin-3-yl]oxetan-3-ol (Intermediate 59b)

A 50-mL round-bottomed vessel, purged and maintained under an inert nitrogen atmosphere, charged with 3-bromo-4-(2-cyclopropoxyphenyl)pindina (59a, 290 mg, 1.00 mmol, 1.00 equiv), ether (30 mL). This was followed by the addition of n-BuLI (2.5 M in hexane) (0.8 mL, 2.00 equiv) dropwise with stirring at -78 °C. The resulting solution was stirred for 15 min at -78 °C. To that was added a solution of oxetan-3-one (144 mg, 2.00 mmol, 2.00 equiv) in tetrahydrofuran (1 mL) dropwise with stirring at -78 °C. The resulting solution was reacted, with stirring, for an additional 1 h at -78 °C. The resulting solution was reacted, with stirring, for an additional 14 h at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3 x 30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 50 mL of water and 1 x 50 mL of sat. sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied on a silica gel column with ethyl acetate. This resulted in 160 mg (57%) of 3-[4-(2-cyclopropoxyphenyl)pdin-3-1]oxetan-3-ol (59b) as a colorless oil. .

Step 3. 4-(2-cyclopropoxyphenyl)-3-[3-[(2,5-dichlorophenyl)methoxy]oxetan-3-yl]pyridine (I59)

A 25 mL round bottom flask was charged with 3-[4-(2-cyclopropoxyphenyl)pdin-3-1]oxetan-3-ol (100 mg, 0.35 mmol, 1, 00 equiv), 2-(bromomethyl)1,4-dichlorobenzene (169 mg, 0.70 mmol, 2.00 equiv), Ν,Ν-dimethylformamide (10 mL). Sodium hydride (60% in oil) (56 mg, 2.33 mmol, 4.00 equiv) was then added. The resulting solution was stirred for 1h at room temperature. The reaction is then ω

σ>

ω &lt; or

<img file="MX376739B_D0228.tif" />

IMPI

206

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 neutralized by adding 15 mL of water. The resulting solution was extracted with 3 x 30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 50 mL of water and 1 x 50 mL of sat. sodium chloride. The mixture was dried over anhydrous sodium sulfate. The residue was applied on a silica gel column with ethyl acetate/hexane (1:1). The crude product was purified by preparative HPLC under the following conditions: Column, Gemini-NX 5u C18 110A, AXIA Packed, 150 x 21.2 mm; mobile phase, water with 10 mmol NH4HCO3 and MeCN (66.0% MeCN to 86.0% in 8 min); detector, 254nm. This resulted in 58 mg (37%) of 59 as a white solid. MS (ES, m/z): 442 [M+H]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ 0.30-0.55 (m, 2H), 0.60-0.80 (m, 2H), 3.68 (s, 1H), 4.15-4.50 (m, 3H), 4.60-4.80 (m, 2H), 5.00-5.20 (m, 1H), 7.93-7.00 (m, 1H), 7.10-7.21 (m, 1H ), 7.35-7.70 (m, 6H), 8.70-8.90 (m, 1H), 8.93-9.12 (m, 1H).

Example 9: (1-(4-(3-aminopropyl)-2,5-dichlorobenzylam¡no)cyclopropyl)(4-cyclopropyl3,4-dihydroquinoxalán-1(2H)-¡l)methanone (Intermediate B1 )

<img file="MX376739B_D0229.tif" />

Step 1. 2,5-dichloro-4-methoxybenzaldehyde (Intermediate B1a)

A stirred solution at 0 °C of 1,4-dichloro-2-methoxybenzene (25.0 g, 141.2 mmol, 1.00 equiv) and TiCL (30.9 mL) in dichloromethane (300 mL) was added ω

σ>

ω &lt; or

<img file="MX376739B_D0230.tif" />

IMPI

207

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 dichloro(methoxy)methane (16.2 g, 140.9 mmol, 1.00 equiv) dropwise. The resulting reaction mixture was stirred for 2h at 60°C then quenched by addition of ice/water. The pH value of the solution was adjusted to 1.0 with concentrated HCl extracted with ethyl acetate (4 x 500 mL), and the combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate. and concentrated under reduced pressure to provide 31.0 g (crude) of B1a as a yellow solid. Step 2. 2,5-dichloro-4-hydroxybenzaldehyde (Intermediate B1b)

A solution of 2,5-dichloro-4-methoxybenzaldehyde (14.0 g, 68.3 mmol, 1.00 equiv), LiCl (11.6 g, 274 mmol, 4.00 equiv) in DMF (150 mL) under an inert atmosphere of nitrogen it was stirred overnight at 140 °C in an oil bath. The reaction mixture was then neutralized by addition of ice/water and the pH value of the solution was adjusted to 1-2 with concentrated HCl. The resulting solution was extracted with ethyl acetate (3 x 400 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with a gradient of ethyl acetate/petroleum ether (1:10-1:5) to give 10.0 g (77%) of B1b as a solid. light yellow. (300Hz, DMSO-d₆): δ 11.99(s, 1H), 10.08(s, 1H), 7.81 (s, 1H), 7.09(s, 1H). Step 3. 2,5-dichloro-4-formylphenyl trifluoromethanesulfonate (Intermediate B1c)

A stirred solution at 0 °C of 2,5-dichloro-4-hydroxybenzaldehyde (3.0 g, 15.71 mmol, 1.00 equiv) and tethylamine (3.2 g, 31.62 mmol, 2, 00 equiv) in dichloromethane (50 mL) was added a solution of tffluoromethanesulfonic anhydride (6.8 g, 24.10 mmol, 1.50 equiv) in dichloromethane (10 mL) dropwise. The resulting reaction mixture was stirred for 30 min at room temperature, then washed with brine (2 x 30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography on silica gel with a gradient eluent of ethyl acetate/petroleum ether (1:50-1:10) gave 3.0 g (59%) of B1c as a white solid.¹H-NMR (300Hz, DMSO-d₆): 10.22(s, 1H), 8.14-8.15(m, 2H).

ω σ>

ω &lt; or

<img file="MX376739B_D0231.tif" />

ΙΜΡΙ

208

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Step 3. tert-Butyl N-[5-(2,5-dichloro-4-formylphenyl)pent-4-yn-1-yl]carbamate (Intermediate B1d)

A 250 mL round bottom flask purged and kept under an inert atmosphere of nitrogen was charged with 2,5-dichloro-4-formylphenyl trifluoromethanesulfonate (1 g, 3.10 mmol, 1.00 equiv), tert. butyl N-(pent-4-yn-1-yl)carbamate (567 mg, 3.09 mmol, 1.00 equiv), A/./V-dimethylformamide (80 mL), DIEA (1.2 g, 9 0.29 mmol, 3.00 equiv), Cul (88 mg, 0.46 mmol, 0.15 equiv), Rd(PPh₃)2Cl2 (326 mg, 0.46 mmol, 0.15 equiv). The resulting solution was stirred for 3h at room temperature. The resulting mixture was washed with 3x80 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (0-20%). The collected fractions were combined and concentrated in vacuo. This resulted in 800 mg (73%) of tert-butyl N-[5-(2,5-dichloro-4-formylphenyl)pent-4-¡n-1-¡l]carbamate (B1d) as a light yellow oil.

Step 4. tert-butyl N-[5-(2,5-dichloro-4-formylphenyl)pentyl]carbamate (Intermediate B1)

A 100 mL round bottom flask purged and maintained with an H2 atmosphere was charged with tert-butyl N-[5-(2,5-dichloro-4-formylphenyl)pent-4-n-1yljcarbamate (800 mg, 2.25 mmol, 1.00 equiv), ethyl acetate (40 mL), Rh/C (1.2 g). The resulting solution was stirred overnight at room temperature. The solids were filtered. The resulting mixture was concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (0-20%). The collected fractions were combined and concentrated in vacuo. This resulted in 320 mg (40%) of tert-butyl N-[5-(2,5-dichloro-4-formylphenyl)pentyl]carbamate (B1) as a pale yellow oil.

Intermediates B2 through B8 (Table 2a) were prepared from known or commercial starting materials according to the procedure used for the preparation of intermediate B1 in Example 9 above.

<img file="MX376739B_D0232.tif" />

209

IMPI §

MEXICAN INSTITUTE OF PROPERTY w

INDUSTRIAL &lt;0

MX/E/2018/085580

Table 2a: Intermediaries B2, B3, B4, B5, B5a, B6, B7 and B8

<td>Intermediary N*</td><td>Compound Structure</td><td>Intermediary #</td><td>Compound Structure</td>

<td>B2</td><td>bochn</td><td rowspan="2">0-5y</td><td rowspan="2"></td>

<td rowspan="2">B-3</td><td rowspan="2">ΥΓ° bochn</td>

<td rowspan="2"> 0-6</td><td rowspan="2">A . 77^:^γ^χ^Χ^^ι □</td>

<td rowspan="2">bl</td><td rowspan="2">BocHN - - CI</td>

<td rowspan="2"> 0-7</td><td rowspan="2"></td>

<td rowspan="2">Β-δ</td><td rowspan="2">yJXC</td>

<td rowspan="2"> 0-8</td><td rowspan="2">Ο _ ü / ¿i 0</td>

<td colspan="2"></td>

Example 10: 5-(5-( tert-butyldiphenylsilyloxy)pentan-2-yl)-2-chlorobenzaldehyde (Intermediate B9)

<img file="MX376739B_D0233.tif" />

ω σ>

ω &lt; or

<img file="MX376739B_D0234.tif" />

IMPI

210

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Step 1. 2-Chloro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (Intermediate B9a)

A 250 mL round bottom flask was charged with 5-bromo-2-chlorobenzaldehyde (5.0 g, 22.78 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(tetramethyl-1, 3,2-dioxaborolan-2-yl)-1,3,2-dioxborolane (6.41 g, 25.24 mmol, 1.10 equiv), dioxane (100 mL), KOAc (6.75 g, 68, 78 mmol, 3.00 equiv) and Pd(dppf)Cl2 (500 mg, 0.68 mmol, 0.03 equiv). The resulting solution was stirred overnight at 80°C. The reaction mixture was diluted with 300 mL of water. The resulting solution was extracted with 300 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (5.5 g) was purified by flash chromatography under the following conditions: Column, silica gel; mobile phase, ethyl acetate : petroleum ether = 100:0 increasing to ethyl acetate : petroleum ether = 95:5 over 30 min; detector, UV 254nm. This resulted in 3.6 g (59%) of 2-chloro-5(tetramethyl-1,3,2-dioxaborolan-2-¡l)benzaldehyde (B9a) as a white solid.

Step 2. tert-butyl(pent-4-yn-1-yloxy)diphenylsilane (Intermediate B9b)

A 1000 mL round bottom flask purged and kept under an inert atmosphere of nitrogen was charged with pent-4-yn-1-ol (15 g, 178.32 mmol, 1.00 equiv), imidazole (30.4 g, 2.50 equiv), dichloromethane (600 mL). This was followed by the addition of TBDPSCI (61.3 g, 1.25 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 1h at room temperature. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3 x 150 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 3 x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with petroleum ether. This resulted in 58.7 g (crude) of B9b as a colorless oil.

ω σ>

ω &lt; or

<img file="MX376739B_D0235.tif" />

IMPI

211

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Step 3. tert-butyl[(4-iodopent-4-en-1-yl)ox¡]d¡phenylsilane (Intermediate B9c)

A 500 mL 3-neck round bottom flask purged and maintained under an inert nitrogen atmosphere was charged with a solution of Ni(dppp)Cl2 (1.01 g, 0.03 equiv) in tetrahydrofuran (62 mL). This was followed by the addition of DIBAL-H (81 mL, 1.30 equiv, 1 mol/L in hexane) dropwise with stirring. To that was added tert-butyl(pent-4-yn-1-yloxy)dphenylsilane (B9b) (20 g, 62.01 mmol, 1.00 equiv) dropwise with stirring at 0 °C. The mixture was stirred for 2hr. A solution of NIS (28 g, 124.46 mmol, 2.00 equiv) in tetrahydrofuran (186 mL) was added dropwise to the mixture with stirring at 0 °C. The resulting solution was stirred for 1h at room temperature. The resulting solution was diluted with 250 mL of ether. The reaction was then quenched by the addition of 250 mL of saturated aqueous Rochelle salt. After stirring for 15 min, the resulting mixture was filtered through cotton. The resulting clear filtrate was extracted with 5 x 100 mL ether and the organic layers combined. The resulting mixture was washed with 3 x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with petroleum ether. This resulted in 23.8 g (77%) of B9c as a pale yellow oil.

Step 4. 5-[5-[(tert-butyldiphenylsilyl)ox¡]pent-1-en-2-yl]-2-chlorobenzaldehyde (Intermediate B9d)

A purged 100 mL round bottom flask kept under an inert nitrogen atmosphere was charged with fer-butyl[(4-iodopent-4-en-1yl)oxy]diphenylsilane (B9c) (5.2 g, 11, 54 mmol, 1.00 equiv), Pd(PPh3)4 (1.3 g, 1.12 mmol, 0.10 equiv), K3PO4 (4.9 g, 23.08 mmol, 2.00 equiv), 2 -chloro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (B9a) (3.1 g, 11.63 mmol, 1.00 equiv), dioxane/H2O (31/3.1 mL) . The resulting solution was stirred for 4 h at 80 °C in an oil bath. The reaction mixture was cooled. The resulting solution was diluted with 100 mL of H2O. The resulting solution was extracted with 4 x 80 mL of ethyl acetate and the organic layers ω

σ>

ω &lt; or

<img file="MX376739B_D0236.tif" />

IMPI

212

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 were merged. The resulting mixture was washed with 1 x 50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (5/100). This resulted in 3.7 g (64%) of B9d as a yellow oil.

Step 5. 5-[5-[(tert-butyldiphenyls¡l¡l)oxy]pentan-2-¡l]-2-chlorobenzaldehyde (Intermediate B9)

A 100 mL round bottom flask purged and maintained with an atmosphere of hydrogen was charged with 5-[5-[(1-ter-butyld¡phenylsilyl)ox¡]pent-1-en-2-yl]-2-chlorobenzaldehyde ( B9d, 600 mg, 1.30 mmol, 1.00 equiv), ethyl acetate (20 mL), Rh/C (600 mg). The resulting solution was stirred overnight at room temperature. The solids were filtered. The resulting mixture was concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (0:1-1:3). This resulted in 300 mg (50%) of B9 as a pale yellow oil.

Example 11: Ethyl 5-(4-chloro-3-formylphenyl)hexanoate (Intermediate B10)

<img file="MX376739B_D0237.tif" />

Step 1. Ethyl 5-(4-chloro-3-formylphenyl)hex-5-enoate (Intermediate B10a)

A 250 mL round bottom flask was charged with 2-chloro-5-(tetramethyl1,3,2-dioxaborolan-2-yl)benzaldehyde (3.5 g, 13.13 mmol, 1.10 equiv), ethyl 5 [(trifluoromethane)sulfonyloxy]hex-5-enoate (3.5 g, 12.06 mmol, 1.00 equiv), K3PO4 (7.7 g, 36.27 mmol, 3.00 equiv), Pd( mp3)4 (1.4 g, 1.21 mmol, 0.10 equiv), dioxane (120 mL), water(20 mL). The resulting solution was stirred for 1 overnight at 80°C in an oil bath. The reaction was then quenched by the addition of 300 mL of water. The resulting solution was extracted with 300 mL of ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (4.5 g) was purified by flash chromatography under the following conditions ω

σ>

ω &lt; or

<img file="MX376739B_D0238.tif" />

ΙΜΡΙ

213

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 (lntelFlash-1): Column, silica gel; mobile phase, ethyl acetate : petroleum ether = 100:0 increasing to ethyl acetate : petroleum ether = 95:5 over 30 min; detector, UV 254nm. This resulted in 2.2 g (65%) of ethyl 5-(4-chloro-3-formylphenyl)hex-5-enoate (B10a) as a light red oil.

Step 2. Ethyl 5-(4-chloro-3-formylphenyl)hexanoate (Intermediate B10)

A 250 mL round bottom flask was charged with ethyl 5-(4-chloro-3-formylphenyl)hex-5-enoate (B10a)(2.2 g, 7.84 mmol, 1.00 equiv), Rh/C ( 2.2 g, 21.36 mmol, 3.00 equiv), ethyl acetate (50 mL). The resulting solution was stirred for 5 h at 30 °C in an oil bath. The resulting solution was diluted with 100 mL of ethyl acetate. The solids were filtered. The resulting mixture was concentrated in vacuo. The crude product (2.5 g) was purified by flash chromatography under the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ethyl acetate:petroleum ether = 100:0 increasing to ethyl acetate:petroleum ether = 95:5 over 30 min; detector, UV 254nm. This resulted in 2.1 g (95%) of ethyl 5-(4-chloro-3-formylphenyl)hexanoate (B10) as a colorless oil.

Example 12: Methyl 5-(6-formyl-5-methylpyridine-2-yl)pentanoate (Intermediate B11)

<img file="MX376739B_D0239.tif" />

ω σ>

ω &lt; or

<img file="MX376739B_D0240.tif" />

ΙΜΡΙ

214

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Step 1. 2-(Methoxycarbonyl)-3-methylpyridine 1-oxide (Intermediate B11a)

A 250 mL round bottom flask (1 atm) purged and kept under an inert atmosphere of nitrogen was charged with methyl 3-methylpnidine-2-carboxylate (8.0 g, 52.92 mmol, 1.00 equiv), dichloromethane (100 mL), m-CPBA (27.3 g, 158.72 mmol, 3.00 equiv). The resulting solution was stirred overnight at 25°C in an oil bath. The resulting solution was diluted with 100 mL of DCM. The resulting mixture was washed with 1 x 100 mL of water and 1 x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with dichloromethane/methanol (20:1). This resulted in 6.0 g (68%) of product (B11a) as a colorless oil.

Step 2. Methyl 6-chloro-3-methylpyridine-2-carboxylate (Intermediate B11b)

A 250 mL round bottom flask (1 atm) purged and kept under an inert atmosphere of nitrogen was charged with 2-(methoxycarbonyl)-3-methylpyridin-1-io-1olate (1.5 g, 8.97 mmol, 1.00 equiv), phosphorous chloride (60 mL). The resulting solution was stirred overnight at 60°C in an oil bath. The resulting solution was diluted with 200 mL of DCM. The resulting mixture was washed with 1 x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (0%-25%). This resulted in 318 mg (19%) of methyl 6-chloro-3-methylpyridine-2-carboxylate (B11b) as a white solid.

Step 3. (6-Chloro-3-methylpyridin-2-yl)methanol (Intermediate B11c)

A 250 mL (1 atm) 3-neck round bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with methyl 6-chloro-3-methylpyridine-2-carboxylate (1.86 g, 10.02 mmol, 1 0.00 equiv), THF (100 mL). This was followed by the addition of DIBAL-H (40 mL, 4.00 equiv) at -78 °C. The resulting solution ω

σ>

ω &lt; or

<img file="MX376739B_D0241.tif" />

IMPI

215

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580 was stirred for 3 h at room temperature in an ethanol/liquid N2 bath. The resulting solution was diluted with 100 mL of ethyl acetate. The reaction was then quenched by the addition of 60 mL of C4H₄KNaOe. The diatomite mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (0-50%). This resulted in 1.3 g (82%) of (6-chloro-3-methyl-p-din-2-¡l)methanol (B11c:) as a colorless oil. Step 4. 2-[[(tert-butyldimethylsilyl)oxy]methyl]-6-chloro-3-methylpyridine (Intermediate B11d)

To a 500 mL 3-neck round bottom flask was charged with (6-chloro-3-methylp-nidine-2-¡l)methanol (6.4 g, 40.61 mmol, 1.00 equiv), dichloromethane (300 mL), imidazole (4.2 g), TBDMSCI (7.6 g). The resulting solution was stirred for 2 h at 0 °C in an ice/salt bath. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3 x 50 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2 x 50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 10.4 g (94%) of 2-[[(tert-but¡ld¡methyls¡l¡l)ox¡]methyl]-6-chloro-3-methylp¡ñd¡ na (B11d) as a brown solid.

Step 5. Methyl 5-(6-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methylpyridin-2-yl)pent-4-inoate (Intermediate B11e)

A 100 mL 3-neck round bottom flask purged and maintained under an inert nitrogen atmosphere was charged with CS2CO3 (6.9 g, 21.18 mmol, 1.92 equiv), (A-taPhosPdCl2)2 (195 mg), 2-[[(fer-butyldimethylsylyl)oxy]methyl]-6-chloro-3-methylpyridine (3 g, 11.04 mmol, 1.00 equiv) in CH3CN (20 mL), methyl pent-4-inoate (3.5 g, 31.21 mmol, 2.83 equiv) in CH3CN (20 mL). The resulting solution was stirred overnight at 95°C in an oil bath. The resulting mixture was concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (1/100-10/100). This resulted in 1.1 g (29%) of methyl 5-(6-[[(terMX/E/2018/085580 but¡ldimethyls¡l¡l)oxy]methyl]-5-methyllp¡rid¡ n-2-yl)pent-4-¡noate (B11e) as a brown oil.

Step 6. Methyl 5-[6-(hydroxymethyl)-5-methylpyridin-2-yl]pent-4-inoate (Intermediate B11f)

To a 100 mL round-bottomed flask filled with methyl 5-(6-[[(tert-butyldimethylsilyl)oxy]methyl]-5-methyl-pyridin-2-yl)pent-4 -¡noate (1.5 g, 4.32 mmol, 1.00 equiv) in tetrahydrofuran (10 mL) TBAF (6.5 mL, 1 M) was added dropwise with stirring. The resulting solution was stirred for 1h at room temperature. The resulting mixture was concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (1/100-20/100). This resulted in 600 mg (60%) of methyl 5-[6-(hydroxymethyl)-5-methylpyridin-2-yl]pent-4-¡noate (B11f) as a brown oil. . Step 7. Methyl 5-[6-(hydroxymethyl)-5-methylpyridin-2-yl]pentanoate (Intermediate B11g)

A 100-mL round-bottomed flask filled with methyl 5-[6-(hydroxymethyl)5-methylp-din-2-yl]pent-4-inoate (700 mg, 3.00 mmol, 1.00 equiv), ethyl acetate (10 mL), and Rh/C (0.7 g) was purged and kept under an atmosphere of H₂. The resulting suspension was stirred for 2 h at 25 °C in an oil bath. The solids were filtered. The resulting mixture was concentrated in vacuo. This resulted in 0.6 g (84%) of methyl 5-[6(hydroxymethyl)-5-methylp-din-2-yl]pentanoate (B11g) as a brown oil.

Step 8. Methyl 5-(6-formyl-5-methylpyridin-2-yl)pentanoate (B11)

A 50 mL round bottom flask was charged with a solution of methyl 5[6-(h¡drox¡methyl)-5-methylpind¡n-2-¡l]pentanoate (202 mg, 0.85 mmol, 1.00 equiv) in dichloromethane (5 mL), MnO₂ (741.5 mg, 8.53 mmol, 10.02 equiv). The resulting solution was stirred overnight at 50°C in an oil bath. The solids were filtered. The resulting mixture was concentrated in vacuo. This resulted in 180 mg (90%) of methyl 5-(6-form¡l-5-methylpindín-2-¡l)pentanoate (B11) as a light brown oil.

ω σ>

ω &lt; or

<img file="MX376739B_D0242.tif" />

IMPI

217

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

Example 13: tert-butyl N-[4-[3-(bromomethyl)-4-chlorophenyl]butyl]carbamate (Intermediate C1)

<img file="MX376739B_D0243.tif" />

Step 1. tert-butyl N-[4-[4-chloro-3-(hydroxymethyl)phenyl]but-3-yn-1-yl]carbamate (Intermediate C1a)

A purged 100 mL round bottom flask kept under an inert nitrogen atmosphere was charged with (2-chloro-5-iodophenyl)methanol (212 mg, 0.79 mmol, 1.00 equiv), tert-butyl N -(but-3-yn-1-yl)carbamate (160 mg, 0.95 mmol, 1.20 equiv), DIEA (0.39 mL, 3.00 equiv), Cul (15 mg, 0.08 mmol , 0.10 equiv), dichloropalladium bis(tn-phenylphosphine) (55.5 mg, 0.08 mmol, 0.10 equiv), and A/,A/-dimethylformamide (8 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 4 x 20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 5 x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 220 mg (90%) of tert-butyl N-[4-[4-chloro-3-(hydroxy¡methyl)phenyl]but-3-¡n-1-¡l]carbamate (C1a ) as a yellow oil. Step 2. tert-butyl N-[4-[4-chloro-3-(hydroxymethyl)phenyl]butyl]carbamate (Intermediate C1b) ω

σ>

ω &lt; or

<img file="MX376739B_D0244.tif" />

IMPI

218

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

MX/E/2018/085580

A 100 mL round bottom flask purged and maintained with an atmosphere of hydrogen was added tert-butyl N-[4-[4-chloro-3-(hydroxymethyl)phenyl]but-3-n-1yl ]carbamate (350 mg, 1.13 mmol, 1.00 equiv), ethyl acetate (20 mL), Rh/C (350 mg). The resulting solution was stirred overnight at room temperature. The solids were filtered. The resulting mixture was concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 300 mg (85%) of tert-butyl N-[4-[4-chloro-3-(hydroxymethyl)phenyl]butyl]carbamate (C1b) as a pale yellow oil. .

Step 3. tert-butyl N-[4-[3-(bromomethyl)-4-chlorophenyl]butyl]carbamate (Intermediate C1)

A 100 mL round bottom flask was charged with tert-butyl N-[4-[4-chloro-3(hydroxymethyl)phenyl]butyl]carbamate (300 mg, 0.96 mmol, 1, 00 equiv), dichloromethane (10 mL), THF (10 mL), NBS (255 mg, 4.33 mmol, 1.50 equiv). This was followed by the addition of triphenylphosphane (375 mg, 1.43 mmol, 1.50 equiv) in several batches at 0-5 °C. The resulting solution was stirred for 2h at room temperature. The resulting mixture was concentrated in vacuo. The residue was applied on a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 270 mg (75%) of tert-butyl N-[4-[3(bromomethyl)-4-chlorophenyl]butyl]carbamate (C1) as a yellow oil.

Example 14: tert-butyl N-[4-[4-(bromomethyl)-5-chloro-2-methylphenyl]butyl]carbamate (Intermediate C2)

<img file="MX376739B_D0245.tif" />

Step 1. tert-butyl N-[4-[5-chloro-4-(hydroxymethyl)-2-methylphenyl]butyl]carbamate (Intermediate C2a)

A 50 mL round bottom flask was charged with tert-butyl N-[4-(5-chloro-4-formyl-2-methylphenyl)but¡l]carbamate (B4) (150 mg, 0.46 mmol, 1 0.00 equiv), methanol (15 mL), and NaBH4 (34.83 mg, 0.92 mmol, 2.00 equiv). The resulting solution was stirred for ω

σ>

ω &lt; or

<img file="MX376739B_D0246.tif" />

IMPI

219

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY